Maternal-Fetal Toxicology, Third Edition,: A Clinician's Guide (Medical Toxicology)

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Author: Gideon Koren

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ISBN: 0-8247-0378-2 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright  2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Series Introduction

Our generation is characterized by an increased awareness of the effects of xenobiotics and environmental agents on humans. The introduction of unique but toxic medications, the development of novel methods of estimating short- and long-term adverse effects, and tighter regulatory demands have all contributed to new insights in the area of medical toxicology. At present, the main sources of information in the field of medical toxicology are reviews of original research and textbooks. Reviews of research generally address a narrow aspect of one issue, whereas textbook reviews need to generalize, within a limited space, which often results in decreased quality. This new series of books aims at filling a gap between these two sources of information. I have aimed at in-depth reviews of areas of interest in medical toxicology, recruiting leading international scientists to discuss the themes. The planned volumes address issues in acute poisoning, chronic adverse drug reactions, regulatory aspects, and so on. We hope to bring new frontiers of medical toxicology to the clinical and scientific communities in a way that will improve the understanding of the complex relationships between xenobiotics and human health. Gideon Koren

iii

Foreword

Almost all mothers will do everything they can to ensure that their babies have the healthiest possible start in life. Although birth defects or congenital malformations have been reported in the earliest recordings of history, teratology, the study of environmentally induced birth defects, did not develop into a modern science until the middle of the 20th century. Although congenital malformations were considered to be serious medical problems, they were thought to be unpreventable and untreatable. With the discovery in the 1940s that certain environmental factors (iodine deficiency and rubella virus) could cause congenital malformations, many embryologists developed an active interest in substances called teratogens that could induce or increase the incidence of human congenital malformations. The occurrence of the thalidomide tragedy in the late 1950s attracted worldwide interest. The publicity accorded this tragedy increased the awareness of the public and the medical and legal professions that some human birth defects are caused by drugs, chemicals, and radiation. It was not long before women, and some medical practitioners, viewed every drug, chemical, and virus as a reproductive hazard. As revealed in this book, many pregnant women exposed to drugs and chemicals that are known not to be teratogenic believe that they have a high risk of having a malformed baby. For a woman who has been exposed to a possible teratogen, obtaining accurate information about the risk involved, if any, is of utmost concern. Information available from newspapers, magazines, and popular books is often frightening and misunderstood. Most physicians and other health professionals receive insufficient training to answer all the questions pregnant women ask about the effects of chemical, physical, or infectious agents on the developing human embryo or fetus. Teratogen information programs have been established in major health centers to v

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Foreword

respond to pregnant women’s inquiries about teratogens, and to advise physicians and other health professionals who are responsible for their care. The third edition of Maternal–Fetal Toxicology: A Clinician’s Guide will be greatly appreciated by all who desire to learn about the teratogenic risks of the many environmental factors that women are exposed to during pregnancy. The main purpose of this book is to present those who counsel women with accurate, up-to-date estimates of the teratogenic risks of exposure to drugs, chemicals, viruses, and radiation during pregnancy. This information is very important to women making a decision to continue or terminate a pregnancy. For many years there has been a need for a practical book on teratogens that can be used in health-care programs for pregnant women. This book describes current teratogen information programs and the process of counseling for teratogenic risk. I strongly recommend this book to all who share my enthusiasm for the developing human and my desire to see every one of them have the best possible chance of developing normally. Keith L. Moore, Ph.D., F.I.A.C. Professor of Anatomy The University of Toronto Toronto, Ontario, Canada

Preface

Approximately one fetus is aborted for every two or three children born in Western countries. Since the thalidomide diaster over four decades ago, medicine has been practiced as if every drug were a potential human teratogen. Women exposed to nonteratogens commonly believe they have a high teratogenic risk. Their physicians often encourage them to terminate their pregnancies, yet only about 30 drugs and chemicals have been proven to be teratogenic. Every year scores of new drugs and hundreds of new chemicals are introduced into the market. In neither case are human reproductive effects known. Furthermore, according to different studies, between 40 and 90% of pregnant women consume one or more medications during gestation. Finally, despite hundreds of scientific studies published yearly on reproductive effects of xenobiotics, little has been done in the past to crystallize a clinical approach to deal with these issues. No single medical specialty is equipped to deal with the complex issues of reproductive toxicology. While geneticists commonly deal with congenital malformations, it is unlikely that they have the experience of pharmacologists in tailoring alternative therapy. Neither group is trained to evaluate such factors as occupational exposures. A multidisciplinary team of pharmacologists, toxicologists, geneticists, obstetricians, neonatologists, occupational and addiction specialists, drug information specialists, psychologists, sonographers, and epidemiologists is needed. In September of 1985 we counseled the first patient in the Motherisk clinic in Toronto. This program was designed to inform, counsel, and follow up pregnant women exposed to drugs, chemicals, or radiation in pregnancy. In order to perform these tasks, new approaches and clinical tools had to be developed by our multidisciplinary team; these are presented in this volume. vii

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Preface

Much of the confusion surrounding the counseling process stems from the wellunderstood ‘‘do not use in pregnancy’’ statements commonly found in the Physicians’ Desk Reference, Compendium of Pharmaceuticals and Specialties, or their equivalents. Since many women are inadvertently exposed to medications before finding out they have conceived, the ‘‘do not use in pregnancy’’ statements are easily translated into ‘‘harmful’’ or ‘‘teratogenic.’’ While the exact rate of pregnancy termination due to fears of adverse fetal effects of xenobiotics is not known, there is indirect evidence that this is not uncommon. Similarly disturbing are the many cases where women are exposed to drugs and chemicals known to adversely affect the fetus without being appropriately informed. The goal of this book is to assist the large number of health professionals who are asked by women and their families to provide answers on potential reproductive effects of xenobiotics and radiation. These include general physicians, obstetricians, poison control specialists, geneticists, occupational specialists, pediatricians, pharmacologists, toxicologists, pharmacists, nurses, and others. With increasing public awareness of environmental toxins, it is likely that concerns surrounding reproductive toxicology will increase over the next few decades. We hope that an appropriate clinical approach will help put the issue in its correct perspective, by avoiding both understatements and ambiguity. In the six years that have elapsed since publication of the second edition of Maternal–Fetal Toxicology: A Clinician’s Guide, the field of teratology information has seen an exponential growth, both in terms of quantity and quality of knowledge. The Motherisk Program in Toronto, in collaboration with several American services, has initiated and brought to completion large-scale, prospective studies on the safety of drugs in pregnancy, some of which are presented in this volume. In addition to revising and updating most chapters, we have added several novel aspects, such as systematic reviews and metaanalyses of specific xenobiotics. This revised and expanded edition includes clinical cases at the beginning of most chapters, with answers at the end. It is hoped that this problembased approach will enhance the clinical relevance of this book as well as increase its educational value. Finally, I wish to thank the members of the Motherisk team, my students, fellows, and colleagues for being active in generating new knowledge in the field of maternal– fetal toxicology, and making any edition obsolete within a few years. Gideon Koren

Contents

Series Introduction Foreword Keith L. Moore Preface Contributors 1. Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance Ronen Loebstein, Arieh Lalkin, and Gideon Koren

iii v vii xiii

1

2. Developmental Risk Assessments Gerald F. Chernoff

23

3. Drugs in Pregnancy Gideon Koren, Anne Pastuszak, and Shinya Ito

37

4. Teratogenic Drugs and Chemicals in Humans Irena Nulman, Gordana Atanackovic, and Gideon Koren

57

5. Treatment for Epilepsy in Pregnancy Irena Nulman, Dionne Laslo, and Gideon Koren

73

6. The Safety of Commonly Used Antidepressants in Pregnancy Gideon Koren, Anne Pastuszak, Sheila Jacobson, and Irena Nulman

85

ix

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Contents

7.

Benzodiazepine Use in Pregnancy and Major Malformations or Oral Cleft: Meta-Analysis of Cohort and Case-Control Studies Lisa R. Dolovich, Antonio Addis, J. M. Re´gis Vaillancourt, J. D. Barry Power, Gideon Koren, and Thomas R. Einarson

105

8.

Drugs and Chemicals Most Commonly Used by Pregnant Women Doreen Matsui, Monica Bologa, Frank Fassos, Michael McGuigan, Michael J. Rieder, and Gideon Koren

115

9.

Periconceptional Folate and Neural Tube Defects: Time for Rethinking Gideon Koren

137

10.

11.

12.

The Effectiveness of Preconceptional Counseling on Women’s Compliance with Folic Acid Supplementation Anne Pastuszak, Dimple Bhatia, Bunmi Okotore, and Gideon Koren Pregnancy Outcome Following Maternal Exposure to Corticosteroids: A Prospective Controlled Cohort Study and a Meta-Analysis of Epidemiological Studies Laura Park-Wyelie, Paolo Mazzotta, Myla E. Moretti, Anne Pastuszak, Lizanne Beique, Laura Hunnisett, Mark H. Friesen, Sheila Jacobson, Sonja Kasapinovic, Debra Chang, Orna Diav-Citrin, C. Laskin, K. Spitzer, Irena Nulman, Thomas R. Einarson, and Gideon Koren Use of the Retinoid Pregnancy Prevention Program in Canada: Patterns of Contraception Use in Women Treated with Isotretinoin and Etretinate Anne Pastuszak, Gideon Koren, and Michael J. Rieder

141

151

169

13.

Drugs and Breast-Feeding Anna Taddio and Shinya Ito

177

14.

Poisoning in Pregnancy Milton Tenenbein

233

15.

Carbon Monoxide Poisoning During Pregnancy Benoit Bailey

257

16.

Direct Drug Toxicity to the Fetus Orna Diav-Citrin and Gideon Koren

269

17.

The Approach to the Mother on Nonmedicinal and Chemical Use in Pregnancy Joyce F. Schneiderman

18.

Maternal and Obstetrical Effects of Prenatal Drug Exposure Raafat Bishai and Gideon Koren

321

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Contents

19. Neonatal Drug Withdrawal Syndromes James B. Besunder and Jeffrey L. Blumer 20. Current Management of the Neonatal Abstinence Syndrome: A Critical Analysis of the Evidence Jochen G. W. Theis, Peter L. Selby, Yazemir Ikizler, and Gideon Koren 21. Fetal Effects of Cocaine: An Updated Meta-Analysis Antonio Addis, Myla E. Moretti, Fayyazuddin Ahmed Syed, Thomas R. Einarson, and Gideon Koren 22. Pregnancy Outcome and Infant Development Following Gestational Cocaine Use by Social Cocaine Users in Toronto, Canada Karen Graham, Annette Feigenbaum, Irena Nulman, Rosanna Weksberg, Thomas R. Einarson, Stan Ashby, Gideon Koren, and Susan Goldberg 23. Long-Term Neurodevelopmental Risks in Children Exposed In Utero to Cocaine: The Toronto Adoption Study Irena Nulman, Gideon Koren, Joanne Rovet, Rachel Greenbaum, Michael Loebstein, and Thomas R. Einarson 24. Biological Markers of Intrauterine Exposure to Cocaine and Cigarette Smoking Gideon Koren, Julia Klein, Rachel Forman, My-Khanh Phan, and Karen Graham 25. Fetal Alcohol Syndrome: The Central Nervous System Tragedy Irena Nulman, Jonathan Gladstone, Bonnie O’Hayon, and Gideon Koren 26. Moderate Alcohol Consumption During Pregnancy and the Incidence of Fetal Malformations: A Meta-Analysis Dimitris Polygenis, Sean Wharton, Christine Malmberg, Nagwa Sherman, Debbie Kennedy, Gideon Koren, and Thomas R. Einarson

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347

373

385

433

447

457

467

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27. Occupational Exposures Known to Be Human Reproductive Toxins Yedidia Bentur, Eli Zalzstein, and Gideon Koren

507

28. The Common Occupational Exposures Encountered by Pregnant Women Yedidia Bentur and Gideon Koren

529

29. Pregnancy Outcome Following Maternal Organic Solvent Exposure: A Meta-Analysis of Epidemiological Studies Kristen I. McMartin, Merry Chu, Ernest Kopecky, Thomas R. Einarson, and Gideon Koren 30. A Proactive Approach for the Evaluation of Fetal Safety in Chemical Industries Kristen I. McMartin and Gideon Koren

547

555

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Contents

The Use of Herbal Medicine in Pregnancy and Lactation: A Clinician’s Guide Michael Gallo, Michael J. Smith, Heather Boon, and Gideon Koren

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32.

Ionizing and Nonionizing Radiation in Pregnancy Yedidia Bentur

603

33.

Prenatal Diagnosis in Clinical Practice David Chitayat and Kathy Hodgkinson

653

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Fetal Malformations Associated with Drugs and Chemicals: Visualization by Sonography Irena Nulman, Benjamin Bar-Oz, Dionne Laslo, Shawn Fried, David Chitayat, and Gideon Koren

673

35.

Maternal Disorders Leading to Increased Reproductive Risk Ruthie Geist and Gideon Koren

697

36.

Teratogen Information Services Around the World Antonio Addis, Lavinia Schu¨ler, Myla E. Moretti, Maurizio Bonati, and Gideon Koren

733

37.

Teratogen Information Services Gideon Koren, Anne Pastuszak, and Myla E. Moretti

747

38.

Motherisk: The Toronto Model for Counseling in Reproductive Toxicology Myla E. Moretti and Gideon Koren

767

The Way Women Perceive Teratogenic Risk: The Decision to Terminate Pregnancy Tommy Ho, Adrienne Einarson, and Gideon Koren

789

Evaluating the Effects of Drugs in Pregnancy: A Guide to Critical Assessment of the Literature Thomas R. Einarson

797

Bendectin/Diclectin for Morning Sickness: A Canadian Follow-Up of an American Tragedy Melanie Ornstein, Adrienne Einarson, and Gideon Koren

807

Index

815

39.

40.

41.

Contributors

Antonio Addis Regional Drug Information Center (C.R.I.F.), Laboratory for Mother and Child Health, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy Stan Ashby The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Gordana Atanackovic The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Benoit Bailey, M.D., M.Sc., F.R.C.P.C. Divisions of Clinical Pharmacology, Toxicology and Emergency Medicine, Department of Pediatrics, Hoˆpital Ste-Justine, Universite´ de Montreal, Montreal, Quebec, Canada Benjamin Bar-Oz, M.D. Department of Neonatology, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel Lizanne Beique, B.Sc.Pharm. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Yedidia Bentur, M.D. Israel Poison Information Center, Rambam Medical Center, Technion–Israel Institute of Technology, Haifa, Israel xiii

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Contributors

James B. Besunder Metro Heath Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio Dimple Bhatia, B.Sc. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Raafat Bishai, M.D., M.Sc., D.C.H. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Jeffrey L. Blumer Rainbow Babies and Children’s Hospital and Case Western Reserve University School of Medicine, Cleveland, Ohio Monica Bologa The Hospital for Sick Children and the Upjohn Company of Canada, Toronto, Ontario, Canada Maurizio Bonati Regional Drug Information Center (C.R.I.F.), Laboratory for Mother and Child Health, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy Heather Boon, B.Sc.Phm., Ph.D. Department of Health Administration, The University of Toronto, Toronto, Ontario, Canada Debra Chang The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Gerald F. Chernoff, Ph.D. Department of Toxic Substances Control, Human and Ecological Risk Division, California Environmental Protection Agency, Sacramento, California David Chitayat The Toronto Hospital and the Hospital for Sick Children, Toronto, Ontario, Canada Merry Chu, M.Sc. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Orna Diav-Citrin, M.D. Hadassah Hospital, The Hebrew University, Jerusalem, Israel Lisa R. Dolovich The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Adrienne Einarson, R.N. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Thomas R. Einarson, Ph.D. Faculty of Pharmacology, The University of Toronto, Toronto, Ontario, Canada

Contributors

xv

Frank Fassos The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Annette Feigenbaum The Motherisk Program, Division of Clinical Genetics, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Rachel Forman The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Shawn Fried The Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Mark H. Friesen, M.Sc.Pharm. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Michael Gallo, B.Sc. Division of Clinical Pharmacology and Toxicology, The Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada Ruthie Geist, M.D. The Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, Ontario, Canada Jonathan Gladstone, M.D. Department of Neurology, The University of Toronto, Toronto, Ontario, Canada Susan Goldberg Department of Psychology, The University of Toronto, Toronto, Ontario, Canada Karen Graham McMaster University, Hamilton, Ontario, Canada Rachel Greenbaum Department of Psychology and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Tommy Ho The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Kathy A. Hodgkinson The Newfoundland and Labrador Genetics Program, St. John’s, Newfoundland, Canada Laura Hunnisett The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Yazemir Ikizler The Addiction Research Foundation, Toronto, Ontario, Canada

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Contributors

Shinya Ito, M.D., A.B.C.P. Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, Ontario, Canada Sheila Jacobson, M.B.B.H., F.R.C.P.C. Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada Sonja Kasapinovic The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Debbie Kennedy The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Julia Klein The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Ernest Kopecky, Ph.D. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Gideon Koren, M.D., F.R.C.P(C), F.A.C.M.T. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Arieh Lalkin Tel Aviv University, Kefar Saba, Israel C. Laskin, M.D. The Obstetric Medicine Program, Division of Rheumatology, Toronto Hospital, and the University of Toronto, Toronto, Ontario, Canada Dionne Laslo, M.A. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Michael Loebstein The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Ronen Loebstein

Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel

Christine Malmberg The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Doreen Matsui The FRAME Program, Division of Clinical Pharamacology, The Children’s Hospital of Western Ontario, London, Ontario, Canada Paolo Mazzotta, M.Sc. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

Contributors

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Michael McGuignan The Poison Control Center and Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada Kristen I. McMartin, M.Sc. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada Myla E. Moretti, M.Sc. The Motherisk Program, The Hospital for Sick Children, Toronto, Ontario, Canada Irena Nulman, M.D. The Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, Ontario, Canada Bonnie O’Hayon, M.D. Division of Clinical Pharmacology and Toxicology, The University of Toronto, Toronto, Ontario, Canada Bunmi Okotore, M.D. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Melanie Ornstein Faculty of Medicine, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario, Canada Laura Park-Wyelie, B.Sc.Pharm. The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Anne Pastuszak, Ph.D.(C) The Fetal Centre, The Hospital for Sick Children, Toronto, Ontario, Canada My-Khanh Phan The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Dimitris Polygenis Faculty of Pharmacy, The University of Toronto, Toronto, Ontario, Canada J. D. Barry Power Faculty of Pharmacy, The University of Toronto, Toronto, Ontario, Canada Michael J. Rieder The FRAME Program, Division of Clinical Pharamacology, The Children’s Hospital of Western Ontario, London, Ontario, Canada Joanne Rovet Department of Psychology and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Joyce F. Schneiderman The Addiction Research Foundation and The University of Toronto, Toronto, Ontario, Canada

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Contributors

Lavinia Schu¨ler, M.D., Ph.D. Federal University of Rio Grande do Sul, Porto Alegre, Brazil Peter L. Selby, M.D. Department of Family Medicine, St. Joseph’s Health Centre, Toronto, Ontario, Canada Nagwa Sherman The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Michael J. Smith, M.S.PharmS., N.D. cine, Toronto, Ontario, Canada

The Canadian College of Naturopathic Medi-

K. Spitzer, B.Sc. The Obstetric Medicine Program, Division of Rheumatology, The Toronto Hospital, and the University of Toronto, Toronto, Ontario, Canada Fayyazuddin Ahmed Syed The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Anna Taddio, Ph.D. Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada Milton Tenenbein University of Manitoba, Winnipeg, Manitoba, Canada Jochen G. W. Theis, M.D. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada J. M. Re´gis Vaillancourt The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Sean Wharton The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Rosanna Weksberg Division of Clinical Genetics, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Eli Zalzstein

Soroka Medical Center, Beer-Sheva, Israel

1 Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance Ronen Loebstein Tel Aviv University, Tel Hashomer, Israel

Arieh Lalkin Tel Aviv University, Kefar Saba, Israel

Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION The dynamic physiological changes that occur in the maternal-placental-fetal unit during pregnancy influence the pharmacokinetic processes of drug absorption, distribution and elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal function and hence drug absorption rates. Ventilatory changes may influence the pulmonary absorption of inhaled drugs. As the glomerular filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced, whereas hepatic drug metabolism may increase, decrease, or remain unchanged. A mean increase of 8 L in total body water alters drug distribution and results in decreased peak serum concentrations of many drugs. Decreased steady-state concentrations have been documented for many agents as a result of their increased clearance. Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotransformation or renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug concentration is responsible for drug effects, the above mentioned changes are probably of no clinical relevance. The placental and fetal capacity to metabolize drugs together with physiological factors, such as differences in the acid-base equilibrium of the mother versus the fetus, determine the fetal exposure to the drugs taken by the mother. As most drugs are excreted into the milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma.

Reprinted from Clinical Pharmacokinetics 1997; 33(5): 328–342.  Adis International Limited. 1

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Loebstein et al.

The milk-to-plasma (M: P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs the amount ingested by the infant will not attain therapeutic levels. Epidemiological surveys have determined that between one- to two-thirds of all pregnant women will take at least one medication during pregnancy. The most commonly used drugs are antimicrobial agents, followed by antiemetics, tranquilizers, and analgesics (1–5). These data demonstrate that drug use during pregnancy is of public concern, as the need to treat the mother must be balanced against the potential adverse effects to the fetus. As pregnancy advances, the complex physiological unit of mother, placenta, and fetus undergoes considerable dynamic physiological changes (6,7). These changes lead to variations in the processes of absorption, distribution, and elimination of drugs. Although most drug therapy in pregnancy is directed to maternal requirements, it is often carried out without considering the important modifications of drug handling by the pregnant woman. Moreover, as previous studies have determined, most drugs easily cross the placenta (8,9), making the fetus an unwanted or even nonbenefiting drug recipient. On the other hand, with the introduction of modern antenatal diagnostic techniques, the idea of treating the fetus in utero, by giving drugs to the pregnant mother, has emerged. Maternal and fetal drug responses during pregnancy are influenced by two factors: (1) changes in absorption, distribution, and elimination of the drug in the mother, which are dictated by pregnancy-induced physiological changes, and (2) the placental-fetal unit, which affects the amount of drug crossing the placenta, the fraction of drug being metabolized by the placenta, and the distribution and elimination of a drug by the fetus. These factors, together with the characteristics of the specific drug, should be taken into consideration when predicting the time course of the drug concentration in the fetomaternal unit.

PHARMACOKINETICS OF THE MATERNAL-FETAL UNIT Although several pharmacokinetic models have been proposed to describe drug disposition in the maternal-placental-fetal unit (10) generally two principal changes characterize pregnancy with respect to drug kinetics (see Fig. 1): The maternal physiological changes The effects of the placental-fetal compartment Alterations in Drug Kinetics Due To Maternal Changes Drug Absorption Gastrointestinal Absorption. The following factors affect the gastrointestinal absorption of drugs: Drug formulation Food composition Chemical composition The pH of the intestinal secretions Gastric emptying time

Pharmacokinetic Changes During Pregnancy

3

Figure 1 Drug disposition in the maternal-placental-fetal system. The factors affecting the pharmacokinetics and drug effects on mother and fetus are (1) altered maternal absorption; (2) increased maternal unbound drug fraction; (3) increased maternal plasma volume; (4) altered hepatic clearance; (5) increased maternal renal blood flow and glomerular filtration rate; (6) placental transfer; (7) possible placental metabolism; (8) placental blood flow; (9) maternal-fetal blood pH; (10) preferential fetal circulation to the heart and brain; (11) undeveloped fetal blood-brain barrier; (12) immature fetal liver enzyme activity; and (13) increased fetal unbound drug fraction. GI ⫽ gastrointestinal.

Intestinal motility Blood flow An increase in plasma progesterone level during pregnancy is believed to be responsible for the reduction in intestinal motility, resulting in a 30 to 50% increase of gastric and intestinal emptying time (6,11). Clinically, this may be important when one needs to achieve a rapid onset of drug effect. There is a reduction in gastric acid secretions (40% less than in the nonpregnant woman) together with an increase in mucous secretions, both of which lead to an increase in gastric pH and, therefore, in buffering capacity (12). Clinically, this would affect the ionization of weak acids and bases and hence their absorption. Nausea and vomiting, which occur frequently during the first trimester, may be another reason for low plasma drug concentrations. Patients should be advised to take their medication at times when nausea is minimal, usually during the evening. The design of different drug formulations takes into account the physicochemical effects of the intestinal secretions so as to allow a relatively predictable rate and site of drug release and absorption. As these factors change dynamically during pregnancy, they may alter the dissolution and absorption of the drug. Pulmonary Absorption. As cardiac output and tidal volumes are increased in pregnancy, hyperventilation and increased pulmonary blood flow occur (13,14). These alterations favor alveolar uptake and therefore should be considered when administering drugs by inhalation. The rate of induction with inhalational anesthetic agents is not necessarily faster because it depends on both pulmonary equilibrium and tissue distribution kinetics.

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However, dose requirements for volatile anesthetic drugs are likely to be reduced during pregnancy, as was demonstrated for halothane, isoflurane, and methoxyflurane (15). Drug Distribution The volume of distribution (Vd) of drugs may be altered during pregnancy as a result of plasma volume expansion by 50% (16). The increased cardiac output is characteristically distributed to different organs: renal blood flow increases by 50% at the end of the first trimester (14,17). The uterine blood flow reaches its peak at term (36–42 L/h) with 80% perfusing the placenta and 20% the myometrium (18). The total mean increase in total body water is 8 L, distributed 60% to the placenta, fetus and amniotic fluid and 40% to maternal tissues (16,17). As a result of this volume expansion, a decrease in the peak serum concentration (C max ) of many drugs has been documented. It is expected, therefore, that drugs distributed mainly to water compartments, and thus having a relatively small Vd, will demonstrate the greatest decrease in serum C max . Moreover, decreased steadystate drug concentrations have been documented for different agents as a result of their enhanced clearance. Drug dosage requirements would be expected to be greater to achieve the same therapeutic effect if these effects were not offset by other pharmacokinetic changes of pregnancy discussed later in this review (see below). Protein Binding As the pregnancy advances, the plasma volume expands at a greater rate than the increase in albumin production, creating physiological dilutional hypoalbuminemia (6,7,19). Moreover, steroid and placental hormones occupy protein binding sites, thus decreasing the protein binding of drugs. The overall effect is a decrease in binding capacity for albumin and, therefore, an increase in the unbound (‘‘free’’) drug (19). Since the unbound fraction of the drug is the pharmacologically active drug, pregnant women would be expected to have an increased drug effect. However, as more free drug is available for biotransformation, the net effect for most agents is an unaltered free drug concentration. In contrast to albumin, serum α 1-acid glycoprotein concentrations were found to remain the same as those in nonpregnancy. However, as there is a significant decrease in this glycoprotein within the fetus, the free fractions of basic drugs such as propranolol, lidocaine (lignocaine), and metocurine are higher in the developing child (20). There is no laboratory or clinical evidence showing increased free drug concentrations of these agents in the fetus. Yet clinicians who do not have access to measurements of unbound drug may erroneously interpret lower concentrations of the total drug as indicative of lower free drug. This issue is discussed in the context of phenytoin later in this review. Drug Elimination Hepatic Drug Elimination. The increased secretion of estrogen and progesterone in normal pregnancy affect hepatic drug metabolism in different ways: a higher rate of hepatic metabolism of certain drugs, such as phenytoin, is possibly a result of stimulated hepatic microsomal enzyme activity induced by progesterone. On the other hand, the hepatic elimination of other drugs, such as theophylline and caffeine, is reduced secondary to competitive inhibition of microsomal oxidases by progesterone and estradiol (21,22). Finally, the cholestatic effect of estrogen may interfere with the clearance of drugs, such as rifampicin (rifampin) (23), which are excreted into the biliary system. The above mentioned changes of pregnancy on hepatic physiology may alter drug metabolism, but their extent can hardly be quantified.

Pharmacokinetic Changes During Pregnancy

5

Renal Drug Elimination. The relationship between creatinine clearance and the elimination of drugs excreted mainly by the kidney has been demonstrated for many agents (24). As renal plasma flow increases by 25–50% (17) and glomerular filtration rate (GFR) by 50% (25), drugs excreted primarily unchanged in the urine—such as penicillin, digoxin, and lithium—demonstrate enhanced elimination and lower steady-state serum concentrations. However, these changes are clinically insufficient and therefore require no alteration on the dose of the above mentioned drugs. Drug Compliance In the absence of evidence-based studies, many pharmaceutical manufacturers warn the public to minimize or even avoid drug use during pregnancy. Together with the unrealistically high perception of the teratogenic risk related to drugs (26) and sometimes misinformation regarding unfounded teratogenic potential of well-tolerated medications, it is not surprising that pregnant women tend to comply less than optimally with drug therapy. The investigation of low drug serum concentrations during pregnancy must, therefore, rule out a decrease in compliance in addition to pharmacokinetic changes.

The Placental-Fetal Compartment Effect Several pharmacokinetic models have been proposed in an attempt to characterize drug behavior in the fetoplacental unit (10). Depending on the drug and available experimental data, the body is represented as a system of one compartment or more. When an administered drug readily equilibrates to achieve a fetal: maternal drug concentration of about unity, a single compartment model may be applied. On the other hand, when the fetal tissue is more slowly accessible, thus representing a deep compartment, a two-compartment model may be more appropriate. In this case the fetal :maternal concentration ratio will be lower during drug administration than during the postdistribution phase. Salicylates and diazepam are examples of such a model as they achieve higher concentrations in fetal than in the maternal plasma (27–29). Such considerations may be important in assessing fetal exposure to different agents on the basis of maternal plasma concentrations. In addition, different physiological factors such as placental blood flow and differences in plasma protein binding and/or in acid-base equilibrium of the maternal versus the fetus, also contribute to the understanding of fetal-maternal drug concentration ratios (Fig. 1). Effect of Protein Binding The fetal and newborn plasma proteins appear to bind various drugs (e.g., ampicillin and benzyl-penicillin) with less affinity than maternal plasma proteins (30). For other drugs (e.g., salicylates), a more extensive binding to the fetal than to the maternal, proteins has been documented (27). Maternal plasma albumin gradually decreases during pregnancy while fetal albumin progressively increases. This dynamic process results in different fetal :maternal albumin concentration ratios at different gestational ages. The fetal albumin concentration reaches its peak at term when it equals or even exceeds maternal albumin concentration (31) because the free (unbound) drug concentration is an important determinant of drug movement across the placenta. Since only the unbound drug is capable of crossing the placental barrier, protein-bound drugs, such as digoxin or ampicillin, reach higher total concentrations in the fetus. On the other hand, drugs with high protein binding, such as dicloxacillin, achieve higher maternal than fetal total concentrations.

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Acid-Base Equilibrium Effect Nonionized highly lipid-soluble molecules penetrate biological membranes more quickly than less lipid soluble ionized molecules. Therefore, the maternal and fetal pHs are important determinants of placental transfer, especially for weakly acidic or basic drugs whose pKa is close to the plasma pH. The fetal plasma pH is usually slightly more acidic than the maternal. Consequently, weak bases will be mainly nonionized and, therefore, able to easily penetrate the placental barrier. However, after crossing the placenta and making contact with the relatively acidic fetal blood, these molecules will become more ionized. This results in an apparent fall in fetal concentrations of the drug and leads to a concentration gradient; therefore a net movement from the maternal to the fetal system (32). This phenomenon is commonly referred to as ion trapping. The magnitude of this ion trapping was demonstrated in a study in which sodium salicylate 20 mg/kg body-weight was intravenously administered to 115 pregnant women at the beginning of labor. Serial blood samples from the mothers and umbilical cords of the newborns were obtained. There was a slow transfer of salicylate from the mothers to the fetuses and an increase in the neonatal :maternal serum concentration ratio to an average of 1.5 after 4 hours (120 mg/L in newborns and 80 mg/L in the mothers) (28). Thus, at least at term, total plasma concentrations of salicylate in the fetus are higher—an important consideration when assessing the magnitude of fetal exposure to salicylate on the basis of the drug concentration of the mother. Fetoplacental Drug Elimination There is some evidence that both the human placenta and the fetus are capable of metabolizing drugs (33–35). All enzymatic processes including phase I (oxidation, dehydrogenation, reduction, hydrolysis, etc.) and phase II (glucuronidation, methylation and acetylation) have been documented in the fetal liver as early as 7–8 weeks postconception (33). However, as most enzymatic processes are immature at that stage, their degree of activity is very low; therefore their contribution to the overall drug-elimination capacity is marginal. On the other hand, the reduced elimination capacity may cause more pronounced and prolonged drug effects in the fetus. The fact that about half of the fetal circulation (umbilical vein) directly reaches the heart and brain, bypassing the liver, may also contribute to this effect. Elimination of the drug from the fetus is primarily by its diffusion back to the maternal compartment. However, as most metabolites are more polar than their parent compounds, they are less likely to cross the placental barrier. This may result in metabolite accumulation in various fetal tissues. As pregnancy progresses, higher amounts of different drugs are excreted into the amniotic fluid, reflecting maturation of the fetal kidney. Rate of Maternal-Fetal Drug Equilibration As the major route of placental drug transfer is by simple diffusion, the net transplacental movement of most xenobiotics is proportional to the concentration gradient of the drug across the placenta and the physicochemical characteristics of the xenobiotic and the placental membrane. As with diffusion across other biological membranes, lipophilic drugs generally cross the placenta more readily than nonlipophilic compounds. Drugs which are nonionized at the physiological pH will diffuse across the placenta more rapidly than more basic or acidic compounds. This distinction is not absolute since some drugs which are ionised at physiological pH, such as valproic acid (valproate sodium) or salicylate, rapidly and efficiently reach the fetus (28).

Pharmacokinetic Changes During Pregnancy

7

For most nonionized lipophilic compounds, the rate-limiting step that determines placental drug transfer is blood flow. Changes in placental blood flow that may be secondary to pathophysiological conditions (e.g. pregnancy-induced hypertension, abruptio placenta) or pharmacological effects (oxytotic drugs, nicotine) can, therefore, affect the rate of placental drug transfer. On the other hand, for more polar drugs with lower rates of placental transfer, the rate-limiting step for placental transfer is diffusion. The rate of maternal-fetal drug equilibration is an important determinant in cases when therapeutic fetal drug concentrations must be achieved as quickly as possible. Clinical examples of such cases are maternal administration of antiarrhythmic agents or antibacterials in order to treat intrauterine fetal arrhythmias or infections. We studied the transplacental pharmacokinetics of digoxin using an in vitro human placental perfusion model (36). After 30 minutes of perfusion with digoxin, the amount of digoxin leaving the maternal circulation and the amount of digoxin appearing in the fetal circulation were constant at a fetomaternal ratio of 0.36 ⫾ 0.04. Based on these data, the time to reach equivalent concentrations on both sides of the placenta, assuming the constant rate of digoxin transfer is maintained, is estimated to be 268 ⫾ 34 minutes. At the end of a 3-hour perfusion study, digoxin concentrations were 3.32 ⫾ 0.43 µg/L in the maternal circulation versus 1.3 ⫾ 0.45 µg/L in the fetal circulation. The transplacental pharmacokinetics of cocaine were studied in pregnant rhesus monkeys (37). Animals were intramuscularly given cocaine hydrochloride 1 mg/kg. The C max of cocaine was reached in the maternal blood within 10 to 20 minutes after administration and cocaine was detected in fetal blood within 5 minutes, reaching C max within 30 to 120 minutes.

PREGNANCY-INDUCED PHARMACOKINETIC CHANGES OF SPECIFIC DRUGS Anticonvulsants Epilepsy is a common neurological disorder, with a prevalence of 1%. In most women with epilepsy, seizures are well controlled during pregnancy: however, if the frequency of the seizures changes, it is usually for the worse (38). The potential problem in the management of these patients arises from altered pharmacokinetics associated with pregnancy. In general, the plasma C max of anticonvulsant drugs falls during pregnancy as a result of a 50% expansion in plasma volume, while steady-state concentrations fall secondary to decrease in protein binding (16) and increased clearance. As most anticonvulsant drugs are acidic or neutral, they are highly bound to serum albumin. During pregnancy, albumin levels fall, with a corresponding fall in the bound drug. The decrease in plasma protein binding leads to more free drug available for biotransformation. Thus, the unbound concentrations (free drug) remain relatively constant, but total plasma concentrations (unbound plus protein-bound) fall. It should be remembered that the constant or even higher free drug concentration may provide better antiepileptic control, as it is the free drug that reaches the brain. For practical reasons, most laboratories measure total plasma concentration (bound plus unbound) rather than the unbound concentration, which is the pharmacologically active component. Phenytoin and valproic acid are both highly protein-bound (approximately 90%) to plasma albumin. Monitoring the total plasma concentrations of these drugs

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can, therefore, be misleading. Only therapeutic drug monitoring that will measure both protein-bound and unbound drug concentrations can be appropriately interpreted. The increase in GFR (25) and renal plasma flow (17) may theoretically enhance the clearance of renally excreted drugs, such as gabapentin and vigabatrin. However, presently there are no studies available regarding the pharmacokinetics of these agents during human pregnancy. Carbamazepine is regarded by many to be the drug of choice for most forms of epilepsy during pregnancy because of its relatively low teratogenic risk (39). Phenytoin has been associated with the fetal hydantoin syndrome and has neurotoxic potential (40– 42). Both valproic acid and carbamazepine have been shown to cause neural tube defects, and in women undergoing carbamazepine therapy a full workup should be performed to rule out this malformation (43,44). Phenobarbital has been much less commonly prescribed in recent years because of its tendency to produce sedation and impair cognitive function. Altered Pharmacokinetics of Commonly Used Antiepileptic Drugs During Pregnancy Carbamazepine. Carbamazepine has a relatively slow absorption, with 70–80% protein binding to albumin. The main eliminating route is by hepatic metabolism, and there may be a decrease in serum concentrations during the first months of therapy as a consequence of autoinduction of metabolism. It is important for the clinician to recognise that the dosage intervals and sample time are critical in interpreting serum concentrations. Large peak-trough fluctuations can be minimized by using a controlled-release formulation (45). As levels tend to be lower in pregnancy, and bioavailability may be lower than with conventional carbamazepine, higher dosages may be required when using controlledrelease medication (46). The concentration of the primary metabolite (carbamazepine-10, 11-epoxide) was reported to increase during pregnancy, possibly as a result of the increased carbamazepine metabolism and impaired conversion of carbamazepine-10, 11-epoxide to carbamazepine10, 11 trans-diol during pregnancy. This increase may be of importance as the metabolite (10, 11 epoxide) is thought to have comparable pharmacological activity to the parent drug (47). Phenytoin. Phenytoin follows nonlinear pharmacokinetics and has a narrow therapeutic window (48). It is highly bound to protein (90–93%) (49,50) and mainly cleared by saturable hepatic metabolism (Table 1). A significant increase in 8-hydroxylation during pregnancy may be responsible, at least partially, for increased phenytoin clearance during pregnancy and consequently for decreased serum concentrations (58). Generally, a fall in total serum phenytoin concentrations greater than 25% or worsening of seizure control should encourage physicians to increase the dose. The fall in total concentrations by itself may not indicate a fall in free drug concentrations. The decrease in the protein binding of phenytoin is probably a major reason for decreasing total drug concentrations in pregnancy, however, as it is the free drug that is available for the enhanced metabolism there should not be a major effect on free drug concentrations. Dose adjustments should ideally be based on free drug concentration monitoring especially for highly protein-bound drugs, such as phenytoin, which are most likely to be affected by pregnancy.

Pregnancy-Induced Pharmacokinetic Changes for Selected Drugs t 1/2β (min)

Drug Ampicillin Cefuroxime Imipenem Piperacillin Azlocillin Nifedipine Labetolol Sotalol Phenytoin

Pregnant

Nonpregnant

⫾ ⫾ ⫾ ⫾

3.9 5 8 10

⫾ ⫾ ⫾ ⫾

18 16 36 314

69.6 ⫾ 6.1 58 ⫾ 8 41 ⫾ 16 53.7 ⫾ 4.6 72 360 160 ⫽ 480 558 ⫾ 42

52.4 44 36 46.5 65.4 81 102 396 900

Vd(L) Pregnant 32.8 17.8 47.1 67.6 15.4

⫾ ⫾ ⫾ ⫾

2.5 1.9 14.8 11.8

106.4 ⫾ 8.1

CL(mL/min)

Nonpregnant 34.5 16.3 18.9 41.9 24.7

⫾ ⫾ ⫾ ⫾

2.7 2.1 5.8 6.2

87.3 ⫾ 7.2

Pregnant 450 ⫾ 282 ⫾ 973 ⫾ 1538 ⫾ 126.1 266 ⫾ 1704 ⫾ 196 ⫾

31 34 47 362 105 531 24

Protein binding (%)

Nonpregnant 370 ⫾ 198 ⫾ 338 ⫾ 540 ⫾ 195.7 27 ⫾ 1430 109 ⫾

Pregnant

Nonpregnant

Reference

90

51 52 53 54 54 55 56 57 50

30 27 85 75 5 7 86

Pharmacokinetic Changes During Pregnancy

Table 1

Abbreviations: CL ⫽ clearance; t 1/2β ⫽ elimination half-life; Vd ⫽ volume of distribution.

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Valproic Acid. Valproic acid is rapidly absorbed and highly protein bound to plasma albumin (88–92%) (45). The interpretation of its pharmacokinetics is limited by large fluctuations in the concentration-time profile, wide therapeutic index and concentration dependent protein binding (59,60). Analysis of unbound valproic acid is not routine and similarly there is no established therapeutic range. Dose adjustments during pregnancy are best made by clinical observation in combination with changes in concentration measurements. New Antiepileptic Drugs. Vigabatrin, lamotrigine, and gabapentin are available for the treatment of epilepsy, but there is little information regarding their pharmacokinetics and safety during human pregnancy. Antibacterials β-Lactams β-Lactam antibacterials are the oldest class of antibacterials used in the treatment of infections during pregnancy. Benzylpenicillin (penicillin G) is still the most common antibacterial used during pregnancy. Other β-lactam agents are structurally related to penicillin and are likely to be used more often than new compounds because of their proven safety profile. The therapeutic effect of β-lactam antibacterials depends primarily on maintaining adequate plasma concentrations during the entire treatment period. Their activity correlates well with pharmacokinetic characteristics [C max, area under the concentration-time curve (AUC), etc.] and time during which plasma concentration exceeds the minimal inhibitory concentration (MIC) for susceptible bacteria (Table 1) (61). The dosage regimen for βlactam antibacterials should be calculated according to the pharmacokinetic profile of the drug and its MIC values (62). Most bacterial infections are confined to the extravascular compartment. β-Lactams enter the extracellular fluid by passive diffusion (63), and thus the tissue concentrations of hydrophilic β-lactams will be low, despite excellent penetration properties into this compartment. Because of that, underestimation of β-lactam antibacterial concentrations can occur when measuring tissue concentrations at the infection site (64,65). There is good evidence that direct correlation exists between β-lactam plasma concentrations and response to infections at an extravascular site, and thus plasma concentration is a predictor for response. β-Lactams are acidic agents. Their binding to albumin ranges from 2.5–97% for different drugs (61). The total AUC values in extravascular sites and plasma are related to the concentration of the non–protein bound concentrations in the plasma. The free drug concentration in the plasma determines the penetration of drugs into tissue (66). This is usually of great importance only when the degree of binding exceeds 80% (67). Plasma protein binding can be dependent on plasma concentration, in which higher levels reduce the extent of protein binding (68). It is important to remember that β-lactams are water soluble and cross the placenta by passive diffusion along the concentration gradient. As this is a slow process, it takes several hours for fetal and maternal concentrations to reach an equilibrium. In the fetal compartment, water soluble drugs circulate in the fetus and are excreted into the amniotic fluid, recycling again in the fetus by gastrointestinal absorption. Thus, water soluble drugs are eliminated from the amniotic fluid slowly and this fluid can be regarded as a reservoir for hydrophilic drugs (69). For more lipophilic drugs, metabolism is an important means

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of elimination. Both the fetal liver and placenta can metabolize lipophilic drugs to some degree (70,71). The common denominator to most studies conducted in pregnancy is the substantially lower serum concentrations, which in many cases should lead to the consideration of higher doses than those given to a nonpregnant woman. Ampicillin The pharmacokinetic of ampicillin in pregnant women has been studied extensively, and alterations in its pharmacokinetics have been found when compared with data from nonpregnant women (72). These altered pharmacokinetics lead to a lower plasma concentration of the drug in pregnant women than in nonpregnant women (61). In a recent study (51), 22 women were given a single dose of ampicillin precaesarean and then again 6 weeks postcaesarean, thereby using the patients as their own control. Pregnancy significantly increased the elimination rate constant, decreased the AUC by 20%, and increased the total body clearance (51). Another study has shown that maternal serum concentrations decline relatively rapidly after intravenous infusion of ampicillin and recovered in fetal serum 30 minutes after maternal infusion, reaching-equilibrium with maternal serum in 1 hour. The concentration of ampicillin in amniotic fluid continued to rise for up to 8 hours, then slowly declined over the next 19 hours (30). The elimination half-life (t 1/2β ) was reported to be 30 minutes during caesarean section (73), 40 and 58 minutes during delivery (74,75), and 40 minutes and 1.6 hours during the third trimester (Table 2) (75,76). Phenoxymethylpenicillin (Penicillin V) Phenoxymethylpenicillin (penicillin V) is the most commonly used antibacterial during pregnancy. Altered pharmacokinetics has been demonstrated in a study comparing 12 pregnant women during the second and third trimesters with 6 nonpregnant women. This study showed significantly faster elimination rates of the drug from the plasma of pregnant women compared with nonpregnant women. The AUC was lower in pregnant women (441 IU/mL/min) compared with nonpregnant women (887 IU/mL/min) as was C max (3.7 IU/mL in pregnant versus 5.6 µ/mL in nonpregnant women) (82). Ureidopenicillins Azlocillin and piperacillin have been demonstrated to cross the human placenta (83,84). In a study of eight women undergoing caesarean section and six nonpregnant women undergoing gynecological operations, the mean C max values after administration of piperacillin 4 g were significantly lower in the pregnant women than in the nonpregnant women (87.5 versus 172.2 mg/L). The total clearance was faster in pregnant women than in nonTable 2 Fetomaternal Concentration Ratio of Selected Antibacterials Drug Ampicillin Cephalosporins Dicloxacillin Gentamycin Methicillin Benzylpenicillin (penicillin G)

Fetomaternal ratio

References

0.38: 0.87 0.13: 1.0 0.07: 0.27 0.21: 1.0 0.83: 1.43 0.06: 0.7

77 78 79 80,81 79 82

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pregnant women (92.28 versus 32.4 L/h), and volume of distribution (Vd) was significantly greater (67.6 versus 41.2 L) (84). In another study, piperacillin 3 g every 4 hours and mezlocillin 4 g every 6 hours were evaluated in 6 postpartum patients. The serum half-life and clearance rates for mezlocillin were 82.4 minutes and 12.12 ⫾ 6.3 L/h, respectively, and for piperacillin 32.9 minutes and 27.36 ⫾ 5.28 L/h, respectively (85). Imipenem Imipenem is a broad-spectrum β-lactam used in combination with cilastatin, a competitive inhibitor of dehydropeptidase, in order to minimise the renal metabolism of the drug (86). A single dose of imipenem was administered to 14 pregnant women in early and late pregnancy and 6 nonpregnant women, the mean plasma C max were 14.7 ⫾ 4.9, 14.9 ⫾ 5.2, and 43 ⫾ 28.3 mg/L in early pregnancy, late pregnancy, and nonpregnant women, respectively. The Vd was significantly larger during early and late pregnancy than in nonpregnant women, and clearance from plasma was significantly faster than in nonpregnant women (53). Cephalosporins First-Generation Cephalosporins. The mean serum concentration of cefalexin (87), cefalothin (88), and cefazolin (89), are all considerably lower in pregnant women when compared with nonpregnant women (Table 2). Second-Generation Cephalosporins. Cefuroxime plasma concentrations in pregnant women at the time of labour and delivery were lower than in nonpregnant women; the half-life was significantly shorter, and clearance and recovery in the urine were significantly higher. The drug effectively passes the placenta and is detected in cord plasma soon after drug administration to the mother (52). Third-Generation Cephalosporins. The penetration of ceftriaxone into the fetus at parturition was studied in 17 pregnant women. After intravenous administration of ceftriaxone 2 g, substantial concentrations were achieved in the umbilical cord blood, amniotic fluid and placenta after 1 hour. The t 1/2 β was approximately 6 hours, identical to that of the mother (90). Bourget et al. (91) studied the pharmacokinetics and protein binding of ceftriaxone during pregnancy. It was found that the pharmacological behavior of ceftriaxone in pregnant women during the third trimester is comparable with that in healthy volunteers. Concentrations of total and free drug measured at 24 hours were greater than the MIC for allegedly susceptible organisms, both on day 1 and at steady state. No dosage schedule required particular adjustment, i.e., neither a loading dose nor maintenance dose increased. Lithium Lower serum concentrations of lithium have been reported during pregnancy. Since this antidepressant agent is eliminated almost entirely by the kidney, the increase in glomerular filtration rate (GFR) during pregnancy is consistent with the observed decrease in serum concentrations. Because of lithium’s narrow therapeutic range, a drop in its serum concentrations may result in suboptimal therapy (92). Some lithium is reabsorbed in the proximal renal tubule competitively by the sodium transporter. Pregnant women with low circulating effective volume secondary due either to dehydration (hyperemesis gravidarum, vomiting) or restricted sodium intake (toxemia), may experience higher lithium concentrations as a

Pharmacokinetic Changes During Pregnancy

13

result of enhanced renal absorption. Finally, during puerperium, with the decrease in GFR to prepregnancy serum concentrations, values are expected to rise, potentially to toxic levels (32). Digoxin As with lithium, digoxin is eliminated mainly by renal excretion. When measured at term, as expected, the digoxin serum concentrations which were found in 5 pregnant women was twofold lower compared with concentrations 1 month later (32,93). Therefore, it is reasonable to expect maternal dose requirements to increase during pregnancy and to fall in the puerperium. Antihypertensive Agents With more reassuring studies regarding the tolerability of calcium channel blockers and β adrenergic blockers during pregnancy (94–96), these agents are expected to become more commonly used to control hypertension during pregnancy. The pharmacokinetics of nifedipine were studied during the immediate postpartum period in patients with preeclampsia (Table 1) (55). The terminal t 1/2 β was found to be shorter than that reported for normotensive volunteers or nonpregnant women with hypertension (1.35 ⫾ 0.3 versus 3.4 ⫾ 0.4 hours). A mean apparent oral elimination clearance of 3.3 ⫾ 1.3 L/h/kg was more rapid than that found in normal volunteers, 0.49 ⫾ 0.09 L/h/kg. Based on these data a dosage interval of every 3–4 hours is suggested when rapid release nifedipine is used in a postpartum patient with preeclampsia. Pharmacokinetic studies of oral labetalol in women with pregnancy-induced hypertension in the third trimester have shown the terminal t 1/2 β to be significantly shorter than that reported for normotensive volunteers or nonpregnant patients with hypertension (1.7 ⫾ 0.27 hours versus 6 to 8 hours) suggesting the need for a shorter dosage interval (56). Pethidine (Meperidine) Pethidine (meperidine) is widely used as an analgesic agent during labor. Its disposition was studied in 11 pregnant women after administration of a single 50 mg intravenous dose through 48 hours postinjection (Table 1) (97). Pethidine clearance was significantly higher in pregnant women (0.678 ⫾ 0.1 L/min) compared with previously reported data collected from nonpregnant women (1.06 L/min). The half-lives of the rapid (α) and terminal (β) elimination phases were significantly greater in pethidine-treated pregnant women (2.3 and 13.3 hours, respectively) compared with nonpregnant women (0.1 and 3.6 hours, respectively). The longer β-elimination half-life may have important clinical implications in the sequential dose administration of this agent. DRUG USE DURING LACTATION Breast-feeding patterns have changed considerably over the past several decades. In the United States the proportion of women breast feeding their babies was estimated at 60% in 1984 compared with 30% in the 1950s (98). In the early 1980s, women in Canada also demonstrated an increasing trend toward breast-feeding compared with the 1960s (99). Factors that affect maternal decisions to breast-feed include:

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Parity Educational level Social class Psychosocial factors Socioeconomic class The use of medications is believed to contribute to a mother’s choice of whether to feed by breast or by bottle (100). Breast milk is produced and secreted in the alveolar cells, from which it is expelled by contractile myoepithelial cells into the duct system. Drugs enter breast milk by either passive diffusion or active transport (101). Since most drugs are excreted into milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma (Table 3) (113,114). As breast milk is slightly more acidic than the plasma, drugs that typically pass into milk are weak bases, lipid-soluble, and poorly bound to proteins (115,116). The milk :plasma (M:P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. M: P ratios for selected drugs are given in Table 3. However, when dealing with infant exposure to drugs in breast milk, in addition to the M:P ratio, the infant’s clearance of the drug also has to be taken into account (117). Some general principles can be used by the clinician when managing cases with drug exposure in a breast-fed infant: The drug concentration in breast milk usually does not exceed the maternal plasma concentration. Even when the M:P ratio for a given drug approaches or exceeds 1.0, the amount of drug ingested by the infant is rarely sufficient to attain the therapeutic concentrations. A short exposure to a drug is usually of less concern than a drug given for a long period of time. The amount of drug ingested by the infant can be minimized by feeding the infant just before or at the time of maternal administration. In cases of long-term drug therapy, the effect on the infant of drug exposure while breast-feeding is to lower concentrations compared with those shown in utero. Table 3 Drug Excretion in Human Breast Milk Drug Amoxicillin Atenolol Carbamazepine Cefotaxime Diazepam Digoxin Lithium carbonate Penicillin Phenytoin Propranolol Theophylline Warfarin

M :P ratio

References

0.014–0.043 1.5–6.8 0.6–0.7 0.029–0.16 0.08–0.13 0.6–0.8 0.25–0.77 0.02–0.2 0.12–0.24 0.5 0.57 ⬍0.01

102 103,104 105 102 106 107 108 109 110 103 111 112

Abbreviation: M:P ⫽ milk to plasma.

Pharmacokinetic Changes During Pregnancy

15

The American Academy of Pediatrics and the Canadian Paediatric Society list the following drugs as contraindicated during breast feeding: bromocriptine, cyclophosphamide, cyclosporin, doxorubicin, ergotamine, lithium, and methotrexate. Amiodarone is not recommended while breast feeding as it can cause iodine-induced fetal hypo- or hyperthyroidism (118). Bromocriptine and ergotamine are contraindicated because of their prolactin-suppressing activity (119,120). All antineoplastic agents are ill advised because of their theoretical ability to induce short-term toxicity (myelosuppression) and long-term carcinogenicity (121–124). Lithium freely passes into human breast milk and significant plasma concentrations have been detected in nursing infants (108). In addition, temporary cessation of breast-feeding is advised for some radioactive compounds. Antithyroid Drugs After radioactive iodine, methimazole and propylthiouracil (PTU) are the most commonly used antithyroid medications (125). Since the amount of PTU the infant would ingest is estimated to be less than 1% of the mother’s dose on a body-weight basis (126) compared with 2–12% with methimazole (127), PTU is considered the drug of choice for lactating women with hyperthyroidism. Despite the low-level exposure, there is still a potential risk of thyroid suppression in the infant; therefore clinical and thyroid-stimulating hormone (TSH) monitoring is recommended. No adverse effect in breast-fed infants has been reported so far (128). Anticonvulsants Carbamazepine, phenytoin, and valproic acid are considered compatible with breastfeeding since the exposure levels of the infant to these drugs is less than 10% of the expected exposure if the drug was given directly to the infant (105,110,129). In contrast, phenobarbital, ethosuximide and primidone result in an infant’s exposure levels of 100, 50 and greater than 10% of the mother’s dose on a body-weight basis (130). These high-level exposures are mainly secondary to the low clearance of phenobarbital and ethosuximide in infants. Therefore, clinical and drug concentration monitoring in breast milk and in the plasma of the infant is recommended. ␤-Adrenergic Blockers Of concern among all β-adrenergic blockers are atenolol and sotalol, which cause relatively high exposure levels: 25 and 20%, respectively (103,131,132); mainly due to their low protein binding. This is clinically important in the early neonatal period when GFR is a low secondary to immature renal function (104). Alcohol The M: P ratio of alcohol (ethanol) is about 1.0 (133,134). Together with the premature metabolising capacity of alcohol in the neonatal and infantile periods, heavy maternal alcohol consumption is incompatible with breast feeding. Motor development was claimed to be slower in infants breast-fed by alcohol-drinking mothers (135); however, this is unlikely unless the mother is drinking alcohol on an almost continuous basis. Other factors such as in utero exposure to alcohol, and therefore fetal alcohol effects in these children, need to be considered in the light of the fact that the infants concentrations of alcohol are probably too low to explain the developmental delay.

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CONCLUSIONS Pregnancy is associated with a plethora of physiological changes that may affect the way the body handles drugs. However, for most agents, the net effect of these changes results in unaltered free drug concentrations and, therefore, unchanged drug effects. Dose requirements are likely to be higher for agents with an enhanced clearance. For more highly protein-bound drugs, pregnancy-related hypoalbuminemia may result in higher free drug concentrations. Dose adjustments for such drugs should ideally be based on free drug concentration monitoring. Although most drugs are excreted into breast milk by passive diffusion, the amount ingested by the infant is rarely sufficient to attain therapeutic concentrations.

REFERENCES 1. Heinonen OP, Slone D, Monson RR, et al. Cardiovascular birth defects and antenatal exposure to female sex hormones. N Engl J Med 1977; 296(2):60–67. 2. Forfal JO, Nelson MM. Epidemiology of drugs taken by pregnant women: drugs that may affect the fetus adversely. Clin Pharmacol Ther 1973; 14:632–642. 3. Brocklebank JC, Ray WA, Federspiel CF, et al. Drug prescribing during pregnancy: a controlled study of Tenessee Medicaid recipients. Am J Obstet Gynecol 1978; 132(3):235–244. 4. Cordero JF, Oakley GP. Drug exposure during pregnancy: some epidemiologic considerations. Clin Obstet Gynecol 1983; 26(2):418–428. 5. Piper JM, Baum C, Kennedy DL. Prescription drug use before and during pregnancy in a Medicaid population. Am J Obstet Gynecol 1987; 157(1):148–156. 6. Hytten FE, Leitch T. The physiology of pregnancy. Oxford: Blackwell, 1971. 7. Quilligan EJ, Kaiser IH. Maternal physiology. In: Danforth DN, ed. Danforth Obstetrics and Gynecology. 3rd ed. New York: Harper & Row, 1982:326–341. 8. Young IM. The placenta: blood flow and transfer. In: Downman CBB, ed. Modern Trends in Physiology. London: Butterworth, 1972:214–244. 9. Mirkin BL, Singh S. Placental transfer of pharmacologically active molecules. In: Mirkin BL, ed. Perinatal Pharmacology and Therapeutics. New York: Academic Press, 1976:1–69. 10. Krauer B, Krauer F. Drug kinetics in pregnancy. In: Gibaldi M, Prescott L, eds. Handbook of Clinical Pharmacokinetics. New York: Adis, 1983:1–17. 11. Parry E, Shields R, Turnbull A. Transit time in the small intestine in pregnancy. J Obstet Gynaecol Br Commonw 1970; 77:900–901. 12. Hume Jr RF, Killam AP. Maternal physiology. In: Danforth DN, ed. Obstetric and Gynecology, 6th ed. Philadelphia: J.B. Lippincot Company, 1990:93–100. 13. Cugell DW, Frank NR, Gaensler EA, et al. Pulmonary function in pregnancy. Am Rev Tuberc 1953; 67:568–597. 14. Kerr MG. Cardiovascular dynamics in pregnancy and labour. Br Med Bull 1968; 24:19–24. 15. Palahniuk RJ, Shmider SM, Eger EI. Pregnancy decreases the requirement for inhaled anesthetic agents. Anesthesiology 1974; 41:82–83. 16. Pizani BBK, Campbell DM, McGillivray T. Plasma volume in normal pregnancy. J Obstet Gynaecol 1973; 80:884–887. 17. Dunihoo DR. Maternal physiology. In: Dunihoo DR, ed. Fundamentals of Gynecology and Obstetrics. Philadelphia: J.B. Lippincott Co., 1992:280–284. 18. Assali NS, Rauramot L, Peltonen T. Measurement of uterine blood flow and uterine metabolism. Am J Obstet Gynecol 1960; 79:86–98. 19. Dean M, Stock B, Patterson RJ, et al. Serum protein binding of drugs during and after pregnancy in humans. Clin Pharmacol Ther 1980; 28:253–260.

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20. Wood M, Alastair JJ, Wood MB. Changes in plasma drug binding and α 1-acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 1981; 29:522–526. 21. Davis M, Simmons CJ, Dordini B, et al. Induction of hepatic enzymes during normal pregnancy. J Obstet Gynaecol Br Commonw 1973; 80:690–694. 22. Juchau MR, Mirkin DL, Zachariah PK. Interactions of various 19-nor steroids with human placental microsomal cytochrome P-450. Chem Biol Interact 1976; 15(4):337–347. 23. Harrison LI, Gibaldi M. Influence of cholestasis on drug elimination: pharmacokinetics. J Pharm Sci 1976; 65:1246–1348. 24. Dettli L. Elimination kinetics and drug dosage in renal insufficiency patients. Triangle 1975; 14(3–4):117–123. 25. Davidson JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol 1974; 81:588–595. 26. Koren G, Bologa M, Pastuszak A. The way women perceive a teratogenic risk: the decision to terminate pregnancy. In: Koren G, ed. Maternal-Fetal Toxicology. 2nd ed. New York: Marcel Dekker Inc., 1994:727–735. 27. Levy G, Procknal JA, Garrettson LK. Distribution of salycilate between neonatal and maternal serum at diffusion equilibrium. Clin Pharmacol Ther 1975; 18(2):210–214. 28. Levy G. Salicylate pharmacokinetics in the human neonate. In: Morselli P, Garattini C, Sereni Y, eds. Basic and Therapeutic Aspects of Perinatal Pharmacology. New York: Raven Press, 1975:319–330. 29. Mandelli M, Morselli PL, Nordio S, et al. Placental transfer of diazepam and its disposition in the newborn. Clin Pharmacol Ther 1975; 17(5):564–572. 30. Bray RE, Boe RW, Johnson WL. Transfer of ampicillin into fetus and amniotic fluid from maternal plasma in late pregnancy. Am J Obstet Gynecol 1966; 96:938–942. 31. Dancis J, Braverman N, Lind J. Plasma protein synthesis in the human fetus and placenta. J Clin Invest 1957; 36:398–404. 32. Koren G. Changes in drug disposition in pregnancy and their clinical implications In: Koren G, ed. Maternal-Fetal Toxicology. 2nd ed. New York: Marcel Dekker Inc., 1994:1–13. 33. Juchau MR, Chao ST, Omiecinski CJ. Drug metabolism by the human fetus. In: Gibaldi M, Prescott L. ed. Handbook of Clinical Pharmacokinetics. New York: Adis, 1983:58–78. 34. Pelkonen O. Drug metabolism in the human fetal liver: relationship to fetal age. Arch Int Pharmacodyn Ther 1973; 202(2):281–287. 35. Pelkonen O, Karki NT. Demonstration of cytochrome P-450 in human foetal liver microsomes in early pregnancy. Acta Pharmacol Toxicol (Copenh) 1971; 30(1):158–160. 36. Derewlany LO, Leeder JS, Kumar R, et al. The transport of digoxin across the perfused human placental lobule. J Pharmacol Exp Ther 1991; 256(3):1107–1111. 37. Binienda Z, Bailey JR, Duhart HM, et al. Transplacental pharmacokinetics and maternal/ fetal plasma concentrations of cocaine in pregnant macaques near term. Drug Metab Dispos 1993; 21(2):364–368. 38. Schmidt D. The effect of pregnancy on the natural history of epilepsy. In: Janz D, Bossi L, Dam M, ed. Epilepsy, Pregnancy and the Child. New York: Raven Press, 1981:3–14. 39. Niebyl JR, Blake DA, Freeman JM, et al. Carbamazepine levels in pregnancy and lactation. Obstet Gynecol 1970; 53:139–140. 40. Brodie MJ. Established anticonvulsants and treatment of refractory epilepsy. Lancet 1990; 336:350–354. 41. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 89:662–668. 42. Howe AM, Lipson AH, Sheffield LJ, et al. Prenatal exposure to phenytoin: facial development and a possible role for vitamin K. Am J Med Genet 1995; 58(3):238–244. 43. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects [letter]. Lancet 1982; 2:937. 44. Valproate: a new cause of birth defects: report from Italy and follow-up from France. MMWR 1983; 32:438–439.

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70. Kyegombe D, Franklin C, Turner P. Drug-metabolising enzymes in the human placenta, there induction and repression. Lancet 1973; 2:405–406. 71. Pelkonen O. Xenibiotic metabolism in the maternal-placental-fetal unit: implications for fetal toxicity. Dev Pharmacol Ther 1984; 1(suppl. 7):11–7. 72. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 1977; 136:370– 376. 73. Boreus L-O. Placental transfer of ampicillin in man. Acta Pharmacol Toxicol (Copenh) 1971; 3(Suppl):250–254. 74. Bastert G, Wallhauser K, Wernicke K, et al. Pharmacokinetische Untersuchungen zum Ubertritt von Antibiotica in das Fruchtwasser am Ende der Schwangerschaft: I. Teil: Ampicillin. Z Geburtshilfe Perinatol 1973; 178:164–173. 75. Voigt R, Schroder S, Meinhold P, et al. Klinische Unter-such Ungen zum einfluss von Schwangerschaft und geburt auf die Pharmacokinetik von Ampizillin. Zentralbl Gynakol 1978; 100: 701–705. 76. Kubacka R, Johnstone H, Tan H, et al. Intravenous ampicillin pharmacokinetics in the third trimester of pregnancy. Ther Drug Monit 1983; 5:55–60. 77. Adamkin DH, Marshall E, Weiner LB. The placental transfer of ampicillin. Am J Perinatol 1984; 1:310–311. 78. Lang R, Shalit I, Segal J. Maternal and fetal serum and tissue levels of ceftriaxone following preoperative prophylaxis in emergency caesarean section. Chemotherapy 1993; 39:77–81. 79. Depp R, Kind AC, Kirby WMN, et al. Transplacental passage of methicillin and dicloxacillin into the fetus and amniotic fluid. Am J Obstet Gynecol 1970; 107:1054–1057. 80. Daubenfeld O, Modde H, Hirsch HA. Transfer of gentamycin to the foetus and amniotic fluid during a steady state in the mother. Arch Gynecol 1974; 217:233–240. 81. Yoshioka H, Monma T, Matsudo S. Placental transfer of gentamycin. J Pediatr 1972; 80: 121–123. 82. Heikkila A, Erkkola R. The need for adjustment of dosage regimen for penicillin V during pregnancy. Obstet Gynecol 1993; 81(6):919–921. 83. Wasz-Hockert O, Nummi S, Vuopala S, et al. Transplacental passage of azidocillin, ampicillin and penicillin during early and late pregnancy. Scand J Infect Dis 1970; 2:125–130. 84. Heikkila A, Erkkola R. Pharmacokinetics of piperacillin during pregnancy. J Antimicrob Chemother 1991; 28:419–423. 85. Martens MG, Faro S, Feldman S, et al. Pharmacokinetics of the acyclureidopenicillins piperacillin and mezlocillin in the postpartum patient. Antimicrob Agents Chemother 1987; 31: 2015–2017. 86. Begue P, Quinet B, Baron S, et al. Clinical and pharmacokinetic study of imipenem/cilastatin in children and newborn infants. Pathol Biol 1989; 5:485–490. 87. Duval J, Mora M, Chartier M, et al. La cephalexine: son transfer placentaire, Nouv Presse Med 1972; 1:1419–1420. 88. MacAulay MA, Charles D. Placental transfer of cephalotin. Am J Obstet Gynecol 1968; 100: 940–946. 89. Bernard B, Barton L, Abate M, et al. Maternal-fetal transfer of cefazolin in the first twenty weeks of pregnancy. J Infect Dis 1977; 136:377–382. 90. Kafetzis DA, Brater CD, Fanourgakis JE, et al. Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk post partum. Antimicrob Agents Chemother 1983; 23:870–873. 91. Bourget D, Fernandez H, Quinquis V, et al. Pharmacokinetics and protein binding of ceftriaxone during pregnancy. Antimicrob Agents Chemother 1993; 37(1):54–59. 92. Schou M, Amidsen A, Steenstrup DR. Lithium and pregnancy; hazards to women given lithium during pregnancy and delivery. BMJ 1973; 2:137–138. 93. Rogers ME, Willerson JT, Goldblatt A, et al. Serum digoxin concentrations in the human fetus, neonate and infant. N Engl J Med 1972; 287:1010–1013.

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94. Butters L, Kennedy S, Rubon P. Atenolol in essential hypertension during pregnancy. BMJ 1990; 301:587–589. 95. Thorley KJ, McAinsh J, Cruickshank JM. Atenolol in the treatment of pregnancy-induced hypertension. Br J Clin Pharmacol 1981; 12:725–730. 96. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996; 174:823– 828. 97. Todd EL, Stafford DT, Bucovaz ET, et al. Pharmacokinetics of meperidine in pregnancy. Int J Gynaecol Obstet 1989; 29(2):143–146. 98. Martinez GA, Krieger FW. 1984 milk-feeding patterns in the United States. Pediatrics 1985; 76:1004–1008. 99. McNally E, Hendricks S, Horowitz I. A look at breast-feeding trends in Canada (1963– 1982). Can J Public Health 1985; 76:101–107. 100. Simopoulos AP, Grave GD. Factors associated with the choice and duration of infant-feeding practice. Pediatrics 1984; 74(4 pt 2):603–614. 101. Berlin CM. The excretion of drug and chemicals in human milk. In: Yaffe SJ, editor. Pediatric Pharmacology: Therapeutic Principles in Practice. New York: Grune & Stratton, 1980:137– 147. 102. Kafetzis DA, Siafas CA, Georgakopoulos PA, et al. Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand 1981; 70:285–288. 103. Thorley KJ, McAinsh J. Levels of the beta-blockers atenolol and propranolol in the breast milk of women treated for hypertension in pregnancy. Biopharm Drug Dispos 1983; 4:299– 301. 104. Schmimmel MS, Eldelman AJ, Wilschanski MA, et al. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989; 114:476–478. 105. Froescher W, Eichelbaum M, Niesen M, et al. Carbamazepine levels in breast milk. Ther Drug Monit 1984; 6:266–271. 106. Wesson DR, Camber S, Harkey M, et al. Diazepam and desmethyldiazepam in breastmilk. J Psychoactive Drugs 1985; 17:55–56. 107. Loughnan PM. Digoxin excretion in human breast milk. J Pediatr 1978; 92:1019–1020. 108. Sykes PA, Quarrie J, Alexander FW. Lithium carbonate and breast feeding. BMJ 1976; 2: 1299. 109. Greene HJ, Burkhart B, Hobby GL, et al. Excretion of penicillin in human milk following parturition. Am J Obstet Gynecol 1946; 51:732–733. 110. Steen B, Rane A, Lonnerholm G, et al. Phenytoin excretion in human breast milk and plsma levels in nursed infants. Ther Drug Monit 1982; 4:331–334. 111. Yurchav AM, Jusco WJ. Theophylline secretion into breast milk. Pediatrics 1976; 57:518– 520. 112. Orme ML’O, Lewis PJ, De Swiet M, et al. May mothers given warfarin breast-feed their infants? BMJ 1977; 1:564–565. 113. Catz CS, Giacoia GP. Drugs and breast milk. Pediatr Clin North Am 1972; 19:151–166. 114. World Health Organization Working Group. Determinants of drug excretion in breast milk. In: Bennett PN, Matheson I, Dukes NMG, et al., eds. Drugs and Human Lactation. Amsterdam: Elsevier, 1988:27–48. 115. Wilson JT. Determinants and consequences of drug excretion in breast milk. Drug Metab Rev 1983; 14:619–652. 116. Atkinson HC, Begg EJ. Prediction of drug concentrations in human milk from plasma protein binding and acid-base characteristics. Br J Clin Pharmacol 1988; 25:495–503. 117. Ito S, Koren G. A novel index for expressing exposure of the infant to drugs in breast milk. Br J Clin Pharmacol 1994; 38:99–102. 118. Braverman LE. Iodine-induced thyroid disease. Acta Med Aus 1990; 17:29–33. 119. Kulski JK, Hartmann PE, Martin JD, et al. Effects of bromocriptine mesylate on the composi-

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120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135.

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tion of the mammary secretion in non-breast-feeding women. Obstet Gynecol 1978; 52:38– 42. Katz M, Kroll D, Pak I, et al. Puerperal hypertention, stroke and seizures after suppression of lactation with bromocriptine. Obstet Gynecol 1985; 66:822–824. Wiernik PH, Duncan JH. Cyclophosphamide in human milk. Lancet 1971; 1:912. Amato D, Niblett JS. Neutropenia from cyclophosphamide in breast milk [letter]. Med J Aust 1977; 1:383–384. Fletcher SM, Katz AR, Rogers AJ, et al. The presence of cyclosporine in body tissue and fluids during pregnancy. Am J Kidney Dis 1985; 5:60–63. Egan PC, Costanza ME, Dodion P, et al. Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep 1985; 69:1387–1389. Tegler L, Lindstrom B. Antithyroid drugs in milk [letter]. Lancet 1980; 2:591. Kampmann JP, Johansen K, Hansen JM, et al. Propylthiouracil in human milk: revision of a dogma. Lancet 1980; 1:736–737. Johansen K, Anderson AN, Kampmann JP, et al. Excretion of methimazole in human milk. Eur J Clin Pharmacol 1982; 23:339–341. Cooper DS. Antithyroid drugs: to breast feed or not to breast feed. Am J Obstet Gynecol 1987; 157:234–235. Von Unruh GE, Froescher W, Hoffman F, et al. Valproic acid in breast milk: how much is really there? Ther Drug Monit 1984; 6:272–276. Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979; 7:624–627. White WB, Andreoli JW, Wong SH, et al. Atenolol in human plasma and breast milk. Obstet Gynecol 1984; 63:42S–44S. Liedholm H, Melander A, Bitzen PO, et al. Accumulation of atenolol and metoprolol in human breast milk. Eur J Clin Pharmacol 1981; 20:229–231. Lawton ME. Alcohol in breast milk. Aust NZJ Obstet Gynaecol 1985; 25:71–73. Kesaniemi YA. Ethanol and acetaldehyde in the milk and peripheral blood of lactating women after ethanol administration. J Obstet Gynaecol Br Commonw 1974; 81:84–86. Little RE, Anderson KW, Ervin CH, et al. Maternal alcohol use during breast feeding and infant mental and motor development at one year. N Engl J Med 1989; 321:425–430.

2 Developmental Risk Assessments Gerald F. Chernoff California Environmental Protection Agency, Sacramento, California

INTRODUCTION For those on the front line communicating risk information to pregnant women, one of the more frustrating questions that can be asked regards the risk of exposures to occupational chemicals and environmental hazards. Whereas information about pharmaceuticals is available from central sources such as the Catalog of Teratogenic Agents (1), information on occupational and environmental exposures is often available only from government agencies such as the U.S. Environmental Protection Agency (2). The information provided by these agencies can be quite limited, consisting of only permissible emission levels (PELs), maximum concentration limits (MCLs), acceptable daily intakes (ADIs), or some other regulatory number derived from a formal risk assessment. What is a risk assessment? What do the regulatory numbers mean? How can they be used in the risk communications process? In this chapter we investigate some of these questions. The intent is not to provide a formula for instant expertise on risk assessments but rather to broaden the reader’s appreciation for how these assessments can be used and misused in counseling concerned individuals. To accomplish this task, we review briefly the basic principles of each of the four steps in the risk assessment process: hazard identification, reference dose determination or dose-response assessment, exposure assessment, and risk characterization (3). After each step has been reviewed, a database of fictional studies on the imaginary chemical AVOID is presented. This database will help illustrate the types of study available for risk assessments and will provide an opportunity to apply the principles of risk assessment to representative data. Finally, questions germane to the evaluation of the AVOID data are listed and the issues that generate the most controversy are discussed briefly.

Originally presented as a workshop at the Fifth International Conference of Teratogen Information Services, March 1992. The material presented in this chapter represents the views of the author and does not necessarily reflect the policy of the Office of Environmental Health Hazard Assessment. 23

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HAZARD IDENTIFICATION Principles 1.

2.

3.

4.

The purposes of hazard identification are to identify the types of adverse health effect that may be associated with exposure to an agent and to characterize the quality and strength of evidence supporting this identification. For the purpose of this exercise only developmental (teratogenic) adverse effects induced by AVOID are considered. Human studies are generally considered to be the best source of information, since ultimately it is the human population that we are attempting to protect. Unfortunately, for most chemicals of concern, good human studies are lacking; even when data do exist, establishing a causal link between the exposure and developmental endpoint is seldom possible. Human developmental studies can generally be divided into two categories, descriptive and analytical (4). a. Descriptive studies, which are useful for generating hypotheses, include case reports, surveillance systems, and ecological and cluster studies. b. Analytical studies, which test a hypothesis to examine cause–effect relationships, include case control, cohort, and human experimental studies. Studies with experimental animals are often the best source of information for hazard identification. These studies can be either regulatory or experimental. a. Regulatory studies are those that are prescribed or recommended by agencies such as the U.S. Environmental Protection Agency and the Food and Drug Administration; they include single- and multigeneration reproductive studies, continuous breeding studies, and developmental studies with exposure in the embryonic and fetal periods or in the perinatal period (5–10). These studies have the advantage of consistent protocols, with full reporting of all the collected data. Unfortunately, they apply to only a limited spectrum of agents, and they are generally not reported in the open scientific literature. b. Experimental studies are those conducted to investigate a hypothesis of interest to the investigator; as such, they do not conform to any one protocol. The results of these studies are reported in the open literature and often are your only source of information for hazard identification. In evaluating the individual human and animal studies, several important factors should be taken into consideration: a. Exposure parameters such as the route, time, and duration of exposure, and the actual or estimated dose of exposure should be well defined; for animal studies, these doses should be within the realm of expected human exposures. b. The endpoints evaluated should be described, and the methodology used in the evaluation should be appropriate. c. The presence of maternal toxicity should be evaluated (11). d. Appropriate statistical procedures should be used to demonstrate the significance of the adverse effect (12). For human studies, the strength of the association and study power should be discussed (13–15). e. The results should be evaluated for the presence of a dose-response relationship. f. The quality of each paper should be assessed using the foregoing considerations.

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5. The evaluation of each individual study should lead to one of three conclusions: a. The study provides data indicative of an adverse effect. b. The study provides data indicative of no adverse effect. For a chemical to be placed in this category, it is essential that the study design be adequate to detect an adverse effect if one is present. c. The study provides inconclusive data. The reasons for placing a study in this category are many but usually involve inadequate or inappropriate study designs or incomplete reporting of the data. 6. After the individual studies have been evaluated, it is necessary to assess the total body of evidence. This is usually accomplished by evaluating the animal data separately from the human data. The following factors should be taken into consideration: a. Consistent adverse findings in two or more studies that use different study designs and populations are generally regarded as evidence of a causal relationship. b. The evidence that an agent is a developmental toxicant may be strengthened by demonstrating biological plausibility of a causal relationship. This is an especially important consideration in evaluating a group of epidemiological studies. c. Pharmacokinetic and pharmacogenetic differences that may account for differences between studies should be evaluated. d. Structural relationships and other evidence for chemical similarity may in some cases be useful in drawing inferences of potential developmental toxicity. 7. The final step in hazard identification is a weight of evidence determination. Different agencies use different schemes, which range from the very simple to the very complex (16,17). Most of these schemes can be reduced to three basic categories: a. Sufficient human evidence: Data from human studies provide sufficient evidence for the scientific community to judge that a causal relationship is or is not supported. Supporting animal data may or may not be available. b. Sufficient experimental animal evidence/limited human data: Data from experimental animal studies and/or limited human data that provide sufficient evidence for the scientific community to judge that the potential for developmental toxicity does or does not exist. c. Insufficient evidence: Data are not available or the data that are available are based on human or experimental animal studies that are flawed in design.

Database Eight studies on AVOID, three in humans and five in animal, make up the database available for the hazard identification step. Each study is briefly summarized below. Study 1 There have been a series of anecdotal reports from the union health and safety committee at the formulation and packaging facility, as well as from rural health clinics, suggesting that pregnant workers exposed to AVOID experience a high incidence of spontaneous abortion. These reports have not been published or reviewed in any scientific forum.

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Table 1 Clinical Symptoms and Newborn Evaluations Reported in Study 2 Case

Clinical symptoms

1 2 3 4

Sweating, Sweating, Sweating, Sweating,

tremors tremors tremors tremors, convulsions

5 6

Sweating, tremors, convulsions Sweating, tremors, coma

Newborn evaluation Normal physical and growth Normal physical and growth Spina bifida with myeloschisis Normal physical; pre- and postnatal growth retardation Fetal alcohol syndrome Normal physical and growth

Study 2 A paper on accidental and purposeful poisoning with AVOID was recently published in a reputable peer-reviewed medical journal. Forty cases were described, and six involved women who were estimated to be in their first trimester of pregnancy at the time of the poisoning. The poisoning was attributed to unsuccessful suicide attempt by AVOID ingestion in five of the cases and to attempted homicide with AVOID-poisoned food in one case. The clinical symptoms recorded at the time of admission to the emergency room for the poisoning and the pediatrician’s evaluation of each newborn in the perinatal period are shown in Table 1. Study 3 An epidemiological study was conducted in a plant where AVOID was formulated and packaged. The study, which was conducted for the plant owners by investigators from Cosmic University, has never been published. The study population consisted of women who had worked in the packaging section of the plant for at least 6 months between 1981 and 1985. Over this 4-year period, the mean combined dose of AVOID from respiration and dermal absorption was estimated to be less than 0.07 mg/kg/day in the packaging department. The highest combined dose during this same period was estimated at 0.26 mg/kg/day. The control group consisted of female clerical staff who worked in plant offices, where it was assumed that there was no exposure to AVOID. After identifying the study and control populations, the investigators sent each woman a questionnaire regarding any pregnancies she may have had while working at the plant. Included were questions on each respondent’s length of time working in the plant, her work location, and the outcome of pregnancy. Response rates to the questionnaire were 37% for the study group and 42% for the controls. Table 2 gives the major results as reported by the investigative team. Study 4 In an unpublished study conducted for the manufacture of AVOID, groups of 20 C57 mated mice were administered AVOID in their diets at doses of 0, 25, or 75 mg/kg/day from days 6–18 of gestation. At the high dose tested, there was a significant decrease in maternal food consumption between days 6 and 12, and several of the females exhibited convulsions. Fetal resorptions and exencephaly were significantly increased. At the middose, there was a nonsignificant increase in cleft palate. Major study results are summarized in Table 3.

Developmental Risk Assessments Table 2 Study 3

27

Summary of Major Results Reported in

Group Respondents Pregnancies Abortions Therapeutic Spontaneous Stillbirths Live births Normal Abnormal Anencephaly Extra finger Heart defect Holoprosencephaly Trisomy 21

Study 56 110

Control 48 86

10 (9%) 10 (9%) 1 (1%) 89 (81%) 85 (96%) 4 (4%) 1 1 1 1 0

1 (1%) 9 (10%) 0 76 (88%) 74 (97%) 2 (3%) 0 0 1 0 1

Study 5 A meeting abstract reported that groups of five C3H mice administered AVOID by intraperitoneal injection at 5 mg/kg/day on days 10, 11, and 12 of gestation exhibited a significant increase in cleft palate (86%) compared to controls. No mention was made of maternal toxicity or the presence of any other malformations in the treated group. Study 6 In an unpublished teratology study conducted for the manufacturer of AVOID, groups of 20 pregnant SD rats were administered AVOID in their diets at doses sufficient to provide 0, 0.2, 2.0, or 20 mg/kg/day from days 6–20 of gestation. At the high dose, several females died between days 10 and 18 of gestation; between days 7 and 15, maternal food consumpTable 3 Summary of Major Results Reported in Study 4 Number of cases per dose (mg/kg/day) group

Mated Pregnant Resorbed litters Live litters Live fetuses Resorbed fetuses Abnormal fetuses Delayed ossification Cleft palate Exencephaly Anophthalmia a

0

25

75

20 15 0 15 125 7 4 4 1 0 0

20 13 0 13 99 6 9 3 7 0 0

20 20 10 a 10 52 a 37 a 42 a 7 0 38 a 2

Significantly different from control ( p ⬍ 0.05).

28

Chernoff

tion and weight gain were significantly depressed, and a statistically significant increase in fetal resorptions and exencephaly was noted. At 2.0 mg/kg/day there was a significant increase in microphthalmia and wavy ribs. Wavy ribs were also noted at 0.2 mg/kg/day, but the incidence did not reach statistical significance. The key results of this study are summarized in Table 4. Study 7 In an unpublished study conducted for the manufacturer, groups of 20 pregnant CR rats were exposed to AVOID by inhalation at doses of 0, 0.16, 0.3, or 0.64 mg/m 3 for 6 hours per day from days 6–20 of gestation. At the high dose there was a slight decrease in maternal food consumption between days 6 and 7 of gestation and a significant increase in microphthalmia. No significant findings were reported at the other doses tested. The key results of this study are summarized in Table 5. Study 8 The final animal study was an unpublished report using groups of 20 NZW rabbits administered AVOID by oral gavage at doses of 0, 0.2, 20, or 200 mg/kg/day from days 7–19 of gestation. Maternal toxicity was observed at the high dose, with a significant decrease in body weight and increase in liver weight. At this dose there was also a statistically significant increase in resorptions and exencephaly. No significant findings were reported at any of the other dose levels tested. Questions to Ask When Evaluating Hazard Identification Data 1. 2. 3.

How do these data conform (or not conform) to the principles used in hazard identification? What is the most sensitive endpoint of potential teratogenicity in the animal and human studies? Should the wavy ribs in rodents be considered relevant to low exposure risks to humans?

Table 4 Summary of Major Results Reported in Study 6 Number of cases per dose (mg/kg/day) group

Mated Pregnant Resorbed litters Live litters Live fetuses Resorbed fetuses Abnormal fetuses Delayed ossification Wavy ribs Exencephaly Microphthalmia a

0

0.2

2.0

20

20 19 1 18 175 10 6 4 4 1 1

20 20 0 20 182 5 13 5 7 0 0

20 18 0 18 179 7 27 a 3 15 a 0 12 a

20 20 6a 6a 32 a 38 a 32 a 32 a 5 29 a 2

Significantly different from controls ( p ⬍ 0.05).

Developmental Risk Assessments Table 5

29

Summary of Major Results Reported in Study 7 Number of cases per dose (mg/m 3 ) group

Mated Pregnant Resorbed litters Live litters Live fetuses Resorbed fetuses Abnormal fetuses Delayed ossification Wavy ribs Microphthalmia a

0

0.16

0.3

0.64

20 20 1 19 193 7 7 3 7 1

20 17 0 17 180 9 10 2 5 4

20 17 2 16 169 4 3 3 0 0

20 20 0 20 198 5 25 a 4 3 21 a

Significantly different from controls ( p ⬍ 0.05).

4. Should the data obtained by IP injection treatment be considered relevant to human exposure? 5. Should the evidence for maternal toxicity at high doses in the animal studies negate considering the adverse effects seen in the fetuses as true developmental effects? 6. From the data given, is there any way to determine whether responses in humans are likely to be similar to those in the experimental animals? 7. Do the data provide sufficient evidence to convince you that AVOID should be considered to be a teratogen? There are no simple or straightforward answers to these questions, and the underlying issues continue to be debated. One area of lively controversy is the role of maternal toxicity in interpreting study results (11,18–20). Can a 20% decrease in maternal weight gain in the early part of organogenesis negate the finding of a high incidence of cleft palate or decreased fetal weight? These issues remain unresolved. Similarly, the importance of skeletal variations such as wavy ribs or partially ossified sternebra remains controversial and as yet unresolved (21–23). At the conclusion of the hazard identification step in the risk assessment process, a choice must be made. It must be decided which of the following conclusions the data support: (1) AVOID is teratogenic in humans; (2) it is highly likely that AVOID is a teratogen in humans; (3) AVOID is a potential human teratogen; or (4) AVOID is not classifiable as to human teratogenicity.

REFERENCE DOSE DETERMINATION Principles 1. The reference dose (RfD) is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is assumed to be without appreciable risk of deleterious developmental effects (24).

30

Chernoff

2. 3.

4.

5.

The RfD is usually derived from the ‘‘no observed adverse effect level’’ (NOAEL) or the ‘‘lowest observed adverse effect level’’ (LOAEL). The most appropriate NOAEL is determined from the body of evidence examined in the hazard identification stage. a. Dose-response data from human studies are generally preferred over animal data provided that the human data are sufficiently quantitative. b. Data on the most sensitive relevant endpoint should be used. To calculate the RfD, the NOAEL is divided by an overall uncertainty factor (UF) ranging from 10 to 10,000 (25). The total UF is calculated by multiplying together appropriate individual UFs of 10: a. UF for intraspecies variability ⫽ 10 b. UF for interspecies variability ⫽ 10 c. UF for different exposure scenarios ⫽ 10 d. UF when using the LOAEL rather than NOAEL ⫽ 10. The RfD may be further reduced by applying a modifying factor greater than zero but less or equal to 10, which may be used to reflect qualitative professional judgments about scientific uncertainties such as the completeness of the overall database and the number of species and animals tested.

Database The data to be used in this section consist of the same eight studies used in the hazardidentification step. Questions to Ask When Evaluating Reference Dose Data 1. 2. 3.

4. 5. 6. 7. 8.

What study is the most appropriate for deriving a no observed adverse effect level (NOAEL) for AVOID? What do you consider to be the appropriate NOAEL? Is the observed NOAEL from the studies a true ‘‘no-effect’’ level? Could it simply reflect the fact that in experiments with relatively small numbers, the failure to observe a statistically significant increase in adverse developmental effects is an artifact of the experimental design, not a true absence of biological effect? What uncertainty factors should be applied to the NOAEL for AVOID? What is the appropriate reference dose (RfD) for AVOID? Does the RfD adequately account for the uncertainties associated with the NOAEL? Is it appropriate to use an RfD derived from a study using one route of exposure for all routes of exposure? Is the RfD a reliable indicator of human risk? Are there any other conditions that should be applied to this number?

Again, there are no simple or straightforward answers to these questions. Of greatest controversy is the use of NOAELs and safety factors (26). It is now generally recognized that the determination of a NOAEL is highly dependent on the sample size and dose levels used. Methods using various mathematical models that are less sensitive to sample size and utilize the full dose-response curve have been proposed as alternatives

Developmental Risk Assessments

31

to the NOAEL/UF approach (27–31). No one method has yet gained favor, and the majority of risk assessments still utilize the NOAEL-derived RfD. After completing the RfD-determination step in the risk-assessment process, you may conclude that the RfD you calculated, and the NOAEL from which it was derived, are sufficient to determine the developmental risks associated with exposure to AVOID. Alternatively, you may wish to conclude that RfDs are of little value and in fact create a false sense of precision in an area involving tremendous uncertainty. A third possible conclusion is that while risks from developmental toxicants cannot be quantified, they should be described in qualitative terms.

EXPOSURE ASSESSMENT Principles 1. An exposure assessment serves to identify the magnitude of human exposure to an agent, the frequency and duration of that exposure, and the routes by which humans are exposed (32). It may be useful to identify the number of exposed people along with other characteristics of the exposed population, such as age, genetic history, and exposure to (other) known teratogens. 2. Exposure may be based on quantitative or qualitative measurements in various media such as air, water, or food. a. Daily intake of individual and combined media exposures should be determined. b. When individuals may be exposed by contact with several media, it is important to consider total intake from all media. c. Daily intake under different conditions of activities in different locations should be determined. 3. Sampling and monitoring of individual exposures is usually conducted by contractors for either the responsible parties or regulatory bodies. 4. Usually only a limited amount of monitoring and only a limited number of samples of various media can be taken for measurement. a. The representativeness of measured values is usually uncertain. b. The degree to which data for a given medium are representative of that medium should be estimated. 5. When data are incomplete or lacking, mathematical models may be used to estimate air and water concentrations. The validity of the model should be checked in context of the exposure scenario. 6. Standard average values and ranges for human intake of various media are available and are generally used unless data on specific agents indicate that such values are inappropriate (33). a. Adults drink approximately 2 L of water per day. b. The average adult inhales 23 m 2 of air per day.

Database Four monitoring studies have been conducted on AVOID: two were conducted in workplace settings: one on air and one on water. A brief description is provided below.

32

Chernoff

Table 6 Exposure Levels Reported in Study 2 Route of exposure Workers Pilots Aerial mix/load Flagger Ground mix/load Ground applications Combined mix/load/applications Gofer

Dermal

Inhalation

0.50 0.02 0.53 0.05 0.02 0.10 0.03

1.13 0.53 1.73 0.85 0.37 1.77 0.70

Study 1 In conjunction with the epidemiology study reported earlier, a 3-day study was conducted in the plant during which time workers packaging AVOID were monitored for exposure via the inhalation and dermal routes. The data collected were used to estimate the mean combined dose, which was calculated to be 0.07 mg/kg/day. The highest dose received by a single worker on any one day was 0.26 mg/kg. Study 2 A study was conducted by a state regulatory agency that used passive dosimetry to monitor field worker exposure to AVOID. From the data collected, the absorbed dosage was calculated. The relative contributions of the inhalation and dermal routes of exposure were back-calculated from the total absorbed dosage, assuming that a certain proportion of AVOID exposure was through inhalation. This proportion was based on measured concentrations of AVOID in the air, standard respiratory rate and retention, and 100% absorption. The calculated absorbed exposure dosage for a person weighing 70 kg expressed micrograms per kilogram per day is shown in Table 6. Study 3 An air-monitoring study was conducted in four rural communities near fields where AVOID was being used. Twenty-four-hour collections were conducted over three 4-day periods in 1987. The mean concentrations (ng/m 3 ) of air-borne AVOID over the 12 sampling days, along with the range of values, were published in a reputable peer-reviewed journal and are shown in Table 7. Study 4 A water-monitoring study was conducted using samples collected from the major river that runs through the agricultural area and past several metropolitan areas downstream. Samples were collected near each of the metropolitan areas, one per month from May Table 7 Sampling Results Reported in Study 3 Location

Mean Range

1

2

3

4

62 2–142

132 ⬍1.4–280

152 76–415

630 145–1720

Developmental Risk Assessments

33

through September 1989. The results of the study, which appear in a government report, indicate that only trace amounts of AVOID were detected. The validity of this study has been challenged by several environmental advocacy groups. Questions to Ask When Evaluating Exposure Data 1. Do the monitoring data adequately describe exposures to AVOID in all possible media? If not, what additional media need to be considered, and why? 2. Should the different types of exposure data be treated the same for purposes of characterizing human risk? 3. Is the mean concentration in the various media the appropriate summary statistic to use to characterize human exposure? Should the upper range or statistical upper confidence limit be used as an alternative? 4. Are the various assumptions about human intake and average exposure to various media valid? 5. Should exposure and risk to workers at the production facility be considered in the same context as exposure and risk to fieldworkers or residents in exposed communities? It should come as no surprise that there are no simple or straightforward answers to these questions. Debate continues on the use of various models for estimating exposures, but generally the issue of greatest concern is the method of extrapolating from one route of exposure to another (34,35). This is typified by the debate over the various routes of exposure following an animal whole-body versus nose-only exposure. With whole-body exposure, it must be decided how much of the agent enters via the respiratory route, how much via the dermal route, and how much via ingestion from grooming behavior and contaminated food. The rates of absorption for these various routes may differ rather dramatically. With nose-only exposures, the majority of the exposure is considered to be respiratory, but dermal adsorption from the nose area and ingestion by swallowing cannot be ruled out. After the exposure-assessment step in the risk-assessment process has been completed, you may conclude that although different exposure estimates are based on different data and assumptions, they are all adequate and sufficient for assessing risks. Alternatively, you may wish to conclude that none of the exposure data are adequate for use in risk assessment and that no quantitative risk assessment should be developed until better information is available. RISK CHARACTERIZATION Principles 1. The purpose of risk characterization, the final step of the risk assessment, is to integrate the information collected and analyzed in the first three steps to characterize the excess risk to humans. 2. An explicit numerical RfD should be included in the characterization. 3. Compare the exposures experienced or expected for different groups of individuals. 4. Estimate the margin of exposure (MOE) for each group by dividing the NOAEL from the critical study used to estimate the RfD by the exposure for each group.

34

Chernoff

5. 6.

Describe risks qualitatively for each population group. Describe the statistical and biological uncertainties in estimating the extent of adverse health effects.

Database The data used in the risk-characterization step are those accumulated in the preceding steps of the risk-assessment process. The risk characterization can be thought of as the conclusion of the risk assessment, summarizing the information from the preceding steps (hazard identification, RfD determination, and exposure assessment). As such, the issues of controversy discussed earlier also apply to this final step.

CONCLUSION Having gained some appreciation of risk assessments, we can now consider how they can be used in the risk-communication process. Paul Peters (personal communications) has observed that there are two types of risk information: ‘‘ready made’’ and ‘‘tailor made.’’ The RfDs developed in the risk assessment process are applicable to all individuals in the population, and as such, represent ‘‘ready made’’ information. They serve as a powerful public health tool in defining the exposure level below which it can be assumed that no adverse developmental effects will occur. In contrast, individual risk counseling requires tailor-made information. Typically, this information is based on interpreting the results of human and animal studies in the context of a pregnant woman’s age, parity, genetic background, and exposure to other chemicals of concern. The ready-made information from the risk assessment can have value beyond the public health perspective. While using an RfD as the sole basis for individual risk counseling is never appropriate, the studies that served as the basis for obtaining the NOAEL on which the RfD is based can serve as the starting material for crafting the tailor-made information needed to communicate risk information to individual pregnant women.

ACKNOWLEDGMENTS I am indebted to the U.S. Environmental Protection Agency’s Workshop on Risk and Decision Making, which served as a model for the workshop on which this chapter is based. I am also grateful to Linda Chernoff and Dr. Paul Peters for their help and insight in planning this project, and to Dr. Gideon Koren for his encouragement to complete the project.

REFERENCES 1. Shepard TH. Catalog of Teratogenic Agents, 6th ed. Baltimore: Johns Hopkins University Press, 1989. 2. U.S. Environmental Protection Agency. Integrated Risk Information Service (IRIS). Online. Washington, DC: Office of Health and Environmental Assessment, 1991.

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3. National Research Council. Risk Assessment in the Federal Government: Managing the Process. Committee on the Institutional Means for the Assessment of Risks to Public Health. Commission on Life Sciences, National Research Council. Washington, DC: National Academy Press, 1983, pp 17–83. 4. Erickson JD. Epidemiology and developmental toxicology, In: Kimmel CA, Buelke-Sam J, eds. Developmental Toxicology. New York: Raven Press, 1981, pp 289–301. 5. U.S. Environmental Protection Agency. Pesticide assessment guidelines, subdivision F. Hazard evaluation: Human and domestic animals, EPA-540/9-82-025. Washington, DC: Office of Pesticides and Toxic Substances, 1982. Available from NTIS, Springfield, VA. 6. U.S. Environmental Protection Agency. Toxic Substances Control Act test guidelines; final rules. Fed Reg 1985; 50:39426–39428 and 39433–39434. 7. U.S. Environmental Protection Agency. Pesticide Assessment guidelines, subdivision F. Hazard evaluation: Human and domestic animals, EPA 540/09-91–123. Addendum 10: Neurotoxicity, series 81–83. Washington, DC: Office of Pesticides and Toxic Substances. 1991. Available from NTIS, Springfield, VA. 8. Organization for Economic Cooperation and Development. Guidelines for Testing of Chemicals’ Teratogenicity, OECD, 1981. 9. U.S. Food and Drug Administration. Guidelines for reproduction and studies for human use. Rockville, MD: Bureau of Drugs, 1966. 10. U.S. Food and Drug Administration. Advisory Committee on Protocols for Safety Evaluation. Panel on reproduction—Studies in the safety evaluation of additives and pesticide residues. Toxicol Appl Pharmacol 1970; 16:264–296. 11. Kimmel GL, Kimmel CA, Francis EZ, eds. Evaluation of maternal and developmental toxicity. Teratogenesis Carcinog Mutagen 1987; 7:203–338. 12. Kimmel CA, Kimmel GL, Frankos V, eds. Interagency Regulatory Liaison Group Workshop on Reproductive Toxicity Risk Assessment. Environ Health Perspect 1986; 86:193–221. 13. Bloom AD. Guidelines for reproductive studies in exposed human populations. Report of Panel II. In: Bloom AD, ed. Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. White Plains, NY: March of Dimes Birth Defects Foundation, 1981, pp 37–110. 14. Stein Z, Kline J, Shrout P. Power in surveillance. In: Hemminki K, Sorsa M, Vaninio H, eds. Occupational Hazards and Reproduction. Washington, DC: Hemisphere, 1985, pp 203– 208. 15. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987; 9:1–30. 16. U.S. Environmental Protection Agency. Guidelines for developmental toxicity risk assessment. Fed Reg 1991; 56:63798–63826. 17. California Department of Health Services. Draft guidelines for hazard identification and doseresponse assessment of agents causing developmental and/or reproductive toxicity, Sacramento, CA: Office of Environmental Health Hazard Assessment, 1991. 18. Schardein JL. Approaches to defining the relationship of maternal and developmental toxicity. Teratogenesis Carcinog Mutagen 1987; 7:255–271. 19. Johnson E, Christian M. When is a teratology study not an evaluation of teratogenicity? J Am Coll Toxicol 1984; 3:431–434. 20. Black DL, Marks TA. Role of maternal toxicity in assessing developmental toxicity in animals: a discussion. Regul Toxicol Pharmacol 1992; 16:189–201. 21. Kimmel CA, Wilson JG. Skeletal deviations in rats: malformations or variations? Teratology 1973; 8:309–316. 22. Chernoff N, Rogers JM, Turner CI, Francis BM. Significance of supernumerary ribs in rodent developmental toxicity studies: postnatal persistence in rats and mice. Fundam Appl Toxicol 1991; 17:448–453. 23. Palmer AK. Incidence of sporadic malformations, anomalies and variations in random-bred

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24. 25. 26. 27. 28. 29. 30. 31. 32. 33.

34.

35.

Chernoff laboratory animals. In Neubert D, Merker HJ, Kwasigroch TE, eds. Methods in Prenatal Toxicology. Stuttgart: Thieme, 1977, pp 52–71. Barnes DG, Dourson M. Reference dose (RfD): Description and use in health risk assessments. Regul Toxicol Pharmacol 1988; 8:471–486. Dourson M, Stara J. Regulatory history and experimental support of uncertainty (safety) factors. Regul Toxicol Pharmacol 1983; 3:224–238. Gaylor DW. Incidence of developmental defects at the no observed adverse effect level (NOAEL). Regul Toxicol Pharmacol 1992; 15:151–160. Crump KS. A new method for determining allowable daily intakes. Fundam Appl Toxicol 1984; 4:854–871. Gaylor DW. Quantitative risk analysis for quantal reproductive and developmental effects. Environ Health Perspect 1989; 79:243–246. Kimmel C, Gaylor D. Issues in qualitative and quantitative risk analysis for developmental toxicology. Risk Anal 1988; 8:15–20. Kodell RL, Howe RB, Chen JJ, Gaylor DW. Mathematical modeling of reproductive and developmental toxic effects for quantitative risk assessment. Risk Anal 1991; 11:583–590. Ryan L. The use of generalized estimating equations for risk assessment in developmental toxicity. Risk Anal 1992; 12:439–447. U.S. Environmental Protection Agency. Guidelines for exposure assessment. Fed Reg 1986; 51:34042–34054. U.S. Environmental Protection Agency. Exposure Factors Handbook, EPA-600/8-89-043. Washington, DC: Office of Health and Environmental Assessment, 1989. Available from NTIS, Springfield, VA. Sachsse K, Zbinden K, Ullman L. Significance of mode of exposure in aerosol inhalation toxicity studies: Head-only versus whole-body exposure. Arch Toxicol Suppl 1980; 4:305– 311. Iwasaki M, Yoshida M, Ikeda T, Tsuda S, Shirasu Y. Comparison of whole-body versus snoutonly exposure in inhalation toxicity of fenthion. Jpn J Vet Sci 1988; 50:23–30.

3 Drugs in Pregnancy Gideon Koren, Anne Pastuszak, and Shinya Ito The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Before marketing a new drug, the manufacturer almost never tests the product in pregnant women to determine its effects on the fetus. Consequently, most drugs are not labeled for use during pregnancy. Typically, descriptions of drugs that appear in the Physicians’ Desk Reference and similar sources contain statements such as, ‘‘Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus.’’ Since the risk has been adequately established for only a few drugs, physicians caring for pregnant women have very little information to help them decide whether the potential benefits to the mother outweigh the risks to the fetus. These typical disclaimers, although understandable from the medicolegal standpoint, put large numbers of women and their physicians in difficult situations for several reasons. One is that at least half the pregnancies in North America are unplanned (1), and every year, hundreds of thousands of women therefore expose their fetuses to drugs before they know they are pregnant. Such women often interpret the statement that use during pregnancy is not recommended as meaning that the drug is not safe during pregnancy. There is evidence that this perception of fetal risk causes many women to consider or even seek termination of otherwise wanted pregnancies (2,3). Another reason is that with the recent increase in the age at which women have children, conditions that necessitate long-term drug therapy are diagnosed in larger numbers of women before pregnancy. Furthermore, for pregnant women with certain conditions once believed to be incompatible with pregnancy, such as systemic lupus erythematosus and heart diseases, the outcome of pregnancy has improved dramatically in the past few decades (4). In this article, we review current knowledge of the fetal and neonatal effects of prescription and over-the-counter drugs given to pregnant women, with an emphasis on the approaches used to determine safety and risk. In addition, we review approaches to communicating such information to pregnant women and their families.

From Drug Therapy, A.J.J. Wood, ed. N Engl J Med 1998; 338:1128–1137.

37

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Koren et al.

HUMAN TERATOGENESIS Teratogenesis is defined as the dysgenesis of fetal organs as evidenced either structurally or functionally (e.g., brain functions) (5). The typical manifestations of teratogenesis are restricted growth or death of the fetus, carcinogenesis, and malformations (6), defined as defects in organ structure or function. These abnormalities vary in severity (e.g., hypospadias that is mild and may be missed, or is severe, necessitating several corrective operations). Major malformations may be life-threatening and require major surgery or may have serious cosmetic or functional effects.

A HISTORICAL PERSPECTIVE Several milestones highlight the problems of drug therapy facing pregnant women, their families, and health professionals.

Thalidomide For decades it was believed that the placenta served as a barrier that protected the fetus from the adverse effects of drugs. The thalidomide disaster drastically changed this perception by demonstrating that fetal exposure to the drug during critical periods of development resulted in severe limb defects and other organ dysgenesis (e.g., kidney and heart defects) (6,7). Despite the high rates of malformations (20 to 30 percent) and their characteristic pattern, the teratogenicity of thalidomide was not suspected for years. The suffering it caused has prompted the belief that every drug has the potential to be a new thalidomide (2,3). Most known human teratogens are associated with much lower rates of malformations, and the syndromes they cause are not always so pathognomonic, making causation more difficult to confirm. Yet 35 years after the recognition of thalidomide-associated embryopathy, fewer than 30 drugs have been proved to be teratogenic in humans when used in clinically effective doses, and even fewer are currently in clinical use (Table 1). Many other commonly used drugs, including salicylates, glucocorticoids, and spermicides, were once thought to be teratogenic but have been shown to be safe in subsequent studies that were larger and better controlled than the initial studies (Table 2).

Bendectin One example of the gap between the perception of teratogenic risk and evidence-based proof of safety is the case of Bendectin. During the late 1950s and the 1960s, this drug, a combination of an antihistamine (doxylamine) and pyridoxine, was the most widely used medication in the United States for nausea and vomiting associated with pregnancy. During the 1970s, many lawsuits claiming that Bendectin was teratogenic were filed against the manufacturer in American courts. Therefore, the drug was withdrawn from the market by its manufacturer in 1982, which left millions of pregnant women without a drug approved by the Food and Drug Administration (FDA) for the treatment of nausea and vomiting. The rate of hospitalization for severe nausea and vomiting during pregnancy

Drugs in Pregnancy Table 1

39

Drugs with Proven Teratogenic Effects in Humans a

Drug Aminopterin b, methotrexate Angiotensin-converting-enzyme inhibitors Anticholinergic drugs Antithyroid drugs (propylthiouracil and methimazole) Carbamazepine Cyclophosphamide Danazol and other androgenic drugs Diethylstilbestrol b Hypoglycemic drugs Lithium Misoprostol Nonsteroidal antiinflammatory drugs Paramethadione b Phenytoin Psychoactive drugs (e.g., barbiturates, opioids, and benzodiazepines) Systemic retinoids (isotretinoin and etretinate) Tetracycline Thalidomide Trimethadione b Valproic acid Warfarin

Teratogenic effect CNS and limb malformations Prolonged renal failure in neonates, decreased skull ossification, renal tubular dysgenesis Neonatal meconium ilcus Fetal and neonatal goiter and hypothyroidism, aplasia cutis (with methimazole) Neural-tube defects CNS malformations, secondary cancer Masculinization of female fetuses Vaginal carcinoma and other genitourinary defects in female and male offspring Neonatal hypoglycemia Ebstein’s anomaly Moebius sequence Constriction of the ductus arteriosus c, necrotizing enterocolitis Facial and CNS defects Growth retardation, CNS deficits Neonatal withdrawal syndrome when drug is taken in late pregnancy CNS, craniofacial, cardiovascular, and other defects Anomalies of teeth and bone Limb-shortening defects, internal-organ defects Facial and CNS defects Neural-tube defects Skeletal and CNS defects, Dandy–Walker syndrome

a

Only drugs that are teratogenic when used at clinically recommended doses are listed. The list includes all drugs proved to affect neonatal morphology or brain development and some of the toxic manifestations predicted on the basis of the pharmacologic actions of the drugs. Data are from Briggs et al. (8). CNS denotes central nervous system. b The drug is not currently in clinical use. c Sulindac probably does not have this effect.

increased by a factor of 2 in both the United States and Canada after Bendectin was withdrawn from the market (Fig. 1). The drug was withdrawn despite a substantial body of evidence that the rate of major malformations among the children of women who had received Bendectin during pregnancy did not differ from the rate in the general population (24,25). Withdrawal of the drug from the American market did not decrease the rate of any specific category of malformation, as would be expected for a truly teratogenic drug estimated to have been used by up to 40 percent of pregnant women at one time (26,27). In Canada, the drug continues to be marketed under the trade name Diclectin. A review committee has advised the Canadian Minister of Health that the drug is safe (27). A recent study revealed that severe nausea and vomiting of pregnancy often lead women to terminate or consider the termination of otherwise wanted pregnancies (28). Other for-

40

Koren et al.

Table 2 Common Drugs Initially Thought To Be Teratogenic But Subsequently Proved Safe Drug

Initial evidence of risk

Diazepam a

Oral clefts a

Oral contraceptives

Birth defects involving the vertebrae, anus, heart, trachea, esophagus, kidney, and limbs (13); masculinizing effects on female fetuses resulting in pseudohermaphroditism (16) Limb defects, tumors, Down’s syndrome, and hypospadias (17) Cleft palate (19) and congenital heart disease Cardiac and limb defects (22,23)

Spermicides Salicylates Bendectin (doxylamine plus pyridoxine) a

Subsequent evidence of safety No increase in risk in large cohort and case-control studies (10–12) No association between first-trimester exposure to oral contraceptives and malformations in general or external genital malformations in two meta-analyses (15,16) No increase in risk in a meta-analysis (18) No increase in risk in large cohort studies (21,21) No increase in risk in two metaanalyses (24,25)

Diazepam taken near term may cause the neonatal withdrawal syndrome or cardiorespiratory instability.

Figure 1 Rates of Hospitalization among Pregnant Women with Severe Nausea and Vomiting and Numbers of Prescriptions for Bendectin and Diclectin in North America, 1979 through 1989. Bendectin was withdrawn from the U.S. market in 1982, whereas Diclectin, the same drug, remained on the market in Canada. Adapted from Neutel and Johansen with the permission of the publisher (26).

Drugs in Pregnancy

41

mulations of doxylamine in combination with pyridoxine are available in other countries (e.g., South Africa, Spain, and Thailand).

Isotretinoin The experience with thalidomide led drug regulators, drug manufacturers, and the medical community to believe that appropriate labeling of teratogenic drugs, with warnings not to take them around the time of conception, would be effective in preventing fetal exposure to the drugs. The naivete´ of this belief became evident after isotretinoin was introduced in North America in the early 1980s for the treatment of acne. For years before its clinical introduction, this drug had been known to cause malformations in animals (29). Despite explicit warning labels, scores of children with retinoid embryopathy were born in the years after the drug was introduced (30). Such warnings are not sufficient, because women taking isotretinoin may not plan their pregnancies, or their birth-control methods may fail. In addition, some women and men are functionally illiterate, and they may not read or understand the content of a drug label (31). The initial experience with isotretinoin led to the development of a more comprehensive program to prevent teratogenesis. The Retinoid Pregnancy Prevention Program includes explicit and detailed printed warnings as well as a line drawing of a malformed child (32), and as part of the program, women are asked to sign a consent form indicating that they agree to use two effective methods of contraception before therapy is started. Since the program was implemented in 1989, a substantial number of fetuses have been exposed to the drug. As many as 30 percent of the women with exposed fetuses did not use any mode of contraception, even though they were cognizant of the high fetal risk (32). Many of these women explained that they did not believe they were fertile, since they had not conceived during periods of months or years when they had not used contraceptive methods (33).

CURRENT TRENDS IN PREVENTING FETAL EXPOSURE TO TERATOGENS The advent of effective injectable hormonal contraceptives has made it possible to minimize the risk of an unplanned pregnancy during therapy with a known teratogen. This approach was first implemented in South America, where sexually active women with cutaneous leprosy were injected with medroxyprogesterone before receiving a prescription for thalidomide (34). Yet numerous new cases of thalidomide-associated embryopathy have been reported in the children of women who continued to take the drug after the period of contraceptive efficacy (three months) or who received the drug from their male partners (34). Because any new drug may be teratogenic, it is important to develop more effective methods to prevent fetal exposure. One such method may be the use of implantable hormonal compounds (e.g., levonorgestrel implants), which can provide long-term, reversible contraception for up to five years. Levonorgestrel implants have documented efficacy in young women in whom oral methods of contraception are likely to fail (35). Implants should be considered by sexually active women who are taking a teratogen medicinally (e.g., phenytoin or warfarin) or as part of a pattern of substance abuse (e.g., alcohol or

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cocaine). Furthermore, women taking teratogenic drugs who are not sexually active should be informed of the availability of effective postcoital contraceptives (35,36).

THE PROCESS OF ESTABLISHING RISK OR SAFETY OF DRUGS IN PREGNANCY Every year, many new drugs are approved and marketed. By this stage, several thousand people have usually participated in studies of the drugs, but the majority have been men. Since there are scarcely any data on fetal effects at the time of marketing, data from studies in animals provide the initial guidelines. The Value of Studies in Animals Typically, studies of reproductive toxicology in animals compare the outcome of pregnancy in groups of animals receiving a range of doses of the drug in question during the period of organogenesis with the outcome in untreated (control) animals. The occurrence of thalidomide-associated embryopathy led to the erroneous belief that human teratogenicity could not be predicted on the basis of studies in animals. However, every drug that has since been found to be teratogenic in humans has caused similar teratogenic effects in animals (Table 3), except misoprostol, which causes a morphologic pattern known as the Moebius sequence in humans. In at least one case, that of isotretinoin, the studies in animals probably prevented a disaster similar to that of thalidomide (29). However, there are drugs that have teratogenic effects in animals when administered in high doses that are not teratogenic in humans given clinically relevant doses. For example, high doses of glucocorticoids (19,70–75) or benzodiazepines (76,77) can cause oral clefts in animals, but clinically relevant doses in humans have no such effects (10–12,75). Similarly, salicylates (78–80) cause cardiac malformations in animals but not in humans (20,21). Such discrepancies have led to unwarranted anxiety on the part of women, their families, and physicians and may have contributed to unnecessary terminations of pregnancies (3). Although studies in animals may identify teratogenic effects, it can be difficult to extrapolate these effects to humans. Epidemiologic Studies In addition to studies in animals, a variety of other approaches are used to identify possible drug teratogenicity and to assess the relation between drug exposure and fetal outcome. The first accounts of adverse fetal outcomes after exposure to a marketed drug are usually published in the form of case reports. These reports can be either very useful or useless in establishing teratogenic risk on the basis of relatively simple statistical considerations. If the drug in question is taken by relatively small numbers of women (e.g., isotretinoin (30)) or causes a rare malformation (e.g., ear agenesis (81)), then a small number of cases can establish a strong association. Warfarin (9), diethylstilbestrol (82), and isotretinoin (83) were originally identified as human teratogens on the basis of case reports. If, on the other hand, the drug is taken by many pregnant women (e.g., Bendectin), a small number of case reports of abnormalities may simply reflect the spontaneous occurrence of malformations in the general population, which ranges from 1 to 5 percent, unless there is a characteristic pattern of malformations (as, for example, with alcohol or thalidomide). To

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43

date, prenatal exposure to many of the known human teratogens has been associated with characteristic patterns of malformations, and this has become an important tenet in establishing teratogenicity. Epidemiologic studies are typically designed to determine whether mothers who took a specific drug during pregnancy have a larger number of malformed children than mothers who did not (cohort studies) or whether mothers of children with a specific malformation took the drug more often than mothers of children without the malformation (case– control studies). With the international development of teratology-information services (84), a new source of data for prospective observational research has emerged. Pregnant women taking prescription or over-the-counter drugs voluntarily call these centers for risk-assessment counseling, usually during the first trimester. Since the exposure data are recorded prospectively, the probability of recall bias is reduced, and follow-up of exposed pregnancies can extend well beyond parturition. Collaboration among these services can yield the large samples needed to study rare events more effectively (53,61,85). Drug manufacturers may perform postmarketing cohort studies of prospectively reported exposures. Such studies were useful in establishing the safety and risk of Bendectin, isotretinoin, fluoxetine, and acyclovir (30,86). Because most studies of teratogenic risk are limited in size, meta-analyses of studies of similar design are becoming more frequent. A detailed, stepwise methodologic approach to meta-analysis of teratologic studies has been described (24). The appropriate use of this approach depends to a large extent on establishing sound a priori criteria for methodologic quality and ensuring the inclusion of data from all available studies, in order to obviate any publication bias against negative results. Long-term studies are increasingly important, because it is becoming clear that the long-term effects of teratogenic drugs on neurobehavioral development can have a more devastating effect on children and their families than structural anomalies. To date, several drugs have been shown to affect brain development, including carbamazepine, isotretinoin, phenytoin, valproic acid, and warfarin (Table 1). Carbamazepine and valproic acid may cause cognitive brain dysfunction as part of the neural-tube defects they induce. Originally, isotretinoin was found to cause structural abnormalities that affected brain development, but recent studies have suggested that even phenotypically normal children may have abnormal neurodevelopment (87). Warfarin was initially associated with chondrodysplasia punctata and mental retardation and has subsequently been found to cause the DandyWalker brain malformation in an estimated 1 to 2 percent of exposed fetuses (6,69). Common Methodologic Issues No single approach can definitively establish the safety or risk of drugs, because of several underlying difficulties. Sample Size Most congenital malformations occur rarely, and many teratogens, even when known to be associated with an increased risk of a given malformation, do not affect the great majority of exposed fetuses. In fact, very few drugs increase the total malformation rate by a factor of more than two (isotretinoin and thalidomide are two such drugs). If, for example, the risk of major malformations in a given population is 3 percent, then at least 220 pregnancies with the specific exposure and a similar number of control pregnancies

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Table 3

Teratogenic Effects of Drugs in Animals and Humans a

Drug Angiotensin-converting— enzyme inhibitors Carbamazepine Cocaine

Ethanol

Isotretinoin

Effects in animals

Effects in humans

Stillbirths and increased fetal loss in sheep and rabbits (37) Cleft palate, dilated cerebral ventricles, and growth retardation in mice (39) Dose-dependent decrease in uterine blood flow, fetal hypoxemia, hypertension, and tachycardia in sheep (41); reduced fetal weight, fetal edema, and increased resorption in rats and mice (42) Microcephaly, growth deficiency, and limb anomalies in dogs, chickens, and mice (44–48)

Prolonged renal failure and hypotension in the newborn, decreased skull ossification, hypocalvaria, and renal tubular dysgenesis (38) Neural-tube defects

CNS, head, limb, and cardiovascular defects in rats and rabbits (29)

Growth retardation involving weight, length, and head circumference (48); placental abruption (44,45) and uterine rupture

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Fetal alcohol syndrome: prenatal and postnatal growth deficiency, CNS anomalies (microcephaly, behavioral abnormalities, and mental retardation), characteristic pattern of facial features (short palpebral fissures, hypoplastic philtrum, and flattened maxilla), and major organ-system malformations (49); with age, facial features may become less distinctive, but short stature, microcephaly, and behavioral abnormalities persist (50) Retinoid embryopathy resulting in some or all of the following abnormalities (50): CNS defects (hydrocephalus, optic-nerve blindness, retinal defects, microphthalmia, posterior fossa defects, and cortical and cerebellar defects); craniofacial defects (microtia or anotia, low-set ears, hypertelorism, depressed nasal bridge, microcephaly, micrognathia, and agencies or stenosis of external ear canals); cardiovascular defects (transposition of great vessels, tetralogy of Falloe, and ventricular or atrial septal defects); thymic defects (ectopia and hypoplasia or aplasia); and miscellaneous defects (limb reduction, decreased muscle tone, spontaneous abortion, and behavioral abnormalities)

Phenytoin

Heart defects in rats (51) CNS abnormalities in rats (54); growth retardation, motor disturbances, microencephaly, and brain lesions in rhesus monkeys (55) Cleft palate, micromelia, renal defects, and hydrocephalus in rabbits, mice, and rats (57–59)

Thalidomide b

Limb-shortening defects in rabbits (most sensitive species) (62)

Valproic acid Warfarin b

Exencephaly in hamsters and mice (64,65) Maxillonasal hypoplasia and skeletal anomalies in rats (68)

a b

Ebstein’s anomaly and other heart defects (52,53) Fetal Minamata disease: diffuse neuronal disintegration with gliosis, cerebral palsy, microcephaly, strabismus, blindness, speech disorders, motor impairment, abnormal reflexes, and mental retardation (56) Fetal hydantoin syndrome (60); prenatal and postnatal growth deficiency, motor or mental deficiency, short nose with broad nasal bridge, microcephaly, hypertelorism, strabismus, epicanthus, wide fontanelles, lowset or abnormally formed ears, positional deformities of limbs, hypoplasia of nails and distal phalanges, hypospadias, hernia, webbed neck, low hairline, impaired neurodevelopment and low performance scores on tests of intelligence (61) Limb-shortening defects (63), loss of hearing, abducens paralysis, facial paralysis, anotia, microtia, renal malformations, congenital heart disease Neural-tube defects (66,67) Fetal warfarin syndrome: skeletal defects (nasal hypoplasia and stippled epiphyses), limb hypoplasia (particularly in distal digits), low birth weight (⬍10th percentile), hearing loss, and ophthalmic anomalies (69); CNS defects with exposure after first trimester; dorsal midline dysplasia (agencies of corpus callosum and Dandy–Walker malformations) or ventral midline dysplasia (optic atrophy) (6)

Drugs in Pregnancy

Lithium Methyl mercury

CNS denotes central nervous system. Initial studies in animals failed to show teratogenicity; hence, documentation in humans preceded that in animals.

45

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will be required to show a risk that is increased by a factor of 2.5, with a power of 80 percent. Effect of Maternal Diseases Apart from drug therapy, many medical conditions themselves increase fetal risks. For example, pregnant women with hypertension or cancer are more likely to have infants with intrauterine growth retardation, and pregnant women with epilepsy or diabetes mellitus are more likely to have infants with malformations (88). Therefore, any attempt to establish the role of fetal exposure to drugs must also address the contributing and confounding risk of the underlying maternal illness. Recall Bias in Retrospective Studies There is ample evidence of partial memory and bias in the way women recall the drugs they took during pregnancy. For example, women treated with a prescribed drug for a chronic illness tend to recall their treatment better than women who took an over-thecounter drug (89). Women who have given birth to malformed children may be more likely to remember the course of their pregnancies, in the effort to understand what went wrong, than women who have given birth to healthy children, thus giving rise to false positive associations. The initial suggestions that benzodiazepines, spermicides, and Bendectin, for example, were teratogenic were based on retrospective case-control studies subsequently refuted by other, larger studies (Table 2). With improved epidemiologic methods, the reliability of the case-control design has improved. For example, recruiting mothers of infants with a different major malformation as controls may eliminate or at least reduce the problem of differential maternal recall. In a recent study, this approach was used to document the effect of the mothers’ knowledge of the study hypothesis (that folic acid deficiency causes spina bifida) on the information they reported (90). Nonrandomized Observational Studies With prospective observational studies, the treatment decisions have not been made by the investigators collecting the data. As a result, the indications for treatment and concurrent exposures are not standardized. Therefore, in comparisons of treated and untreated pregnant women or pregnant women who received two different drugs, preexisting confounding factors are not randomly distributed between the two groups. For example, in comparing the outcome of pregnancy in women who received carbamazepine and women who received phenytoin, one must address the issue of whether the two groups of women had the same type and severity of seizure disorder. Observational studies of neurobehavioral development require longer follow-up than observational studies of other abnormalities, and interpretation of the results is often complicated by numerous confounding factors. Maternal and paternal IQ, socioeconomic status, and educational levels all affect cognitive development in children (91). Any attempt to address the developmental effects of drugs without controlling for these factors is likely to be futile. Voluntary Reporting The information received by drug manufacturers is often a mix of prospective and retrospective case reports. The quality of the information about exposure is usually poor, and outcome data are sparse because of high rates of loss to follow-up. Most important, women and health professionals who contact manufacturers are likely to report adverse fetal out-

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comes, not uneventful ones. For example, the pivotal study that described retinoid embryopathy contained two parts: prospectively collected data from a study cohort, with a malformation rate of 36 percent, and data from voluntary retrospective reporting to the manufacturer, with a malformation rate of 80 percent (30). Meta-Analyses A common concern regarding the use of metaanalysis is the inevitable combination of data from studies that are not equivalent in terms of quality and methods. In addition, there is the concern that negative studies (i.e., those that do not reject the null hypothesis) are less likely to be published than positive studies and that an overall positive association may therefore merely reflect unbalanced reporting.

COUNSELING WOMEN ABOUT TERATOGENIC RISKS In one study, women exposed to nonteratogenic drugs who sought counseling estimated, on average, that they had a 25 percent risk of major malformations, which is in the range of the teratogenic risk associated with thalidomide (2). After counseling, this estimate was substantially reduced, thereby preventing numerous terminations of otherwise wanted pregnancies (2,3). The same women correctly estimated the risk of major malformations in the general population (5 percent), indicating that the high risk they assigned to their own pregnancies was not due to a misunderstanding of the concept of base-line risk. What are the sources of this misperception? Numerous lay publications misinform women by assigning risks to drugs not known to be teratogenic in humans (2,3). Women often report that their physicians have encouraged them to terminate otherwise wanted pregnancies just to be on the safe side, suggesting that many physicians are unfamiliar with the current literature on the safety of drugs taken during pregnancy. Physicians counseling women who are pregnant or are planning a pregnancy should make sure that they understand clearly the nature and magnitude of a risk associated with a drug. Women’s attitudes toward voluntary abortion differ. In addition, the same information about the nature and magnitude of a teratogenic risk may prompt different decisions by different women, according to the clinical situation and specific circumstances. For example, women with epilepsy that has been treated effectively with phenytoin since their childhood may be glad to hear that although the drug is teratogenic, the overall risk of malformations is not high (61). In contrast, women who have been treated with phenytoin for a single grand mal seizure and who have normal children born before phenytoin was prescribed may find it unacceptable to continue an unplanned pregnancy after learning about the higher-than-normal risk of adverse effects. During counseling, it is important to ensure that a woman understands the concept of base-line teratogenic risk and the fetal or perinatal risks, if any, associated with her medical condition. For example, a woman with manic depression treated with lithium in the first trimester will need to understand not only the slightly increased risk of fetal cardiac anomalies associated with the drug (less than 1 percent) (53) but also the increased genetic risk of manic depression in her child. The counselor should be sure to communicate the same information to the woman’s physician so that she does not receive conflicting advice. To receive up-to-date, evidence-based information on the safety and risk of drugs during pregnancy, physicians can consult a teratogen-information service. Table 4 lists

48 Table 4 Selected Teratogen-Information Services Canada Motherisk Program, Toronto (416) 813-6780 World Wide Web address: http:/ /www.motherisk.org United States Organization of Teratology Information Services (801) 328-2229 (for referral to nearest service) World Wide Web address: http:/ /orpheus.ucsd.edu/ctis/ California Teratogen Information Service (619) 543-2131 (800) 532-3749 (only in California) District of Columbia Reproductive Toxicology Center (202) 293-5137 Florida Teratogen Information Service (352) 392-3050 (800) 392-3050 (only in Florida) Illinois Teratogen Information Service (312) 908-7441 (800) 252-4847 (only in Illinois) Indiana Teratogen Information Service (317) 274-1071 Massachusetts Teratogen Information Service (781) 466-8474 (800) 322-5014 (only in Massachusetts) Nebraska Teratogen Project (402) 559-5071 New York Teratogen Information Service (716) 874-4747 (ext. 477) (800) 724-2454 (ext. 270) (only in New York) Texas Teratogen Information Service (800) 733-4727 Utah Pregnancy Riskline (801) 328-2229 Vermont Pregnancy Risk Information (802) 658-4310 (800) 531-9800 (only in Vermont)

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the World Wide Web addresses and telephone numbers of services in the United States and Canada.

THE FDA CLASSIFICATION OF TERATOGENICITY To guide physicians in the interpretation of the teratogenic risk associated with prescription drugs, the FDA has established a system that classifies drugs on the basis of data from humans and animals, ranging from class A drugs, which are designated as safe for use during pregnancy, to class X drugs, which are contraindicated during pregnancy because of proven teratogenicity. This system has resulted in ambiguous statements that may be difficult to interpret and use for counseling and that can cause anxiety among women. In addition, the classification is often not changed when new data become available. For example, until recently, combined oral contraceptives were classified as class X drugs. Yet metaanalyses revealed that these combinations of estrogen and progestin were not associated with an increased risk of major malformations, in general (15), or genitourinary malformations, in particular (16). Each year, thousands of women become pregnant while taking these contraceptive hormones because of noncompliance or less-than-perfect efficacy, and their fetuses are exposed to the drugs during embryogenesis. In a similar fashion, tricyclic antidepressant drugs are classified as D (‘‘positive evidence of human fetal risk’’), even though no such evidence exists and the available data suggest that these drugs are safe (85). The Teratology Society has proposed that the FDA abandon the current classification system in favor of more meaningful, evidence-based, narrative statements (92). At an FDA hearing held on September 15, 1997, this proposal received public support. Other countries (e.g., Sweden, Australia, the Netherlands, Switzerland, and Denmark) have different classification systems, although all are based on a hierarchy of estimated fetal risk.

DRUGS OF CHOICE IN PREGNANCY Many pregnant women require drug therapy because of pregnancy-induced conditions such as nausea and vomiting, chronic conditions diagnosed before pregnancy, or acute conditions (e.g., those that require surgical treatment with the use of anesthetic agents). Several principles should guide the selection of therapy during pregnancy. Since fetal safety is a major concern, effective drugs that have been in use for long periods are preferable to newer alternatives. Table 5 lists selected drugs considered to be safe on the basis of either single large cohort studies or metaanalyses of several studies. Newer drugs may be more specific or have fewer adverse effects in adults, but their safety for fetuses is less likely to be known. For example, although acetaminophen with or without codeine may not be effective in many patients with migraine, it is widely used during pregnancy. Other, more potent antimigraine drugs are either too new (e.g., sumatriptan) or have known reproductive risks (e.g., ergotamine alkaloids that cause uterine contraction). To minimize the fetal risk, drug doses at the lower end of the therapeutic range should be prescribed during pregnancy. However, because of increased body weight and more rapid clearance of many drugs (e.g., lithium, digoxin, and phenytoin) during late pregnancy, some women may need higher-than-normal doses (94). Pregnant women should be discouraged from taking over-the-counter drugs, and such drugs should not be taken without counseling, since many factors, including the stage

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Table 5

Selected Drugs that Can Be Used Safely During Pregnancy, According to Condition a

Condition Acne Allergic rhinitis

Constipation

Cough Depression

Diabetes Headache Tension

Topical: erythromycin, clindamycin, benzoyl peroxide Topical: glucocorticoids, cromolyn, decongestants, xylometazoline, oxymetazoline, naphazoline, phenylephrine; systemic: diphenhydramine, dimenhydrinate, tripelennamine, astemizole Docusate sodium, calcium, glycerin, sorbitol, lactulose, mineral oil, magnesium hydroxide Diphenhydramine, codeine, dextromethorphan Tricyclic antidepressant drugs, fluoxetine

Alternative Drugs Systemic: erythromycin, topical tretinoin (vitamin A acid)

Isotretinoin as contraindicated

Bisacodyl, phenolphthalein

Lithium

Insulin (human)

Insulin (beef or pork)

Acetaminophen

Aspirin and nonsteroidal antiinflammatory drugs, benzodiazepines β-adrenergic-receptor antagonists and tricyclic antidepressant drugs (for prophylaxis)

Acetaminophen, codeine, dimenhydrinate

Comments

When lithium is used in first trimester, fetal echocardiography and ultrasonography are recommended because of small risk of cardiovascular defects Hypoglycemic drugs should be avoided Aspirin and nonsteroidal antiinflammatory drugs should be avoided in third trimester Limited experience with ergotamine has not revealed evidence of teratogenicity, but there is concern about potent vasoconstriction and uterine contraction

Koren et al.

Migraine

Drugs of Choice

Labetalol, methyldopa

β-adrenergic-receptor antagonists, prazosin, hydralazine

Hyperthyroidism

Propylthiouracil, methimazole

Mania (and bipolar affective disorder)

Lithium, chlorpromazine, haloperidol

β-adrenergic-receptor antagonists (for symptoms) For depressive episodes: tricyclic antidepressant drugs, fluoxetine, valproic acid

Nausea, vomiting, motion sickness

Diclectin (doxylamine plus pyridoxine)

Peptic ulcer disease

Antacids, magnesium hydroxide, aluminum hydroxide, calcium carbonate, ranitidine Topical: moisturizing creams or lotions, aluminum acetate, zinc oxide cream or ointment, calamine lotion, glucocorticoids; systemic: hydroxyzine, diphenhydramine, glucocorticoids, astemizole Heparin, antifibrinolytic drugs, streptokinase

Pruritus

Thrombophlebitis, deepvein thrombosis a

Angiotensin-converting-enzyme inhibitors should be avoided because of risk of severe neonatal renal insufficiency Surgery may be required; radioactive iodine should be avoided If lithium is used in first trimester, fetal echocardiography and ultrasonography are recommended because of small risk of cardiac anomalies; valproic acid may be given after neural-tube closure is complete

Drugs in Pregnancy

Hypertension

Chlorpromazine, metoclopramide (in third trimester), diphenhydramine, dimenhydrinate, meclizine, cyclizine Sucralfate, bismuth subsalicylate

Topical: local anesthetics

Streptokinase is associated with a risk of bleeding; warfarin should be avoided

Data are from Smith et al. (98).

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of pregnancy, can influence the risk to the fetus. For example, a nonsteroidal antiinflammatory drug may be taken safely for pain during the first trimester of pregnancy, but there is increasing evidence that some nonsteroidal antiinflammatory drugs constrict or even close the fetal ductus arteriosus during late pregnancy (95).

CONCLUSIONS In addition to the risk associated with fetal exposure to teratogenic drugs, there is a risk associated with misinformation about the teratogenicity of drugs, which can lead to unnecessary abortions or the avoidance of needed therapy. The medical community and drug manufacturers should make a concerted effort to protect women and their unborn babies from both risks.

ACKNOWLEDGMENTS Supported by grants from the Medical Research Council of Canada, the National Health and Welfare Research Program, the Medical Research Council—Pharmaceutical Manufacturers Association of Canada Program, Physicians Services, Novartis, Roche Canada, Duchesnay, and the Motherisk Research Fund.

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40. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324:674–677. 41. Wood JR Jr, Plessinger MA, Clark KE. Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987; 257:957–961. 42. Fantel AG, Macphail BJ. The teratogenicity of cocaine. Teratology 1982; 26:17–19. 43. Weathers WT, Crane MM, Sauvain KJ, Blackhurst DW. Cocaine use in women from a defined population: prevalence at delivery and effects on growth in infants. Pediatrics 1993; 91:350– 354. 44. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991; 44:405–414. 45. Chasnoff IJ. Cocaine, pregnancy, and the growing child. Curr Probl Pediatr 1992; 22:302– 321. 46. Ellis FW, Pick JR. An animal model of the fetal alcohol syndrome in beagles. Alcohol Clin Exp Res 1980; 4:123–134. 47. Shoemaker WJ, Koda LY, Shoemaker CA, Bloom FE. Ethanol effects in chick embryos: cerebellar Purkinje neurons. Neurobehav Toxicol 1980; 2:239–242. 48. Sulik KK, Johnston MC, Webb MA. Fetal alcohol syndrome: embryogenesis in a mouse model. Science 1981; 214:936–938. 49. Clarren SK. Recognition of fetal alcohol syndrome. JAMA 1981; 245:2436–2439. 50. Streissguth AP, Aase JM, Clarren SK, Randels SP, LaDuc RA, Smith DF. Fetal alcohol syndrome in adolescents and adults. JAMA 1991; 265:1961–1967. 51. Wilby OK, Tesh SA, Ross FW, Tesh JM. Effects of lithium on development in vitro and in vivo in the rat. Teratology 1987; 35:69, abstract. 52. Nora JJ, Nora AH, Toews WH. Lithium, Ebstein’s anomaly, and other congenital heart defects. Lancet 1974; 2:594–595. 53. Jacobson SJ, Jones K, Johnson K, et al. Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 1992; 339:530–533. 54. Tatetsu M. Experimental manifestation of ‘‘congenital Minamata disease.’’ Psychiatr Neurol Jpn 1968; 70:162. 55. Dougherty WJ, Coulston F, Golberg L. Toxicity of methylmercury in pregnant rhesus monkeys. Toxicol Appl Pharmacol 1974; 29:138, abstract. 56. Matsumoto H, Koya G, Takeuchi T. Fetal Minamata disease: a neuropathological study of two cases of intrauterine intoxication by a methyl mercury compound. J Neuropathol Exp Neurol 1965; 24:563–574. 57. McClain RM, Langhoff L. Teratogenicity of diphenylhydantoin in New Zealand white rabbits. Toxicol Appl Pharmacol 1979; 48:A32, abstract. 58. Finnell RH. Phenytoin-induced teratogenesis: a mouse model. Science 1981; 211:483–484. 59. Harbison RD. Studies on the mechanism of teratogenic action and neonatal pharmacology of diphenylhydantoin. (Ph.D. thesis. Iowa City: State University of Iowa, 1969.) 60. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 87:285–290. 61. Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994; 271:767–770. 62. Fratta ID, Sigg EB, Maiorana K. Teratogenic effects of thalidomide in rabbits, rats, hamsters, and mice. Toxicol Appl Pharmacol 1965; 7:268–286. 63. McBride WG. Thalidomide and congenital abnormalities. Lancet 1961; 2:1358. 64. Nau H. Species differences in pharmacokinetics and drug teratogenesis. Environ Health Perspect 1986; 70:113–129. 65. Finnel RH, Bennett GD, Karras SB, Mohl VK. Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite. Teratology 1988; 38:313–320. 66. Jager-Roman E, Deichi A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986; 108:997–1004.

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67. Lammer EJ, Sever LE, Oakley GP Jr. Teratogen update: valproic acid. Teratology 1987; 35: 465–473. 68. Howe AM, Webster WS. The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 1992; 46:379–390. 69. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68:122–140. 70. Baxter H, Fraser FC. The production of congenital defects in the offspring of female mice treated with cortisone. McGill Med J 1950; 19:245–249. 71. Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954; 55:502– 508. 72. Buresh JJ, Urban TJ. The teratogenic effect of the steroid nucleus in the rat. J Dent Res 1970; 43:548–554. 73. Wilson JG, Fradkin R, Schumacher HJ. Influence of drug pretreatment on the effectiveness of known teratogenic agents. Teratology 1970; 3:210–211, abstract. 74. Pinsky L, DiGeorge AM. Cleft palate in the mouse: a teratogenic index of glucocorticoid potency. Science 1965; 147:402–403. 75. Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology 1995; 51: 45–46. 76. Shepard TH. Catalog of teratogenic agents. 7th ed. Baltimore: Johns, Hopkins University Press, 1994. 77. Miller RP, Becker BA. Teratogenicity of oral diazepam and diphenylhydantoin in mice. Toxicol Appl Pharmacol 1975; 32:53–61. 78. Klein KL, Scott WJ, Wilson JG. Aspirin-induced teratogenesis: a unique pattern of cell death and subsequent polydactyly in the rat. J Exp Zool 1981; 216:107–112. 79. Wilson JG, Ritter EJ, Scott WJ, Fradkin R. Comparative distribution and embryotoxicity of acetylsalicylic acid in pregnant rats and rhesus monkeys. Toxicol Appl Pharmacol 1977; 41: 67–78. 80. Beall JR, Klein MF. Enhancement of aspirin-induced teratogenicity by food restriction in rats. Toxicol Appl Pharmacol 1977; 39:489–495. 81. Mastroiacovo P, Corchia C, Botto LD, Lanni R, Zampino G, Fusco D. Epidemiology and genetics of microtia-anotia: a registry based study on over one million births. J Med Genet 1995; 52:453–457. 82. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence: a report of 7 cases including 6 clear-cell carcinomas. Cancer 1970; 25:745–757. 83. Rosa FW. Teratogenicity of isotretinoin. Lancet 1983; 2:513. 84. Koren G, Pastuszak A. Teratogen information services. In: Koren G, ed. Maternal-fetal toxicology: a clinician’s guide. 2nd ed. rev. New York: Marcel Dekker, 1994:683–705. 85. Pastuszak A, Schick-Boschetto B, Zuber C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine. JAMA 1993; 269:2246–2248. 86. Goldstein DJ, Corbin LA, Sundell KL. Effects of first-trimester fluoxetine exposure on the newborn. Obstet Gynecol 1997; 89:713–718. 87. Adams J. Neural and behavioral pathology following prenatal exposure to retinoids. In: Koren G, ed. Retinoids in clinical practice: the risk-benefit ratio. New York: Marcel Dekker, 1993: 111–128. 88. Gonen R, Shilalukey K, Magee L, Koren G, Shime J. Maternal disorders leading to increased reproductive risk. In: Koren G, ed. Maternal-fetal toxicology: a clinician’s guide. 2nd ed. rev. New York: Marcel Dekker, 1994:641–682. 89. Feldman Y, Koren G, Mattice K, Shear H, Pellegrini E, MacLeod SM. Determinants of recall and recall bias in studying drug and chemical exposure in pregnancy. Teratology 1989; 40: 37–45. 90. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993; 269:1257–1261.

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4 Teratogenic Drugs and Chemicals in Humans Irena Nulman, Gordana Atanackovic, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A 28-year-old epileptic woman, treated for 6 years with valproic acid, reports amenorrhea of 12 weeks. Pregnancy test is positive, and the patient, who had tried unsuccessfully to conceive for several years, is very happy. What would you advise her? INTRODUCTION Since the thalidomide disaster, drugs and chemicals have been scrutinized carefully for their potential human teratogenicity. However, despite valiant efforts in this direction, several objective limitations hinder our ability to detect human teratogens. 1. Most birth defects occur rarely; therefore, even an increased risk posed by a teratogen may not be easily identified. While thalidomide caused more than 20% of major malformations following first-trimester exposure, most suspected teratogens increase the baseline risk of major malformations very slightly (1–3%), even when they significant increasing the risk of a specific pattern. For example, valproic acid increases by 200fold the risk for neural tube defects (NTDs), yet its impact on the overall risk for major malformations is less than 0.5% (1). Consequently, a woman exposed to valproic acid may still have better than a 95% chance of having a healthy baby. As a result, it may be necessary to study a large number of infants exposed in utero to a certain drug to prove or disprove its teratogenic potential. Most studies are limited in their statistical power because their numbers are not large enough. 2. For obvious reasons, pharmaceutical manufacturers warn the public not to use drugs in pregnancy owing to a lack of information about their safety. Consequently, the accumulation of data on a specific drug is often sketchy and uncontrolled. While most manufacturers try to record and follow up voluntary reports of exposures in pregnancy, it has to be recognized that such data are incomplete and may be biased. For example, it is conceivable that disproportionately high numbers of families having malformed children will report their drug exposure to the manufacturer or to the regulatory agencies, whereas families with healthy babies are less likely to do so. This tendency was recently documented in a large study on the teratogenicity of retinoic acid. In the prospective section 57

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of that cohort, 38% of the infants were malformed, whereas 80% of those reporting retrospectively cited major malformations. This means that a large number of families having normal children after first-trimester exposure to retinoic acid did not report voluntarily to either the manufacturer or the Centers for Disease Control (CDC) (2,3). 3. As part of the regulatory process, the teratogenic potential of drugs has to be tested in animals. The failure of animal models to detect the teratogenicity of thalidomide before the human disaster occurred has resulted in a growing feeling that we cannot extrapolate from animal studies to humans. Differences in pharmacokinetics, metabolism, embryology, target-organ sensitivity, and other factors may account for such discrepancies. Yet almost all known human teratogens have been shown to cause similar effects in animals, warfarin (Coumadin) being the exception (4). Moreover, in the case of retinoic acid (Accutane), the most potent human teratogen currently available, animal data clearly prevented a postmarketing disaster similar to that of thalidomide (5). CASE REPORTS Cases associating in utero exposure to a certain drug or chemical with an adverse outcome may be either most helpful or useless, depending on the following statistical considerations. In the case of a drug that is rarely used in pregnancy, a small number of cases showing the same pattern of malformations may be most indicative, since these cases may already exceed manyfold the baseline risk for the occurrence of such malformations. For example, if a new drug has been reported to cause 10 cases of cleft palate out of the total 100 known cases of first-trimester exposure, then it has a 10% risk of causing cleft palate. This calculated risk exceeds by 100-fold the known risk of cleft palate, which is 0.1%. Based on this approach, several human teratogens, including warfarin and retinoic acid, were incriminated long before prospective studies confirmed these associations. At the other extreme, it will be impossible to prove teratogenicity based on case reports when the drug is commonly used (e.g., salicylates) and the malformation is not rare. Salicylates are consumed by thousands of pregnant women every year; therefore, based on statistical chance only, one would expect to find within this group offspring with any described malformation. Bendectin (the combination of pyridoxin and doxylamine) was for decades one of the most widely used antiemetic drugs to cope with pregnancy-associated morning sickness. The drug was wrongly incriminated as causing congenital malformations based on case reports: hundreds of thousands of pregnant women were exposed to this drug, 1– 3% of their offspring would have had major malformations just because of their baseline risk. Subsequently, controlled studies (both case-control and prospective) failed to confirm an association between Bendectin and human teratogenicity; however, the American manufacturer withdrew the drug from the market owing to excessive insurance costs (see Chap. 32). In Canada, this antiemetic is available under the trade name Diclectin, and recently the Canadian Health Protection Branch has specifically labeled it as an antiemetic appropriate for use in pregnancy. EPIDEMIOLOGICAL STUDIES Several approaches are commonly employed in studying the potential reproductive effects of drugs and chemicals.

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The retrospective study tries to identify women exposed in pregnancy to the drug in question and to evaluate the outcome of the exposed offspring. A variety of methodological problems may complicate the interpretation of such data. It may not be possible to identify and assess all cases, and it is conceivable that cases with an adverse outcome will be overrepresented. For example, the Danish lithium registry is a voluntary reporting system of exposure to the drug in pregnancy. Of its 300 cases reported by 1993, about 10% represented cardiac malformation; however, it is probable that parents of healthy babies born after such exposures had less motivation to report to the registry than those with an adverse outcome (6). Another major disadvantage of such cohorts, owing to the rare occurrence of most congenital anomalies, is the need for very large numbers of individuals exposed to the drug. To overcome this shortcoming, the case-control study focuses on offspring with a specific malformation and tries to assess maternal exposure to the drug in question. The percentage of maternal use is then compared to that of a group of mothers of infants not having the tested malformation. A major problem with all retrospective studies, both cohorts and case-control, is the need to rely on maternal recall of drug exposure (i.e., time and dose). In a recent study, mothers we had interviewed first at the time of their exposure in pregnancy tended not to remember significant parts of this information when questioned again after giving birth (7). Mitchell has significantly improved the reliability of casecontrol studies by developing questionnaires that reduce the effect of maternal recall characteristic of the previously used open-ended questionnaire (8). In prospective studies, the information about exposure and other possible pregnancy risk factors is collected at the time of exposure or soon after it. Although this is likely to be the most accurate approach to assess potential teratogenicity, such studies are lengthy and costly because very large numbers of test subjects are needed to overcome the rareness of most congenital malformations. Whereas full discussion of methodological problems associated with each approach is beyond the scope of this chapter, it is clear that proving the teratogenicity of a specific drug in humans may be a complex process, demanding a high degree of scrutiny. In many cases evidence is accumulated through several different approaches (e.g., case reports, case control, and prospective studies). The combination of increased awareness to human teratogenicity with the abovementioned difficulties in differentiating normal background from slightly increased rates of malformations has led to unjustified incrimination of useful medications that were later found out to be nonteratogenic. These include oral contraceptive hormones, diazepam, Bendectin, and spermicides. Typically, a devastating potential, as reflected above in the case of Bendectin, may result from wrong incrimination of a nonteratogen, as many women may terminate an otherwise wanted pregnancy. Presently, it is felt that several criteria must be met before an agent is incriminated as a human teratogen (9): An abrupt increase in the frequency of a particular defect or association of defects (syndrome) Coincidence of this increase with a known environmental change, such as widespread use of a new drug or sudden exposure to a chemical Known exposure to the environmental change early in pregnancy yielding characteristically defective infants Absence of other factors common to all pregnancies yielding infants with the characteristic defect(s)

Table 1

Drugs and Chemicals Proven to Be Teratogenic in Humans

Alcohol

Relative risk for teratogenicity

Clinical intervention

Fetal alcohol syndrome (FAS): evidence of unique pattern of facial anomalies such as short palpebral fissures, flat midface, long and narrow upper lip, flattened philtrum: evidence of antenatal and/or postnatal growth retardation—low birth weight for gestation age, decelerated weight not due to nutrition Alcohol-related neurodevelopmental disorder (ARND) such as decreased cranial size at birth, brain abnormalities such as microcephaly, partial or complete agenesis of the corpus callosum, cerebellar hypoplasia, neurological hard or soft signs such as impaired fine motor skills, neurosurgery hearing loss. Alcohol-related birth defects (ARBD) such as cardiac, renal, skeletal, ocular, auditory and other)

In alcoholic women consuming above 2 g/kg/day of ethanol over the first trimester: two- to threefold higher risk for congenital malformations (about 10%)

Growth retardation, cleft palate, microphthalmos, hypoplastic ovaries, cloudy corneas, agenesis of kidney, malformations of digits, cardiac defects, multiple other anomalies

Based on case reports, between 10 and 50% of malformations were due to different drugs. It is possible that adverse outcome was overrepresented.

Calculate accurate dose of alcohol. Prospective: Counsel patient to discontinue exposure. If patient is alcoholic, refer her to an addiction center. Counsel patient to use effective contraception. During pregnancy: Alleviate fears in mild or occasional drinkers who may terminate pregnancy based on unrealistic perception of risk. Level 2 ultrasound should be performed to rule out visible malformation. When the diagnosis of heavy drinking in early pregnancy has been made, the attendant fetal risk should be discussed; in some cases termination of pregnancy may be chosen by the patient. Counsel patient to discontinue drinking if the pregnancy is continuing. After delivery: Aggressive follow-up; early diagnoses of alcohol-related abnormalities to prevent secondary disabilities. Level 2 ultrasound to rule out visible malformations Supplement folic acid to women receiving antifolates (e.g., methotrexate)

Ref. 10,11

12,30

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Alkylating agents (busulfan, chlorambucil, cyclophosphamide, mechlorethamine)

Fetal adverse effects

60

Drug/chemical

Benzodiazepines

Hydrocephalus, meningocephalocele, anencephaly, malformed skull, cerebral hypoplasia, growth retardation, eye and ear malformations, malformed nose and cleft palate, malformed extremities and fingers Aminopterin syndrome: Cranial dysostosis, hydrocephalus, hypertelorism, anomalies of external ear, micrognathia, posterior cleft palate Increased risk for major malformations or oral cleft alone

Based on case reports 7–75% of patients were malformed. It is possible that adverse outcome was overrepresented.

Level 2 ultrasound to rule out visible malformations

4

Meta-analysis of case-control studies showed an association between major malformation and/or oral cleft alone (odds ratios 3.01; 95% CI, 1.32–6.84) NTDs estimated at 1% with carbamazepine

Level 2 ultrasound to rule out visible malformations.

31,32

Periconceptional folate; maternal and/or amniotic α-fetoprotein; ultrasound to rule out NTD. Measure maternal carboxyhemoglobin levels. Treat with 100% oxygen for 5 h after maternal carboxyhemoglobin returns to normal because fetal equilibration takes longer. If hyperbaric chamber available, should be used, as elimination t1/2 of CO is more rapid. Fetal monitoring by an obstetrician; sonographic follow-up. Level 2 ultrasound for measurement of fetal head size.

14,41

Increased risk for neural tube defects (NTDs)

Carbon monoxide

Cerebral atrophy, mental retardation, microcephaly, convulsions, spastic disorders, intrauterine or postnatal death

Based on case reports, when the mother is severely poisoned, there is a high risk for neurological sequelae; there is no risk in mild, accidental exposures

Cocaine

Small head circumference, low birth rate, intracranial bleeding

A dose-response relationship was found between cocaine use and perinatal outcome.

15,16

40

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Carbamazepine

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Antimetabolic agents (aminopterin azauridine, cytarabine, 5-FU, 6-MP, methotrexate)

Table 1

Continued Fetal adverse effects Cleft palate Reduction in birth weight and head circumference, dose-response relationship

Warfarin

Fetal warfarin syndrome: nasal hypoplasia, chondrodysplasia punctata, brachydactyly, skull defects, abnormal ears, malformed eyes, CNS malformations, microcephaly, hydrocephalus, skeletal deformities, mental retardation, optic atrophy, spasticity, Dandy Walker malformations Female offspring: clear cell vaginal or cervical adenocarcinoma in young female adults exposed in utero (before 18th week): irregular menses (oligomenorrhea), reduced pregnancy rates, increased rate of preterm deliveries, increased perinatal mortality and spontaneous abortion Male offspring: cysts of epididymis, cryptorchidism, hypogonadism, diminished spermatogenesis Lower scores in developmental tests

Diethylstilbestrol (DES)

Lead

Clinical intervention

Odds Ratio (OR)-2.5(CI 1.5–4.4) metaanalysis. Antenatal exposure at 24 weeks or later causes up to a 9% reduction (p ⬍ 0.014) in birth weight and up to a 4% reduction (p ⬍ 0.0024) in head circumference. 16% of exposed fetuses have malformations; another 3% have hemorrhages; 8% are stillborn.

Level 2 ultrasound to rule out visible malformations.

35,36

Prospective: switch to heparin for the first trimester. Deliver by cesarean section. Women should be followed up in a high-risk perinatal unit.

17

Exposure before 18 weeks of gestation: ⱕ1.4\1000 of exposed female with carcinoma. Congenital morphological changes in vaginal epithelium in 39% of exposures

Diagnosis: direct observation of mucosa and Shiller’s test. Treatment: mechanical excitement or destruction in relatively confined area. Surgery and radiotherapy for diffused tumor.

18

Higher risk when maternal lead is above 10 µg/dL.

Maternal lead levels ⬎ 10 µg/ dL: investigate for possible source of contamination. Levels ⬎ 25 µg/dL: consider chelation.

19

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Corticosteroids

Relative risk for teratogenicity

62

Drug/chemical

Possibly higher risk for Ebstein’s anomaly; no detectable higher risk for other malformations

Methyl mercury, mercuric sulfide

Microcephaly, eye malformations, cerebral palsy, mental retardation, malocclusion of teeth

Women of affected babies consumed 9–27 ppm mercury; greater risk when ingested at 6–8 gestational months. Relative risk was not elucidated, but 13 of 220 babies born in Minamata, Japan, at the time of contamination had severe disease.

Misoprostol

Spontaneous abortions, fetal death. Mo¨bius syndrome (paralysis of sixth and seventh cranial nerves) Increased risk for major malformations without a single pattern, increased risk for miscarriage

RR 3.15; CI 1.20–8.27

Organic solvents

PCBs

6

20,21

37,38

OR 25.7: CI 8.30–89.4

13% (1.8–99.5) OR–1.64 (CI 1.16–2.30) for major malformations OR–1.25 (0.99–1.58) for spontaneous abortions 4% (6 of 159) to 20% (8 of 39)

Minimize exposure, avoid toxicity by protection and ventilation.

33,34

These figures, which are from cases poisoned by high consumption of PCB-contaminated rice oil, cannot be extrapolated to cases in which maternal poisoning has not been verified. Women working near PCBs (e.g., hydroelectric facilities) should use effective protection.

22

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Stillbirth Signs at birth: white eye discharge, 30% (32 of 108); teeth present, 8.7% (11 of 127); irritated/swollen gums, 11% (11 of 99); hyperpigmentation (‘‘cola’’ staining), 42.5% (54 of 127); deformed/small nails, 24.6% (30 of 122); acne, 12.8% (16 of 125).

Women who need lithium should continue therapy, with sonographic follow-up. Patients may need higher doses because of increased clearance rate. Good correlation between mercury concentrations in maternal hair follicles and neurological outcome of the fetus. Hair mercury content above 50 ppm was used successfully as a cut point for termination. In acute poisoning, the fetus is 4– 10 times more sensitive than the adult to methylmercury toxicity. Increase the awareness of teratogenicity of the drug.

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Lithium carbonate

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Table 1

Continued Fetal adverse effects

Penicillamine Phenytoin

Subsequent history: bronchitis or pneumonia, 27.2% (30 of 124); chipped or broken teeth, 35.5% (38 of 107); hair loss, 12.2% (14 of 115); acne scars, 9.6% (11 of 115); generalized itching, 27.8% (32 of 1150). Developmental: children do not meet milestones; have lower scores than unexposed controls; show evidence of CNS damage. Skin hyperlastosis Fetal hydantoin syndrome: low nasal bridge, inner epicanthal folds, ptosis, strabismus, hypertelorism, low-set or abnormal ears, wide mouth, large fontanel, anomalies and hypoplasia of distal phalanges and nails, skeletal abnormalities, microcephaly and mental retardation, growth deficiency, neuroblastoma, cardiac defects, cleft palate and/or lip

Relative risk for teratogenicity

Few case reports; risk unknown 5–10% of typical syndrome; about 30% of partial picture. Relative risk of 7 for offspring IQ ⱕ84 (see Chap. 4)

Clinical intervention

Neurologist should consider changing to other medications. Keep phenytoin concentrations at lower effective levels. Level 2 ultrasound to rule out visible malformations. Vitamin K to neonate. Epilepsy itself increases teratogenic risk.

Ref.

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Drug/chemical

Trimethadione

Thalidomide

Tetracycline

Valproic acid

Spontaneous abortions; deformities of cranium, ears, face, heart, limbs, liver; hydrocephalus, microcephalus, heart defects Cognitive defects even without dysmorphology Fetal trimethadione syndrome: intrauterine growth retardation, cardiac anomalies, microcephaly, cleft palate and lip, abnormal ears, dysmorphic face, mental retardation, tracheoesophageal fistula, postnatal death Limb phocomelia, amelia, hypoplasia, congenital heart defects, renal malformations, cryptorchidism, abducens paralysis, deafness, microtia, anotia Yellow, gray-brown, or brown staining of deciduous teeth, destruction of enamel

Lumbosacral spina bifida with meningomyelocele; CNS defects, microcephaly, cardiac defects, cognitive impairment

For isoretinoin: 38% risk: 80% of malformations are CNS.

Based on case reports: 83% risk, 32% infantile or neonatal death.

There is a risk of about 20% risk when exposure to drug occurs in days 34–50 of gestation.

From 4 months of gestation and on, teratogenicity occurs in 50% of fetuses exposed to tetracycline and in 12.5% to oxytetracycline. There is a 1–2% risk of neural tube defects.

Treated women should have an effective method of contraception. Pregnancy termination. If diagnosed too late, sonographic follow-up to rule out confirmed malformations. No need for this antiepileptic to date.

2

Thalidomide is an effective drug for some forms of leprosy. Treated women should have an effective mode of contraception. If there is exposure between 14 and 16 weeks of gestation, there is no known risk.

27

Level 2 ultrasound and maternal α-fetoproteins or amniocentesis to rule out neural tube defects. Epilepsy itself increases teratogenic risk.

26

Teratogenic Drugs and Chemicals in Humans

Systemic retinoids (isotretinoin, etretinate)

28

1,39,41

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COUNSELING WOMEN ABOUT KNOWN TERATOGENS Table 1 presents details of drugs and chemicals known to be teratogenic in humans, with a major reference for each. When a clinician confronts an exposure of a pregnant patient to a known teratogen, it is important to convey the available information to the family in a way that will prevent both understatements and ambiguity. An accurate estimate of the risk for an adverse outcome should be provided, because pregnant women tend to have an unrealistically high perception teratogenic risk even when exposed to nonteratogens (see Chap. 29). In the Motherisk Program, we find that the same estimated risk may be unacceptably high for some families and reasonable for others. For example, epileptic women who are well controlled with phenytoin and have failed to have their epilepsy controlled with other anticonvulsants are often reluctant to change their medication in pregnancy. Conversely, we recently consulted the mother of three healthy children who was treated briefly with phenytoin following a single seizure. When it became apparent that she was pregnant again, an electroencephalogram was taken. The results were normal, and it was planned to discontinue the drug. For this patient, the teratogenic risk of phenytoin was perceived as unacceptable. Not included in Table 1 are scores of drugs that cause direct fetal toxicity consistent with their pharmacological effects. These are detailed in Chapter 13. Proven human teratogens are by no means a homogeneous group of compounds; however, they can be divided by several criteria into subgroups. Obsolete Drugs Diethylstilbestrol and trimethadione are currently unlikely to create a problem in pregnancy because they are not used clinically. Thalidomide, which was banned after the disaster three decades ago, is an important drug for some forms of leprosy. It is presently used in South America for leprosy in women who receive injectable forms of contraceptive hormone. However, there have recently been reports of a new wave of malformed children due to inappropriate use. Retinoic acid, which bears a rate of teratogenicity similar to that of thalidomide, is widely used, mostly for treatment of cystic acne in adolescents and young adults, who are the most likely group to fail contraceptives. In fact, the U.S. Food and Drug Administration (FDA) is reevaluating conflicting reports on the number of pregnancies and birth defects associated with retinoic acid in order to decide the future of this drug in the American market. Existence of Alternative Therapy Several teratogenic drugs may have value as alternative therapies in pregnancy; however, each case is characterized by unique problems. Although there are alternatives to lithium carbonate (e.g., tricyclics) for manic-depressive disorders, some patients may not respond favorably to replacement drugs. Moreover, recent evidence suggests lithium to be safe during pregnancy (6). The same argument is valid for phenytoin and valproic acid, and in each case the physician caring for the woman planning pregnancy should evaluate other alternatives. Heparin, which does not cross the placenta, may substitute for warfarin during the first trimester; the former must be injected, however, and compliance may become a major problem.

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From a pharmacological standpoint, in very few instances is there no alternative drug for human teratogens: retinoic acid, however, appears to be very efficacious in complicated types of acne, and no other compound shares the same mechanisms of action. This is a strong argument in favor of not removing the drug from the market despite its known teratogenic risk. Thousands of patients would thus be deprived of an irreplaceable therapy. Clearly, this drug is completely contraindicated in pregnancy. Alkylating agents and antimetabolites (azathioprine, chlorambucil, etc.) represent a specific therapy that may need to be continued uninterrupted. The main teratogenic effects of these drugs are associated with first-trimester exposure; current analysis done by us in Toronto reveals that in most cases, when cancer is diagnosed early in pregnancy, the women choose to terminate the pregnancy. However, to date there is increasing use of some of these agents in collagen diseases and nephritis as well as after organ transplants; it is likely that the number of women seeking prospective advice on these drugs will increase. Magnitude of the Public Health Issue Alcohol is undoubtedly the most common human teratogen. Because 10 million Americans are alcoholics, large numbers of fetuses are exposed to the amount of alcohol associated with fetal alcohol syndrome (FAS). It has been estimated that one baby in every 2500 live births has FAS, which means 1600 new cases in the United States per year (10). The combined rate of FAS and alcohol-related neurodevelopmental disorder is estimated to be at least 9.1 per 1000, nearly one in every 100 live births (25). Clearly the number of consumers of this teratogen is several orders of magnitude larger than that for any other teratogenic compound. With increasing public awareness of the adverse fetal outcome associated with alcohol, many women and families fear the potential adverse effects of alcohol consumed before conception was realized, even when much smaller amounts than those associated with FAS are involved. Although there is some preliminary evidence of a dose-response relationship to alcohol teratogenicity in humans (11), even two drinks a day during embryogenesis has not been associated with increased morphological or developmental risks (12). The problem of verifying the degree of drinking is major. Recently, for example, we documented that women who have had an adverse outcome of pregnancy tend to decrease the amount of alcohol reported postnatally compared to their initial report during pregnancy (7). The commonly used anticonvulsants are established human teratogens. Congenital heart defects, cleft lip and/or palate, genitourinary defects, and cognitive impairment were associated with use of anticonvulsant medication (41). Interaction of valproic acid and carbamazepine with folic acid may lead to neural tube defects (2% and 1% respectively). Valproic acid was also found to be associated with cognitive and behavioral impairment in school-age children (39). Phenytoin is undoubtedly another drug that, through its common use, creates a public health issue. It has been estimated by Hanson et al. (22) that between 5 and 10% of fetuses exposed in utero to the drug will exhibit the full picture of fetal hydantoin syndrome (FHS). Since 0.5% of pregnant women are epileptic and about half of them are treated with phenytoin, the rate of FHS should be somewhere between 0.019 and 0.025% of births (23). This means that with an annual birth rate of 4 million in the United States, between 500 and 100 newborns every year suffer from this serious syndrome. The risk for major malformations is increasing with the number of anticonvulsive medications used. Lindhout et al. reported a 5% risk of birth defects in

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children of women with epilepsy who took two drugs concomitantly, 10% in those who took three drugs, and more than 20% when four drugs were used (42). However, proper seizure control is the primary goal in treating women with epilepsy. Patients should understand the risks associated with uncontrolled seizures as well as the potential for teratogenicity of the anticonvulsive medications. Retinoic acid, evolving as a commonly used drug for acne in young adults, has the potential of becoming a similar public health issue if not a worse one. However, no peerreviewed data have been published on the number of pregnancies occurring while women are being treated with Accutane. Unlike phenytoin, which may be essential during pregnancy, the use of retinoic acid is absolutely contraindicated in pregnancy, and treatment of acne can be postponed without risk to the mother. Benzodiazepines are commonly used for anxiety, insomnia, drug withdrawal, and epilepsy. Bergman et al. found that 2% of pregnant women in the United States receive benzodiazepines during pregnancy (26). Antepartum exposure to benzodiazepines has been found to be associated with an increased risk for fetal cleft lip and/or cleft palate in some studies but not others. These contradictory results have led to a meta-analysis that found a small but significantly increased risk for major malformation or oral cleft alone according to data from the case-controlled studies (27). Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip. Many women of childbearing age are occupationally exposed to organic solvents. The most common female-dominated occupations are the health care professions and the clothing and textile industries. In the occupational setting, exposure to a multitude of solvents usually occurs. Because exposure usually involves more than one agent and different circumstances, adequate human epidemiological studies are difficult to interpret. The counseling of women who have been exposed to organic solvents is problematic because it is difficult to estimate the airborne or blood levels, the predominant chemicals and/or their by-products, the odor threshold, and the circumstances of exposure. Smelling organic solvents is not indicative of a significant exposure, as the olfactory nerve can detect levels as low as several parts per million, which is not necessarily associated with toxicity. Many organic solvents are teratogenic and embryotoxic in laboratory animals. The various malformations described include hydrocephaly, anencephaly, skeletal defects, cardiovascular abnormalities, blood changes, and neurodevelopmental deficits. In some of these studies, exposure levels were high enough to cause maternal toxicity, which biologically may be a source of fetal toxicity as well. Because many human studies are subject to recall and response bias, not always controlled for confounders, and not powerful, they are not confirmative enough. A metaanalysis concluded that maternal occupational exposure to organic solvents is associated with a tendency toward an increased risk for spontaneous abortions (n ⫽ 2899 patients; OR 1.25, CI 0.99–1.58) and major malformations (n ⫽ 7036 patients; OR 1.64, CI 1.16– 2.30) (28). Another prospective controlled study found that occupational exposure to organic solvents during pregnancy is associated with an increased risk for major malformations (RR 13; CI 1.8–99.5) in women who experienced symptoms of toxicity during exposure. Symptomatic exposure appears to predict higher fetal risk for malformations. More of these exposed women had previous miscarriages while working with organic solvents than did the comparison women who were not exposed (46.2% versus 19.2%) (29). Corticosteroids are used widely as agents for a variety of conditions. They are known to cross the placenta (both animal and human) and to exert teratogenic effects, inducing cleft palate in animals. Prospective follow-up studies failed to show an association between

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first-trimester exposure to corticosteroids and major birth defects. However, a meta-analysis of epidemiological studies pulled out clustering of cleft palate cases in the exposed group compared to controls. Those findings suggest a lower but yet significant teratogenic potential of corticosteroids (35). Moreover, French et al. in a prospective study followed up 477 infants who were exposed to corticosteroids at 24 weeks’ gestation or later (due to high risk of premature birth). This study showed that repeated corticosteroid courses were associated with reductions in birth weight and head circumference. At the age of 3 years, though, growth and severe disability outcomes did not appear to be related to increasing number of corticosteroid courses (36). Taking into consideration that there is evidence-based increased risk for cleft palate and birth weight, corticosteroids should not be the drugs of first choice in pregnancy. Since the risk is not as great as that associated with some other known human teratogens, those pregnant women who have an inadvertent exposure to corticosteroids should be reassured. Misoprostol, a prostaglandin E1 analog, has been indicated for use in preventing gastrointestinal lesions induced by nonsteroidal anti-inflammatory drugs and in treating duodenal and gastric ulcers. However, misoprostol has been abused because of its known side effect of inducing abortion. In Brazil, where elective abortions are illegal and misoprostol is available over the counter, it has been estimated that 10% of all pregnant women use it as abortifacient. Although a prospective observational cohort study on this population did not find an association with an increased risk for major malformations, it did find that the rate of miscarriages and fetal death were significantly higher among fetuses exposed to misoprostol in utero (37). In addition, an analytical case-control study suggested that gestational misoprostol use is associated with an increased risk for Mo¨bius sequence (38). Since the drug has been used on purpose to abort an unplanned or unwanted pregnancy, there is little to be done to protect the unborn. Cocaine use has increased rapidly over the last two decades for recreational purposes. It is now estimated that more than 10 million Americans currently use cocaine. As a rapid increase in use has occurred in women of childbearing age, much concern has been expressed about the potential effects of the drug during pregnancy. Animal studies show that cocaine affects fetal growth and brain development. The human studies confirmed that fetuses exposed to cocaine in utero have increased rates of stillbirth, smaller head circumference, lower birthweight, and increased rates of intracranial bleeding. Significant depression of interactive behavior and a less effective organizational response to environmental stimuli—suggestive of effects on neurologic integrity—were found in children of preschool age (40). The exposures’ effects on fetal development should be clearly outlined in counseling woman of reproductive age on cocaine. Environmental Contamination The common denominator of methyl mercury, carbon monoxide, and polychlorinated biphenyls (PCBs) is that their human teratogenic effect has been shown only following maternal exposure to excessive amounts. Extrapolation from these exposures to the background amounts of carbon monoxide or PCBs in the environment is not justified. Yet because the lower part of the dose-response curves has not been described, it is possible that moderate exposure may have clinical implications: heavy smokers, for example, have a carboxyhemoglobin level of 10% and even more; such levels have been shown to be associated with lower birth weights and, according to preliminary reports, with a less favorable developmental outcome (29).

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Environmental lead may differ from the compounds above; recent studies suggest adverse developmental effects even with levels within the subtoxic range (above 10 µg/ dL but below 25 µg/dL) (19). Answer Valproic acid causes neural tube defects (NTDs) in about 2% of first-trimester exposures. Maternal α-fetoproteins and ultrasound at 16 weeks of gestation are accepted as the screening test. Positive cases are tested by determination of amniotic fluid α-fetoproteins. With these diagnostic means, NTDs are detected in almost 100% of cases.

REFERENCES 1. Fabro S, Brown NA, Scialli AR. Valproic acid and birth defects. Reprod Toxicol 1983; 2:9– 11. 2. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–841. 3. Koren G. Retinoic acid embryopathy. N Engl J Med 1986; 315:262. 4. Schardein J. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985. 5. Rosa FW, Wilk AL, Kelsey FO. Vitamin A congeners. In: Sever JL, Brent RL, eds. Teratogen Update. New York: Alan R Liss, 1986, pp 61–70. 6. Jacobson SJ, Jones K, Johnson K, et al. A prospective multicenter study of pregnancy outcome following lithium exposure during the first-trimester of pregnancy. Lancet 1992; 339:530– 533. 7. Feldman Y, Koren G, Mattice D, et al. Determinants of recall and recall bias in studying drug effects in pregnancy. Teratology 1989; 40:37–46. 8. Mitchell AE, Cottler LB, Shapiro S. Effect of questionnaire design on recall of drug exposure in pregnancy. Am J Epidemiol 1986; 123:670–676. 9. Wilson JG. Environmental and Birth Defects. New York: Academic Press, 1973, p 58. 10. Rosett HZ, Weiner L. Alcohol and the Fetus. New York: Oxford University Press, 1984. 11. Graham JM, Hanson JW, Darby BL, et al. Independent dysmorphology evaluation at birth and 4 years of age for children exposed to varying amounts of alcohol in utero. Pediatrics 1988; 81:772–778. 12. Mills JL, Graubard BI. Is moderate drinking during pregnancy associated with an increased risk of malformations? Pediatrics 1987; 80:309–314. 13. Emerson DJ. Congenital malformations due to attempted abortion with aminopterin. Am J Obstet Gynecol 1982; 84:356–357. 14. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324:674–676. 15. Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1977; 129:69–103. 16. Koren G, Sharav T, Pastusz-ak A, et al. A multicenter prospective study of reproductive outcome following carbon monoxide poisoning in pregnancy. Reprod Toxicol 1991; 5:397–403. 17. Iturbe-Alessio J, Fonesca MDC, Mutchiniko Santos MA, et al. Risks of anticoagulant therapy in pregnant women with artificial heart valve. N Engl J Med 1986; 315:1390–1393. 18. Herbst AL, Uffelder H, Posbanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young girls. N Engl J Med 1971; 284:878– 881. 19. Bellinger D, Levitou A, Waternaux C, et al. Longitudinal analysis of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med 1987; 316:1037–1043.

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20. Amin-Zakil, Majeed MA, Greenwood MR, et al. Methylmercury poisoning in the Iraqi suckling infant: a longitudinal study over 5 years. J Appl Toxicol 1981; 1:210–214. 21. Harada M. Congenital Minamata disease: intrauterine methyl mercury poisoning. Teratology 1978; 18:285–288. 22. Rogan WJ, Gladen BC, Kun-Long H, et al. Congenital poisoning by polychlorinated biphenyls and their contaminants Taiwan. Science 1988; 241:334–336. 23. Rosa FW. Teratogen update: penicillamine. Teratology 1986; 22:127–131. 24. Ehrenbard LT, Chaganti RSK. Cancer in the fetal hydantoin syndrome. Lancet 1981; 2:97. 25. Hansen JW. Fetal hydantoin syndrome. Teratology 1976; 13:185–188. 26. Goldman AS, Zachai EH, Yaffe SJ. Fetal trimethadione syndrome. Teratology 1978; 17:103– 106. 27. Newman CGH. Clinical aspects of thalidomide embryopathy—a continuing preoccupation. Teratology 1985; 32:133–144. 28. Cohlan SQ. Tetracycline staining of the teeth. Teratology 1977; 15:127–130. 29. Sexton MJ, Fox NL, Hebel JR. The effects of neonatal exposure to tobacco on behavioral outcomes in three-year-old children. Teratology 1988; 37:491. 30. Sampson PD, Streissguth AP, Bookstein FL, et al. Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder. Teratology 1997; 56:317–326. 31. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life. Lancet 1992; 340:694–696. 32. Dolovich LR, Addis A, Vaillancourt JMR, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: metaanalysis of cohort and case-control studies. BMJ 1998; 317: 839–843. 33. McMartin KI, Chu M, Kopecky E, et al. Pregnancy outcome following maternal organic solvent exposure: a meta-analysis of epidemiologic studies. Am J Industr Med 1998; 34:288– 292. 34. Khattak S, Moghtader G, McMartin K, et al. Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study. JAMA 1999; 281:1106–1109. 35. Diav-Citrin O, Park L, Pastuszak A, et al. Pregnancy outcome following maternal exposure to corticosteroids: a prospective controlled cohort study and a meta-analysis of epidemiological studies. Teratology 1998; 57:188. 36. French NP, Hagan R, Evans SE, et al. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999; 180(1):114–121. 37. Schuller L, Pastuszak AL, Sanseverino MT, et al. Pregnancy outcome after abortion attempt with misoprostol. Teratology 1997; 55:36. 38. Pastuszak AL, Schuller L, Coelho KA, et al. Misoprostol use during pregnancy is associated with an increased risk for Moebius sequence. Teratology 1997; 55:36. 39. Koch S, Jager-Roman E, Losche G, et al. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome. Acta Paediatr 1996; 85(6):739–746. 40. Koren G, Nulman I, Rovet J, et al. Long-term neurodevelopmental risks in children exposed in utero to cocaine. Ann NY Acad Sci 1998; 846:306–313. 41. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42(4 suppl 5):149–160. 42. Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25(1):77–83.

5 Treatment for Epilepsy in Pregnancy Irena Nulman, Dionne Laslo, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Pregnant women with epilepsy represent 0.5% of all pregnancies. Proper seizure control is the primary goal in treating these women. The commonly used antiepileptic drugs (AEDs) are established human teratogens. Factors such as epilepsy, AED-induced teratogenicity, the patient’s genetic predisposition, and the severity of her convulsive disorder may contribute to the adverse outcome of an epileptic woman’s pregnancy. The interaction of an AED with folic acid and vitamin K metabolism may lead to an increased risk for neural tube defect (NTD) and early neonatal bleeding. Psychological, hormonal, and pharmacokinetic changes in pregnancy may escalate seizure activity. Preconceptional counseling should include patient education as to the risks of uncontrolled seizures and the possible teratogenicity of AEDs. Genetic counseling should be performed if both parents have epilepsy or the disease is inherited. Seizure control should be achieved at least 6 months prior to conception and, if clinically possible, by the lowest effective dose of a single AED according to the type of epilepsy. The new AEDs are not recommended in pregnancy and require further research to prove their safety to humans. In addition, 5 mg/day of folic acid should be administered 3 months preconceptionally and during the first trimester to prevent malformations induced by inadequate levels of folic acid. Antenatal management should include an assessment of the patient for AED-associated birth defects through detailed ultrasound examination and levels of maternal serum α-fetoproteins. Therapeutic drug monitoring should be performed monthly or as clinically indicated. If phenobarbital, carbamazepine, or phenytoin is administered, maternal vitamin K supplementation should begin 4 weeks before the expected date of delivery. In order to prevent convulsions during labor, proper seizure control should be achieved during the third trimester. A benzodiazepine or phenytoin is found to be effective for seizure cessation during labor and delivery. Vitamin K should be administered to the newborn immediately after birth. The neonate should be examined carefully for epilepsy and AED-associated dysmorphology. Advising the patient on postpartum management regarding contraception and breast-feeding will help maximize the best possible outcome for the newborn and the mother. With proper preconceptional, antenatal, and postpartum management, up to 95% of these pregnancies have been reported to show favorable results.

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Table 1 Congenital Malformations in Humans Caused by Antiepileptic Drugs Malformations Congenital heart defects Cleft lip and/or palate NTD a Genitourinary defects Cognitive impairment Dysmorphic syndrome a

Phenytoin

Valproic acid

Carbamazepine

Phenobarbital

⫹ ⫹ ⫺ ⫹ ⫹ ⫹

⫹ ⫹ ⫹ ⫹ ⫹ ⫹

⫺ ⫺ ⫹ ⫹ ⫾ ⫹

⫹ ⫹ ⫺ ⫹ ⫾ ⫹

NTD, neural tube defect; ⫾, inconclusive evidence.

Epilepsy, although not common among pregnant women, is the most common neurological disorder during gestation. Increased public awareness of the progress in diagnosis and management of epilepsy have enabled many epileptic women to bear children and manage careers (1,2). Pregnant women with epilepsy constitute 0.5% of all pregnancies, and medical professionals should be aware that—with appropriate selection of treatment and prudent preconceptional, antenatal, and postpartum management—up to 95% of these pregnancies have been reported to have favorable results (3). The evaluation of the risk and safety of pregnancy in such women is complicated by a variety of factors. Women with epilepsy are at risk for menstrual abnormalities, reproductive endocrine disorders, and reduced fertility (4). Polycystic ovaries as well as hypo- or hypergonadotrophic hypogonadism are more common in women with epilepsy than in general population. The investigators relate those abnormalities to the effect of seizures on the hypothalamic-pituitary-gonadal axis (5) and to the possible side effect of AEDs (6,7). Even when not exposed in utero to medications, infants of mothers with epilepsy have higher rates of major and minor malformations (8,9) when compared to the general population. To add to the complexity, several commonly used AEDs are established human teratogens. A large number of studies in humans is supported by results acquired from animal investigations showing a consistent increased risk for congenital malformation following AED exposure in utero. Table 1 presents congenital malformations in humans caused by AEDs for which there is consensus among scientists. No agreement has been reached among experts about which of the commonly used AEDs is safest for the unborn baby. Research indicates that the incidence of major and minor malformations is influenced by the number of anticonvulsant medications, the dose of the drug, timing of use during gestation, pharmacokinetics, and differences in metabolism (8,10). Some investigators hypothesize that anticonvulsant-induced teratogenicity occurs in genetically predisposed individuals (11). Other researchers have reported that epilepsy per se—the type and severity of the seizure disorder—also contributes to the dysmorphology (12). Considering the complex interaction between genetic and environmental factors, it is difficult to attribute congenital abnormalities in children of epileptic mothers to any single factor (13), especially in view of the lack of large enough studies with sufficient power to control for such determinants. MECHANISMS AND CLINICAL IMPLICATIONS OF TERATOGENICITY Several mechanisms have been proposed for AED-induced teratology. Some anticonvuls ant medications (e.g., phenytoin) form intermediate oxide metabolites that are known to

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be embryotoxic. Free active oxide radicals have been shown to bind to proteins and nucleic acids and may interfere with DNA and RNA synthesis. Critical amounts of free radicals may increase the risk of perinatal death, intrauterine growth retardation, and malformations (14). Scavenging enzymes capable of conjugating these free radicals to inactive substances may prevent fetal damage, and variabilities in such enzymes may explain variable fetal outcome. Unstable intermediates can also be metabolized to nonreactive hydrodiones by epoxide hydrolase. It has been proposed that fetuses with low levels of free radical– scavenging enzymes and low activity of epoxide hydrolase are at increased risk to develop malformations associated with phenytoin. Polytherapy may lead to excessive amounts of unstable epoxides, such as arene oxides, and inhibit epoxide metabolism, especially in fetuses with a genetic defect in fetal epoxide hydrolase activity (15). Evidence for increased risk for major malformations with an increase number of AEDs comes from several epidemiological studies. Lindhout et al. (16) reported a 5% risk for birth defects in children of epileptic women who took two drugs concomitantly, 10% in those who took three drugs, and more than 20% when four drugs were used. The authors reported a malformation risk of only 3% (versus 2% as in untreated epileptic women or in general population) when the seizures were controlled with only one AED. The occurrence of specific malformations depends on the timing of exposure during embryogenesis (10,17). Neural tube defects (NTDs) occur before closure of the neural tube, between days 21 and 28 after the first day of the last menstrual period (LMP). Cleft lip occurs with exposure before day 35 and cleft palate before day 70, whereas congenital heart defects occur with exposure before day 42 post-LMP (18). Exposure after the first trimester should not affect rates of dysmorphology except for the toxic effects on the brain, which develops throughout pregnancy (19). The most commonly observed major malformations are heart defects, orofacial clefting, genitourinary malformations, and NTDs (13). Minor anomalies that were described as a part of the fetal hydantoin syndrome (20) were later hypothesized to be associated with maternal epilepsy and not necessarily with the AEDs (9,21,22). We have recently detected different patterns of minor anomalies to be caused by phenytoin, carbamazepine, and untreated epilepsy (9). Because the vast majority of NTDs can be ruled out by maternal or amniotic fluid α-fetoproteins combined with ultrasound, these examinations should be routinely performed in women taking carbamazepine or valproic acid. At present some practicing neurologists consider carbamazepine to be the drug of choice in pregnancy (18). Carbamazepine poses a risk of 1% for the NTDs (23), compared to 2% for valproic acid (24). It does not cause acne, hirsutism, or facial coarsening, as does phenytoin. While the fetal hydantoin syndrome has been consistently associated with cognitive damage to some children (20), studies with carbamazepine do not suggest similar damage (25), although the literature is not consistent (26,27) and further studies at the preschool and school-age levels are needed. Koch et al. have suggested that valproic acid–exposed children had higher rates of neurological dysfunction. Serum concentrations of valproic acid at birth correlated with the degree of neonatal hyperexcitability and the degree of dysfunction when the children were reexamined at the age of 6 years (28). In a recent consensus opinion, it was suggested that the anticonvulsive medication that is most effective for the type of epilepsy and seizure control for a given patient should be used (18). Women in need of polytherapy are likely to suffer from more severe forms of epilepsy and drug-drug interaction, thus further increasing the risk for adverse pregnancy outcome (10).

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Another mechanism that has been implicated in AED-mediated teratogenicity is folate deficiency (10). Up to a 90% reduction in serum folate levels was reported in patients treated with phenytoin, carbamazepine, and barbiturates. Conversely, valproic acid did not reduce levels of folate directly but interfered with its metabolism (29,30). Folate supplementation was found to be effective in preventing several malformations, in particular NTDs. The Medical Research Council study (31) reported a 70% reduction of NTD recurrence among pregnant women who were supplemented with 4 mg of folic acid before conception and during gestation. The current recommendations call for 5 mg of folic acid per day in women being treated with valproic acid or carbamazepine (2,32). Although there are no data at present to document the efficacy of this regimen in women with epilepsy, the potential benefit of such approach outweighs the theoretical risk of high levels of folate (33). Vitamin B 12 levels should be assessed before folic acid supplementation is begun so as to avoid neurological symptoms of vitamin B 12 deficiency (34). The genetic influence of the maternal epileptic syndrome and seizure effects on fetal development in regards of congenital malformation are not well defined. A control group with a large enough sample size of unmedicated women with epilepsy was not assessed by any research group. Even if collected, such a control group might represent less severe forms of epilepsy with low frequency of seizures. The effect of seizure activity during pregnancy on fetal well-being has been investigated by several groups (35). Isolated, short seizures are generally not believed to have an adverse effect on the fetus. Spontaneous abortions, injury to the mother and fetus, fetal hypoxia, bradycardia, and antenatal death were reported (3,36,37) with repeated tonicclonic seizures, complex partial seizures, and status epilepticus. There is ample evidence that physiological changes during pregnancy may affect the duration and frequency of seizures. Seizure rates have been reported to increase in 17–37% of women with epilepsy (2,36). When seizures recur in a well-controlled woman during pregnancy, they most often appear during the first and second trimesters (33). Poor patient compliance, sleep disturbances, nausea, vomiting, and decreased levels of free (unbound) drugs are the main risk factors believed to decrease seizure control (18,38). Increases in estrogen levels during pregnancy may reduce seizure threshold levels (39). Progesterone reduces intestinal motility, thus interfering with the secretion of mucus as well as gastric pH, and it may affect drug absorption (38). Changes in seizure frequency during pregnancy may also stem from fluid and sodium retention, hyperventilation, and emotional and psychological problems (40). A potential problem in the management of seizures may also arise from altered pharmacokinetics of AEDs associated with pregnancy.

PREGNANCY-INDUCED PHARMACOKINETIC CHANGES OF ANTIEPILEPTIC DRUGS The plasma concentration of anticonvulsant drugs tends to fall during pregnancy as a result of a 50% expansion in plasma volume, decreased protein binding (41), increased clearance rate, and a tendency toward reduced patient compliance due to fears of teratogenicity. As most anticonvulsant drugs are acidic or neutral, they are highly bound to serum albumin. During late pregnancy, albumin levels fall, with a corresponding decrease in the fraction of bound drug, which causes total (unbound and protein-bound) plasma concentration to fall. The decrease in plasma protein binding makes more free drug available for

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biotransformation and clearance. Although the free AED levels fall much less than the total levels, they often do decline significantly during pregnancy (18,42). Monitoring the total plasma concentrations of AEDs can, therefore, be misleading. In complex clinical cases, therapeutic drug monitoring that can measure both protein-bound and unbound drug concentrations can be helpful. The measurement of free drug concentrations of highly bound drugs should be considered in cases where seizure control is not achieved. It should be remembered that the constant or even higher free drug concentration may provide appropriate antiepileptic control, as it is the free drug that reaches the brain. The increase in glomerular filtration rate (GFR) (43) and renal plasma flow (44) may theoretically enhance the clearance of renally excreted drugs such as gabapentin and vigabatrin. However, there are presently no studies available regarding the pharmacokinetics of these agents during human pregnancy. Carbamazepine Carbamazepine has a relatively slow absorption, with 70–80% protein binding to albumin. Hepatic metabolism is the main route of elimination, and there may be a decrease in serum concentrations during the first months of therapy as a consequence of autoinduction of metabolism. Dosage intervals and sample times are critical in interpreting serum concentrations, and large peak-trough fluctuations can be minimized by using a controlled-release formulation (45). As drug levels tend to be lower in pregnancy and bioavailability may be lower than with conventional carbamazepine, higher dosages may be required when a controlled-release medication is used (46). The concentration of the active metabolite (carbamazepine-10,11-epoxide) was reported to increase during pregnancy, possibly as a result of the increased carbamazepine metabolism and impaired conversion of carbamazepine-10,11-epoxide to carbamazepine10, 11 trans-diol. This increase is of potential importance, as the metabolite (10, 11epoxide) is believed to have pharmacological activity comparable to that of the parent drug (47). Phenytoin Phenytoin follows nonlinear pharmacokinetics and has a narrow therapeutic window (48). It is highly bound to protein (90–93%) (49,50) and cleared mainly by saturable hepatic metabolism. A substantial increase in 8-hydroxylation during pregnancy may be responsible, at least partially, for its increased clearance rate and consequently decreased serum concentration (51). Generally, a fall in total serum phenytoin concentration may cause lack of seizure control and may require increases in dose. However, as indicated above, the total concentration by itself may not indicate a fall in free drug concentrations. The decrease in the protein binding of phenytoin may be an important mechanism for decreasing total drug concentrations in pregnancy, as it is the free drug that is available for the enhanced metabolism. Valproic Acid Valproic acid is rapidly absorbed and highly protein-bound to plasma albumin (88–92%) (52). The interpretation of its pharmacokinetics is limited by large fluctuations in the concentration-time profile, wide therapeutic index, and concentration-dependent protein

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binding (53,54). Analysis of unbound valproic acid is not routine; similarly, there is no established therapeutic range. Dose adjustments during pregnancy are best made by clinical observation in combination with therapeutic drug monitoring. Divided doses are preferred to avoid high levels of valproic acid in serum (18). Phenobarbital Phenobarbital has been prescribed less frequently during the last few years because of its tendency to produce sedation and impaired cognitive function. It has a high oral bioavailability (90%) and is only 50% protein-bound. Like phenytoin and carbamazepine, it induces hepatic microsomal oxidative enzymes and may affect the therapeutic efficacy of other drugs. Neonates exposed prenatally to phenobarbital should be monitored for withdrawal symptoms for 2–6 weeks starting at day 7 of life because of the long elimination halflife of phenobarbital (100 hours).

NEW ANTIEPILEPTIC DRUGS The new AEDs that are not highly protein-bound (topiramate, felbamate, oxcarbazepine) or non–protein bound (gabapentin, vigabatrin) are eliminated from the body through renal clearance (vigabatrin, gabapentin), which has no effect on the cytochrome P-450 enzyme system (gabapentine, lamotrigine, vigabatrin), which have no antifolate effects, and which have no arene oxide metabolites and if given in monotherapy may be considered for use for women with epilepsy, but there is little information regarding their pharmacokinetics and safety during pregnancy. Animal studies have been extremely helpful in elucidating the mechanisms of adverse effects and teratogenicity of new AEDs. They are very informative in testing hypotheses and assessing nutritional and environmental factors that may interfere with or modify normal embryonic or fetal development. Although animal studies help to clarify pharmacokinetic changes in pregnancy and to define the risk factors associated with teratogenicity (55), they may be imperfect predictors of human teratogenicity. Animals may show increased sensitivity because of higher dose ranges than used in humans (tiagabine) (56) or species-specific effect (topiramate), but today reports regarding animal reproductive toxicology of new AEDs appear to be promising. Although results of animal studies regarding the teratogenic effects of the new AEDs are encouraging, it is too early tell whether such data will apply to humans. The Lamotrigine Pregnancy Registry report (September 1, 1992 through March 31, 1998) contains a description of all prenatal exposure to lamotrigine voluntarily and prospectively reported to the registry. There were no (CI, 0–12.6) birth defects in 34 neonates after first-trimester exposure to lamotrigine monotherapy and 5.6% (95% CI, 2.3–12.3) birth defects in 107 neonates after combined monotherapy and polytherapy exposure in prospective reports. In prospective reports of all trimesters of exposure combined, there were no birth defects in 37 pregnancy outcomes. The registry findings of 5.6% of birth defects in the monotherapy and polytherapy groups are not higher when compared with that expected in pregnant women with epilepsy (8,9). There was no consistent pattern of malformations among defects reported. The Lamotrigine Pregnancy Registry Advisory Committee concluded that the number of exposed pregnancy outcomes represents a sample

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of insufficient size for reaching definitive conclusions regarding safety of lamotrigine in pregnancy.

EFFECT OF ANTIEPILEPTIC DRUGS ON VITAMIN K The association between maternal anticonvulsant therapy and neonatal hemorrhage was reported 40 years ago (57) and supported by a number of subsequent studies and reports (58). These hemorrhages, which typically occur during the first 24 hours after birth (in contrast to the classic neonatal bleeding which occurs on day 2 or 3 after delivery (59), may be severe, involving the skin as well as the brain, pleural, and peritoneal cavities. The mechanism and origin of these hemorrhages is not fully understood, but vitamin K deficiency was observed in neonates exposed in utero to enzyme-inducing AEDs such as carbamazepine, phenytoin, phenobarbital, and primidone. These medications readily cross the placenta and induce liver enzymatic pathways, resulting in increased degradation of vitamin K, and they produce proteins that are induced by vitamin K absence (PIVKA). These proteins are present when vitamin K is absent in neonates exposed in utero to AEDs. The decarboxylated form of prothrombin, PIVKA II, is the most sensitive marker for vitamin K deficiency (60) and was proven informative in studies of neonatal vitamin K levels. Although vitamin K does not easily cross the placenta from the maternal to the fetal circulation, prenatal supplementation of vitamin K results in valuable effects in preventing neonatal bleeding (61). The consensus guidelines (10) regarding women receiving enzyme-inducing AEDs call for antenatal maternal vitamin K supplementation at 20 mg orally throughout the last 4 weeks of gestation and 1 mg of vitamin K parenterally to the neonate immediately after delivery. If PIVKA are found in cord blood specimens, fresh frozen plasma should be given at a dose of 20 mL/kg over a period of 1 to 2 hours (10). While some experts still debate the value of maternal antenatal supplementation during the last month of pregnancy, general agreement has been reached regarding the necessity of parenteral neonatal prophylaxis (2).

PRECONCEPTIONAL COUNSELING Women should be counseled about the potential risk of increased seizure activity during pregnancy so as to make sure that they do not avoid taking their medication. Poor compliance, resulting in increased seizure activity, has tangible risks. Preconceptional counseling should optimally begin at least 3 month before conception to allow for adequate supplementation of folic acid. Adequate patient education regarding the increased incidence of major malformations (62) and possible adverse effects of AEDs to the fetal central nervous system (25,63) should be achieved. Genetic counseling should be offered if both partners have epilepsy or the epileptic disorder is inherited. Gradual drug discontinuation (over at least 3 months) should be considered if the patient has been seizure-free for 2 or more years. An epileptic woman who is planning a pregnancy should be encouraged to quit smoking, maintain good nutrition, and get enough sleep (18). If treatment with anticonvulsant medications cannot be avoided, proper seizure control should be achieved by the lowest effective dose of the single AED that best controls seizures in the given patient or, alternatively, pregnancy should be delayed until seizure

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control is reached. It should be remembered that polytherapy and/or higher daily doses of AEDs are associated with higher rates of congenital malformation. If valproic acid is indicated, divided doses are preferred to avoid high levels of valproic acid in plasma (18,64). The combination of valproic acid, carbamazepine, and phenobarbital has been reported to be more teratogenic than other combinations (33). Folate supplementation at 5 mg/day should start 3 months before conception and continue until the end of the first trimester. If possible, serum folate levels should be monitored to confirm sufficient supplementation.

ANTENATAL MANAGEMENT More than 50% of all pregnancies are unplanned (65); if the pregnancy is diagnosed while the woman is seizure-free, there is no proven benefit to changing the patient’s drug because any morphological teratogenic effects will be irreversible by 10 weeks of gestation (18). The patient should be advised regarding appropriate prenatal diagnosis for AED-associated abnormalities. For example, targeted fetal ultrasound examination at 18 weeks can diagnose up to 95% of fetuses with open NTD (66,67) as well as other anomalies (68). Early transvaginal ultrasonography at 11–13 weeks to assess for NTD is presently possible (33). Detailed sonographic imaging of the fetal heart at 18–20 weeks, followed by fetal echocardiography, which can identify up to 85% of cardiac defects. Imaging of the fetal face for cleft lip at 18–20 weeks may be performed, but the sensitivity of this assessment has yet to be established (33). Amniocentesis with amniotic fluid α-fetoprotein and acetylcholinesterase may support blood serum findings caused by structural malformations. Epoxide hydrolase activity in amniocytes has been suggested to predict those fetuses at risk for phenytoin-mediated anomalies; however, this test has not yet been confirmed for routine clinical use. Vitamin K supplementation of the mother is recommended, as detailed above. Optimally, therapeutic drug monitoring should be performed every 1–2 months or more frequently if seizure control is not achieved.

LABOR, DELIVERY, AND BIRTH Tonic-clonic seizures occur during labor or after delivery in 1–2% of women with epilepsy (18). Monitoring plasma AED levels during the third trimester and regular administration of medication(s) are essential to prevent seizures due to inappropriately low serum concentrations (3). Convulsive seizures at the time of labor and delivery are commonly treated with intravenous administration of benzodiazepines or phenytoin. Intravenous administration of phenytoin should be given under cardiac monitoring to detect possible dysrhythmias (66). Emergency cesarean section is often performed in the case of status epilepticus or when there are repeated tonic-clonic, psychomotor, or absence seizures (37). Obstetric intervention in the form of induction of labor, mechanical rupture of membranes, forceps delivery, or cesarean section is more common among women with epilepsy, as are such obstetric complications as vaginal bleeding, anemia, and preeclampsia (3).

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MANAGEMENT DURING THE PUERPERIUM Vitamin K should be administered to the newborn immediately after birth. The neonate should be examined carefully for AEDs and epilepsy-associated dysmorphology. If the neonate was exposed to phenobarbital or primidone, observation for withdrawal symptoms should be performed during the first 7 months of life. Maternal anticonvulsant drug levels should be carefully maintained with appropriate changes in dosage, bearing in mind that the decreased clearance rate postnatally may be associated with toxicity. The patient should be counseled regarding postpartum contraception. The use of oral contraceptive agents is not contraindicated in women with epilepsy (67). For patients treated with hepatic enzyme–induced anticonvulsants, a higher dose of estrogen (50 µg) in combination with an oral contraceptive pill will be needed to compensate for the higher rate of clearance of the hormone. The issues of breast-feeding should also be discussed with the mother, as most women with epilepsy can breast-feed. Phenytoin and valproic acid are highly proteinbound; therefore, only low levels of these drugs are present in breast milk. Carbamazepine and phenobarbital are present in higher concentrations. Because of the sedative effect of phenobarbital, breast-feeding by women taking this drug is not recommended. When the mother is taking phenobarbital and breast-feeding, the infant must be monitored for the risk of lethargy and poor suck.

CONCLUSIONS Proper seizure control is the primary goal in treating women with epilepsy. Patients should understand the risks associated with uncontrolled seizures as well as the teratogenicity of the anticonvulsive medication in question. If AEDs cannot be avoided, a first-line drug for the seizure type should be used at the lowest effective dose. Judicious preconceptional, antenatal, and postpartum management leads to favorable maternal and neonatal outcome in the vast majority of patients.

REFERENCES 1. Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980; 21(3):261–271. 2. Byrne B. Epilepsy and pregnancy. Ir Med J 1997; 90:173–174. 3. Yerby MS. Pregnancy and epilepsy. Epilepsia 1991; 32(suppl 6):S51–S59. 4. Medeiros YS, Calixto JB. Inhibitory effect of diphenylhydantoin on myometrium from pregnant women in vitro: A comparative study with nicardipine and trifluoperazine. Pharmacol Res 1990; 22(5):597–603. 5. Nappi C, Meo R, Di Carlo C, et al. Reduced fertility and neuroendocrine dysfunction in women with epilepsy. Gynecol Endocrinol 1994; 8:133–145. 6. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Menstrual disorders in women with epilepsy receiving carbamazepine. Epilepsia 1995; 36:676–681. 7. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329:1383–1388. 8. Kaneko S. Antiepileptic drug therapy and reproductive consequences: functional and morphological effects. Reprod Toxicol 1991; 5(3):179–198.

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9. Nulman I, Scolnik D, Chitayat D, et al. Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy and medications. Am J Med Genet 1997; 68(1):18–24. 10. Kaneko S, Otani K, Fukushima Y, et al. Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia 1988; 29:459–467. 11. Janz D. On major malformations and minor anomalies in the offspring of parents with epilepsy: review of the literature. In: Janz D, Dam M, Richeus A, et al., eds. Epilepsy, Pregnancy, and the Child. New York: Raven Press, 1982:211–222. 12. Majewski F, Steger M, Richter B, et al. The teratogenicity of hydantoins and barbiturates in humans, with considerations on the etiology of malformations and cerebral disturbances in the children of epileptic parents. Int J Biol Res Pregnancy 1981; 2(1):37–45. 13. Dansky LV, Finnell RH. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades. 2: Human studies. Reprod Toxicol 1991; 5(4):301–335. 14. Finnel RM, Buehler BA, Kerr BM, et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992; 42(4 suppl 5):25–31. 15. Buehler BA, Delimout D, Van Waes M, et al. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990; 322(22):1567–1572. 16. Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25(1):77–83. 17. Sulik KK, Johnston MC, Daft PA, et al. Fetal alcohol syndrome and DiGeorge anomaly: critical ethanol exposure periods for craniofacial malformations as illustrated in an animal model. Am J Med Genet 1986; (suppl 2):97–112. 18. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42(4 suppl 5):149–160. 19. Spreen O, Tupper D, Risser A, et al. Chronology of neural development. In: Human Developmental Neuropsychology. New York: Oxford University Press, 1984, pp 26–28. 20. Hanson JW, Myrianthopoulos NC, Harvey MA, et al. Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 1976; 89(4):662–668. 21. Gaily E, Granstrom ML. Minor anomalies in children of mothers with epilepsy. Neurology 1992; 42(4 suppl 5):128–131. 22. Gaily E, Granstrom ML, Hiilesmaa V, et al. Minor anomalies in the offspring of epileptic mothers. J Pediatr 1988; 112:520–529. 23. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324(10):674–677. 24. Omtzigt JG, Los FJ, Grobbee DE, et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992; 42(4 suppl 5):119–125. 25. Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1993; 271(10):767–770. 26. Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996; 75(6):517–520. 27. Jones KL, Lacro RV, Johnson KA, et al. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320(25):1661–1666. 28. Koch S, Jager-Roman E, Losche G, et al. Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological oncome. Acta Paediatr 1996; 85(6):739–746. 29. Ogawa Y, Kaneko S, Otani K, et al. Serum folic acid levels in epileptic mothers and their relationship to congenital malformations. Epilepsy Res 1991; 8(1):75–78. 30. Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992; 42(4 suppl 5):32–42. 31. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338(8760):131–137.

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32. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996; 334(3):168–175. 33. Malone FD, D’Alton ME. Drugs in pregnancy: anticonvulsants. Semin Perinatol 1997; 21(2): 114–123. 34. Shuster EA. Epilepsy in women (Symposium on Epilepsy—Part VII). Mayo Clin Proc 1996; 71(10):991–999. 35. Yerby M, Koepsell T, Daling J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia 1985; 26:631–635. 36. Lopes-Cendes I, Andermann E, Candes F, et al. Risk factors for changes in seizure frequency during pregnancy of epileptic women: A cohort study (abstr). Epilepsia 1992; 33(suppl 3): 57. 37. Hiilesmaa VK. Pregnancy and birth in women with epilepsy. Neurology 1992; 42(4 suppl 5): 8–11. 38. Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet 1997; 33(5):328–343. 39. Morrell MJ. Hormones, reproductive health and epilepsy. In: Wyllie E, ed. The treatment of Epilepsy: Principles and Practice, 2nd ed. Baltimore: Williams & Wilkins, 1997. 40. Koren G. Changes in drug disposition in pregnancy and their clinical implications. In: Koren G, ed. Maternal-Fetal Toxicology: A Clinician’s Guide, 2nd ed. New York: Marcel Dekker, 1994, pp 3–13. 41. Pirani BB, Campbell DM, MacGillivray I. Plasma volume in normal first pregnancy. J Obstet Gynaecol Br Commonw 1973; 80(10):884–887. 42. Yerby MS, Freil PN, McCormick K. Antiepileptic drug disposition during pregnancy. Neurology 1992; 42(suppl 5):12–16. 43. Davison JM, Hytten FE. Glomerular filtration during and after pregnancy. J Obstet Gynaecol Br Commonw 1974; 81(8):588–595. 44. Dunihoo DR. Maternal Physiology. In: Dunihoo DR, ed. Fundamentals of Gynecology and Obstetrics. Philadelphia: Lippincott, 1992, pp 280–284. 45. Yerby MS, Friel PN, Miller DQ. Carbamazepine protein binding and disposition in pregnancy. Ther Drug Monit 1985; 7(3):269–273. 46. Tomson T, Almkvist O, Nilsson BY, et al. Carbamazepine-10, 11-epoxide in epilepsy: a pilot study. Arch Neurol 1990; 47(8):888–992. 47. Bourgeois BFD, Wad N. Individual and combined antiepileptic and neurotoxic activity of carbamazepine and carbamazepine-10, 11-epoxide in mice. J Pharmacol Exp Ther 1984; 231: 411–415. 48. Armijo JA, Cavada E. Graphic estimation of phenytoin dose in adults and children. Ther Drug Monit 1991; 13(6):507–510. 49. Brodie MJ. Management of epilepsy during pregnancy and lactation. Lancet 1990; 336(8712): 426–427. 50. Perucca E, Richens A, Ruprah M. Serum protein binding of phenytoin in pregnant women. Proc Br Pharmacol Soc 1981; 11:409P–410P. 51. Bologa M, Tang B, Klein J, et al. Pregnancy-induced changes in drug metabolism in epileptic women. J Pharmacol Exp Ther 1991; 257(2):735–740. 52. Thomson AH, Brodie MJ. Pharmacokinetics optimisation of anticonvulsant therapy. Clin Pharmacokinet 1992; 23(3):216–230. 53. Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate: a 5-year follow-up study of 100 children with epilepsy. Acta Neurol Scand 1982; 65(5):504– 523. 54. Pugh CB, Garnett WR. Current issues in the treatment of epilepsy. Clin Pharmacol 1991; 10(5):335–358. 55. Wilson JG. Current status of teratology—general principles and mechanisms derived from animal studies. In: Wilson JG, Fraser FC, eds. Handbook of Teratology, vol. 1. New York: Plenum Press, 1977, pp 47–74.

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56. Gabitril package insert, Abbott Laboratories. September 2, 1998. 57. Van Creveld S. Nouveau aspects de la maladie he´imorragique du nouveau-vie. Arch Fr Pediatr 1958; 6:721–735. 58. Moslet U, Hansen ES. A review of vitamin K, epilepsy and pregnancy. Acta Neurol Scand 1992; 85(1):39–43. 59. Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemostas 1995; 21(3):317–329. 60. Anai T, Hirota Y, Oga M, et al. PIVKA-II (protein induced by vitamin K absence-II) status in newborns exposed to anticonvulsant drugs in utero. Nippon Sanka Fujinka Gakkai Zasshi 1991; 43(3):347–350. 61. Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Supplementation for vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993; 168(3 part 1):884–888. 62. Nakane Y, Okuma T, Takahashi R, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 1980; 21(6):663–680. 63. Fujioka K, Kaneko S, Hirano T, et al. A study of the psychomotor development of the offspring of epileptic mothers. In: Sato T, Shinagawa S, eds. Antiepileptic Drugs and Pregnancy. Amsterdam: Excerpta Medica, 1984, pp 196–206. 64. Samren EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997; 38:981–990. 65. Sophocles AM, Brozovich EM. Birth control failure among patients with unwanted pregnancies: 1982–1984. J Fam Pract 1986; 22(1):45–48. 66. American Collage of Obstetricians and Gynecologists. Seizure Disorders in Pregnancy. ACOG educational bulletin No. 231, December 1996. Committee on Educational Bulletins of the International Journal of Gynaecology and Obstetrics. Int J Obstet Gynaecol 1997; 56(3):279– 286. 67. Mattson RH, Cramer JA, Darney PD, et al. Use of oral contraceptives by women with epilepsy. JAMA 1986; 256(2):238–240. 68. Koren G, Nulman I. Fetal malformations associated with drugs and chemicals: visualization by sonography. In Koren G, ed. Maternal-Fetal Toxicology: A Clinician’s Guide. 2nd ed. New York: Marcel Dekker, 1994, pp 627–639.

6 The Safety of Commonly Used Antidepressants in Pregnancy Gideon Koren, Anne Pastuszak, Sheila Jacobson, and Irena Nulman The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A woman with manic-depressive disorder, dependent on lithium, has just found out she is pregnant. She considers termination of pregnancy, a move that was supported by two other doctors. What should be your advice?

INTRODUCTION A substantial number of women of reproductive age need antidepressant therapy, and many of the conditions represented cannot be well controlled without such medications during pregnancy. The information available on the reproductive safety of the major classes of antidepressants has been sparse. Recently, two large prospective studies, the result of a collaboration by several teratogen information services, have shed light on pregnancy outcome following first-trimester exposure to lithium, tricyclic antidepressants, and fluoxetine. This chapter reviews the results of these studies and their practical implications.

LITHIUM IN PREGNANCY It is estimated that 0.1% of pregnant women use lithium (1). This drug crosses the placenta, and concentrations are much the same in maternal and cord serum. Therapeutic and supratherapeutic doses of lithium have caused craniofacial defects in rodents (2), but malformations have not been demonstrated in primates (3). Since 1970, isolated instances of congenital anomalies (specifically Ebstein’s anomaly) as well as normal outcomes have been reported in association with lithium exposure during pregnancy (4–6). In 1968 the Danish Registry of Lithium Babies was established to obtain further information about infants and children who had been exposed to lithium during the first trimester of pregnancy. Data collected by a voluntary retrospective reporting system included cases from Scandinavia, Canada, and the United States. Of a total of 225 cases 85

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reported by 1983, 25 (11%) had major congenital malformations (7). Eighteen (72%) of these patients had cardiac anomalies; of these, one-third were Ebstein’s anomaly, which is a rare congenital heart defect with an incidence of 1 in 20,000 in the general population. On the basis of this information, lithium has become widely regarded as a human teratogen. Voluntary retrospective reports of reproductive outcome have many serious methodological shortcomings. In particular, there is evidence that bias toward reporting of adverse outcomes is common (8). With an unknown denominator (total number of exposures), an increased risk cannot be defined. Furthermore, two case-control studies (1,9) have not demonstrated increased use of lithium in mothers giving birth to children with Ebstein’s anomaly [although one of them reported Ebstein’s anomaly after exposure to lithium (9)], and a retrospective study (10) of 350 women with major affective disorders showed no difference in outcome between infants exposed to lithium and those who had been exposed to other psychotropic drugs, although four cardiac defects were seen in 59 lithium-exposed infants and none in the 38 controls (10). To evaluate the teratogenic potential of lithium in pregnancy, we conducted a controlled, prospective study of women using lithium who contacted teratogen information services in two American and two Canadian university programs (11). Patients and Methods We enrolled 148 women who called one of four teratogen information services to obtain information about the potential risks of therapeutic drugs during pregnancy: these centers were Motherisk (Toronto), the California Teratogen Information Service (CTIS), the Philadelphia Pregnancy Healthline, and Fetal Risk Assessment from Maternal Exposure (FRAME) (London, Ontario). The prospective collection of the study and follow-up data were consistent between centers. Motherisk and FRAME referred patients to a weekly clinic, where at interview a physician obtained information about drugs or other chemicals taken during or before pregnancy, including indication, dose, toxicity of the drug and its toxic effects, and monitoring. A medical and obstetric history was also elicited, as well as occupational exposures and family history. At this visit advice was offered and appropriate referrals were made. After the expected date of delivery, each woman was telephoned and a follow-up history of the pregnancy was obtained. The mother was asked for details about pregnancy outcome, perinatal complications, birth weight, physical findings, and developmental milestones. In addition, the physician caring for the baby was contacted to confirm this information and to provide a written report of the delivery and health status of the child. The CTIS and the Philadelphia Pregnancy Healthline obtained all initial information by telephone interview. In San Diego, postnatal follow-up was done by one of the investigators in the clinic, who collected details of delivery and postnatal course. The Philadelphia Pregnancy Healthline obtained all follow-up data by telephone; detailed records from physicians caring for the babies were also obtained. Patient enrollment into the study began with the initiation of each program: CTIS, 1979; Philadelphia Pregnancy Healthline, 1984; Motherisk, 1985; FRAME, 1989 until February 1991. All pregnant women who called and reported lithium ingestion during part or all of their first trimester were prospectively enrolled. Lithium exposures as early as 3 weeks’ gestation were included, since the half-life of lithium is long (2.4 days) in patients receiving long-term therapy (11). Thus detectable serum concentrations can still be present 2

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weeks after cessation of treatment. All patients were offered fetal echocardiography at 18 weeks’ gestation to rule out cardiac anomalies. If prenatal echocardiography had not been done, infants were referred for postnatal echocardiographs. Patient enrollment was as follows: CTIS, 101; Motherisk, 25; Philadelphia Pregnancy Healthline, 19; and FRAME, 3. Controls were women who were seen at the Motherisk clinic for counseling about drugs that are not known or suspected to be teratogenic. Each study patient was matched with a woman of similar age (to within 2 years). Prenatal and postnatal evaluation was the same as described for the Motherisk program. Echocardiography was not done in this group, since this procedure was not deemed to be medically or ethically justifiable. We used Marden’s definition of a major anomaly—that is, one that has an adverse effect on either the function or social acceptability of the individual (13). We used chi-square analysis to compare the frequency of malformations in study and control groups and the frequency of smoking in the two groups. We calculated risk ratios and 95% confidence intervals (Taylor series) to establish the relation between lithium exposure and malformations, then for cardiac malformations and Ebstein’s anomaly. Birth weight, gestational age, and developmental milestones were compared with Student’s t-test for paired data. Correlations between values were studied by least-squares regression analysis. Results Of the 148 subjects, 10 were lost to follow-up postnatally; however, they were included in part of the analysis because all had had prenatal echocardiography. A total of 68 patients had echocardiographs (46%). Maternal age ranged from 15–40 years (mean 30, SD 5 years). All patients were receiving lithium for major affective disorders. The mean daily lithium dose was 927 (SD 340) mg; the range was 50–2400 mg. Pregnancy outcome did not differ between patients and controls with respect to the total number of live births, frequency of major anomalies, spontaneous or therapeutic abortions, ectopic pregnancy, and prematurity (Table 1). Three major congenital malforTable 1

Pregnancy Outcomea

Outcome

Lithium (n ⫽ 138)

Control (n ⫽ 148)

Normal live births Full-term Premature (⬍36 weeks) Congenital defects Spontaneous abortion Therapeutic abortionb Stillbirth Ectopic pregnancy Unknown

105 99 6 3 13 15 1 1 10

123 116 7 3 12 9 0 1 0

a

(76%) (72%) (44%) (3%) (9%) (10%)

(7%)

(83%) (785) (5%) (2%) (8%) (6%)

Ectopic pregnancies and spontaneous and therapeutic abortions are expressed as percentages of all outcomes (n ⫽ 148). Stillbirths and normal live births are expressed as percentages of known outcomes (n ⫽ 138). Congenital defects are expressed as a percentage of all live births. b One therapeutic abortion because of Ebstein’s anomaly diagnosed in utero.

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Table 2 Comparison of Sample Characteristics in Lithium-Exposed and Control Groups: Mean (SD) and Range

Birth weight, grams Gestational age, weeks Maternal age, years

Lithium group

Control group

p-value

3475 (660) (539–5024) 39.1 (3.0) (23–42.4) 30.0 (5.3) (15–40)

3383 (566) (950–4896) 39.2 (2.5) (26–43) 29.8 (5.3) (16–40)

0.026 0.562 0.614

mations occurred in each group: 2.8% of live births in the lithium group and 2.4% in controls. The 10 pregnancies for which final outcome was not known were not included in this part of the analysis. There were four sets of twins in the lithium group; one pair was born at 23 weeks’ gestation, and both infants died shortly after birth as a result of complications of prematurity. There was one set of twins in the control group. Two children in the lithium group had neural tube defects: one had hydrocephalus and meningomyelocele and had also been exposed to carbamazepine during the first trimester; the other had spina bifida and tethered cord. A third infant (a twin) was born at 23 weeks, had meromelia, and died shortly after birth. One fetus in the lithium group had a severe form of Ebstein’s anomaly; this was diagnosed at 16 weeks’ gestation and the pregnancy was terminated. This fetus had also been exposed to fluoxetine, trazodone, and l-thyroxine in the first trimester. In the controls, one child had a ventricular septal defect, one had congenital hip dislocation, and one had cerebral palsy and torticollis. The risk ratio for all congenital defects was 1.2 (95% confidence interval 0.2–5.7) when only live births were compared. When the case of Ebstein’s anomaly was included (since this pregnancy probably would have gone to term if the anomaly had not been detected), the risk ratio became 1.5 (0.4–6.7). The risk ratio for cardiac anomalies was 1.1 (0.1–16.6). The mean age at which postnatal follow-up was done in the lithium-exposed group was 61 (SD 87.5) weeks (range, 1 week–9 years). Lithium-exposed infants weighed a mean of 92 g more than controls ( p ⫽ 0.01) at birth (Table 2). Gestational age and frequency of prematurity did not differ between the groups. Because all controls were enrolled in Toronto, we examined whether the difference in birth weight was related to geographic factors in the various study groups. However, when the Motherisk data were analyzed separately, the difference in birth weight persisted and remained significant ( p ⫽ 0.018). There were more cigarette smokers among the women using lithium than among the controls (31.8 versus 15.5%; p ⫽ 0.002). Data on attainment of major developmental milestones (smiling, lifting head, sitting, crawling, standing, talking, and walking) were available for 21 lithium-exposed patients enrolled by Motherisk and 1 patient enrolled by FRAME. Study and control groups did not differ in age of attainment of any of the milestones (data not shown). Discussion Discontinuation of lithium therapy can have devastating results for the mental and physical health of young women with major affective disorders. On the other hand, many women

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who inadvertently conceive while on lithium therapy choose to terminate pregnancy because of a perception of teratogenic risk based on the unfounded retrospective reports. As far as we are aware, this is the first prospective study of infants exposed to lithium during the first trimester of pregnancy. The recent establishment of teratogen information services has provided a very good opportunity to investigate large numbers of patients exposed to substances of interest within short periods. Our service is specifically designed to counsel pregnant women, and we are contacted directly by those exposed to lithium, almost invariably at the time of exposure. Accurate information about time of exposure and drug dosage is crucial to assess any causal relation between any xenobiotic and outcome. Moreover, information about other risk factors, such as illicit drugs and smoking, is obtained prospectively. Case-control studies rely on maternal recall, which can be poor and is subject to bias (14). Our results accord with those of earlier prospective cohort and case-control studies (1,9,10), suggesting that the risk of congenital defects in babies after lithium exposure is lower than that reported by the Danish Registry of Lithium Babies. The registry investigators claim that lithium is associated with a 10% incidence of cardiac malformations and a 3% incidence of Ebstein’s anomaly; they believe that the drug is a major teratogen. Because the registry is a voluntary, retrospective database, neither the number of cases not reported nor the number of unreported normal outcomes of lithium exposure is known. Our results cannot rule out an association between lithium and major anomalies, even though there was no difference in the number of anomalies between the study and control groups. Since Ebstein’s anomaly is very rare, a much larger sample size would be needed to define the real risk of this abnormality. That the single cardiac malformation in our study group was Ebstein’s anomaly indicates that lithium as a cause of this disorder is rare. Since fewer than half our patients had echocardiographs, some cardiac malformations might have been missed, including milder forms of Ebstein’s anomaly. This might also be true for the control group, in which no echocardiographs were done. Since all patients were examined by a physician, however, it is unlikely that clinically significant lesions were missed. The infant with hydrocephalus and meningomyelocele who was exposed to lithium in utero had also been exposed during the first trimester to carbamazepine, a drug that has been associated with an increased incidence of neural tube defects (14). The fetus that had Ebstein’s anomaly was also exposed in the first trimester to several other drugs, none of which has been associated with cardiac anomalies; lithium remains the most likely causative factor. The teratogenicity of lithium might be dose-related, as has been shown in animals (2). The doses used at the time the Danish registry data were obtained could have been higher than present recommended doses. This could explain the discrepancy between their results and ours. However, there is no evidence that lithium doses have changed during this time (16). In addition, lithium has a very narrow therapeutic window, above which toxic effects are common. Most patients are prescribed the highest dose they can tolerate that will maintain serum concentrations in the therapeutic range (15). We therefore believe that a dose relation does not account for the different findings of the two studies. The probable reason is the different methods of data collection used by the two groups. Although the difference in the number of elective abortions was not statistically significant between the groups, the rate was higher in the lithium group than in the controls

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(10 versus 6%). The increased trend to voluntary termination might have been due to the perceived teratogenic risk of lithium, since women who believe that they are at such risk are more likely to terminate their pregnancies (17). Counseling provided by the teratogen information services and referral for appropriate screening tests such as echocardiography might have reduced the perception of teratogenic risk of lithium. As a result, the number of terminations in our study was probably lower than it would have been; thus the figures for elective abortion are higher than ours in centers where no such counseling is provided. American Medicaid data indicate termination rates exceeding 50% in women exposed to lithium during pregnancy (F. Rosa, personal communication). The babies exposed to lithium were heavier than controls, and fetal macrosomia has been associated with lithium therapy (18,19). Yoder (19) proposed that lithium may have an insulin-like effect on carbohydrate metabolism. We did not find that demographic variations contributed to the difference in weight between the groups, and the proportion of diabetic patients did not differ. In addition, the proportion of cigarette smokers in the lithium group was twice that in the controls. One would therefore expect the babies in the lithium group to be smaller than those in the control group. Hence, the effect of the drug on birth weight might be even larger than is evident in this study. Although only a few babies were assessed for developmental milestones, no differences were seen, which is consistent with findings of earlier reports (20). We conclude on the basis of our results and those of others (1,9,10) that lithium is not a major human teratogen. We believe that women with major affective disorders who wish to have children may continue lithium during pregnancy and do not need to terminate pregnancy provided that level 2 ultrasound and fetal echocardiography are done to rule out the presence of major cardiac anomalies. Fluoxetine and Tricyclic Antidepressants During the First Trimester Fluoxetine (Prozac) is a new antidepressant that causes selective inhibition of neuronal serotonin (5-HT) uptake. Presently, the drug is used by millions of patients with major depression in North America. The manufacturer (Eli Lilly Ltd.) suggests that the drug not be given to women of childbearing potential, since the safe use of fluoxetine during human pregnancy has not been conclusively established. In rats and rabbits treated with 9 and 11 times the maximum daily human dose, fetal morphology and pregnancy outcome were not shown to be compromised (21). Experiential data have so far been limited to voluntary reports collected by the manufacturer. In a retrospective analysis of 38 women who reported first-trimester exposure to fluoxetine, there were 16 normal live births, 8 elective abortions, 3 miscarriages, 9 cases that were lost to follow-up, 1 infant born with hepatoblastoma, and 1 twin pregnancy with 1 miscarriage. In a postmarketing report summarizing the outcome of 226 prospective spontaneous reports of pregnant patients exposed to fluoxetine, outcome data were available for only 113 babies. There were 64 normal live births, 8 premature births, 18 elective abortions, 16 miscarriages, 3 twin pregnancies, and 1 infant born with transposition of the great arteries, although fluoxetine exposure occurred in the second trimester, well after embryological formation of the arteries (22). Voluntary reports collected by manufacturers regarding gestational exposures to drugs are fraught with major methodological problems. The original sources of these data are unknown and are not compared to appropriate control groups. Moreover, the quality

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of ascertainment and follow-up is often poor, and—as documented above (22)—there is an almost 50% loss of follow-up data. There is ample evidence that abnormal outcome is more likely to be reported voluntarily; thus, in the absence of a denominator of all pregnant women treated with fluoxetine, it is impossible to ascertain the frequency of defects associated with this drug and to compare them with the baseline risk in the general population. The recommendation that women of reproductive age not conceive while on fluoxetine totally ignores that almost half the pregnancies in North America are unplanned. Indeed, during the last few years, teratology information services throughout North America have received hundreds of calls from pregnant women who conceived in an unplanned manner while on fluoxetine therapy. Following the success of the first collaboration by teratology information services that investigated the first-trimester use of lithium (11), we undertook to collect prospectively data on pregnancy outcome following fluoxetine in the first trimester and compare these to two control groups, one exposed to tricyclic antidepressants and the other to nonteratogens. Patients and Methods Our prospective collaborative study enrolled pregnant women who contacted one of four teratogen information services (TIS) requesting counseling about the teratogenic potential of fluoxetine. The participating centers were Motherisk (Toronto), Pregnancy Healthline (Pennsylvania), Pregnancy and Risk Information Service (New Jersey), and Pregnancy RiskLine (Utah). All women contacting these services during pregnancy were included. Prospective collection of information and follow-up data were consistent between centers, although collection was performed in different manners. Motherisk referred all women concerned about first-trimester fluoxetine exposure to a weekly clinic, during which information was obtained in an interview with a team physician regarding indication, dose, toxicity, and dates of initiation and discontinuation. Four women were referred to Motherisk by a geneticist outside Toronto who collected the cases prospectively in a similar manner. In addition, obstetrical, medical, genetic, and drug exposure history was obtained from both the mother and biological father of the fetus. Eight to 12 months after delivery details about the outcome of pregnancy, birth weight, presence or absence of birth defects, and perinatal and neonatal complications were documented. All follow-up information was corroborated by written documentation from the child’s physician. Pregnancy Hotline, Pregnancy and Risk Information Service, and Pregnancy RiskLine recorded maternal information similar to that gathered by Motherisk by telephone interviews. Postnatal followup data, similar to those collected in Toronto, were obtained by telephone in Pennsylvania, Utah, and New Jersey. The Pennsylvania Service also used follow-up cards received in the mail. Photocopies of each center’s fluoxetine cases were sent to Toronto for matching and statistical analysis after all names and addresses had been deleted. Each woman exposed to flf1flf1fluoxetine during the first trimester was age-matched (⫾2 years) to two controls closest in date to the date of consultation of the fluoxetine case. The first control group consisted of pregnant women who voluntarily sought counseling at Motherisk after first-trimester exposure to tricyclic antidepressants; the second control group consisted of pregnant women who voluntarily sought counseling at Motherisk regarding exposure to a nonteratogen. A nonteratogen is defined as a medication or environmental agent that has been proven in large studies not to increase the baseline teratogenic risk (e.g., acetaminophen,

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penicillins, dental x-rays). Both control groups were selected from our computerized database. Although the primary outcome of interest was the rate of birth defects in pregnancies exposed to fluoxetine as compared to the tricyclic and nonteratogen groups, maternal characteristics (age, obstetrical history, alcohol and cigarette use), pregnancy outcome (maternal weight gain, method of delivery, use of forceps, rates of live births, elective abortions, and miscarriages) and offspring characteristics (gestational age and birth weight) were also compared. Chi-square analysis and Fisher’s exact test were used to compare proportions, Student’s t-test was employed to compare paired data (two groups) and analysis of variance (three groups) to compare continuous data. Wilcoxon sign-rank (two groups) and Kruskal-Wallis (three groups) were procedures used to compare data that did not follow normal distribution. Data are expressed as mean plus or minus standard deviation. Results The participating centers followed prospectively a total of 128 pregnant women treated with fluoxetine for depression during the first trimester (45 in Toronto, 44 in Philadelphia, 21 in New Jersey, and 18 in Utah). The mean daily maternal dose of fluoxetine was 25.8 ⫾ 13.1 mg (range, 10–80 mg/day) (n ⫽ 122), and mean weight-adjusted dose (for 75 cases where maternal weight was available) was 0.19 ⫾ 0.1 mg/kg. The drug was taken during the first trimester by all 128 women, during the first and second trimesters by 2, and throughout the pregnancy by 6. Because of the limited number of patients taking tricyclic antidepressants in the Motherisk database suitable for matching (within 2 years of maternal age), our reported data are divided into comparisons between 128 fluoxetine cases and 128 age-matched nonteratogen controls (NTC), and comparisons among 74 fluoxetine cases, 74 age-matched tricyclic antidepressant (TCA) cases, and 74 age-matched NTC. There were no differences in any of the characteristics of the women using fluoxetine across the four participating centers. There was no difference in the rate of major birth defects when the live births exposed to fluoxetine were compared to the NTC live births (2 versus 1.8%, p ⫽ 0.38) or when the smaller fluoxetine groups was compared to both of its controls [3.4 versus 0 (TCA) versus 3% (NTC), p ⫽ 0.8] (Table 3). Table 4 details all major and minor birth defects as well as neonatal complications. There was no statistical difference in pregnancy outcome, maternal weight gain during pregnancy, gestational age at delivery, birth weight, or use of forceps at delivery whether the fluoxetine group was compared to NTC only or to both age-matched control groups (Table 3). Conversely, however, there was a tendency for a higher percentage of miscarriages in the 128 fluoxetine patients compared with NTC, but it did not reach statistical significance [14.8 versus 7.8% reported rate (RR), 1.9; 95% confidence interval (CI), 0.92– 3.92]. A similar trend was observed in the smaller sample size, although the TCA also had a miscarriage rate similar to the fluoxetine group (13.5 versus 12.2 versus 6.8%). There was no statistical difference between rates of vaginal or cesarean section deliveries between the fluoxetine group and age-matched controls. Infants born to depressive women of both groups (fluoxetine and TCA) tended to have more neonatal complications, although when looked at individually, none of those recorded was significantly more common (Table 4). Because one patient from Utah was gravida 33 (para 9, miscarriages 23, likely as a result of diagnosed maternal trisomy 8), obstetrical history data deviated from a normal Gaussian distribution and consequently nonparametric analysis was performed. Excluding

Pregnancy Outcome in Cases (Fluoxetine-Exposed) and Age-Matched Controls (TCA and NTC)

Characteristics Outcome Live birth Elective abortion Spontaneous abortion Major congenital anomalies Weight gain (kg) Gestational age (weeks) ⬍37 weeks ⬎42 weeks Birth weight (g) ⱖ4000 (g) Forceps used Delivery Vaginal Emergency C/S Repeat C/S

Fluoxetine (n ⫽ 128)

NTC (n ⫽ 128)

98/128 11/128 19/128 2/98 17.8 ⫾ 6.3 39.4 ⫾ 1.7 6/85 1/85 3459.7 ⫾ 660.2 15/84 8/38

110/128 8/128 10/128 2/110 16.3 ⫾ 6.0 39.4 ⫾ 1.8 7/85 2/85 3421.1 ⫾ 563 9/81 9/83

61/82 9/82 12/82

62/83 17/83 4/83

p value 0.14a 0.1b 0.3b 0.69 0.96 0.22b 0.38b 0.68 0.08b 0.13 0.04

Fluoxetine (n ⫽ 74)

TCA (n ⫽ 74)

NTC (n ⫽ 74)

p value 0.34a

58/74 6/74 10/74 2/58 17.2 ⫾ 6.2 39.4 ⫾ 1.6

60/74 5/74 9/74 0/60 16.8 ⫾ 5.8 39.1 ⫾ 2.3

67/74 2/74 5/74 2/67 15.9 ⫾ 5.3 39.6 ⫾ 1.9

0.31b 0.3b 0.53 0.40

3421.9 ⫾ 664.1

3515.9 ⫾ 672.3

3408.6 ⫾ 602.2

0.62

4/23

6/42

5/41

0.85

32/42 4/42 6/42

32/43 5/43 6/43

31/41 8/41 2/41

0.43

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Table 3

Chi-square for 2 ⫻ 3 table. Fisher (two groups) and chi-square (three groups) (miscarriages versus live birth, excluding elective abortions). Abbreviations: NTC ⫽ nonteratogen control; TCA ⫽ tricyclic antidepressant; C/S ⫽ caesarean section. a

b

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Table 4 Major Malformations and Neonatal Complications Fluoxetine Major malformations

Neonatal complicationsa

a

Jejunal obstruction Ventricular septal defect Jaundice needing therapy (2) Shoulder dystocia and apnea (1) Patent ductus arteriosus and cyanosis (1) Sepsis and seizures (1) Hemangioma (2) Lacrimal stenosis (1) Aspiration pneumonia (1) Club feet (1) Congenital dislocation of hip (1)

Tricyclic antidepressants None

Metatarsus adductus (1) Congenital dislocation of hip (1) Slight hypotonia (1) β-Hemolytic streptococcus (1) Apnea (1) Hydrocele (1) Respiratory distress syndrome (1) Meconium aspiration and sepsis (1) Metatarsus varus (1)

Nonteratogens Pulmonary atresia Ventricular septal defect Jaundice (1) Clipped tongue (1)

The number of infants with the complication is indicated in parentheses.

this patient from the statistical analysis did not alter the results in any way. There was no statistical difference in gravidity, parity, and previous elective and previous spontaneous abortions between the three groups, although comparison of the fluoxetine and NTC groups revealed a higher mean gravidity and parity in the fluoxetine group (Table 5). There was a similar distribution of abstainers of ethanol and tobacco in all groups (Table 5). Discussion Many women of reproductive age suffer from depression, which necessitates chronic therapy with antidepressants. According to O’Hara et al., as many as 10% of pregnant women meet the criteria for major or minor depression (23). Exposing any fetus to drugs is perceived by most women as being associated with an increase in teratogenic risk (24), and women with psychiatric disorders are likely to be more prone to emotional instability due to unfounded perceptions of teratogenic risk following such exposures. While manufacturers and health providers often suggest that depressed women not be treated during gestation, such practice may endanger their health and hence the safety of their pregnancies. This reality, coupled with the fact that half of North American pregnancies are unplanned, implies that there is urgent need for credible data on the safety/risk ratio of antidepressant use in pregnancy. This need is in sharp contradistinction to the complacency exhibited by many pharmaceutical manufacturers in helping to collect such data and many of the regulatory agencies in enforcing such collection. Presently, systematic collection of postmarketing data on pregnancy exposure to drugs is not mandatory, and many manufacturers feel that their duties and responsibilities are met by disclaiming their product’s use in pregnancy, thus often orphaning pregnant women from essential drugs. Our study, like the earlier lithium project (11), demonstrates

Maternal Characteristics of Cases (Fluoxetine-Exposed) and Age-Matched Controls (TCA and NTC)

Characteristics Maternal age (years) Gestational age at first consultation (weeks) Obstetrical history Gravidity Parity Elective abortions Spontaneous abortions Ethanol Abstainers ⬍2.5 drinks per week ⱖ2.5 drinks per week Tobacco Abstainers ⬍0.5 package per day ⬍1 package per day ⱖ1, ⬍1.5 pack per day

Fluoxetine (n ⫽ 128)

NTC (n ⫽ 128)

p value

31.6 ⫾ 5.7

31.2 ⫾ 4.9

0.51

⫾ ⫾ ⫾ ⫾

0.01b 0.01b 0.3b 0.13b

2.9 0.9 0.5 0.5

⫾ ⫾ ⫾ ⫾

3.2 1.1 0.9 2.5

2.1 0.6 0.3 0.2

1.3 0.8 0.7 0.7

Fluoxetine (n ⫽ 74)

TCA (n ⫽ 74)

NTC (n ⫽ 74)

p value

31.7 ⫾ 5.2 8.5 ⫾ 4.9

31.6 ⫾ 5 8.6 ⫾ 6.3

31.0 ⫾ 4.3 8.9 ⫾ 5.8

0.66 0.93a

2.5 0.9 0.5 0.2

⫾ ⫾ ⫾ ⫾

1.6 0.9 0.8 0.6

2.3 0.7 0.4 0.4

⫾ ⫾ ⫾ ⫾

1.7 1 0.8 0.8

2.0 0.7 0.3 0.2

⫾ ⫾ ⫾ ⫾

1.2 0.8 0.6 0.4

⬎0.05c ⬎0.05c ⬎0.05c ⬎0.05c

62/109 35/109 12/109

68/125 49/125 8/125

0.31 0.8d

41/62 14/62 7/62

35/72 32/72 5/72

40/73 27/73 6/73

0.12 0.02d

74/105 17/105 11/105 3/105

93/125 21/125 6/125 5/125

0.42 0.61e

42/61 11/61 6/61 2/61

46/73 19/73 7/73 1/73

52/73 15/73 2/73 4/73

0.38 0.55e

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Table 5

a

Analysis of variance. Wilcoxon sign-rank analysis. c Kruskal-Wallis analysis. d Chi-square analysis: abstainers versus admitted drinkers. e Chi-square analysis: abstainers versus admitted smokers. Abbreviations: NTC, nonteratogen control; TCA, tricyclic antidepressant. b

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the ability of TIS to prospectively collect and ascertain large cohorts of women exposed during the first trimester to specific medications. Because pregnant women contact these services at the time of exposure, complete documentation of exposure and other potential confounders is possible, as well as prospective follow-up of pregnancy. We have chosen to compare pregnant women exposed to fluoxetine to two control groups: one comprising women treated with tricyclic antidepressants, the selection of which was intended to control for potential effects of depression, and a second group of women who were exposed to nonteratogens, a group that should represent healthy pregnant women. All three groups were drawn from pregnant women counseled by TIS in an attempt to obviate potential bias introduced by different referral patterns. Prospective collection of pregnant women exposed to the drug in question and detailed ascertainment of the outcome of pregnancy have allowed us to construct a meaningful denominator and subsequently to calculate and compare rates of outcome measurements between the fluoxetine and control groups. Although this study is based on maternal reports, the Motherisk program routinely corroborates these reports with physicians’ written reports; the former have been found to be very accurate. Because the elimination halflife of fluoxetine ranges between 2 and 6 days, it is likely that many women were still exposed to the drug into their second trimester (e.g., five half-lives or 30 days after cessation of therapy). The rate of major malformations in live births exposed to fluoxetine during the first trimester was within the expected normal range (1–3%) and comparable to the two control groups. Although the strength of this study to rule out minimal increased risk above baseline is limited (n ⫽ 128), it is very unlikely that fluoxetine is a major human teratogen. The similar rate of major malformations in the control group indicates that the power of a much larger cohort would not likely be sufficient to identify a different trend. The sample size of this prospective cohort would have the power to detect a fourfold increased risk of major malformations, assuming a baseline risk of 2% in the NTC group, with a power of 80% and an α of 0.05. When compared to control women not exposed to teratogens, the fluoxetine group had a tendency for a higher rate of reported miscarriages; this did not reach statistical significance (14.8 versus 7.8%; RR 1.9, 95% CI 0.92–3.92). Our cohort has a limited power to show that an RR of 1.9 is significant; for such an RR to be statistically significant, more than 700 women would be needed in each group. The three-group comparison reveals that women exposed to TCA also had a similar tendency for a higher rate of reported miscarriages, which suggests that this tendency may be associated with the depression and/or the emotional instability or other putative biological changes associated with these psychiatric conditions. Another possible explanation is that when questioned during follow-up interviews, some women reported a miscarriage when in fact they had chosen to terminate their pregnancy. Our methodology did not have means to corroborate their reports. Our recent prospective study with lithium in pregnancy has shown similar miscarriage rates between the lithium and control groups (9.4 versus 8.1%, respectively; Table 6), which is similar to our present control group, whereas women exposed to lithium tended to electively terminate more often. This may suggest that the report obtained by the present study is genuine and that either the depressive condition or some of its therapies (fluoxetine and TCA) are inducing higher rates of miscarriage. To date, no other studies address this potential association between depression or its therapies and reported rates of miscarriage. Comparison of gestational age at first consultation revealed that the lower spontaneous abortion rate in the NTC group was not due to these patients contacting

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Table 6 Rates of Spontaneous Abortion and Live Births in Women with Depression Exposed to Fluoxetine, Tricyclic Antidepressants, or Lithiuma

Fluoxetine Miscarriages Live births a

10/74 19/128 58/74 98/128

Tricyclic antidepressants (TCA)

Nonteratogen controls (NTC)

9/74

5/74

60/74

67/74 110/128

Lithium

Controls

13/138 10/128 105/138

12/148 123/148

NTC (n ⫽ 128) versus lithium controls, p ⫽ 0.19 (Fisher’s exact); fluoxetine (n ⫽ 74) versus TCA (n ⫽ 74) versus lithium, p ⫽ 0.76 (chi-square); fluoxetine (n ⫽ 128) versus lithium, p ⫽ 0.08 (Fisher’s exact); TCA (n ⫽ 74) versus lithium, p ⫽ 0.17 (Fisher’s exact).

Motherisk later in gestation compared to the fluoxetine and the TCA groups; the stages in pregnancy were identical [8.5 ⫾ 4.9 weeks (fluoxetine) versus 8.6 ⫾ 6.3 weeks (TCA) versus 8.9 ⫾ 5.8 weeks (NTC), p ⫽ 0.93] (Table 5). Very sparse published information exist on the potential teratogenicity of TCAs (25); the present prospective study failed to show this group as teratogenic. Women exposed to fluoxetine has an obstetric history as well as patterns of ethanol and tobacco use that were, in general, not different from those of the two control groups. Moreover, their characteristics are comparable to the general population of women contacting Motherisk. The mean dose of fluoxetine consumed by the participating women was within the recommended range; therefore it is unlikely that the lack of evidence of teratogenicity is due to a suboptimal dose. Neurodevelopment of Children Exposed in Utero to Antidepressant Drugs Despite the wide use of tricyclic antidepressant drugs and fluoxetine by women of reproductive age, the paucity of information on fetal effects has not allowed physicians to reassure women that either exposure during the first trimester or continuous therapy throughout gestation is safe. This lack of data has created anxiety among women planning pregnancies and pregnant women as well as among their families and physicians. Although neither tricyclic antidepressant drugs nor fluoxetine causes major malformations, the possibility of long-term damage to the developing central nervous system may deter women from taking these drugs even when clinically indicated. This study was designed to assess prospectively cognitive and language development and behavior in children exposed in utero to tricyclic antidepressant drugs or fluoxetine.

METHODS The Motherisk Program The Motherisk Program is an information and consultation service for women, their families, and health professionals regarding drug, chemical, radiation, and infectious exposures during pregnancy and lactation. Women with major depression who contact the program are invited to visit the clinic to be counseled by a physician.

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Selection of Patients We recruited three groups of mother-child pairs for this study. Two of the groups included the offspring of all women counseled by the program during the first trimester of their pregnancy regarding therapy with either tricyclic antidepressant drugs (since the inception of the Program in September of 1985) or fluoxetine (since its introduction in Canada in 1988). We excluded from the study any woman in whom antidepressant drug therapy had been discontinued before conception, if the woman was exposed to more than one antidepressant drug or to known teratogens during the pregnancy, or if the mother refused to participate in our follow-up program as described below. We also studied a control group of mothers not exposed to any drug, chemical, radiation, or infection known to affect the fetus adversely. The latter group, also collected prospectively, comprised women who had taken innocuous drugs such as acetaminophen or oral penicillin or had been exposed to dental x-rays. The control mothers were chosen from the list of women who had the closest visiting dates to the others in the study groups (⫾2 months). The study was approved by the Hospital’s Research Ethics Board and informed consent was provided by all women.

Assessments Antenatal Assessment During the initial assessment at or up to several weeks after pregnancy was diagnosed, we collected data on alcohol ingestion, medicinal and recreational drugs, smoking, lifestyle, medical and nutritional status, and sexually transmitted diseases. A detailed medical, genetic, and obstetric history was obtained from the mother and details concerning the time of exposure were recorded, as were the doses of tricyclic antidepressant drugs or fluoxetine and any concomitant drug therapy. Postnatal Assessment The first postnatal assessment occurred 6 to 9 months after delivery. During this interview the mother was questioned about the course of her pregnancy subsequent to the first meeting, including verification of the duration and dose of tricyclic antidepressant or fluoxetine treatment during gestation, maternal illnesses, and perinatal and postnatal complications. Details about the type of delivery, the perinatal period, and the times of developmental milestones were collected. This assessment also included a written report from the physician caring for the child. Neurobehavioral Testing All infants and children were assessed by a psychometrist who did not know the nature of the intrauterine exposure. To test for neurocognitive development, infants between 16 and 30 months of age were given the Baley Scales of Infant Development (26) and children above that age were tested with the McCarthy Scales of Children’s Abilities (27). The infant’s temperament and behavior were evaluated using the age-appropriate Carey Temperament Scale (28,29); in toddlers above 24 months, the age-appropriate Achenbach Behavior Checklist was used (30). Language skills were assessed in all infants and children with the Reynell Developmental Language Scales (31). Maternal IQ was assessed by the Wechsler Adult Intelligence Scale-Revised (32) and socioeconomic status with the Hollingshead Four Factor Inventory (33).

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The mother’s level of depression and function from the birth of the infant to the time of the present assessment were assessed using the Global Assessment Scale, which rates the woman’s lowest level of functioning by selecting the lowest range that describes her functioning on a continuum of mental illness (34); the Center for Epidemiologic Studies Depressed Mood Scale (CES-D), a 20-item scale that measures depression symptoms for both epidemiological research and clinical purposes (35); and the Index of Parental Attitudes (IPA), a 25-item scale designed to measure the extent, severity, or magnitude of parent–child relationship problems as seen and reported by a parent (36). Maternal assessments were conducted at the time of examination of the offspring. As part of these assessments, we recorded whether the mother continued drug therapy in the postpartum period and for how long. The outcome measures in each group (tricyclic antidepressant drugs, fluoxetine, and control) were compared by one-way ANOVA and Tukeys-HSD. All tests were two-tailed. Subsequently, multiple regression analysis was conducted in order to determine the effects of potential confounders on the outcome measures. Differences in proportions among the groups were compared by the chi-square test. Results A total of 129 pregnant women taking a tricyclic antidepressant drug were counseled by the Motherisk Clinic since its inception in 1985; 24 were lost to follow-up, 8 refused follow-up, 3 were exposed to known teratogens, 12 reported spontaneous abortions, and 2 had therapeutic abortions. In total, we tested 80 infants exposed in utero to tricyclic antidepressant drugs; of the 80 mothers, 62 were treated for depression and 18 for other indications including migraine (9 women), pain (6 women), and bladder control (3 women). A total of 40 women took a tricyclic antidepressant drug during the first trimester, 36 throughout pregnancy, 2 during the first and second trimesters, and 2 during the first and third trimesters. A total of 29 women took amitriptyline, 20 imipramine, 10 clomipramine, 9 desipramine, 8 nortriptyline, and one each maprotiline, doxepin, amoxapine, and trimipramine. Since its introduction in Canada in 1988, 88 pregnant women taking fluoxetine were counseled. Of these, 6 were lost for follow-up, 8 refused participation, 12 had spontaneous abortions, and 7 had therapeutic abortions. This group, therefore, consisted of 55 infants, 37 of whose mothers had taken fluoxetine during the first trimester and 18 of whose mothers had taken the drug throughout pregnancy. The control group consisted of 84 mother-child pairs exposed to nonteratogenic drugs. The characteristics of the mothers in the three groups are shown in Table 7. The women in the fluoxetine group were of significantly higher gravidity and parity, had more previous therapeutic abortions, and had a lower mean socioeconomic status. The women of both antidepressant drug groups tended to consume more alcohol and smoke more cigarettes during the index pregnancy than women in the control group. The women in the groups taking tricyclic antidepressant drugs and fluoxetine had similar scores on the three tests used to quantify their levels of depression and function since after the birth of the index child (Table 7). At birth and at the time of testing, the weight, height, and head circumference percentiles of the infants in the three groups were similar (Table 8), and there were no differences in the rates of perinatal complications. The incidence of major malformations among the three groups was also similar; three exposed to tricyclic antidepressant drugs (ventricular septal defect, hypospadias, and pyloric stenosis), two exposed to fluoxetine (ventricular

Table 7 Characteristics of Women Who Were Taking Tricyclic Antidepressant Drugs or Fluoxetine During Pregnancy and Pregnant Control Subjectsa Tricyclic antidepressant drugs (n ⫽ 80)

Fluoxetine (n ⫽ 55)

Control (n ⫽ 84)

31 ⫾ 4 2⫾1

31 ⫾ 4 3⫾2

30 ⫾ 5 2⫾1

1⫾1

1⫾1

Previous spontaneous abortion Previous therapeutic abortion Weight gain during (kg) Socioeconomic status score

0.3 ⫾ 0.6

0.2 ⫾ 0.5

0.39 0.001 (fluoxetine vs. the other two groups) 0.4 ⫾ 0.6 0.001 (control vs. the other two groups) 0.2 ⫾ 0.4 0.61

0.3 ⫾ 0.6

0.6 ⫾ 1.1

0.1 ⫾ 0.4

16 ⫾ 6.5 46 ⫾ 12

16 ⫾ 8 40 ⫾ 13

14 ⫾ 6 44 ⫾ 13

IQ Alcohol use during pregnancy (no. of women)c None Light Heavy Cigarette smoking during pregnancy (no. of women)d None Light Heavy Severity of depressione Global Assessment Scale CES Depressed Mood Scale Score on best days Score on worst days Index of Parental Attitudes

100 ⫾ 14

97 ⫾ 13

97 ⫾ 14

36 44 0

19 34 2

56 27 0

0.001 (control vs. the other two groups)

54 25 1

29 25 1

65 18 1

0.001 (control vs. the other two groups)

62 ⫾ 15

60 ⫾ 15

—

0.10

10 ⫾ 9 33 ⫾ 16 11 ⫾ 10

13 ⫾ 10 35 ⫾ 15 11 ⫾ 9

— — —

0.08 0.48 0.81

Characteristic Age at conception (years) Gravidity Parity

p valueb

0.001 (fluoxetine vs. the other two groups) 0.39 0.04 (fluoxetine vs. the other two groups) 0.34

Plus-minus values are means ⫾ SD. The p values correspond to the overall heterogeneity of the three groups, or in the case of severity of maternal depression, the two drug groups, according to Tukey’s multiple-range test. Significant differences between specific groups are noted in parentheses. c Light alcohol ingestion was defined as the consumption of up to two drinks per week and heavy alcohol ingestion as the consumption of more than two drinks per week. Information was not available for one woman in the control group. d Light cigarette smoking was defined as smoking of up to five cigarettes per day and heavy cigarette smoking as smoking of more than five cigarettes per day. e The score on the Global Assessment Scale can range from 1 (indicating the need for constant supervision) to 100 (indicating normal function). The score on the Center for Epidemiologic Studies (CES) Depressed Mood Scale can range from 0 (normal) to 60 (severe depression). The score on the Index of Parental Attitudes can range from 0 (no problems) to 100 (major attitudinal problems); scores above 30 are considered to indicate clinically important problems. a

b

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Table 8 Physical Characteristics of Infants at Birth and at the Time of Testing According to Whether They Were Exposed In Utero to Antidepressant Drugsa

Characteristic Gestational age at birth (weeks) Birth weight (g) Weight at testing (percentile) Height at testing (percentile) Frontooccipital circumference at testing (percentile) a b

Tricyclic antidepressant drugs (n ⫽ 80) 39 3490 58 52 46

⫾ ⫾ ⫾ ⫾ ⫾

2 642 30 29 26

Fluoxetine (n ⫽ 55) 39 3567 54 47 45

⫾ ⫾ ⫾ ⫾ ⫾

2 683 30 27 28

Control (n ⫽ 84)

p valueb

⫾ ⫾ ⫾ ⫾ ⫾

0.10 0.18 0.32 0.62 0.80

40 3373 51 49 48

1 540 31 31 27

Plus-minus values are means ⫾ SD. Testing occurred between 16 and 86 months of age (mean, 33 ⫾ 14). The p values correspond to the overall heterogeneity of the three groups.

septal defect and patent ductus arteriosus), and two among the controls (cyanotic heart disease and ventricular septal defect). The mean global IQ values in the three groups of infants were similar, both for younger children (tested with the Bayley’s scales) and older ones (tested with the McCarthy test) (Table 9). After adjustment for independent variables that may affect language development, the scores of the Reynell verbal or expressive tests were similar in the three groups. Regarding temperament, there was no difference in temperament styles in either the group taking tricyclic antidepressant drugs or the fluoxetine group when compared to the controls. Similarly, there were no differences in scores of mood, arousal functions, activity level, distractibility, or behavior problems. Multiple regression analysis of the effect of duration of antidepressant drug therapy (first trimester versus the whole pregnancy) revealed no differences for either infants exposed to tricyclic antidepressant drugs or fluoxetine as compared with the control infants on any of the neurobehavioral tests. In the tricyclic antidepressant drug group, 18 women were treated for conditions other than depression. Their offsprings’ IQ, Reynell scores, and scores of temperament, mood, arousal, activity, or distractibility were not different from those of the rest of the group (data not shown).

DISCUSSION In planning our study, we wished to address potential confounders that may affect infant achievements on standard neurocognitive development and behavioral tests regardless of the mother’s therapy, including maternal IQ and socioeconomic class. Because the depressed mother usually raises the infant, the infant’s emotional, cognitive, and behavioral development may be adversely affected as a result of postnatal mother-child interactions. For example, disturbances in affect regulation, attachment, temperament difficulties, depression, and cognitive and other developmental achievement have all been described in infants of depressed mothers (37). To address these potential confounders, we quantified the mother’s depression and her resulting function using widely used research tools (35– 37). Despite wide variability in the degree of depression, the mean scores of the women

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Table 9

Results of Neurobehavioral Tests in Infants According to Whether They Were Exposed In Utero to Antidepressant Drugsa Adjusted differences (95% CI)c

Testb Bayley Mental Developmental Index McCarthy General Cognitive Index Reynell Verbal Comprehension Scale Reynell Expressive Language Scale

Tricyclic antidepressant drugs (n ⫽ 80)

Fluoxetine (n ⫽ 55)

⫾ ⫾ ⫾ ⫾

117 ⫾ 17 114 ⫾ 16 1.2 ⫾ 1.2 ⫺0.2 ⫾ 1.0

118 117 1.3 0.3

17 10 0.8 0.9

Control (n ⫽ 84)

Tricyclic antidepressant drugs vs. control

Fluoxetine vs. control

⫾14 ⫾ 13 ⫾ 0.9 ⫾ 1.0

2.4 (⫺4.5 to 9.4) 2.7 (⫺2.3 to 7.6) 0.3 (⫺0.1 to 0.5) 0 (⫺0.3 to 0.3)

2.1 4.7 0.3 ⫺0.1

115 114 1.1 0.1

(⫺5.0 (⫺4.0 (⫺0.1 (⫺0.4

to to to to

9.2) 13.4) 0.6) 0.3)

Plus-minus values are means ⫾ SD. The children were tested between 16 and 86 months of age (mean, 33 ⫾ 14). The Bayley and McCarthy scores are typical for this age. The normal range for both tests is 100 ⫾ 1 SD. Lower scores mean lower cognitive function. The mean Reynell score in normal children of this age is 0 ⫾ 1 (range of possible scores, ⫺3 to ⫹3). c Multiple regression analysis was used after adjustment for children’s age; maternal IQ, socioeconomic status, score on the Center for Epidemiologic Studies Depressed Mood Scale, and score on the Global Assessment Scale; and duration of exposure to drug (first trimester versus entire pregnancy). CI denotes confidence interval. a

b

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receiving tricyclic antidepressant drugs and those receiving fluoxetine were similar on the three tests. In a like manner, other maternal factors known to affect child achievements in standard cognitive tests were quantified by us, including socioeconomic status and maternal IQ. We failed to find any differences in cognitive, language, and behavioral development among the children exposed to tricyclic antidepressant drugs and fluoxetine as compared with the unexposed control group. Because half of the pregnancies in North America are unplanned, many women take a tricyclic antidepressant drug or fluoxetine during the first few weeks of their pregnancy. However, the reassurance available to women that firsttrimester exposure to these drugs will not affect brain development in their unborn babies is not likely to reassure those who need continuous pharmacotherapy throughout gestation. When maternal depression is not optimally controlled, there is ample evidence for adverse outcome in infants and young children in a variety of domains, including cognitive, language, and behavioral development as well as higher rates of perinatal risk (38). In our study, one-third of the women taking fluoxetine and almost half of those taking a tricyclic antidepressant drug continued the medication throughout pregnancy, allowing us to compare first-trimester to whole-pregnancy exposure to these drugs. We found that exposure to either tricyclic antidepressant drugs or fluoxetine throughout gestation did not affect the IQ or language and behavioral development of the offspring as measured during preschool years. In summary, in utero exposure to either tricyclic antidepressant drugs or fluoxetine does not adversely affect child neurodevelopment. Answer Lithium has a minimal teratogenic risk for the rare Einstein’s anomaly. Fetal echocardiography can help rule out severe cases of this malformation before 20 weeks of gestation.

REFERENCES 1. Zalstein E, Koren G, Einarson T, et al. A case-control study on the association between first trimester exposure to lithium and Ebstein’s anomaly. Am J Cardiol 1990; 65:817–818. 2. Smithberg M, Dixet PK. Teratogenic effects of lithium in mice. Teratology 1982; 26:239–246. 3. Gralla EJ, McIlhenny HM. Studies in pregnant rats, rabbits and monkeys with lithium carbonate. Toxicol Appl Pharmacol 1972; 21:428–433. 4. Nora JJ, Nora AH, Toews WH. Lithium, Ebstein’s anomaly, and other congenital heart defects. Lancet 1974; 2:594–595. 5. Long WA, Park WW. Maternal lithium and neonatal Ebstein’s anomaly: evaluation with crosssectional echocardiography. Am J Perinatol 1984; 1:182–184. 6. Fries H. Lithium in pregnancy. Lancet 1970; 1:1233. 7. Frankenberg FR, Lipinski JF. Congenital malformations. N Engl J Med 1983; 309:311–312. 8. Koren G. Retinoid embryopathy. N Engl J Med 1986; 315:262. 9. Kallen B. Comments on teratogen update: lithium. Teratology 1988; 38:597–598. 10. Kallen B, Tandberg A. Lithium and pregnancy. Acta Psychiatr Scand 1983; 68:134–139. 11. Jacobson SJ, Jones K, Johnson K, et al. Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 1992; 339:530–533. 13. Maren PM, Smith DW, McDonald MJ. Congenital anomalies in the newborn infant, including minor variations. J Pediatr 1964; 64:357–371. 14. Koren G. Teratogenic drugs and chemicals in humans. In: Koren G, ed. Maternal-Fetal Toxicology. New York: Marcel Dekker, 1990, p 17.

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15. Rosa F. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324:674–677. 16. Goodman L, Gilman A, eds. The pharmacological Basis of Therapeutics, 7th ed. New York: Macmillan, 1985, p 429. 17. Koren G, Bologa M, Pastuszak A. The way women perceive teratogenic risk: the decision to terminate pregnancy. In: Koren G, ed. Maternal-Fetal Toxicology. New York: Marcel Dekker, 1990, pp 373–381. 18. Belik J, Yoder M, Pereira GR. Fetal macrosomia: an unrecognized adverse effect of maternal lithium therapy. Pediatr Res 1983; 17:304A. 19. Yoder MC, Belik J, Lannon RA, et al. Infants of mothers treated with lithium during pregnancy have an increased incidence of prematurity, macrosomia and perinatal mortality. Pediatr Res 1984; 18:404A. 20. Schou M. What happened later to the lithium babies? Acta Psychiatr Scand 1976; 54:193–197. 21. Byrd RA, Brophy GT, Markham JK. Developmental toxicology studies of fluoxetine hydrochloride administered orally to rats and rabbits. Teratology 1989; 39:444. 22. Goldstein DJ. Outcome of fluoxetine-exposed pregnancies: proceedings of the Fourth International Conference of Teratogen Information Services, Chicago, April 18–20, 1991. 23. O’Hara MW, Neunober DJ, Zekoski GH. Prospective study of postpartum depression: prevalence and predictive factors. J Abnorm Psychol 1984; 93:158–171. 24. Koren G, Pastuszak A. Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical and radiation exposure during the first trimester. Teratology 1990; 41:657–661. 25. Cohen LS, Heller VL, Rosenbaum JF. Treatment guidelines for psychotropic drug use in pregnancy. Psychosomatics 1989; 30:25–33. 26. Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: Psychological Corporation, 1993. 27. McCarthy D. McCarthy Scales of Children’s Abilities. New York: Psychological Corporation, 1972. 28. Fullard W, McDevitt S, Carey W. Toddler Temperament Scale for 1- to 3-Year-Old Children. Philadelphia: Temple University Press, 1978. 29. McDevitt SC, Carey WB. The measurement of temperament in 3–7 year old children. J Child Psychol Psychiatry 1978; 19:245–253. 30. Achenbach TM. Manual for the Child Behavior Checklist/4–18 and 1991 profile. Burlington, VT: University of Vermont Department of Psychiatry, 1991. 31. Reynell JK. Reynell Developmental Language Scales Manual. 2nd ed. Windsor, England: NFER-NSON, 1985. 32. Wechsler D. Wechsler Adult Intelligence Scale, rev ed. New York: Psychological Corporation, 1981. 33. Hollingshead AB. Four factor index of social status. New Haven, CT: Yale University Department of Sociology, 1975. 34. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The Global Assessment Scale: a procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976; 33:766–771. 35. Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977; 1:385–401. 36. Hudson WW. The Clinical Measurement Package: A Field Manual. Homewood, IL: Dorsey Press, 1982. 37. Goodman SH. Understanding the effects of depressed mothers on their children. Prog Exp Pers Psychopathol Res 1992; 15:47–109. 38. Morrison HL, ed. Children of depressed parents: risk, identification, and intervention. New York: Grune & Stratton, 1983.

7 Benzodiazepine Use in Pregnancy and Major Malformations or Oral Cleft: Meta-Analysis of Cohort and Case-Control Studies Lisa R. Dolovich, Gideon Koren, and J. M. Re´gis Vaillancourt The Hospital for Sick Children, Toronto, Ontario, Canada

Antonio Addis Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

J. D. Barry Power Ottawa, Ontario, Canada

Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION Benzodiazepines are commonly used for anxiety, insomnia, and epilepsy. Their use is substantial, even by pregnant women. Bergman et al. found that 2% of pregnant women in the United States who were receiving Medicaid benefits filled one or more prescriptions for benzodiazepines during pregnancy (1). As about half of pregnancies in the United States are unplanned (2), many women may inadvertently expose the fetus to benzodiazepines during the first trimester. Therefore, women require valid information regarding the risks of benzodiazepine use during pregnancy to avoid exposure to teratogens but also to ensure that they are not denied medication during pregnancy because of unfounded fear of unknown consequences. Antepartum exposures to benzodiazepines have been associated with teratogenic effects (for instance, facial cleft, skeletal anomalies) in some animal studies (3,4) but not others (5,6). Early case-control studies in humans found that maternal benzodiaze-

Reprinted from the British Medical Journal 1998; 317:839–843.

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pine exposure increased the risk of fetal cleft lip and cleft palate (7,8). Subsequent reports implicated benzodiazepines as the cause of major malformations (9–11) and a benzodiazepine syndrome similar to fetal alcohol syndrome (9,12,13). Numerous studies, however, have refuted these findings (1,14–16). These contradictory results have led to considerable controversy surrounding the use of benzodiazepines in pregnancy. We carried out a meta-analysis to examine whether exposure to benzodiazepines during at least the first trimester is associated with increased risk of major malformations or oral cleft. METHODS Data Sources We systematically searched Medline (1966 to December 1997 via Ovid), Embase (1980 to December 1997), Reprotox (a database of reviews on reproductive toxicity topics), references in textbooks on drugs in pregnancy, references of included studies, and review articles. Benzodiazepine(s) (exploded as a subject heading or the various preparations put in as text words) was combined with the following words as subject headings or text words: fetal diseases, infant, fetal organ maturity, cleft lip, cleft palate, major malformations, and prenatal exposure. The Toronto-based Motherisk Program—a consultation service for drug, chemical, and radiation exposure during pregnancy—helped to locate unpublished papers and provided one unpublished study and one abstract. The original authors provided unpublished data. Study Selection Searches were reviewed or completed independently and in duplicate. Cohort or casecontrol studies in any language considered pertinent were retrieved and included if they examined the relation between human maternal exposure to benzodiazepines in at least the first trimester and major malformations or oral cleft alone and included an unexposed concurrent control group. Major malformations were those described by Heinonen et al., which, among others, include cleft palate and cleft lip (17). Hereafter oral cleft is used for cleft lip or cleft palate, or both. Studies examining only certain subtypes of malformations or studies in patients with epilepsy were included but considered separately from the main analysis. Only studies where exposure occurred during the first trimester were considered as the fetus is most susceptible to teratogens during the period between the first and eighth weeks of organogenesis, the lip forms between weeks 4 and 8, and the oral palate forms between weeks 5 and 12. Studies were excluded if they were case series or reports, editorials, reviews, animal studies or used only stillbirths or abortions or the data could not be extracted. All published studies deemed suitable were retrieved. Unpublished studies were treated methodologically in the same way as published studies. The methods sections with study identifiers removed were reviewed independently and in duplicate to determine inclusion. Consensus or a third party whose decision was final resolved disagreements. Data Extraction Once the study was included data were extracted and quality assessed independently and in duplicate. Discrepancies were resolved through consensus. Study quality was assessed

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by using predetermined criteria. These aspects of study quality are provided in the results section as descriptive information. Data Analysis Studies of different design—namely, cohort and case-control studies—were analysed separately because of differing threats to their internal validity (18,19). Data were analysed by calculating the odds ratio and 95% confidence interval with a random effects model (20). We also calculated χ 2 tests for heterogeneity (21). Further sensitivity analyses were performed for case-control studies to assess the impact of recall bias through the use of normal babies compared with malformed babies as controls. In a further examination of homogeneity of effects we plotted the data with the rates of malformations in the control groups on the X axis and in the exposed subjects on the Y axis as suggested by L’Abbe´ et al. (22). We first visually inspected the plot for evidence of obvious outliers. We then regressed the malformation rate in the exposed group on that of the controls. The slope of that regression line was compared with the null hypothesis (that is, a slope of 1) by using standard techniques as a test for effects. We also examined residuals to determine if any observations were outliers (that is, ⬎1.96 SE) from a statistical point of view. Publication bias was examined through visual inspection of a funnel plot whereby odds ratios were plotted against study sample size.

RESULTS Over 1400 studies were considered. Most were not retrieved because two independent reviewers considered that they did not relate to the question under review. Of the studies considered, 74 studies were retrieved and 51 of these were excluded. Studies were excluded because they had no concurrent control group (eighteen), they did not examine major malformations (nine), they were carried out on animals (one), benzodiazepines were not studied (one), exposure was not during the first trimester (one), studies were review articles or commentaries (five), data presented were duplicated in an included trial (six), results for benzodiazepines were not reported separately from other agents (five), only a range of results were reported (one), only partial data were provided (two), benzodiazepine exposure was not linked to malformations (one), and the study was not available in North America (one). A complete list of excluded studies is available from the authors. Thirteen studies that examined major malformations (11,13,14,23–32), 11 studies that examined oral cleft alone (1,7,10,13,27,30,31,33–36), and three studies that examined other specific malformations (37–39) were included (some providing information for more than one evaluation). One study unpublished at the time of consideration has since been published (26). Of the 23 included studies, 20 (87%) predefined exposure (1,10,11,13,14,23,25– 28,30–39) and 22 (96%) predefined the outcome (1,7,10,11,13,14,23,25–32,34–40). Exposure was ascertained mainly through interview with the mother (61% of studies) (7,10,14,25–30,33,34,36–38) and outcome was confirmed mainly by using physician examination or records (44% of studies) (11,13,14,25,28,30,32,34,39,40) or malformation registries (30% of studies) (7,10,29,31,35–37). Equal diagnostic examination between exposed and unexposed groups occurred in all but three studies (14,25,35). Hartz et al. gathered and confirmed information about malformed babies from different sources but

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did not do so for control babies (14). Czeizel et al. sent surveys to up to three controls if initial controls did not respond (35). Laegreid et al. used blood samples to confirm benzodiazepine exposure and had blood sample results for 78% of cases but only 66% of controls (25). Various benzodiazepines were used or prescribed, although 48% of the studies (11 of 23) examined the use of chlordiazepoxide or diazepam only (10,11,14,23,28,30,32– 34,37,40). Only two studies provided any information regarding the duration of maternal exposure (25,26). The indications for use were infrequently provided (11,25,26,41). Sixtyone percent (14 of 23) of studies reported concurrent use of at least some prescription medications (1,10,11,13,25,26,28–32,37–39). Associations with Major Malformations Data pooled from seven cohort studies did not show an association between fetal exposure to benzodiazepines during pregnancy and major malformations (odds ratio 0.90; 95% confidence interval 0.61–1.35; homogeneity χ 2 ⫽ 1.74; p ⫽ 0.62; Table 1, Fig. 1) (11,14,23– 27). Two cohort studies carried out in patients with epilepsy were located. Results of both were not significant (30,31). Combination of four case-control studies showed that major malformations were associated with the use of benzodiazepines during pregnancy (3.01; 1.32–6.84; χ 2 ⫽ 9.87;

Table 1 Association of Major Malformations in Fetuses with Prenatal Benzodiazepine Exposure Exposed First author (year) Cohort studies Nonepileptic patients: Milkovich (1974) (11) Crombie (1975) (23) Hartz (1975) (14) Kullander (1976) (24) Laegreid (1992) (25) Pastuszak (1996) (26) Ornoy (1997) (27) Combined effect Epileptic patients: Nakane (1980) (30) Robert (1986) (31) Case-control studies Greenberg (1977) (29) Bracken (1981) (28) Noya (1981) (32) Laegreid (1990) (13) Combined effect a b

χ 2 ⫽ 1.74; p ⫽ 0.62. χ 2 ⫽ 9.87; p ⫽ 0.008.

Not exposed

No malformed

Total

No malformed

Total

5 3 11 2 1 1 9

86 200 257 89 17 106 335

10 382 2,179 198 1 3 10

229 19,143 46,233 5,664 29 115 363

16 0

117 4

42 8

490 144

36 39 1 8

60 72 24 10

800 1,331 0 10

1,612 4,266 24 68

Odds ratio (95% CI)

1.35 0.75 0.90 0.63 1.75 0.36 0.97 0.90

(0.45–4.07) (0.24–2.35) (0.49–1.66) (0.16–2.60) (0.10–29.92) (0.04–3.47) (0.39–2.43) (0.61–1.35) a

1.69 (0.91–3.13) 1.78 (0.09–35.94) 1.52 2.61 3.13 23.20 3.01

(0.9–2.58) (1.63–4.16) (0.12–80.68) (4.29–125.55) (1.32–6.84) b

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Figure 1 Association of major malformations with prenatal exposure to benzodiazepines.

p ⫽ 0.008) (13,28,29,32). All included case-control studies that evaluated major malformations used normal babies as controls so subgroup analyses based on types of controls could not be done. Regression analyses for both cohort and case-control studies showed no obvious heterogeneity. Associations with Oral Cleft Data pooled from three cohort studies showed no relation between fetal exposure to benzodiazepines during pregnancy and oral cleft (1.19; 0.34–4.15; χ 2 ⫽ 0.01; p ⫽ 0.997; Table 2, Fig. 2) (1,27,33). The analysis of six case-control studies produced a significant odds ratio for oral cleft of 1.79 (1.13–2.82; χ 2 ⫽ 11.39; p ⫽ 0.01) (7,10,13,34–36). Subgroup analysis of the case-control studies with normal babies as controls showed no significant association with oral cleft (1.63; 0.89–2.96; χ 2 ⫽ 3.81; p ⫽ 0.15) (7,13,35). Similarly, no significant association was found in analyses of case-control studies with malformed babies as controls (2.03; 0.88–4.71; χ 2 ⫽ 6.90; p ⫽ 0.10) (10,34,36). Regression analyses for both cohort and case-control studies showed no obvious heterogeneity. In general, for the analyses of major malformation and oral cleft the risks for casecontrol studies were grouped at a different end of the distribution than the risks for cohort studies, showing that the relative risks within each study design are of the same magnitude but the absolute differences in risk are of a different order of magnitude between studies (case-control about 10 times greater than cohort). This finding suggests a possible systematic difference between study designs. Funnel plot analyses produced funnel shaped plots, indicating that there was no obvious publication bias. Two case-control studies examined the association of benzodiazepine use with fetal cardiac malformations. One did not show an association between exposure and outcome; the other did (37,38). One study examined benzodiazepine use with malformations of the central nervous system and did not find any association between exposure and outcome (39).

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Table 2 Results of Studies Examining Association of Specific Malformations with Prenatal Exposure to Benzodiazepines Exposed Author (year) Cohort studies (oral cleft) Nonepileptic patients Shiono (1984) (33) Bergman (1992) (1) Ornoy (1997) (27) Combined effect Epileptic patients Nakane (1980) (30) Robert (1986) (31) Case-control studies Oral cleft Safra (1975) (10) Saxen (1975) (7) Rosenberg (1983) (34) Rodriguez (1986) (36) Czeizel (1987–88) (35) Laegreid (1990) (13) Combined effect Cardiac malformations Tikkanen (1992) (37) Correa-Villasenor (1994) (38) Malformations of central nervous system Winship (1984) (39) a b

Not exposed

No No malformed Total malformed

Total

32,395 102,985 363

Odds ratio (95% CI)

1 0 0

854 1,354 335

31 62 0

1.22 1.21 1.08 1.19

(0.17–8.98) (0.17–8.71) (0.07–17.39) (0.34–4.15) a

3 0

117 4

12 1

7 27 13 8 48 2

16 40 67 61 91 10

42 511 590 442 1,153 4

262 1,044 3,011 7,990 2,311 68

4.07 2.17 0.99 2.58 1.12 4.00 1.79

2 57

10 92

404 3,318

1,152 6,855

0.46 (0.10–2.19) 1.74 (1.14–2.65)

14

750

14

750

1.00 (0.47–2.11)

490 1.05 (0.29–3.78) 144 10.63 (0.38–298.57)

(1.44–11.54) (1.11–4.24) (0.54–1.82) (1.22–5.45) (0.74–1.71) (0.63–25.43) (1.13–2.82) b

χ 2 ⫽ 0.01; p ⫽ 0.997. χ 2 ⫽ 11.39; p ⫽ 0.01.

DISCUSSION Data taken from cohort studies showed no significant association between benzodiazepines taken during the first trimester and either major malformations or malformations of the oral cleft alone. However, data from case-control studies showed a small but significant increased risk for these events. This finding may reflect the substantially higher sensitivity of case-control studies to examine the risk of specific malformations or it may be chance. The tests of heterogeneity also showed that the cohort studies were not heterogeneous for both major malformation and oral cleft, whereas the case-control studies for oral cleft were heterogeneous, which decreases the reliability of these marginally significant results. A case series of eight children exposed to benzodiazepines in utero suggested the existence of a benzodiazepine syndrome (9). This syndrome was described as dysmorphic features, growth aberrations, and abnormalities of the central nervous system (9,12,13). Our results, however, do not confirm the presence of this syndrome. Even before this

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Figure 2 Association of oral cleft with prenatal exposure to benzodiazepines.

report alternative causes for these findings, such as Zellweger syndrome or other genetic abnormalities, have been suggested (42).

Possible Confounding and Bias Concomitant exposure to other medications can result in an overestimation of the risk of benzodiazepines. Fourteen studies, eight of which were case-control, allowed exposure to other potentially teratogenic medications (1,10,11,13,25,26,28–32,37–39). This large number confounds the results. In most studies no information on duration or indication for use of benzodiazepines was provided. Therefore it was difficult to determine if any of the populations included have an increased or decreased risk of major malformations. Studies that evaluated the risk of fetal malformations in women with epilepsy were separated from the main analysis as fetuses born to such women already have an increased risk of major malformations (43). Information is lacking regarding the risk of developing specific malformations. The use of a normal baby as a control in a case-control study can produce recall bias, as mothers of malformed babies may be more likely to recall exposures than mothers of normal babies. The subgroup analysis that compared benzodiazepine use in mothers of healthy babies as controls compared with mothers of malformed babies as controls produced similar effect sizes, suggesting that recall bias did not have a large effect on study outcome. The present meta-analysis has several limitations. The number of reports was relatively small and may have limited the power of our analysis. Also, although the overall sample was large, most cases for analyses of both oral cleft and major malformations were derived from only three studies (1,14,23). With regard to assessment of malformations, the studies used wide-ranging definitions for identification of malformations to be considered. When we examined the association of benzodiazepines with cleft lip and cleft palate we

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had to combine these two malformations as oral cleft because many studies combined these malformations as one entity and it was not possible to stratify the data (1,10,13,36). This study differs from previous reviews. Altshuler et al. reported an association between benzodiazepines and oral cleft, but the review included studies that did not have any control groups or studies that did not have concurrent control groups (44). That method of analysis may have seriously increased the strength of association found and the heterogeneity found when studies were combined and thereby produced different results. McElhatton provided a narrative review that succinctly summarized the opposing information, but because the studies presented were not combined systematically or quantitatively, the conclusions remain controversial and inconclusive (45).

CONCLUSIONS Because women commonly use benzodiazepines and half of all pregnancies are unplanned, counselling of women on the safety of such exposure is clinically important. Pooled data from cohort studies showed no apparent association between benzodiazepine use and the risk for major malformations or oral cleft alone. There was, however, a small but significantly increased risk for oral cleft according to data from the available case-control studies. More case-control studies examining these events are needed especially because the available studies are not homogeneous. Even when the ‘‘worst-case scenario’’ is assumed, benzodiazepines do not seem to be major human teratogens, but because some cases of cleft lip can be visualized by fetal ultrasound, level 2 ultrasonography should be used to rule out this malformation.

ACKNOWLEDGMENTS This project was completed as part of a requirement for a doctor of pharmacy course on critical appraisal, PHM 605, at the University of Toronto. Contributors: LRD coordinated the study, including discussion of core ideas, design of study, information retrieval, study selection, data extraction, statistical analysis, data analysis and interpretation, and writing the paper; AA participated in discussion of core ideas, design of study selection, data extraction, data analysis and interpretation, and editing the paper; JMRV and JDBP participated in discussion of core ideas, designing the study, information retrieval, study selection, data extraction, and writing the paper; GK and TRE helped initiate the project, participated in research design, analysis, and interpretation and in editing the paper. LD will act as guarantor for the study. Funding: No additional funding. Conflict of interest: None.

REFERENCES 1. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzodiazepine during fetal life. Lancet 1992; 340:694–696. 2. Skrabanek P. Smoking and statistical overkill. Lancet 1992; 340:1208–1209.

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3. Miller RP, Becker BA. Teratogenicity of oral diazepam and diphenylhydantoin in mice. Toxicol Appl Pharmacol 1975; 32:53–61. 4. Walker BE, Patterson A. Induction of cleft palate in mice by tranquillizers and barbiturates. Teratology 1974; 10:159–163. 5. Beall JR. Study of the teratogenic potential of oral diazepam and SCH 12041. Can Med Assoc J 1972; 106:1061. 6. Chesley S, Lumpkin M, Schatzki A, et al. Prenatal exposure to benzodiazepine: I. Prenatal exposure to lorazepam in mice alters open-field activity and GABA receptor function. Neuropharmacology 1991; 30:53–58. 7. Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts. Lancet 1975; ii:498. 8. Saxen I, Lahti A. Cleft lip and palate in Finland: incidence, secular, seasonal, and geographical variations. Teratology 1974; 9:217–224. 9. Laegreid L, Olegard R, Walstrom J, Conradi N. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 1989; 114:126–131. 10. Safra MJ, Oakley GP. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 1975; ii:478–480. 11. Milkovich I, van den Berg BJ. Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. N Engl J Med 1974; 291:1268–1271. 12. Laegreid L, Olegard R, Wahlstrom J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; i:106–109. 13. Laegreid L, Olegard R, Conradi N, et al. Congenital malformations and maternal consumption of benzodiazepines: a case-control study. Dev Med Child Neurol 1990; 32:432–441. 14. Hartz SC, Heinonen OP, Shapiro S. et al. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med 1975; 292:726–728. 15. St Clair SM, Schirmer RG. First trimester exposure to alprazolam. Obstet Gynecol 1992; 80: 843–846. 16. Jick H, Holmes LB, Hunter JR, et al. First trimester drug use and congenital disorders. JAMA 1981; 246:343–346. 17. Heinonen OP, Sloane D, Shapiro S. Birth Defects and Drugs in Pregnancy: Maternal Drug Exposure and Congenital Malformations. Littleton, MA: Publishing Sciences Group, 1977. 18. Horwitz RI, Feinstein AR. Methodologic standards and contradictory results in case-control research. Am J Med 1979; 66:556–564. 19. Levine M, Walter S, Lee H, et al. Users’ guides to the medical literature. IV. How to use an article about harm. JAMA 1994; 271:1615–1619. 20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Cont Clin Trials 1986; 7:177–188. 21. Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res 1993; 2:121–145. 22. L’Abbe´ KA, Detsky AS, O’Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987; 107:224–233. 23. Crombie DL, Pinsent RJ, Fleming DM, et al. Fetal effects of tranquilizers in pregnancy. N Engl J Med 1975; 293:198–199. 24. Kullander S, Kallen B. A prospective study of drugs and pregnancy. I. Psychopharmaca. Acta Obstet Gynecol Scand 1976; 55:25–33. 25. Laegreid L, Hagberg G, Lundberg A. Neurodevelopment in late infancy after prenatal exposure to benzodiazepines—a prospective study. Neuropediatrics 1992; 23:60–67. 26. Pastuszak A, Milich V, Chan S, et al. Prospective assessment of pregnancy outcome following first trimester exposure to benzodiazepines. Can J Clin Pharmacol 1996; 3:167–171. 27. Ornoy A, Moerman L, Lukashova I, Arnon J. The outcome of children exposed in-utero to benzodiazepines. Teratology 1997; 55:102A. 28. Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol 1981; 58:336–344.

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29. Greenberg G, Inman WH, Weatherall JA, et al. Maternal drug histories and congenital abnormalities. BMJ 1977; 2:853–856. 30. Nakane Y, Okuma T, Takahashi R, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epileptsia 1980; 21:663–680. 31. Robert E, Lofkvist E, Mauguiere F, Robert JM. Evaluation of drug therapy and teratogenic risk in a Rhone-Alpes district population of pregnant epileptic women. Eur Neurol 1986; 25: 436–443. 32. Noya CA. Epidemiological study on congenital malformations. Rev Cubana Hig Epidemiol 1981; 19:200–210. 33. Shiono PH, Mills JL. Oral clefts and diazepam use during pregnancy. N Engl J Med 1984; 311:919–920. 34. Rosenberg L, Mitchell AA, Parsells JL, et al. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983; 309:1282–1285. 35. Czeizel A. Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reprod Toxicol 1987–1988; 1:183–188. 36. Rodriguez PE, Salvador PJ, Garcia AF, Martinez FM. Relationship between benzodiazepine ingestion during pregnancy and oral clefts in the newborn: a case-control study. Med Clin 1986; 87:741–743. 37. Tikkanen J, Heinonen OP. Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy. Teratology 1992; 46:447–454. 38. Correa-Villasenor A, Ferencz C, Neill CA, et al. Ebstein’s malformation of the tricuspid valve: genetic and environmental factors. Teratology 1994; 50:137–147. 39. Winship KA, Cahal DA, Weber JP, Griffin JP. Maternal drug histories and central nervous system anomalies. Arch Dis Child 1984; 59:1052–1060. 40. Gregroire G, Derderian F, LeLorier J. Selecting the language of the publications included in a meta-analysis: is there a tower of Babel bias? Pharmacoepidemiol Drug Safety 1994; 3:S18. 41. Viggedal G, Hagberg BS, Laegreid L, Aronsson M. Mental development in late infancy after prenatal exposure to benzodiazepines—a prospective study. J Child Psychol Psychiatry 1993; 34:295–305. 42. Winter RM. In utero exposure to benzodiazepines. Lancet 1987; i:627. 43. Samrem EB, van Duijn CM, Hiilesmaa VK, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsias 1997; 38:981–990. 44. Altshuler LI, Cohen L, Szuba M, et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996; 153:592–606. 45. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8:461–475.

8 Drugs and Chemicals Most Commonly Used by Pregnant Women Doreen Matsui and Michael J. Rieder The Children’s Hospital of Western Ontario, London, Ontario, Canada

Monica Bologa The Hospital for Sick Children and the Upjohn Company of Canada, Toronto, Ontario, Canada

Frank Fassos, Michael McGuignan, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A woman who has had repeated miscarriages tells you that she was found to have lupus antibodies and that a specialist in the university hospital put her on low-dose aspirin for the rest of her current pregnancy. She has heard bad things about salicylates in pregnancy. How would you counsel her?

INTRODUCTION The thalidomide tragedy of the late 1950s has caused many medical practitioners to view every drug and chemical as harmful to the pregnant woman. The reality is that only a few compounds have been proven to be teratogenic in humans (see Chap. 3), whereas the vast majority probably do not pose a reproductive hazard. In a recent analysis, we demonstrated that pregnant women exposed to drugs and chemicals known not to be teratogenic assigned themselves an unrealistically high teratogenic risk of 25%. This assigned risk is comparable to the risk associated with thalidomide (1). There is a clear need for authoritative information and consultation services to help pregnant women and their physicians understand fetal risks. The advice provided should be based on unbiased, up-to-date information on the reproductive effects of drugs, chemicals, and radiation. In September 1985, we started a consultation program for women concerned about antenatal exposure to drugs, chemicals, and radiation as well as exposure during lactation. A detailed description of the Motherisk Program appears elsewhere (2,3). A summary of the data from the first 6 months of telephone consultations (total ⫽ 450) appears in Table 1, which lists, in descending order of occurrence, the most common drugs and chemicals 115

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Table 1 Most Common Antenatal Exposures Asked About in the Motherisk Clinic in Toronto 1.

2.

3.

4.

5.

6.

Antibiotics n ⫽ 55 (12.8%) Erythromycin: 16 Ampicillin: 12 Penicillin: 9 Trimethoprim-sulfamethoxazole: 9 Tetracycline: 6 Cephalosporins: 3 Analgesic-anti-inflammatory medication n ⫽ 37 (8.6%) Acetaminophen: 22 Acetylsalicylic acid: 6 Percocet, Tylenol #3: 3 Percodan 222, 282: 3 Codeine: 3 Paints, organic solvents n ⫽ 34 (7.9%) Water-based: 11 Oil-based: 10 Unspecified: 10 Lead: 3 Cold medications n ⫽ 32 (7.5%) Sympathomimetic action (decongestants): 6 Antihistamines: 11 Sympathomimetic ⫹ antihistaminic action: 8 Antitussives (dextromethorphan) ⫹ throat antiseptics: 7 Environmental pesticides n ⫽ 28 (6.5%) Unspecified: 16 Organophosphates: 7 Carbamates: 5 Cosmetic products for hair care n ⫽ 24 (5.6%) Dye: 10 Permanent-wave solution: 4 Both: 7 Bleach: 3

7. Video display terminals: 20 (4.7%) 8. Antiasthmatic medications n ⫽ 17 (4%) Adrenergic stimulants (Ventolin, Berotec): 9 Corticosteroid (Beclovent, Beconase): 5 Theophylline: 3 9. X-rays: 17 (4%) 10. Pediculocides n ⫽ 13 (3%) Chlorinated insecticides (Lindane): 5 Pyrethrins—piperonyl butoxide (R&C brand shampoo): 4 Unspecified: 4 11. Anxiolytic medications n ⫽ 11 (2.6%) Diazepam and related drugs: 7 Chlordiazepoxide: 4 12. Corticosteroids: 10 (2.3%) 13. Oral contraceptives: 8 (1.9%) 14. Rubella vaccine: 7 (1.6%) 15. Sugar substitutes: 6 (1.4%) 16. Local anesthesia (usually for dental work): 5 (1.1%) 17. H 2-receptor antagonists (ranitidine, cimetidine): 5 (1.1%) 18. Antihelmintic medications: 5 (1.1%) 19. Antifungal medications: 4 (0.9%) 20. Antitrichomonal medications (metronidazole): 4 (0.9%) 21. Laxatives: 4 (0.9%) 22. Antiemetics (Gravol brand): 4 (0.9%) 23. Mercury compounds: 4 (0.9%) 24. Ammonia: 4 (0.9%) 25. Natural gas (gas furnace and fuel gas): 4 (0.9%) 26. Antimalarial medications: 3 (0.7%) 27. General anesthesia: 3 (0.7%)

of concern to women who called the Motherisk Program. By being prepared to answer questions about the listed exposures, the health professional is likely to cover more than 80% of the common exposures during pregnancy. This chapter, which reviews many of the exposures mentioned above, has been updated to include other exposures about which inquiries have been found to be common in recent years. In the majority of cases a representative article for each exposure

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is referenced. For more information, the reader may refer to one of several textbooks (4–7).

ANTI-INFECTIVE MEDICATIONS Antibiotics Although an initial animal study suggested an association between erythromycin and congenital malformations (8), this relationship was not confirmed by subsequent studies in animals or humans (9). Erythromycin estolate is contraindicated in pregnancy because it appears to increase the risk of cholestatic hepatitis (10). Penicillin and ampicillin are commonly used antibiotics in pregnancy. Neither animal nor human studies have provided evidence that either antibiotic is harmful to the fetus (11–13). Similarly, cephalosporins have not been demonstrated to have teratogenic potency in humans or animals (13–15). Both trimethoprim and sulfonamides have been shown to cross the placenta (16); however, neither drug has not been incriminated as a teratogen (17,18). Acute hemolytic anemia may occur in fetuses with glucose-6-phosphate dehydrogenase (G6PD) deficiency exposed to sulfonamides in utero. When used during late pregnancy, sulfonamides may cause neonatal hyperbilirubinemia owing to displacement of bilirubin from albumin binding sites (19). The main risk from tetracycline is a yellow-brown discoloration of teeth due to deposition of the antibiotic in calcifying teeth (20,21). The risk exists only later than 4– 5 months of gestation, when the deciduous teeth begin to calcify. As for other malformations, large studies are contradictory or negative. Some authors could not demonstrate an increase in malformations associated with tetracycline (22,23). Others found a statistical association with minor malformations (inguinal hernia, hypospadias) (7). In a recent casecontrol study, the rate of treatment with doxycycline during the second and third months of gestation was not significantly higher in any group of congenital abnormalities (24). It is generally felt that tetracyclines are embryotoxic (in their effect on teeth) rather than teratogenic (25,26). Norfloxacin and ciprofloxacin are now common therapies for urinary tract infections; however, their use during pregnancy is not recommended because of arthropathy, which has been noted in beagle dogs. Use of these new quinolones during the first trimester was not associated with an increased risk of malformations or musculoskeletal problems in a small study of 35 pregnant pregnant women (27).

Pediculocides There are no reports of an increased incidence of malformations associated with the topical use of antilouse medication. Lindane (γ-benzene hexachloride) is a chlorinated insecticide. Animal studies showed no teratogenicity associated with the use of this drug (4). The manufacturer recommends caution in pregnancy, although there are no reports of congenital defects in humans. As lindane is readily absorbed and potentially neurotoxic (28), percutaneous absorption should be minimized by decreasing the concentration of the solution (⬍1%) and the duration of exposure (few minutes) (29).

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Pyrethrins with piperonyl butoxide are poorly absorbed and their potential toxicity is lower than that of lindane. Therefore they are generally considered safer in pregnancy (30). Sulfur compounds are often used as alternative scabicides in children, pregnant women, and patients with massively excoriated skin. Approximately 1% of the topically applied sulfur compound is absorbed, but it does not appear to cause systemic toxicity. There are no reports of teratogenicity from sulfur compounds. In animal studies, despite some evidence of adverse reproductive effects, sulfur compounds had no developmental toxicity (31). Antihelminthic Medications Among the various drugs used for the treatment of helminthic infestations, the common ones used during pregnancy were pyrantel pamoate, pyrvinium pamoate, and piperazine. These drugs act within the gastrointestinal (GI) lumen, and their intestinal absorption is ideally small. Piperazine is readily absorbed from the GI tract, whereas the absorption of pyrantel pamoate and pyrvinium pamoate is low (⬍15% for pyrvinium pamoate) (32). Animal studies on piperazine (in rats and pigs) and on pyrantel pamoate (in rats, pigs, and goats) were all negative (33,34). There are no data available on human exposure during pregnancy for pyrantel pamoate or pyrvinium pamoate. In a prospective study of three mother-child pairs with first-trimester exposure to piperazine, no evidence was found that would suggest a relationship to malformations (7). In a case report, piperazine tartrate was effective and safe in eliminating a helminthic infection (35). Antifungal Medications Few of the antifungals have been proven to be teratogenic in animal studies. Systemic administration of flucytosine or griseofulvin has caused multiple malformations in different animal species (36–38). In human studies, systemic griseofulvin has been associated with congenital malformations. In one report, three abortions and two congenital malformations were described (39). More recently, an association between high-dose fluconazole therapy during pregnancy and multiple congenital anomalies has been suggested (40,41). In contrast, a prospective study of 226 women exposed to a low-dosage regimen of this antifungal agent during the first 12 weeks of pregnancy did not demonstrate an increased risk for congenital anomalies (42). A study of prescription frequency of therapy of vaginitis during the first trimester did not find significant excesses in total or specific birth defects (43). Vaginal application should be avoided after the amniotic membranes have ruptured (29). Harm to the fetus has not been demonstrated with the use of topical azoles (44). Clotrimazole has been used topically in pregnancy, and no associations with congenital malformations have been reported (45). Miconazole has been associated with an increase in fetal mortality in different animal studies when administered during active organogenesis (46). In humans, there is no reported adverse effect of miconazole on the fetus (47). Nystatin is poorly absorbed, and its use has not been associated with teratogenesis (45,48). Antitrichomonal Medication Rats given up to five times the human dose of metronidazole showed no apparent adverse effect on either fertility or fetal development. Lifetime studies in hamsters were negative

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(49). Two infants with midline facial defects were reported whose mothers were treated with metronidazole during the first trimester for amebiasis (50). However, metronidazole has not been incriminated as a teratogen in more than 800 pregnancies, including almost 300 with first-trimester exposure (51). Further evidence is provided by two meta-analyses, both of which concluded that metronidazole does not appear to be associated with an increased teratogenic risk (52,53).

Antimalarial Medication Chloroquine and hydroxychloroquine are the drugs of choice for prophylaxis and treatment of sensitive malaria species during pregnancy (54). There was no evidence of teratogenicity in a study of 169 infants exposed to 300 mg of chloroquine base per week in utero (55) or in a study at the Motherisk Clinic, where 14 healthy babies were born to women exposed to one of these drugs in the first trimester of pregnancy (56). Currently these drugs are used for the treatment of systemic lupus erythematosus in doses much higher than those used for malaria prophylaxis. The safety of these higher doses has not been established, although normal pregnancy outcomes have been described (57,58). There is less experience with the use of mefloquine during pregnancy. There were no congenital malformations among 11 babies born to women who had taken mefloquine prophylaxis during the first trimester of pregnancy (59). The other antimalarials—quinine, primaquine, and pyrimethamine with dapsone (Maloprim) or with sulfadoxine (Fansidar)—have been incriminated as possible abortifacients and should be avoided during pregnancy (54).

ANALGESICS AND ANTI-INFLAMMATORY MEDICATION Acetaminophen is believed to be nonteratogenic at therapeutic doses (60,61). However, the effect of very high doses has not been assessed. There is a case report of a woman who consumed 1.3 g of acetaminophen daily throughout pregnancy for headache and nausea. She also developed severe anemia, which required several transfusions. During the fifth month, polyhydramnios developed; eight amniocenteses recovered 16 L of fluid. The infant died of severe renal insufficiency (62). However, an association between the drug intake and infant’s anomalies cannot be established on the basis of a single case report. Aspirin is one of the most frequently ingested drugs in pregnancy (63). Intake of aspirin during the first trimester has not been associated with adverse effects (60). Aspirin intake during late pregnancy, especially within 1 week of delivery, may affect neonatal coagulation and may cause premature closure of the ductus arteriosus. An increased incidence of intraventricular hemorrhage (IVH) in premature or low-birth-weight infants has been associated with maternal aspirin intake: 12 out of 17 aspirin-exposed newborns (71%) developed IVH compared with 41 out of 91 non-aspirin-exposed infants (41%) (64). Aspirin consumption late in pregnancy may also produce adverse effects in the mother—such as antepartum and/or postpartum hemorrhage, prolonged gestation, and prolonged labor— resulting from the inhibition of prostaglandin synthetase (65). In a study of 45 pregnant patients with rheumatic disease treated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin, no teratogenic effect was found

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(66). However, use of all NSAIDs should be avoided during the third trimester due to their antiprostaglandin synthesis action. Codeine is a widely used narcotic analgesic. It has not been associated with an increased risk of malformations (67); however, use of large doses of codeine near term may result in a neonatal narcotic withdrawal syndrome (68–70).

COLD MEDICATIONS Decongestants Sympathomimetic amines are teratogenic in some animal species (71); however, phenylephrine and pseudoephedrine as well as other sympathomimetic agents have not been shown to increase the risk of teratogenicity in humans (72). An association was found between the intake of sympathomimetic drugs in the first trimester of pregnancy and minor malformations, like inguinal hernia and clubfoot (7), but this was not confirmed by other studies. Although the use of certain decongestants during pregnancy has been suggested as a risk factor for gastroschisis (73,74), further evidence is required. Antihistamines Most of the antihistamine compounds available in over-the-counter preparations have not been implicated as bearers of untoward effects. A large prospective study of antihistamine exposure in pregnancy showed that only with brompheniramine was there a statistically significant association with teratogenicity: 10 of 65 cases of first-trimester exposures (in the Collaborative Perinatal Project: CPP) had malformed offspring (7). However, a recent meta-analysis failed to show teratogenicity of brompheniramine (75). The use of antihistamines in the first trimester does not appear to increase the risk for major birth defects (76). Diphenhydramine, despite an initial report of possible association with an increased incidence of oral clefts, is now considered to have no significant teratogenic potential. More recently nonsedating antihistamines have become popular; however, less data are available regarding their use during pregnancy. Neither cetirizine nor astemizole were associated with an increased teratogenic risk in a limited number of patients (77,78). Antitussives Dextromethorphan has not been implicated as a potential teratogen.

ANTIASTHMATIC MEDICATIONS None of the medications used for the treatment of acute asthmatic attacks has been incriminated as a teratogen. The current approach is to treat asthmatic attacks optimally during pregnancy, since the complications of untreated asthma far outweigh unproven reproductive effects (79,80) associated with the medications. Salbutamol has not been shown to be teratogenic in animals. The drug may cause fetal tachycardia and maternal hyperglycemia, resulting in increased serum insulin and potential postnatal hypoglycemia (81,82). In a prospective study of 259 pregnant women

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with asthma, use of inhaled β 2-agonists was not associated with an increased frequency of adverse maternal or fetal outcomes, including congenital malformations (83). First-trimester exposure to theophylline in 121 women with asthma was associated with malformations in three (2.5%) infants, a rate similar to that expected in the general population (84). Transient toxicity manifested as jitteriness and tachycardia has been reported in newborns whose mothers took theophylline during pregnancy (85). Systemic corticosteroids have been shown to induce cleft palate and lip in numerous animal species (86,87). However, reports of more than 1100 pregnancies have failed to demonstrate teratogenicity in humans (7,88). Systemic exposure from inhaled corticosteroids is believed to be small and no harm to the fetus from inhaled steroids has been documented (89). In a study of the effects of inhaled beclomethasone in 45 pregnancies, the prevalence of congenital malformations (1 of 43 live births) was felt to be within the normal range (90).

CORTICOSTEROIDS Corticosteroids are indicated for a variety of conditions that occur during pregnancy, including asthma, arthritis, nephrotic syndrome, and inflammatory bowel disease (see discussion on corticosteroids under ‘‘Antiasthmatic Medications,’’ above).

ANXIOLYTIC MEDICATIONS Initial studies reported a three- to fourfold increased risk of cleft palate in the offspring of women exposed to diazepam (91,92). This would increase the specific risk to 3–4 per 1000 in the general population. (When compared to the general population baseline teratogenic risk of 1–5 per 100, the figures are not alarming.) Conversely, other studies did not confirm this finding (93–95). In surveys, no such association was detected (96,97). A large single dose (⬎30 mg) or sustained prenatal diazepam use can lead to the ‘‘floppy infant syndrome’’ (98), in which the infant demonstrates hypotonia, respiratory embarrassment, difficulty in suckling, and hypothermia (98,99).

ANTIEMETICS Dimenhydrinate is the chlorotheophylline salt of diphenhydramine. Two prospective studies (7,100) showed no increased risk of teratogenicity from the use of dimenhydrinate. These data are supported by negative results in animals (101). Bendectin, a combination of doxylamine and pyridoxine, was developed as an antinauseant for use during pregnancy. Shortly after it came on the market, isolated case reports of limb-reduction defects led to a large number of litigations against the manufacturer, although cohort and case-control studies did not show a higher than baseline risk for malformations (102,103). The manufacturer removed the product from the American market in 1983 because of the exceedingly high costs of insurance. A company in Quebec now makes an identical product, which has been approved in Canada to be used in pregnancy.

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LAXATIVES Laxatives are among the most frequently used drugs during pregnancy, and there is no evidence to indicate adverse effects on human development from the majority of them. Since their action is local, their absorption and, therefore, access to the fetus is minimal (32). Most animal studies were negative; however, a few cathartics or laxatives are teratogenic or embryotoxic in animals, inducing minor skeletal changes (104). Processed hydrophilic bulking agents appear to be safe during pregnancy (105). Docusate (sodium, potassium, or calcium) is a common ingredient in many laxative preparations. A prospective study of 116 patients exposed to docusate sodium during pregnancy revealed no evidence of an association with malformations (7). Chronic use of large doses of the laxatives throughout pregnancy may cause hypomagnesemia in the mother and offspring (106). Ten studies involving 937 pregnant women treated with a variety of senna preparations showed few side effects (107). Castor oil may induce uterine contractions and therefore is contraindicated in pregnancy (32).

H 2-RECEPTOR ANTAGONISTS There are no reports of teratogenicity associated with either ranitidine or cimetidine. Animal studies were negative in the rabbit for ranitidine and negative in the mouse, rat, and rabbit for cimetidine (108,109). Cimetidine has been used at term with antacids to prevent gastric acid aspiration and subsequent pneumonitis (Mendelson’s syndrome). No adverse effects were noted in the neonate in these studies (110,111). Transient liver impairment has been described in one newborn after cimetidine exposure at term (112). In a prospective study of 178 pregnant women, no increase in major malformations was found following first-trimester exposure to H 2 blockers (113).

ORAL CONTRACEPTIVES The literature on the teratogenic effect of oral contraceptives is extensive. Although limbreduction defects, neural tube defects, cardiovascular lesions, and renal, anal, tracheal, and esophageal malformations from steroidal estrogens have been suggested, a large number of studies contradict these reports (114–118). Most studies, both positive and negative, have been heavily criticized for their methodology. The current consensus of opinion is: ‘‘Oral contraceptives present no major teratogenic hazard’’ (118). Wilson and Brent have summarized recent data by saying that ‘‘the use of exogenous hormones during human pregnancy has not been proved to cause developmental abnormalities in non-genital organ and tissue . . .’’ (119). Lack of an association between oral contraceptives and birth defects was supported by a meta-analysis of available prospective studies (118). Progesterone Current literature on the teratogenic effects of progesterone is voluminous. Several synthetic progestins have been documented to cause female pseudohermaphroditism (121). Of the progestins reported, ethisterone and norethindrone are the most active and account for most of the 200 cases of masculinization reported to date. Natural progestin (i.e.,

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progesterone) appears to be responsible for very few cases of sex changes. The overall risk appears to be 0.3–2.2%, with one early series describing 18% with norethindrone (122). The small amount of progestogens present in oral contraceptives is unlikely to cause virilization of a female fetus (114). A recent meta-analysis showed no significant relationship between first-trimester exposure to sex hormones generally (or to oral contraceptives specifically) and external genital malformations (123). It is currently believed that these hormones do not contribute measurably to the frequency of hypospadias (124).

VACCINES In follow-up of 514 susceptible women inadvertently immunized with rubella vaccine within 3 months of conception or during pregnancy who elected to go to term, there was no evidence of congenital abnormalities compatible with congenital rubella among their infants (125). Two infants with asymptomatic glandular hypospadias (which has been suggested to be part of the congenital rubella syndrome constellation of symptoms) have been reported; however, both had negative rubella-specific IgM titers in cord blood at birth (126). According to a 1989 Centers for Disease Control (CDC) report, the observed risk for congenital rubella syndrome following rubella vaccination continued to be zero (at that time) (127). Other investigators have concluded that the available data support the statement that the fetal risk associated with vaccination during pregnancy is so small as to be negligible (128). Although pregnancy is a contraindication for vaccination, vaccination is not normally a reason for termination of pregnancy (125). Vaccination against hepatitis B has become more widespread. No congenital abnormalities were observed among the infants born to 10 women exposed to hepatitis B vaccine during the first trimester of pregnancy (129).

ANESTHESIA Local Teratogenicity (skeletal anomalies, cataracts) has been associated with the use of lidocaine hydrochloride in animals (130). In humans, lidocaine crosses the placenta and may cause some neonatal depression and neurobehavioral changes after maternal intravenous administration of doses slightly higher than the antiarrhythmic doses (29). Lidocaine does not cause malformations after topical administration or injection for local anesthesia (131).

General There is no evidence that a single course of general anesthesia in early pregnancy is teratogenic. A recent study (131) supports the findings of a prospective study (132), demonstrating the safety of nitrous oxide. Similarly, thiopental, enflurane, and halothane were not shown to cause untoward embryonal or fetal effects (131,133,134). These results are different from occupational exposure to inhalational anesthetics, where cumulative exposure may be hazardous to the developing fetus (38) or may cause an increased risk for miscarriages (131).

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SUGAR SUBSTITUTES There is no strong evidence to indicate that the use of moderate amounts of artificial or nonsugar sweetening agents has any adverse effect on human fetal development. One study outlined an increased prevalence of behavior problems (hyperactivity, irritability, and nervousness as well as mental retardation) and physical anomalies (deformities of bones) among offspring of mothers who were users of artificial sweeteners during pregnancy as compared to nonusers (135). However, the type of sweetening agent was not identified in the above-mentioned reports. Saccharin was shown to have no teratogenic activity in a number of studies in mice, rats, and rabbits (136,137). Some commercially available by-products (e.g., the benzoic forms) were teratogenic in a few animal studies, inducing ocular and other developmental anomalies (137). Aspartame is broken down in the small intestine into aspartic acid, methanol, and phenylalanine. Aspartic acid does not readily cross the placenta (138). Methanol is oxidized to formaldehyde and subsequently to formic acid; however, the rate of formate synthesis does not exceed the rate of its urinary excretion (139). Furthermore, the amount of methanol ingested per can of aspartame-sweetened beverage would be less than that from an equal volume of fruit juice (138). Phenylalanine is concentrated on the fetal side of the placenta but does not pose any risk to the fetus at the doses studied (139).

COSMETIC PRODUCTS FOR HAIR CARE Dyes The most frequent consultations to the Motherisk Clinic involved the ‘‘permanent’’ formulations. These are complex compounds of a variety of chemical classes, which may include phenylenediamine, toluenediamine, resorcinol, aminophenol, naphthol, 1-methyl-[ 20 H]aminobenzene, nonoxynol, oleic acid, isopropyl alcohol, ammonium hydroxide, trisodium acetate, ascorbic acid, sodium sulfite, and sodium hydroxide (140). Questions about the safety of hair products were raised as a result of some studies showing mutagenic activity in the Ames test (141). Recently, a study of 13 Chinese hair dyes showed negative Ames test results (142). There are no human studies available on these substances. Studies in laboratory animals (rats, rabbits) are available for some, and no teratogenicity has been shown for most. Some compounds (phenylenediamine and toluene compounds, possibly aminophenol and resorcinol) are considered to be potentially mutagenic and teratogenic (140,142). As to potential toxicity, aromatic nitro and amino compounds can become cyanogenic at toxic levels, thus theoretically raising the possibility that the fetus will be affected as well. However, documentation of these potentially toxic effects has involved cases of industrial intoxication, with digestive absorption of large amounts of chemicals (140). The transcutaneous absorption of these substances is not well defined, but the amount of hair coloring agents entering the systemic circulation is probably small (79). In a study of 12 hair dye formulations tested for systemic toxicity by topical application to rabbits, no clinical or histomorphological evidence of systemic effects was found. These formulations (three semipermanent formulations and nine oxidation dyes) were also tested for teratogenic effects following dermal application to pregnant rats. The course of

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pregnancy was not significantly affected, and no biologically significant soft tissue or skeletal changes were noted (141). In another study, five oxidation dyes were administered by gavage to pregnant rats. No signs of toxicity were observed during the treatment period. Even after administration of doses exceeding 110-fold the human exposure, there were no significant changes in fetal development and structure (143), but a significant decrease in the mean maternal weight gain was recorded. No evidence of a teratologic effect was demonstrated in pregnant rabbits exposed by gavage to a composite of dyes and base components found in commercial semipermanent hair color products (144). Permanent Wave Solutions Permanent waves in hair are produced by the use of two solutions: the waving fluid, which is an alkaline thioglycolate solution (e.g., ammonium thioglycolate, thioglycerol), and the fixation/neutralization solution, which is an acid hydrogen peroxide solution. The waving solution may have irritant properties; the ammonium thioglycolate may cause respiratory symptoms owing to immediate-type hypersensitivity. No teratogenicity has been suggested by use of these products in animals. The hydrogen peroxide, which has a local irritant effect, is rapidly degraded to water and oxygen and does not cause systemic effects (79). Bleach Hair bleaching formulas contain hydrogen peroxide and ‘‘per-’’ salt, such as ammonium persulfate, which may cause contact allergy, rhinitis, or serious respiratory symptoms owing to immediate-type hypersensitivity (79). In general, most exposures involve low dose levels. If there should be evidence of apparent toxicity, the pregnant woman should be seen by a physician. There are no reports of reproductive effects in either humans or animals.

PAINTS AND ORGANIC SOLVENTS Organic solvents are ubiquitous in the industrialized environment, appearing as individual agents or in complex associations. These compounds are volatile, and their vapors may gain access to the maternal and fetal circulations. While the most common site of toxicity is the central nervous system (CNS), the wide structural diversity of organic solvents results in potentially different teratogenic effects (145). Many industrial solvents are teratogenic in laboratory animals. While malformations depend on the specific solvent and animal species, malformations that have been described include poor fetal development, hydrocephalus, exencephaly, liver abnormalities, blood changes, and skeletal and cardiovascular defects. In vitro studies show that some organic solvents are weak mutagens (146). Chronic exposure to benzene induces chromosomal changes in human hematopoietic cells and may lead to an increased risk of leukemia or aplastic anemia. This compound is teratogenic or embryolethal in some animal species (147). Induction of birth defects in humans by industrial solvents is controversial. A widely quoted case-control study claimed increased exposure to organic solvents among mothers of children with CNS malformations when compared to mothers of normal controls (148).

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Several epidemiological studies have demonstrated that women who work in laboratories or other industrial environments have an increased risk of miscarriage (145,149,150) or, in their offspring, gastrointestinal malformations such as omphalocele, gastroschisis, and esophageal stenosis or atresia (147). A small but statistically significant association with major malformations was found in a recent meta-analysis of studies of maternal occupational exposure to organic solvents (151). Thus, it is important when working with these chemicals to follow the recommended precautions to limit exposure. Most pregnant women who use oil-based paints apply them to one or more rooms of their home, generally in preparation for the new child. It is unlikely that such a brief, low-dose exposure will cause any of the conditions that may be associated with occupational exposure throughout pregnancy. Water-based paints, or latex paints, pose no increased reproductive risk because they have low volatility. Lead is a common constituent in glass-staining materials. It is teratogenic in laboratory animals, causing skeletal and CNS defects, oral clefts, and fetal death (145,152). In humans, lead is known to induce abortions; however, no increase in teratogenic risk has been described. Because of its abortifacient properties, there are occupational regulations for women’s exposure to lead (153). In a study of 71 pregnancies in women working with lead, 11% ended in miscarriages and neonatal mortality was almost 40% (154). When the course of 253 pregnancies of women residing in America’s ‘‘lead belt’’ was compared with an equal number of pregnancies occurring elsewhere, there were more cases of premature rupture of membranes and more preterm babies in the first group. Malformations were not reported (155). One infant with a high blood lead level and erythrocyte protoporphyrin at birth developed neurological disability at 13 months of age (156). A recent study pointed to a possible association between umbilical lead above 10 µg/dL and slightly lower scores in the Bayley test (157). Pregnant women who may have occupational exposure to lead during pregnancy should be referred to a reproductive toxicologist or other health professionals with similar expertise.

AMMONIA Ammonia vapors can cause respiratory tract irritation but no systemic toxicity (158). The different halogenated ammonia compounds and ammonia salts have been associated with negative studies as well as some positive reports of developmental anomalies, which were most likely caused by the halogen, not by the ammonia (159).

ENVIRONMENTAL PESTICIDES Increasing interest in the reproductive toxicity of pesticides and other agricultural chemicals arose after the extensive use during the Vietnam War of the defoliant Agent Orange, which was believed to be associated with an increased incidence of spontaneous abortions, stillbirths, and malformations (153). However, current data do not reveal strong evidence of fetotoxicity unless the dose was excessive. Insecticides are basically divided into organophosphates, aromatic carbamate esters, and chlorinated compounds. Many of them have teratogenic potential in laboratory animals, inducing various structural abnormalities (skeletal and brain defects) (160–162). Organophosphates are commonly used insecticides with irreversible cholinesterase-

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inhibiting properties (162). In animal studies, dose levels that were not maternally lethal did not produce fetotoxicity, fetal lethality, or malformations (163). Malathion is a common household organophosphate insecticide that is also used topically for the treatment of lice. There are no reports of human teratogenicity from the use of malathion, and animal studies were negative (164). Carbamates exert a reversible cholinesterase-inhibiting activity (162). In animal studies, neither propoxur nor carbofuran caused fetal lethality or developmental abnormalities at dose levels that were not maternally lethal (163). Methyl benzimidazole carbamate (MBC) has a demonstrated capacity to interfere with mitosis in different species (fungi, viruses, bacteria, cells of bovine brain). Although the studies concluded that MBC was a potential teratogen, a study in rats and rabbits revealed some degree of embryolethality but no visceral or skeletal malformations (165). Although the cholinesterase inhibitors are commonly used, there is a lack of human reports on their reproductive effects. Very few of the women consulting the Motherisk Clinic with concerns about environmental pesticides had been exposed to toxic amounts of these compounds; rather, they had been in an area where pesticides were sprayed and consequently they could smell them. It is conceivable that in the absence of symptomatic maternal toxicity, such short exposure will not cause embryonal or fetal damage. Whenever a woman exposed to these chemicals experiences any degree of clinical toxicity, she and her fetus should be closely monitored by a physician. MERCURY COMPOUNDS In our survey, the concerns about mercury almost always involved the accidental ingestion of metallic (elemental) mercury in the form of dental amalgams or the contents of a thermometer. Swallowed elemental mercury is not absorbed to a significant degree from the GI tract and does not pose any risk of systemic toxicity. The amount of mercury vapor released from dental amalgam is very low and should not cause teratogenic effects (166). Once absorbed, practically all mercury compounds are teratogenic in animals and humans (167). The most potent teratogen is methyl mercury, the causative agent of the well-defined Minamata disease (168). NATURAL GAS Natural gas is approximately 85% methane. In high concentrations, methane is an asphyxiant, but it does not cause systemic toxicity (169). Of more concern is the combustion product carbon monoxide (CO). Carbon monoxide is a known teratogen, causing CNS abnormalities in the fetus (170). A prospective multicenter study of acute CO exposure in pregnancy was conducted by Motherisk and included some women who had been exposed to CO from a malfunctioning furnace. Mild poisoning was not associated with an increased fetal risk; however, adverse fetal outcome was noted with severe maternal CO toxicity (171). These results are consistent with a previous review of the literature (172). Pregnant women exposed to leaking or malfunctioning gas furnaces should have their carboxyhemoglobin level determined and should be referred to a specialized service. Fuel gas—a mixture of methane, ethane, propane, and butane—is considered to be potentially teratogenic in animals. Pregnant mice exposed to 58% concentrations of fuel gas on day 8 of gestation produced offspring with hydrocephalus and exencephaly (173).

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VIDEO DISPLAY TERMINALS Suspicion that the use of video display terminals (VDTs) had adverse effects on the embryo and fetus started after several clusters of miscarriages and malformations were reported (174). However, investigation reconfirmed that VDTs do not emit x-rays, microwaves, or other radiation at levels that would be harmful (175,176). Current data indicate that VDTs do not increase the risk to either the pregnant woman or the fetus (175–177).

X-RAYS Exposure to radiation doses less than 5 rad is not associated with an increase in congenital malformations (178). In the dose range of 5–15 rad, there may be an increased teratogenic risk. For dosages of more than 15 rad, there appears to be a two- to threefold increase in the incidence of major malformations (179,180). The usual exposure from diagnostic xrays should generally be far below the teratogenic range. In any case, the radiologist involved should be contacted to estimate the apparent dose of exposure.

GENERAL INSTRUCTIONS When advising a pregnant woman over the telephone about the potential reproductive effects of drugs, chemicals, or radiation, the health professional should rule out other risk factors that may affect her pregnancy outcome. These factors include age, obstetrical history, other exposures including alcohol and smoking, genetic background, paternal exposures, and the underlying medical condition. Socioeconomic status also plays an important role in the normal nutrition and progress of a pregnancy. The interviewer should advise the woman that in every pregnancy there is a 1–5% risk of major malformations and that even if her exposure does not appear to increase the teratogenic risk, the baseline risk still exists. Clinical Case Answer Salicylates, alone or combined with low-dose corticosteroids, have been shown to prevent repeated miscarriages in selected groups of women. These drugs have not been shown to affect the fetus adversely. Theoretically, they may cause premature closure of the fetal ductus arteriosus or bleeding complications, but these complications were not documented with small doses.

NOTE ADDED IN PROOF Since this chapter was written, more recent studies have provided additional information on three of the drug and chemical classes discussed earlier in this chapter. A case-control study showed a relationship between exposure to systemic corticosteroids during the first trimester of pregnancy and an increased risk of cleft lip (with or without cleft palate) in the newborn infants (OR ⫽ 6.55) (181). The results of a metanalysis of studies of benzodiazepine use during pregnancy were also recently published. Data from case-control

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studies showed a small increased risk for major malformations or oral cleft alone. The investigators concluded that although benzodiazepines do not seem to be major human teratogens, level 2 ultrasonography should be used to rule out visible forms of cleft lip (182). In a recent prospective study of the outcome following maternal occupational exposure to organic solvents, significantly more major malformations occurred among fetuses of women exposed to organic solvents than controls (RR ⫽ 13.0). The risk was increased among women who reported symptoms associated with their exposure (183).

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160. Kavlock RJ, Chernoff N, Gray LE, et al. Teratogenic effects of benomyl in the Wistar rat and CD-1 mouse, with emphasis on the route of administration. Toxicol Appl Pharmacol 1982; 62:44–54. 161. Ottolenghi AD, Haseman JK, Suggs F. Teratogenic effects of aldrin, dieldrin, endrin in hamsters and mice. Teratology 1974; 9:11–16. 162. Banerjee J. Inhibition of human fetal brain acetylcholinesterase: marker effect of neurotoxicity. J Toxicol Environ Health 1991; 33:283–290. 163. Courtney KD, Andrees JE, Springer J, Dalley L. Teratogenic evaluation of the pesticides baygon, carbofuran, dimethoate, and EPN. J Environ Sci Health 1985; B20:373–406. 164. Kanja LW, Skaare JV, Ojwang SBO, Maitai CK. A comparison of organochlorine pesticide residues in maternal adipose tissue, maternal blood, cord blood, and human milk from mother/infant pairs. Arch Environ Contam Toxicol 1992; 22:21–24. 165. Janardhan A, Sattur PB, Sisodia P. Teratogenicity of methyl benzimidazole carbamate in rats and rabbits. Bull Environ Contam Toxicol 1984; 33:257–263. 166. Larsson KS. Teratological aspects of dental amalgam. Adv Dent Res 1992; 6:114–119. 167. Koos BJ, Longo LD. Mercury toxicity in the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1976; 126:390–409. 168. Roeleveld N, Zielhaus GA, Gabreels F. Occupational exposure and defects of the central nervous system in offspring: review. BMJ 1990; 47:580–588. 169. Windholz M, ed. The Merck Index, 9th ed. Rahway, NJ: Merck, 1976. 170. Longo LD. The biological effects of carbon monoxide in the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1977; 129:69–103. 171. Koren G, Sharav T, Pastuszak A, et al. A multicentre, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol 1991; 5:397– 403. 172. Norman CA, Halton DM. Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. Ann Occup Hyg 1990; 34:335–347. 173. Kato T. Embryonic abnormalities of the CNS caused by the fuel-gas inhalation of the mother animal. Folia Psychiatr Neurol Jpn 1958; 11:301–324. 174. Aldridge JFL. Visual display units and health. Practitioner 1985; 229:539–545. 175. Schnorr TM, Grajewski BA, Hornung RW, et al. Video display terminals and the risk of spontaneous abortion. N Engl J Med 1991; 324:727–733. 176. Cluff S. Health hazards of video display terminals. Modern Med Can 1986; 41:501–509. 177. Parazzini F, Luchini L, La Vecchia C, Crosignani PG. Video display terminal use during pregnancy and reproductive outcome—a meta-analysis. J Epidemiol Commun. Health 1993; 47:265–268. 178. Bentur Y, Horlatsch N, Koren G. Exposure to ionizing radiation during pregnancy: perception of teratogenic risk and outcome. Teratology 1991; 43:109–112. 179. Brent RL. Evaluating the alleged teratogenicity of environmental agents. Clin Perinatol 1986; 13:615–648. 180. Brent RL. The effects of embryonic and fetal-exposure to x-rays, microwaves and ultrasound. In: Brent RL, Beckman DA, eds. Clinics in Perinatology: Vol 13. Teratology Philadelphia, Saunders, 1988, pp 301–330. 181. Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: A case-control study. Teratology 1998; 58:2–5. 182. Dolovich LR, Addis A, Regis Vaillancourt JM, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: Meta-analysis of cohort and case-control studies. BMJ 1998; 317:839–843. 183. Khattak S, K-Moghtader G, McMartin K, et al. Pregnancy outcome following gestational exposure to organic solvents. JAMA 1999; 281:1106–1109.

9 Periconceptional Folate and Neural Tube Defects Time for Rethinking Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A patient of yours who is now 6 weeks into gestation has heard that maternal supplementation of folic acid may decrease the risk for neural tube defects. She wants you to recommend vitamin pills that will have enough folate. How much daily folate does she need?

INTRODUCTION The Motherisk Program in Toronto evaluates and counsels pregnant women, their families, and health professionals on the teratogenic risks of drugs, chemicals, environmental agents, and infections. At present we deal with 60 inquiries a day, mainly from Ontario but also from other parts of Canada and the United States. In addition to performing follow-up of our own patients and conducting prospective studies, we continuously review and analyze new published studies. When important information becomes available, we feel it is our mandate to publicize such data, which may have a direct impact on the health of many unborn babies. We believe the new data on preconceptual folate supplementation qualify as such a major breakthrough.

THE PROBLEM Neural tube defects (NTD) affect about 0.6 to 1.5 per 1000 born babies in Canada. Consisting mainly of anencephaly and meningomyelocele, NTDs are serious lethal or severely debilitating congenital malformations. It is estimated that the risk of a recurrence of NTD in a woman who has had a previous NTD is about 3–4% (1). During the last decade effective antenatal methods have been developed to diagnose NTD in utero, with secondtrimester ultrasound combined with amniotic or maternal blood α-fetoprotein offering an almost 100% sensitivity in some centers (2). Presently, ultrasound is recommended at 16 137

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and 19 weeks. In most centers, amniocentesis for raised α-fetoprotein is the diagnostic approach, whereas maternal α-fetoprotein and ultrasound are used for screening. However, these tests are not performed routinely on women with unknown risk for NTD (e.g., because of previous NTD or because they are receiving valproic acid, carbamazepine, or retinoids). Evidence has been accumulated during the last two decades suggesting that low preconceptual consumption of folate and vitamins is associated with an increased risk of NTD. These retrospective studies could not distinguish between the potential effects of vitamins versus folate, however. The main criticism of these observational studies was that women consuming low amounts of folate and vitamins may have clustering of many other nutritional and socioeconomic risk factors, leading them to increased teratogenic risk (3). However, this controversy was laid to rest when the British Medical Research Council study, a multinational, double-blind, placebo-controlled effort, clearly proved the protection effect of pharmacological folate dose (4 mg/day) over placebo on the recurrence rate of NTD in women who had a previous NTD. Vitamins alone (without folate) had no protective effect (1). It was subsequently argued that this protective effect may not be relevant to the prevention of the occurrence of a first NTD in the general population. However, a recently completed double-blind, placebo-controlled study from Hungary has clearly shown the protective effect of folate at 0.8 mg/day plus vitamins over placebo (4) in women with no previous history of NTD. It is probable that in a heterogeneous society such as that in Canada, different ethnic groups have different magnitudes of risk for NTD; however, this new evidence suggests that, at least in part, NTDs are caused by folate deficiency. An association between folate deficiency and other malformations (e.g., cleft lip or palate) has been suggested but has not been verified. In Canada, the recommended dose of dietary folate for the general population was 0.2 mg/day. This recommendation stems from the concept that 0.2 mg/day of folate is high enough to prevent saturation of hepatic stores of folate. With the new data presented above, it is quite clear that this decrease in recommended dose of folate may increase the risk of NTD in Canada. Recently, the national Health and Welfare changed its recommendations to 0.4 mg/day. There is recent evidence that large segments of North American women below or near poverty have median intakes of folic acid of 0.15 mg/day. Even among those above poverty, many have very low folate intake (e.g., 25% of women have average folate intake of only 0.142 mg/day) (5). Moreover, insulin-dependent diabetic mothers and women with potentially low folate levels, due to inflammatory bowel disease and other disease states, may be at a higher risk than the normal population. At present it is not clear whether 0.4 mg/day of folate is inferior to the 0.8 mg/day tested in Hungary; however, it is very probable that intake of 0.2 mg/day is below the preventive dose.

RETHINKING THE SOLUTION Because NTDs are induced in the first 28 days of pregnancy, adequate maternal folate intake must start preconceptionally. Since, however, almost half of all pregnancies in North America are unplanned, it is evident that recommendations alone are not likely to reach many women and are very likely to miss high-risk women of low socioeconomic status who tend to consume substantially less folate.

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A variety of methods have been suggested to ensure that women of reproductive age receive adequate folate supplements (6). Educating women to consume more fruits and vegetables might achieve that goal, but supplementation of basic food sources such as bread, salt, cereals, or milk might turn out to be more efficacious because it does depend on changing the behavior patterns of women. The potential deleterious effects of incorporating folic acid in basic food supplementation must be carefully reviewed, however. Some masking of B 12 deficiency may occur in patients with combined deficiencies of vitamin B 12 and folic acid (7). NTDs induced by folate deficiency are now proven to be preventable at the primary level (versus secondary prevention by pregnancy termination). This is an exciting opportunity, similar in magnitude to the prevention of cretinism by means of iodine supplements. The health community, in concert with the various governments, should address these issues as soon as possible. Any delay in response will result in unnecessary occurrence of NTDs, with immense suffering and cost to the children, their families, and the public at large. Clinical Case Answer At 6 weeks of gestation, supplementation of folate will not reverse an NTD if it was already formed. The point here is that folate must be given periconceptionally at a dose of 400 µg/day.

REFERENCES 1. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131–137. 2. Nodel AS, Green NK, Holmes LB, et al. Absence of need for amniocentesis in patients with elevated levels of maternal alpha fetoprotein and normal ultrasonographic examinations. N Engl J Med 1990; 323:557–561. 3. Mills JL, Rhoads GG, Simpson JL, et al. The National Institute of Child Health and Human Development Neural Tube Defect Study Group. N Engl J Med 1989; 321:430–435. 4. Czeizel A. Controlled studies of multivitamin supplementation on pregnancy out-come. In: Keen CL, Bendich A, Willhite CC, eds. Maternal Nutrition and Pregnancy Outcome. New York: New York Academy of Sciences, May 17–20, 1992, San Diego, CA. 5. Block G, Abrams B. Vitamin and mineral status of women of childbearing potential. In: Keen CL, Bendich A, Willhite CC, eds. Maternal Nutrition and Pregnancy Outcome. New York: New York Academy of Sciences, May 17–20, 1992, San Diego, CA. 6. Oakley G. Periconceptional folic acid supplementation for the prevention of spina bifida and anencephaly. In: Keen CL, Bendich A, Willhite CC, eds. Maternal Nutrition and Pregnancy Outcome. New York: New York Academy of Sciences, May 17–20, 1992, San Diego, CA. 7. Babior BM, Bunn HF, Megaloblastic anemias. In: Braunwald E, Isselbacher KJ, et al., eds. Harrison’s Principles of Internal Medicine. 1987, pp 1498–1504.

10 The Effectiveness of Preconceptional Counseling on Women’s Compliance with Folic Acid Supplementation Anne Pastuszak, Dimple Bhatia, Bunmi Okotore, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Folic Acid and Neural Tube Defects The accumulated data from the last 14 years—in the form of randomized controlled trials (1,2), nonrandomized intervention studies (3,4), and observational studies (5–8)—have provided evidence that periconceptional folic acid ingestion can reduce the number of pregnancies resulting in neural tube defects (NTDs) in high-risk patients and low-risk primigravidas (9). From the available evidence, there is potential to avert at least 50% (10) and as many as 72% (3) of incident cases of NTDs if women at high risk for NTD recurrence consume 4.0 mg/day of folic acid during the critical stage of neural tube development in a subsequent pregnancy. Similarly, there is potential to decrease the incidence rate of NTDs in low-risk pregnancies by 40–60% if women consume 0.4 mg/day of folic acid during the critical stage of neural tube closure (10,11). Reflecting these levels of evidence, current Canadian guidelines from the Society of Obstetricians and Gynecologists of Canada (12), the Canadian Council of Medical Geneticists (13), the Canadian Task Force on the Periodic Health Examination (14), and the recent Canadian National Workshop on Folic Acid Supplementation recommend that low-risk women of reproductive age who are planning pregnancy should supplement their diets with 0.4 mg/day folic acid and high-risk women of reproductive age who are planning pregnancy should supplement their diets with 4.0 mg/day. A major issue in translating this breakthrough knowledge into a primary prevention strategy is that on average, Canadian and American women consume only half of the needed 0.4 µg/day (15) and that at least half of pregnancies are unplanned (16). Therefore, the issue of informing women on their preventable risk for NTDs prior to conception becomes most crucial. The Motherisk Program is a teratology information service (TIS) at the Hospital for Sick Children in Toronto, which provides evidence-based fetal risk assessments to pregnant women and health professionals. Self-selected callers who contact the program and request information about the safety or risk of maternal exposure to prescription or over141

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the-counter medications, chemicals, radiation, or infectious diseases during any stage of gestation, preconception, or during lactation are interviewed initially by a counselor over the telephone who has the prerogative to refer the patient to a once-weekly clinic for additional counseling. Risk assessments may be different for women who are planning a pregnancy, are at various stages postconception, or are breast-feeding; because of this, data regarding the start and stop dates of maternal exposure, fetal or neonatal age at exposure, and maternal medical and obstetrical history are documented on a standardized intake form. Callers whose exposures occurred pre- or postconceptionally undergo a risk assessment that is compared to the baseline risk of 1–3% for major congenital anomalies in the general population. In addition to receiving an explanation about the baseline risk, women who are planning a pregnancy at the time they call are advised to supplement their daily diet with folic acid prior to conception and to continue this dose throughout pregnancy. Women are told that, ideally, supplementation should start once birth control is discontinued. However, given that the majority of pregnancies is unplanned, Motherisk uses the phrase prior to conception. Counselors explain that in order for folic acid to be maximally effective, it is imperative that it be consumed during the time that the neural tube closes, which, in the human embryo, occurs 24–30 days after fertilization. The goal at Motherisk is to ensure that, through risk-factor modification, women who are planning a pregnancy supplement their diet with folic acid in amounts appropriate for their established risk status; low-risk women are to supplement with 0.4 mg/day and high-risk women, with 4 mg/day. The objective of the present study was to assess the effectiveness of our folic acid supplementation counseling program by comparing compliance in a group of counseled women to that of a group of uncounseled women.

STUDY DESIGN This was a prospective study in which we artificially manipulated a study factor—patient knowledge about folic acid supplementation—and subsequently measured patient compliance with this advice. This design is analogous to an intervention in a cross-section of a population without randomization.

PATIENTS AND METHODS Intake data from all callers to Motherisk are routinely entered into a computerized database. This was used to retrieve the charts of patients planning a pregnancy who called during the 15-week period of May 2 to August 19, 1994. To be included in the study, the patient’s intake form had to show that she was planning a pregnancy, that she had no prior knowledge about the need to supplement with folic acid, and that counseling on folic acid supplementation had been given to her by the program. During the months of November 1994 and April 1995, we attempted to contact these women to record their compliance with our advice. A supplementary questionnaire form included the following questions: Do you recall receiving advice from Motherisk about folic acid supplementation? Do you recall the

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suggested dose? Other than the Motherisk Program, what other sources of folic acid information have you received? Are you currently taking the dose we suggested? If no, why not? If yes, what dose are you taking? How often? In what form? When did you start this dose? When did you stop this dose? Have you conceived since your initial call? If no, are you still planning a pregnancy? If yes, what is your current gestational age? Has an ultrasound been done? Please describe what you do in your occupation. In addition to verbal counseling, women are receiving through the mail an information pamphlet prepared by the Motherisk team. As a control group for the planning women with no prior knowledge about folic acid, we collected a group of women who were at ⱕ14 weeks’ gestation at the time of their first call to Motherisk. The following supplementary questions were asked of them: Are you currently taking a multivitamin? If no, why not? If yes, what brand, what dose, when did you start, and when did you stop? Why are you taking this vitamin? Did someone recommend that you take it? If yes, who did, and when did this occur? Have you had your first prenatal visit yet? If yes, when? By choosing this group, we corrected for the possibility that, prior to calling, women may have received information on folic acid supplementation from sources other than the Motherisk Program. We used the Blishen, Carrol, and Moore socioeconomic index for occupations (17) in Canada, as this is most applicable in situations where access to socioeconomic data is limited to occupational titles. This scale (from 0, lowest, to 100, highest) is based on 1981 Canadian census data and is a composite of the prevailing income and education levels in each occupation; it is not a measure of occupational prestige. Z comparisons between the counseled and uncounseled groups were performed by Student’s t-test for unpaired data or the chi-square test where appropriate.

RESULTS In the 15-week study period, there were 3438 Ontario callers who requested information from Motherisk, 319 (9.3%) of whom were planning a pregnancy and not routinely taking folic acid at the time of the initial call. Of those, we followed up and reported on the compliance of a cohort of 145 women. The demographics of these women are presented in Table 1, showing the majority to be between 30 and 34 years of age, nulliparous, and in the middle of the socioeconomic scale. At the time of follow-up, 66 of the 145 women had conceived (46%). Regardless of whether any had conceived, 105 women (72%) were taking folic acid at the time of the follow-up call and 40 (28%) were not. Of the 105 women who supplemented, 103— who were rated as at low risk by the counselor at the initial call—were taking 0.4–1.0 mg of folic acid per day and 2 women were taking 5 mg/day. Those who did not take folic acid cited various reasons for their ultimate decision not to supplement (Table 2). All 145 women were asked to identify from which sources other than Motherisk they obtained information about folic acid. A total of 36 (25%) cited their health professional, 36 (25%) cited a magazine or newspaper, 3 (2%) cited a friend, 1 (1%) cited a relative, 4 (3%) cited other sources, 32 (22%) cited a combination of the previous, and 33 (23%) said they had not heard about the beneficial effects of folic acid before (Table 3). Women who took folic acid (72%) were different from women who did not comply (28%) in that they were more likely to abstain from cigarettes, alcohol, and cocaine use and were more likely to have received multiple reminders about folic acid (Table 1).

Table 1 Characteristics Between Women Planning Pregnancy, Who Subsequently Did and Did Not Supplement with Folic Acid

Maternal age at initial call Gravidity at initial call Gravida 0 Gravida 1 Gravida 2 Gravida 3 ⱖGravida 4 Parity at initial call Parity 0 Parity 1 Parity 2 ⱖParity 4 Socioeconomic score# 0–19 20–39 40–59 60–79 80–99 100 Time interval between initial call and follow-up Folic acid product used Jamieson (1 mg) Materna (1 mg) Orifer-F (0.8 mg) Centrum Forte (0.4 mg) Other (0.4–0.99 mg) Other (ⱖ1 mg) Pregnant at follow-up? Yes No Cigarette use at follow-up None ⬎20 per week Alcohol use at follow-up None ⬍5 drinks per week ⱖ5 drinks per week Cocaine use at follow-up None At least once since initial call Use of folate-depleting drug(s) at followup? No Yes a

Took folic acid

Did not take folic acid

p value

32.0 ⫾ 4.2 years range 23–43

32.5 ⫾ 4.9 years range 23–48

0.52

40 31 17 8 8

(38%) (30%) (16%) (8%) (8%)

55 (52%) 28 (27%) 17 (16%) 5 (5%) mean 51.9 37 (35%) 13 (12%) 33 (31%) 21 (20%) 0 1 (1%) 30.5 ⫾ 9.6 weeks range 12–45 36 37 2 4 15 11

12 17 7 4

(30%) (42%) (18%) (10%) 0

21 (52%) 14 (35%) 3 (8%) 2 (5%) mean 50.2 15 (38%) 6 (15%) 12 (30%) 7 (18%) 0 0 28.7 ⫾ 8.7 weeks range 14–45

0.47 0.7 0.91 0.81

0.6 0.95 0.89 0.97 0.49 — 0.6 0.31

(34%) (35%) (2%) (4%) (14%) (10%)

60 (57%) 45 (43%)

6 (15%) 34 (85%)

98 (93%) 7 (7%)

31 (78%) 9 (22%)

0.02

97 (92%) 8 (8%) 0

27 (68%) 10 (25%) 3 (8%)

0.006

105 (100%) 0

38 (95%) 2 (5%)

25 1*

15 0

This SES index does not provide scores for persons with certain occupations. In our uncounseled population, there were 3 students, 4 unemployed, 4 who were self-employed, and 41 who described themselves as homemakers. b At follow-up, the patient reported that she started carbamazepine therapy for grandmal seizures and supplemented with 5 mg/day folic acid.

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Table 2 Reasons Cited by Patients at Follow-up for the Decision Not to Take Folic Acid No longer planning, no further reasons given Husband laid off, recent divorce, planning IVF a in future Concurrent illness and drug therapy were too preoccupying Folic acid made her sick Her physician didn’t believe in the benefits of folic acid Didn’t know that it had to be taken prior to pregnancy Had heard nothing about folic acid No reasons given Didn’t think ‘‘the fuss’’ was ‘‘for real’’ Didn’t really think this issue applied to her Didn’t have enough information to convince her Found out she was 6 weeks pregnant 1 week after initial call a

14 1 each 4 1 1 1 6 5 1 1 2 1

In vitro fertilization.

At follow-up, 66 of the 145 women (46%) had conceived; 55 (83%) were still gravid at the time of the call, 6 had miscarried, 1 had a tubal pregnancy, and 4 had delivered healthy infants without congenital defects. Of these 66, a total of 60 (91%) had complied with the Motherisk advice and taken folic acid; 47 (71%) took folic acid prior to, during, and after the critical period for neural tube development; whereas 13 (20%) started folic acid supplementation once pregnancy was diagnosed. Six women (9%) had conceived without supplementation during the critical period. At follow-up, 79 women (54%) had not conceived; of these, 45 were taking folic acid and 42 women were still planning a pregnancy, while 34 were not taking folic acid and 14 of them were still planning a pregnancy. In our control group of 147 women who were ⱕ14 weeks gestation at the initial contact and who reflected folic acid supplementation in the general population of uncounseled pregnant patients, 90 (61%) were already taking folic acid at the time of their call to Motherisk. However, only 25 (17%) of them initiated use of folic acid prior to conception, significantly less than among the counseled women [47 of the 66 (71%) who conceived, p ⫽ 0.0001]. The average age in this population was 29.6 ⫾ 4.9 years; however, those who took a multivitamin were older than those who did not (30.3 years versus 28.5 years, p ⫽ 0.03). Those not supplementing cited various reasons for this decision (Table 4).

Table 3

Sources of Folic Acid Information as Described by Patients

Source Health professional Magazine or newspaper Friend Relative Motherisk only Other Multiple

Number who Took folic acid 26 31 3 1 14 3 27

(25%) (30%) (3%) (1%) (13%) (3%) (26%)

Number who Did not take folic acid

p value

10 (25%) 5 (12%) 0 0 19 (48%) 1 (2%) 5 (12%)

0.85 0.06 0.67 0.61 0.0001 0.06 0.14

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Table 4 Women Who Were ⱕ14 Weeks post LMPa at the Time of the Initial Call to the Motherisk Program Age Gravidityb Parity Gestational age post-LMP, weeks Patient’s risk for neural tube defects Patients with first prenatal visit prior to initial call to Motherisk Patients taking multivitamins If no, why not?

Was date started prior to conception? Did someone recommend you take a supplement? If yes, who? a b

29.6 years ⫾ 4.9 G 0 (1), G 1 (45), G 2 (49), G 3 (30), G 4 (13), G 5 (4), G 6 (1), G 7 (3), G 8 (1) P0 (67), P1 (58), P2 (14), P3 (5), P4 (1), P5 (0), P6 (2), P7 (0) 0 to ⬍2 (0), 2 to ⬍4 (2), 4 to ⬍6 (15), 6 to ⬍8 (37), 8 to ⬍10 (34), 10 to ⬍12 (23), 12 to ⬍14 (28), 14 to ⬍16 (8) Low (146), high (1) 54 (37%)

90 (61%) Believes she is healthy enough without (9), multivitamins make her sick (11), her physician says its not necessary (3), pregnancy just confirmed/will start soon (4), has severe hyperemesis (1), got out of the habit (1), stopped because of diarrhea (1), no one has told her to/given her any (8), no reason given by patient (10), cannot swallow prenatal vitamins (1), disorganized/hasn’t bought any yet (3), forgot to take them (1), never used vitamins in previous pregnancies (3), just got them (1) Yes 25 (27%), no 65 (71%), unsure 1 (1%) Yes 65 (71%), no 26 (29%) Physician (57), nurse (2), Employee of health food store (2), dietician (1), relative (1), pharmacist (2)

LMP ⫽ last monthly period. Numbers in parentheses are the number of patients or where indicated, percentages.

DISCUSSION In a recent report of compliance with folic acid supplementation in low-risk women of reproductive age, Clark and Fisk (18) reported that of 411 women attending an antenatal clinic for their first pregnancy visit (9–26 weeks, median 15), only 5% supplemented with folic acid and started this prior to conception; 8 (2%) did so through diet modification and 12 (3%) through folate tablets. In our baseline group of 147 women, 25 (17%) supplemented with folic acid and started this prior to conception. Our figure is significantly higher than that of Clark and Fisk, possibly due to the additional 2–3 years that have elapsed since their publication; yet it reflects a very low chance that uncounseled women will be protected against the risk of neural tube defects. In a recent random-digit-dialing telephone survey that interviewed 1005 women aged 18–45 in the United States (19), only 25% of nonpregnant women of childbearing age reported taking a folic acid–containing supplement daily. Our study documents that by counseling women prior to pregnancy, we have significantly improved women’s compliance with folic acid supplementation. In a recent

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study (submitted), we have shown that only a small proportion of family physicians in Toronto routinely and correctly advise women on folate supplementation. Taken together with these present results, it is evident that if physicians or other health professionals fulfill this counseling role, they can achieve very effective results in preventing fetuses from being exposed to low levels of folic acid. It is conceivable that the women in our study are inherently more motivated to comply, given that they represent a self-selected population of women who voluntarily seek advice from a TIS on pregnancy risks and how to avoid them. Yet, without counseling, only 17% of the women we surveyed effectively protected their fetuses with sufficient folic acid. Regardless of this selection bias, our study highlights that a counselling program can effectively influence patient behavior. Counseling and education do not, however, always result in compliance with supplementation. The extent to which a woman’s behavior coincides with medical advice is influenced by her perception of disease severity, the clinical setting, the dose schedule, and the associated side effects of therapy. Non-compliance with supplementation may result from a woman’s inability to perceive the impact of neural tube defects as a disease in relation to other more publicized, prevalent conditions such as AIDS, breast cancer, or Down’s syndrome. Noncompliance may also result directly consequence from the patient’s failure to read or hear about the benefits of supplementation, her feeling that she is not susceptible, or her view of NTDs as insignificant. She may also feel that the costs of supplementation are too high or that her personality is not conducive to risk-prevention behaviour. During the 1950s a group of social psychologists developed a theoretical framework for explaining the likelihood of an individual to undertake a recommended preventative health action (20). Termed the Health Belief Model, it is based on the decision-making concepts of attractiveness of the goal to the individual and on a personal estimate of the likelihood of attaining this goal. Applying this model to exposure to the success of folic acid supplementation counselling, it follows that whether or not a woman will comply with supplementation is dependent upon a complex, interactive interplay of (1) her perceptions of personal susceptibility to having a child with a neural tube defect, (2) her perceived potential benefits derived from supplementing, (3) the degree of severity of the consequences of a neural tube defect, and (d) preexisting physical, psychological, financial and other barriers or costs related to supplementing throughout pregnancy. Certain cues to action must occur in order to trigger behaviour in patients so that they will adhere to recommendations. This interaction between individual perception, modifying characteristics, and internal and external cues to action which ultimately affect whether or not a woman will supplement must be identified before any primary prevention program can have a fair chance of success. The Motherisk Program has recently demonstrated the ability to modify patients’ perceptions of risk (21) and thus prevent unnecessary pregnancy terminations by women exposed to nonteratogenic drugs. This counselling technique can has been transferred to the present group of patients who are planning a pregnancy. Despite showing that more than 70% of patients who conceived took folic acid during the critical time for neural tube closure, we did document that 30% of women did not take it correctly, prior to conception. In addition, of the 79 who did not conceive, 34 were not taking folic acid daily and 14 of these were still planning to conceive. To overcome this noncompliance, we have prepared a one-page patient fact sheet on folic acid. This is being mailed after the first telephone consultation to all patients who are planning

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Figure 1 The Health Belief Model adapted to conditions of folic acid supplementation. Prediction of compliance is not straightforward, since numerous factors interact to affect supplementation. Only if all factors are perceived as maximally beneficial by the patient will the supplementation campaign work with full effectiveness.

to conceive at the time of their initial call in order to reiterate the importance of the message given over the telephone.

CONCLUSION This is the first study to demonstrate that a TIS can successfully intervene to modify women’s compliance with folic acid supplementation. By comparing a group counseled to supplement with folic acid to a group not previously counseled, we have shown that one-on-one counseling resulted in correct supplementation in 71% of those who conceived. In the current absence of either a provincial or a national policy for folic acid supplementation, we expect that there will be many women who have never heard or read about the beneficial effects of periconceptional folic acid. Effective counseling by health professionals can play a pivotal role in reducing the risk of neural tube defects.

ACKNOWLEDGMENT Supported by a grant from The Hospital for Sick Children Foundation.

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REFERENCES 1. Laurence KM, James N, Miller M, et al. Double-blind randomized controlled trial of folate treatment before conception to percent recurrence of neural-tube defects. BMJ 1981; 282: 1509–1511. 2. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131–137. 3. Smithells RW, Nevin NC, Seller MJ et al. Further experience of vitamin supplementation for the prevention of neural tube defect recurrences. Lancet 1983; 1:1027–1031. 4. Vergel RG, Sanchez LR, Heredero BL, et al. Primary prevention of neural tube defects with folic acid supplementation: Cuban experience. Prenat Diagn 1990; 10:149–152. 5. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988; 260:3141–3145. 6. Bower C, Stanley FJ. Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in Western Australia. Med J Aust 1989; 150:613–619. 7. Mills JL, Rhoads GG, Simpson JL, et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Engl J Med 1989; 321:430–435. 8. Milunsky A, Jick A, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262:2847–2852. 9. Czeizel A, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327:1832–1835. 10. CDC. Recommendations for use of folic acid to reduce the number of spina bifida cases and other neural tube defects. JAMA 1993; 269:1233–1238. 11. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrence of neural tube defects. JAMA 1993; 269:1257–1261. 12. SOGC Genetics Committee: Recommendations on the use of folic acid for the prevention of neural tube defects. J Soc Obstet Gynecol Can 1993; Mar (suppl):41–46. 13. Van Allen M, Fraser FC, Dallaire L, et al. Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Can Med Assoc J 1993; 149:1239– 1243. 14. Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1994 update: 3. Primary and secondary prevention of neural tube defects. Can Med Assoc J 1994; 151:159–166. 15. Health and Welfare Canada, Nurition. Canada Food Consumption Patterns Report, Ottawa, 1977. 16. Better news on population. Lancet 1992; 339:1600. 17. Blishen BR, Carroll WK, Moore C. The 1981 socioeconomic index for occupations in Canada. Can Rev Soc Anth 1987; 24:465–486. 18. Clark NAC, Fisk NM. Minimal compliance with the Department of Health recommendation for routine folate prophylaxis to prevent fetal neural tube defects. Br J Obstet Gynecol 1994; 709–710. 19. Centers for Disease Control. Knowledge and use of folic acid by women of childbearing age— United States, 1995. MMWR 44:716–718. 20. Becker MH, Maiman LA, Kirscht JP, et al. Patient perceptions and compliance: recent studies of the Health Belief Model. In: RB Haynes, DW Taylor, DL Sackett, eds. Compliance in Health Care. Baltimore: Johns Hopkins University Press, 1979, pp 78–120. 21. Koren G, Pastuszak A. Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical and radiation exposure during the first trimester. Teratology 1990; 41:657–661.

11 Pregnancy Outcome Following Maternal Exposure to Corticosteroids A Prospective Controlled Cohort Study and a Meta-Analysis of Epidemiological Studies Laura Park-Wyelie, Paolo Mazzotta, Myla E. Moretti, Anne Pastuszak, Lizanne Beique, Laura Hunnisett, Mark H. Friesen, Sheila Jacobson, Sonja Kasapinovic, Debra Chang, Irena Nulman, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Orna Diav-Citrin The Hebrew University, Jerusalem, Israel

C. Laskin and K. Spitzer The Toronto Hospital and The University of Toronto, Toronto, Ontario, Canada

Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION Prednisone—a glucocorticoid used in the treatment of asthma, in transplantation, and in collagen-vascular and other disorders—has been shown to cross the human placenta (1– 3). Despite the well-documented effects of short-term, antenatally administered steroids on improving pulmonary function in the human fetus (4), experimental studies have shown that prolonged, prenatal exposure to prednisone may cause a reduction in fetal growth and birth weight (5). Large doses administered to pregnant mice, rats, and rabbits during organogenesis have caused cleft palate in the exposed offspring (6–8). The same teratogenic effect appears as that seen with the naturally occurring glucocorticoid, cortisone, on the developing palate of mice (9). Direct extrapolation from animals to humans is provisional. In case reports where women were treated during the first trimester, prednisone was prescribed for a plethora of diseases [Hodgkin’s disease (10), leukemia (11,12), renal transplantation (13–15), systemic lupus erythematosus (SLE) (16–24), antiphospholipid antibodies (25–27), asthma (28–30), rheumatoid arthritis (31), regional enteritis (32), glomerulonephritis (33), subchorionic hematomas (34), Takayasu’s arteritis (35), idiopathic thrombocytopenic purpura (36–38), pemphigus vulgaris (39), ulcerative colitis (40), recurrent fetal loss (41), ne151

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phrotic syndrome (42), and chronic renal failure (43)]. Although a variety of birth defects in their offspring were reported, there was no consistent pattern of fetopathy. The increased incidence of low birth weight and stillbirths may be attributable to the underlying maternal condition for which the steroids were administered. There are two case reports of women treated with cortisone during the period of organogenesis [for SLE (44) and idiopathic steatorrhea (45)]. In the first case, the infant was born with a cleft palate of the soft tissue and, in the second, a stillborn male infant was born with a palate that had a large postalveolar cleft. In both cases, cortisone exposure had occurred during the critical window of palate development, between the 45th and 84th days postconception. The most rigorous epidemiological data come from those observational and interventional studies in which women with unexplained recurrent fetal loss (46–51), or autoimmune thrombocytopenia (52) were either randomized or allocated to receive prednisone throughout pregnancy. In these publications, there was no evidence to suggest that the baseline risk for cleft palate was elevated. In light of the paucity of controlled data, we investigated the relative fetal safety of maternal prednisone therapy in a prospective, controlled, observational study. In addition, we conducted a meta-analysis to determine the risk, if any, of steroid use on the fetus with respect to major malformations and, more specifically, oral clefts.

SUBJECTS AND METHODS Prospective Study This was a prospective, controlled, observational cohort study in which the exposed patients (group 1) were women who voluntarily telephoned the Motherisk Program for information about the fetal safety/risk of maternal prednisone exposure during pregnancy. Women were included in the exposed cohort if they had taken systemic prednisone for any indication in the first trimester and if their exposure details and medical history had been collected prospectively by one of our teratology information counselors and documented on the clinic’s standardized intake forms. A second corticosteroid-exposed group consisted of pregnant women who were enrolled in a randomized double-blind clinical trial of aspirin and prednisone (ASA/P) for recurrent fetal loss at the Toronto Hospital (group 2) (53) plus additional women treated with corticosteroids with the same protocol and indication (see below). Women were included if they were between 18 and 39 years of age, medically healthy, had at least two consecutive pregnancy losses prior to 32 weeks, and were positive for at least one of the following on two of three occasions at screening: lupus anticoagulant, anticardiolipin IgG, antilymphocyte IgM antibody, anti–double stranded DNA antibody, activated partial thromboplastin time antinuclear antibody, or anti–single stranded DNA antibody. After confirmation of pregnancy, each woman was randomized to receive either the investigative treatment or placebo. Women in the treatment arm received prednisone, initially as 0.8 mg/kg/day for 4 weeks, which was then reduced to 0.5 mg/kg/day until delivery or fetal loss, and aspirin, 100 mg/day until 36 weeks gestation. Women treated with prednisone who became pregnant after they completed the ASA/P trial, and women who received prednisone at their physician’s discretion were also included. Although considered openlabel patients, they were treated with the same protocol, assessed in an identical fashion, and followed up prospectively.

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The original control group for this randomized controlled trial (RCT) (53) could not be used because of the poor quality of data for pregnancy outcome owing to a large portion of missing data. Therefore, as the unexposed control group, we chose a cohort of pregnant women who voluntarily contacted the Motherisk Program for safety/risk information about either topical retinoic acid for uncomplicated acne or oral astemizole for seasonal allergies (group 3), neither of which has been associated with an increased risk for major malformations (54,55). This comparison group was intended to represent the baseline population of pregnant women. We prospectively collected the following information from every caller: dose, indication and dates of initiation and discontinuation of the medication of concern, and the obstetric, medical, genetic and drug exposure history of the mother. Approximately 1 year after the expected date of delivery, as calculated by the date of the last menstrual period, all patients were telephoned by a Motherisk team member who collected details about the outcome of pregnancy, birth weight, and presence or absence of birth defects, and perinatal and neonatal complications. Follow-up details were subsequently corroborated by written documentation from the child’s physician. Similar maternal and outcome data of those patients from the University of Toronto clinical trial were abstracted from the clinical trial study forms and recoded on the Motherisk follow-up forms prior to statistical analysis. The primary outcome of interest was the rate of major birth defects attributable to corticosteroids, which was compared among the three groups. If other etiologies were identified which were proven to cause the specific malformation, these cases were not counted as malformations likely caused by corticosteroids (see Table 5 for details). The reports of all anomalies were reviewed and classified as major or minor malformations. The relative risk (RR) and 95% confidence intervals (CI 95) for major defects were calculated for each intergroup comparison. Secondary outcome measures included pregnancy outcome and offspring characteristics (gestational age at birth and birth weight). All data were entered into a spreadsheet for statistical analysis using Statview SE1Graphics (Abacus Concepts, Berkeley, California, 1987) for Macintosh computers. For the three-group comparisons of continuous data, a single-factor factorial, nonrepeated analysis of variance (ANOVA) was used and the Fisher’s Least Significant Difference post hoc test for multiple comparisons was used to identify mean differences between groups. Categorical data were compared using chi-square analysis (χ 2 ) or Fisher’s exact test, when appropriate, and significance for multiple categorical comparisons was determined by calculating an adjusted p value ( p adj ) for each computed observed p value ( p obs ) using the following formula: p adj 5 1 2 (1 2 p obs ) n comparisons (56). Meta-Analysis The databases Medline (1966–December 1999), EMBASE (1988–October 1999), and Current Contents (Jan–July 1997) were searched using the following criteria. The search items abnormalities, drug-induced, teratogen, and birth defect were combined using the Boolean operator OR. The search item glucocorticosteroid was combined with the previous search using the Boolean operator AND. A preliminary review of the titles (and abstracts when available) was made to determine whether the article was relevant to our topic. Abstracts of meetings published in the journals Teratology and Pediatric Research for the years 1995–1998 were also reviewed to cover new studies potentially not published yet as full papers. Bibliographies were reviewed for retrieved articles to identify any additional relevant articles. The reviewers were blinded by eliminating all reference to the

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authors, journal, and study location. This was done to reduce the potential bias in the selection of articles, data extraction, and quality assessment. Controlled studies that examined first-trimester human systemic exposure for any corticosteroids, any doses, all indications, any duration, and all languages were included. Both case-control and cohort studies were acceptable for analysis; however, studies consisting of less than 10 corticosteroid-treated patients were excluded. Major malformations were defined using the criteria described by Heinonen et al. (1977) (57). Trials examining topical or inhaled steroids were excluded. A third author was used as an arbitrator in the case of discrepancies between raters. Inclusion of studies was agreed upon by mutual consent between reviewers and the reasons for exclusion were identified. The same procedure was followed during the data extraction and quality assessment scoring. Accepted studies had to report on the rates of major malformations in the corticosteroid and control groups. Data from the accepted studies were extracted in the form of 2 3 2 tables. The following four values were extracted from each study: number of neonates exposed to corticosteroids exhibiting major malformations, number of neonates exposed to corticosteroids without major malformations, number of neonates not exposed to corticosteroids with malformations, and number of neonates not exposed to corticosteroids without malformations. In the case of a woman with multiple pregnancies, each pregnancy was considered to be an independent event. Stillbirths and abortions were excluded from data extraction unless the study specifically mentioned assessment of malformations. The following demographic data of all the accepted studies were recorded where available: disease of the mother, number of neonates, types and doses of corticosteroid used, and type of birth defect. Abstracted data were entered into 2 3 2 tables using the Cochrane Review Manager version 4.0.3. software for IBM-compatible computers. For each of the studies, a MantelHaenszel summary and cumulative OR (with a 95% CI) was calculated. The null hypothesis (of no variation in outcome between n studies) was not rejected (and the pooling of outcomes was considered valid) if the chi-square test of homogeneity was less than the upper 95th percentile of the chi-square distribution with n 2 1 degrees of freedom. An OR of 1 reflected no effect of exposure on fetal outcome, whereas an OR . 1 reflected an increased risk for malformations among corticosteroid exposed groups. A sensitivity analysis was performed to determine the association between corticosteroids exposure and cleft palate. In addition, we calculated an incidence rate of major malformations from the included studies in addition to the studies that were rejected only because they had no control groups but which otherwise met the inclusion criteria. Assessment of the quality of the studies was performed using a quality assessment score for epidemiological studies published by us recently (58). Interrater agreement was measured for inclusion of articles, data extraction, and quality assessment of articles. The correlation between the quality of scores for our studies and the OR was tested in order to determine whether the quality of the studies was biasing our results. The mean, raw mean, and the meta-analytic mean were calculated for the incidence rate of major malformations.

RESULTS Prospective Study During 1985–1995, a total of 184 women met inclusion criteria and completed the postnatal follow-up. In the Motherisk cohort, prednisone was used for Crohn’s disease (by 34 women, 18%), asthma (by 30 women, 16%), ulcerative colitis (by 28 women, 15%), rheu-

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matoid arthritis (by 18 women, 10%), Bell’s palsy (by 7 women, 4%), transplant (by 8 women, 4%), lupus (by 20 women, 11%), sarcoidosis (by 4 women, 2%) and other indications (by 35 women, 19%). Although duration, dose and route of prednisone exposure varied, 138 (75%) women were exposed in the first trimester of pregnancy (Table 1). In the University of Toronto clinical trial, all women randomized to receive oral prednisone and aspirin took an average daily dose of 45 mg 6 14 mg prednisone during pregnancy. Compared to groups 1 and 3, women in group 2 were older; they had more pregnancies that ended in fetal loss and fewer live-born children (Table 2). Compared to the baseline controls (group 3), women in group 1 were more likely to be primigravidas and to have identified themselves as smokers. The rates of previous terminations of pregnancy and reported patterns of alcohol consumption among the three groups were not statistically different (Table 2). In group 1, a total of 184 women delivered 157 infants (three sets of twins); in group 2, a total of 123 women delivered 86 infants (one set of triplets, and two sets of twins); group 3 included 188 women who delivered 171 live-born infants. Women in group 2 were less likely to deliver live-born infants and more likely to experience fetal loss in the first 26 weeks (Table 3). The rate of live-born infants was similar between groups 1 and 3 (157/184 versus 171/188, p 5 0.2) however, the number of elective pregnancy terminations was higher in group 1 (16/184 versus 2/188, p 5 0.01). There was one stillbirth in group 3 and a fetal death (at 26 weeks) in each of groups 1 and 3. The proportion of male to female infants was similar among all three groups. When compared to babies delivered to mothers in groups 1 and 3, babies in group 2 were smaller, born earlier, and more likely to be premature (Table 3). When compared to babies in group 3, babies born to mothers in group 1 were smaller (mean 3112 versus 3428 g, p 5 0.0001), born earlier (mean 38 versus 39.5 weeks, p 5 0.0001) and more likely to be premature (27/158 versus 9/172, p 5 0.0003). Despite these differences, the majority of infants in groups 1, 2, and 3 were appropriate for gestational age (AGA) (139/ 157, 72/78, 158/168, respectively, p 5 0.2) and there was no preponderance of small for

Table 1

Characteristics of Prednisone Exposure in Groups 1 and 2

Therapy duration (weeks) Daily dose (mg) Route PO IV PO and IV Exposure #13 weeks #26 weeks 13–26 weeks Throughout .13 weeks .26 weeks Polytherapy Prednisone plus amniosalicylic acid Prednisone plus azathioprine Prednisone plus other

Group 1 (n 5 184)

Group 2 (n 5 123)

21 6 16 (161) 27 6 29 (173)

21 6 12 (100) 45 6 14 (122)

165/167 (99%) 1/167 (0.5%) 1/167 (0.5%)

126/126 (100%) 0 0

38/184 16/184 11/184 84/184 22/184 13/184 122/182 38/124 13/124 73/124

0 0 0 126/126 (100%) 0 0 124/124 (100%) 0 0 124/124 (100%)

(21%) (9%) (6%) (45%) (12%) (7%) (67%) (31%) (10%) (59%)

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Table 2

Baseline Characteristics of Mothers in the Study Program p values Group 1 (n 5 184)

Maternal age (years) Gravidity G1 G2 Parity P0 P1 Prior miscarriages SA 0 SA 1 Previous abortions TA 0 TA 1 Smoking None Alcohol None

Group 3 (n 5 188)

30 6 5 (186)

33 6 4 (119)

31 6 5 (186)

75 (41%) 112 (61%)

7 (6%) 119 (97%)

86 (46%) 102 (54%)

0.0003

0.6

0.0003

83 (45%) 104 (56%)

91 (74%) 35 (28%)

51 (27%) 137 (73%)

0.0003

0.0003

0.002

153 (83%) 34 (18%)

7 (6%) 119 (97%)

151 (80%) 37 (20%)

0.0003

0.99

0.0003

173 (94%) 14 (8%)

110 (89%) 16 (13%)

175 (93%) 13 (7%)

0.3

0.99

0.02

154/185 (83%)

70/184 (83%)

175 (93%)

0.99

0.01

0.04

152/185 (82%)

7/84 (88%)

141 (75%)

0.97

0.3

0.8

Indicates significance at p 5 0.05. SA Spontaneous abortion. TA Therapeutic abortion.

1 vs. 2

1 vs. 3

2 vs. 3

a

a

Three groups 0.0003

Park-Wyelie et al.

a

Group 2 (n 5 123)

Pregnancy Outcome Characteristics p values

Outcome Live-born infants Miscarriage ,26 weeks Medical abortion Fetal death at 26 weeks Stillbirth Neonatal death Male: female Gestational age (weeks) Premature (,37 weeks) Birth weight (g) AGA: SGA : LGA a Vaginal delivery

Group 1 (n 5 184)

Group 2 (n 5 123)

Group 3 (n 5 188)

157 (85%)b 13 (7%) 16 (9%) 1 (0.5%) 0 0 86 : 68 38 6 3 (157) 27/158 (17%) 3112 6 684 (157) 139: 11 : 7 112/155 (72%)

86 (70%)c 38 (31%) 0 0 0 1 (0.8%) 35 : 43 35 6 3 (87) 63/87 (72%) 2614 6 716 (76) 72 : 3 : 1 47/68 (69%)

171 (91%) 13 (7%) 2 (1%) 1 (0.5%) 1 (0.5%) 0 81 : 84 39.5 6 2 (127) 9/172 (5%) 3428 6 578 (172) 158: 4: 6 131/172 (76%)

1 vs. 2

1 vs. 3

2 vs. 3

0.01 0.0003 0.01

0.2 1 0.01

0.0001 0.0003 0.96

0.99

0.7

0.9

d

d

0.9 0.7

d

d

0.3 0.9

Three groups

d

0.0001

d

0.0001

Pregnancy Outcome After Corticosteroid Exposure

Table 3

0.99 0.4

a

AGA 5 appropriate for gestational age; SGA 5 small for gestational age ,3rd percentile, LGA 5 large for gestational age .97th percentile. Includes three sets of twins (six infants). c Includes two sets of twins and one set of triplets (seven infants). d Indicates significance at p 5 0.05. b

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Table 4 Classification of Birth Defect Status Between Groups p values

No anomalies Major anomalies a

Group 1 (n 5 111)

Group 2 (n 5 65)

Group 3 (n 5 172)

105 (94%) 6 (6%)

63 (92%) 2 (3%)

169 (98%) 3 (2%)

1 vs. 2

1 vs. 3

2 vs. 3

Three groups

0.71

0.16

0.62

0.23

Only major malformations that may be attributable to corticosteroids are included (see Table 5).

gestational age (SGA) or large for gestational age (LGA) babies (Table 3). There was no statistical difference in the rate of vaginal or cesarean section deliveries among the groups. When pregnancies resulting in multiple births were temporarily excluded from analysis of gestational age at birth and weight, mean differences remained statistically different. There was no statistical difference in the rate of major anomalies between the groups (group 1, 6/111; group 2, 2/65; group 3, 3/171, p 5 0.2) (Table 4). The eight major defects reviewed by the dysmorphologist and presented in Table 5 show no consistent phenotype when examined by group of exposure. The RR for major anomalies between groups 1 and 2 was 2.3 [95% CI 0.3,20.5] ( p 5 0.7); between groups 1 and 3, it was 2.0 [95% CI 0.5,9.0] ( p 5 0.4); and between groups 2 and 3, it was 0.9 [95% CI 0.1, 8.3] ( p 5 1.0). None of these was statistically significant. Table 5 Description of all Recorded Major Anomalies in Infants in the Prospective Study Abnormality

Group

Prednisone exposure

Polydactylya

1

Hirschprung’s disease Double-outlet right ventricle, valvar and subvalvar pulmonary stenosis, hypothyroid, hypospadias Multiple birth defects, congenital toxoplasmosisa Undescended testicle (required intervention)

1 1

5 mg/day throughout plus 50 mg/day azathioprine 80 mg/day from 2–2 3/7 weeks 30 mg/day from 0–4.5 weeks

1 1

Cleft palate, hypospadias

1

Severe cerebral palsy, one ventricle enlarged Erb’s palsy a (arm nerve damage due to delivery, hip click, neurological defects) Aortic valve stenosis Pyloric stenosis Dysplastic kidney (stillbirth)

2

a

2 3 3 3

unknown dose from 12–12.5 weeks plus cotrimoxazole 25 mg/day throughout plus 80 mg/day ASA b and 50 mg progesterone in first trimester 15 mg/day throughout plus 200 mg/day carbamazepine, 40 mg/day nifedipine, 100 mg/day atenolol 37.5–60 mg/day from 4–35 weeks plus 100 mg/day ASA until 35 weeks 37.5–22.5 mg/day from 5.5–35 weeks plus 100 mg/day ASA until 35 weeks None None None

These three malformations were not attributable to corticosteroids (polydactyly with family history; mental retardation following maternal toxoplasmosis; Erb’s palsy following birth trauma). These were excluded from the calculation of RR. b ASA 5 acetylsalicylic acid.

Summary of Patient, Drug, and Size of Study for Studies Included in the Meta-analysis

Study and year

Pathology of mother

Study type

# of cases

Popert ’62

Cohort

Warrell and Taylor ’68

Cohort

Heinonen et al. ’77 Mogadam et al. ’81

Cohort Cohort

Mintz et al. ’86 Robert et al. ’94 Czeizel and Rockenbauer ’97

Cohort SLE Case-control N/A Case-control Asthma, hay fever, rheumatoid arthritis, Addison’s disease, subfertility

204 1448 56,557

Rodriguez-Pinilla & Martinez-Frias, ’98 Carmichael & Shaw, ’99

Case-control N/A

12,304

Park-Wyllie et al., 2000 (present study)

Rheumatoid arthritis, SLE, ankylosing spondylitis, psoriatic arthropathy Asthma, eczema, ulcerative colitis, SLE, uticaria, sarcoidosis N/A Inflammatory bowel disease

Case-control Crohn’s disease, asthma, lupus Cohort

Crohn’s disease, ulcerative colitis, rheumatoid arthritis, SLE & other

Corticosteroid(s)

Dosage (prednisolone equivalent)

22

Prednisolone, cortisone, corticotropin

2.5–27.5 mg/day

69

Prednisolone

2.5–40 mg/day

Corticosteroid and/or corticotropin Corticosteroid or corticosteroid and sulfasalazine Prednisone Corticosteroids Dexamethasone, prednisone, cortisone, betamethasone, methylprednisolone, triamcinolone Prednisolone, hydrocortisone, prednisone, triamcinolone Prednisone, cortisone, dexamethazone, triamcinole Prednisone

N/A N/A

50,282 521

1396 372

10 mg/day N/A 5–100 mg/d

Pregnancy Outcome After Corticosteroid Exposure

Table 6

10–30 mg/d N/A 5–80 mg/d

SLE 5 systemic lupus erythematosis. N/A 5 not available.

159

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Meta-analysis From the search of the literature, 455 articles were identified. Ten studies met our inclusion criteria and were entered into the meta-analysis (Table 6) (57,59–67). The Motherisk study (1997) described at the beginning of this manuscript was considered as a single study including only group 1 and 3 (67). The main reasons for excluding studies were absence of a control arm, inadequate reporting of fetal outcome, and inability to verify first-trimester exposure. Eight studies were excluded from the analysis because they lacked a control group; however, these studies reported sufficient information to calculate an incidence rate but not OR (68–75). Three studies were excluded because the number of treated patients was less than 10. Of the 10 accepted studies, 6 were cohort studies (57,59–62,67) and 4 were casecontrol studies (63–66). The time frame of study publications was 1962–1999. The studies included women with varying underlying diseases including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, asthma, inflammatory bowel disease, and arthropathy. Study sample sizes ranged from 22 to over 50,000 neonates. The specific corticosteroids and dosage regimens that were used by the mothers were not detailed in 4 of the 10 studies (57,61,63,66). Of the total, 4 studies examined the effects of fetal exposure to corticosteroids and other medications (61,65–67), while the remaining 6 studies followed women who were presumably only on corticosteroids. Of the 4 case-control studies, one focused solely on the presence of oral clefts as pregnancy outcome for women exposed to corticosteroids in the first trimester (65). When performing the Mantel-Haenszel Summary OR of cohort studies examining major malformations, statistical significance was not achieved [cumulative OR 5 1.45 (95% CI 0.81,2.60)] and the trials were homogeneous (χ 2 5 4.16 with five degrees of freedom) (Fig. 1) However, of the 6 trials included, Heinonen et al. (1997) did not separate major and minor malformations in the exposed group. Since one of our primary outcomes was major malformation rates in corticosteroid-exposed pregnancies compared with nonteratogen controls, analysis was repeated with and without Heinonen’s study, yielding marginally significant results: the Mantel-Haenszel Summary OR was 3.03 (95% CI 1.08,8.54) with a χ 2 5 2.40 with four degrees of freedom (Fig. 1).

Figure 1 Individual and Cumulative Mantel-Haentzel Summary Odds Ratio for Corticosteroid Exposed Cohort Studies for Major Malformations with and without Heinonen (1977).

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Table 7 Malformations Reported in Exposed and Control Subjects from the Cohort Studies Included in the Meta-analysis Corticosteroid-treated group Cleft palate* (3 cases) Ancephalic (2 cases) Congenital deafness Left ventricular atresia (died within 1 month) Hirschprung disease Double-outlet right ventricle; valvar and subvalvar pulmonary stenosis; hypospadias Undescended testicles Other major malformation (undefined) (6 cases)

Control group Aortic valve stenosis Pyloric stenosis Dysplastic kidneys Spina bifida Other major malformation (undefined)

* I also had microglossia and one with hypospadias.

Specific malformations reported by the cohort studies are listed in Table 7. The pooled sample of malformations in fetuses exposed to corticosteroids revealed that cleft palate was the most commonly reported anomaly with three cases being identified, compared to none among the controls. There were 4 case control studies examining the risk of oral clefts. All 4 had a significantly increased OR, with an overall OR of 3.35 [95% CI 1.97,5.69] (Fig. 2). For both cohort and case-control studies, Spearman’s rho did not show a significant correlation between the quality of the studies and their OR (r 5 20.32, p 5 5.38). An incidence rate of 3.5% was calculated using the meta-analytic means and the means of 15 studies. The raw average showed a very similar incidence rate of 3.9%.

DISCUSSION Although the list of epidemiologically proven human teratogens is small, labeling a medication as the cause of a major birth defect has serious clinical implications. In situations where known teratogens are drugs of choice (carbamazepine, warfarin, isotretinoin, lithium, methotrexate, phenytoin, valproic acid), counseling women of childbearing potential to use effective birth control to avoid drug exposure in gestation can possibly avoid fetal

Figure 2 Individual and Cumulative Mantel-Haentzel Summary Odds Ratio for Corticosteroid Exposed Case-Control Studies Focusing on Oral Clefts.

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exposure. When exposure postconception is inevitable, however, evidence-based risk assessment is important for the woman in order to let her make an informed decision on the future of the pregnancy. Prospective Study While prednisone has never been proven to be a human teratogen, there are clinicians who extrapolate animal studies to suggest that the drug can cause cleft lip or palate. They therefore counsel their patients to avoid prednisone therapy during pregnancy. This may have been a factor for some of the 16 women in group 1, who chose to terminate their pregnancies after prednisone exposure. Prednisone is used for a variety of indications by women of reproductive age, making it very likely that risk assessment will be sought by many who intend to conceive while on prednisone therapy. The positive predictive value of animal testing for teratogenicity in humans is not high (76). Interspecies pharmacodynamic differences may account for the difference in susceptibility between humans and animals. Glucocorticoids may mediate their teratogenic effect in animals through a receptor that does not exist in the human embryonic palate (77). In light of the limited number of published pregnancy outcomes following prednisone use for recurrent fetal loss, our study reports outcome for 314 women exposed to prednisone and is the first and largest controlled study to specifically compare the rate of major defects between exposed women (111 with various diseases and 65 with a history of unexplained fetal loss) and a nonexposed cohort. The observed rates of anomalies (6, 3, and 2%, respectively) are within the expected baseline rate and none of the RR from the intergroup comparisons achieved statistical significance. The RR of 2.0 with confidence limits that span 1 may reflect inadequate power. For 2.0 to be statistically significant at an α of 0.05, 90% power, and a baseline incidence of major defects of 5%, we would need at least 300 infants in each group. As likely however, is that this RR of 2.0 reflects potential confounding by the underlying maternal diseases in our Motherisk exposed cohort. When women with prednisone exposure and relatively uncomplicated medical histories were compared to healthy women without prednisone exposure, the RR was 0.9 ( p 5 0.9). Combining groups 1 and 2 in order to pool all cases of prednisone exposure and contrasting this rate of major birth defects to that in the baseline group, we again report no association between prednisone exposure and major birth defects. It is not surprising that the women in group 2 delivered fewer live-born infants, as the association between autoantibodies and lupus anticoagulant in women with a history of recurrent fetal loss is well established (78,79). Recurrent fetal loss is an expected manifestation of numerous autoimmune diseases and an otherwise likely expectation for this population of women. It is most likely that the reduced birth weight and lower gestational ages at delivery of the babies in group 1 compared to baseline controls is due to the underlying maternal diseases. Among the six major defects that could be attributed to corticosteroids in groups 1 and 2, there was no apparent pattern. There was, however, one reported case of an infant born with an isolated cleft palate and impaired neuro-development. His mother took prednisone along with carbamazepine (not known to elevate the risk for cleft lip and/or palate) as well as nifedipine and atenolol throughout pregnancy. Although this does not confirm prednisone as a teratogen, in utero exposure did occur during the critical window of palate

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163

development (between the 45th and 84th days postconception) and prednisone is metabolized to prednisolone, which can be oxidized by placental enzymes to cortisone. There are two previous case reports of maternal cortisone use and cleft palate (44,45). We cannot, however, exclude the fact that this case may have arisen de novo, as the baseline incidence for cleft palate alone is 1 in 2500 (80). In group 1, there was one case of Hirschprung’s disease, which may be familial or may be associated with other syndromes. Although the mother of this infant took prednisone during pregnancy, prednisone may not have caused this outcome.

Meta-analysis To our knowledge, no systematic analysis examining the relationship between first-trimester exposure to corticosteroids and rates of major malformations has been published. Lack of well-designed trials that specifically address major malformations compound the controversy surrounding corticosteroid-induced malformations. The animal studies and case studies suggesting an association with cleft palate prompted us to critically review the existing evidence. The cumulative OR for cohort and case-control studies included in the meta-analysis showed a non-significant increased risk for major malformations associated with corticosteroid exposure, with the Heinonen study and a significant risk without this study (Fig. 2). However, a subanalysis of the cohort studies that specified the malformations revealed three cases of cleft palate among 390 corticosteroid exposures compared with no cases of cleft palate among 708 unexposed fetuses. Some of the studies could not be used because they did not contain any details as to the nature of the major malformations. Of the four case-control studies identified, one focused on the association between corticosteroid use in the first trimester and the incidence of oral clefts. Separately and when combined, the four studies produced a significant summary OR for oral clefts and the trials were homogeneous. Although our meta-analysis could only detect an increased risk for major malformations without the largest trial, it did show a greater than threefold increase in the risk for oral clefts when the fetus was exposed to corticosteroids during the first trimester. As important, it forwards evidence of clustering of cleft palate cases among cohort studies, which is consistent with the existing animal experience. Taken together, these data make epidemiological sense, as oral clefts make up only a small part of all major malformations. The apparent increased risk of oral clefts caused by corticosteroids has to be balanced against potentially serious implications for the mother and indirectly to the fetus if steroid therapy is discontinued or not initiated. Our study may allow clinicians to make a more informed decision for the use of corticosteroid therapy in pregnancy, showing a small but significantly increased risk of oral clefts after first-trimester exposure.

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77. Pratt, RM. Receptor-dependent mechanisms of glucocorticoid and dioxin-induced cleft palate. Environ Health Perspect 1985; 61:35–40. 78. Gleicher N. Pregnancy and autoimmunity. Acta Hematol 1986; 76:68–77. 79. Rai RS, Regan L, Clifford K, et al. Antiphospholipid antibodies and β 2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995; 10:2001–2005. 80. Harper PS. Practical genetic counselling, 4th ed. Oxford, England: Butterworth-Heinemann, 1993.

12 Use of the Retinoid Pregnancy Prevention Program in Canada: Patterns of Contraception Use in Women Treated with Isotretinoin and Etretinate Anne Pastuszak and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Michael J. Rieder The Children’s Hospital of Western Ontario, London, Ontario, Canada

INTRODUCTION When thalidomide was demonstrated to be a potent human teratogen, it was immediately removed from the market. Conversely, isotretinoin and etretinate were introduced to the market with full knowledge of their animal teratogenicity, which had been established in preclinical animal studies (1). Isotretinoin (13-cis retinoic acid; Accutane) is used in the therapy of severe, cystic acne that has proven to be recalcitrant to standard therapy, and etretinate (Tegison) is prescribed for patients with psoriasis and other disorders of keratinization. Both are currently contraindicated in pregnancy. Based on the half-lives of elimination, women discontinuing isotretinoin are advised not to conceive before 1 calendar month has elapsed, and those stopping etretinate are frequently advised that the safe time to wait before conceiving has not yet been established. In some cases, the prescribing physician will define a waiting period of 2 to 3 years before the patient should conceive. Tragically enough, despite clear labeling of isotretinoin as contraindicated during pregnancy, birth defects consequent to in utero exposure were reported soon after its distribution. The pattern of isotretinoin embryopathy is now well known and includes serious craniofacial, central nervous system, cardiovascular, and thymic malformations. Ear abnormalities include microtia, low-set ears, and anotia; central nervous system defects include microcephalus, hydrocephalus, and reduction malformations of the brain; cardiovascular defects include transposition of the great arteries, tetralogy of Fallot, ventral septal defects, and aortic arch abnormalities (2).

Reprinted from Reproductive Toxicology 1994; 8(1)63–68. Copyright  1994 Elsevier Science Ltd.

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Acknowledging that routine labeling of isotretinoin as teratogenic was not sufficient to prevent fetal exposure, the manufacturer, together with the Food and Drug Administration in the United States, developed a Pregnancy Prevention Program (PPP) for isotretinoin, which contains printed material to be used by the prescribing physician in educating the female patient about the serious risk for birth defects (3). Etretinate has not yet been conclusively labeled as a major human teratogen in the medical literature. However, because it is a synthetic retinoid and a derivative of vitamin A, like isotretinoin, extreme caution has been exercised when counseling women of reproductive age about conception during and after etretinate therapy. This unprecedented program contains an information brochure for patients, a qualification checklist, and a line drawing of a hypothetical isotretinoin-exposed fetus. In addition, female patients are asked to sign a consent form acknowledging that they have been instructed through the PPP, that they are aware of the need to use contraception during isotretinoin therapy, and that they will undergo pregnancy testing before, during, and after isotretinoin therapy. The PPP stresses and suggests the simultaneous use of two forms of contraception in an attempt to further reduce the likelihood of fetal exposure. The PPP for isotretinoin was distributed to all isotretinoin-prescribing physicians in Canada in October 1988, and a similar PPP for etretinate followed in 1989. Despite such a campaign to better inform women about the teratogenic risks of retinoids, fetal exposure to these drugs still occurs. Special attention needs to be paid to the potential reasons that lead to fetal exposure, because any strategy that aims to reduce such adverse occurrences must begin with an understanding of the mechanisms that lead to them. We prospectively analyzed a group of isotretinoin- and etretinate-exposed women who contacted the Motherisk Program for counseling about reproductive risks. Using a standardized questionnaire, we investigated and report maternal demographic characteristics, degree of use of the PPP, and pattern of contraception use by such women after they were seen by the physician who prescribed the synthetic retinoids.

PATIENTS AND METHODS Study Subjects The Motherisk Program is a teratogen information service in Toronto that counsels health professionals and members of the lay public about the reproductive safety of exposure to drugs, chemicals, radiation, and infections in pregnancy and lactation. A detailed description of the program can be found elsewhere (4,5). The majority of the callers are from Ontario; however, the service is known across Canada. In the case of isotretinoin and etretinate, the manufacturer, Hoffmann-La Roche Ltd., informed inquiring individuals of the services that Motherisk may provide. All women who voluntarily contacted the Motherisk Program from November 1, 1988, to January 30, 1991, requesting counseling in regard to maternal exposure to isotretinoin or etretinate were included in our study and seen in our clinic at their earliest convenience. If the patient was from a remote area of Ontario or another part of Canada, she was interviewed by telephone. These patients can be categorized as pregnant women who had exposed their fetuses in utero, women inquiring about the safety of a future pregnancy given a previous retinoid exposure, and women who conceived before the recommended waiting period had elapsed.

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A standardized intake questionnaire was designed and used to collect the following information for each patient: maternal age, ethnicity and marital status, gravidity, parity, previous elective and spontaneous abortions, gestational age at first visit to Motherisk, socioeconomic status, and pattern of ethanol and tobacco exposure. We also questioned about the method of birth control used during retinoid therapy and inquired about which contents of the PPP the patient recalled seeing in her physician’s office before she filled her retinoid prescription. Age and contraceptive use of women exposed to etretinate is purely observational, due to the small sample size. To determine whether these women were notably different from the typical patients using our service, isotretinoin-exposed cases were compared to a matched control group. These were patients counseled on the same day as the isotretinoinexposed case about nonteratogenic nonretinoids (drugs proven in large studies to be safe in pregnancy). This procedure controlled for month and year of visit to Motherisk because all cases are entered into our computerized database in chronologic order.

STATISTICAL ANALYSIS We compared the ages, mean gestational ages at first consultation, number of cigarettes smoked per day among smokers, gravidity, parity, and the mean number of spontaneous and therapeutic abortions between the two groups using a paired Student’s t-test. Socioeconomic status for both groups was estimated with the use of the occupational status titles and the Blishen and Carroll scale for women (6) and compared using the nonparametric Wilcoxon signed rank test. Distribution of marital status, ethnicity, and range of alcoholic drinks consumed per day were compared using the Fisher’s exact test.

RESULTS During the defined time period, 26 isotretinoin-exposed women and 7 etretinate-exposed women were counseled. Of the 7 etretinate-exposed women (mean age, 27.5 years ⫾ 4.1 years), 2 (29%) used no form of contraception either concurrent with therapy or for the number of months after discontinuation that was recommended by the prescribing physician, while 4 women (57%) used some form of contraception. One woman conceived 15 months after cessation of etretinate therapy despite having been instructed to wait for 3 years. By her own will, she stopped her oral contraceptives 1 month after discontinuing etretinate. Serum HPLC analysis in our laboratory at 12 weeks gestation detected no etretinate (lowest limit of sensitivity, 5 ng/mL), and none of the metabolites, acitretin and 13cis acitretin. Serial ultrasound examinations during pregnancy failed to detect malformations, and the patient gave birth to a morphologically normal baby in April 1991. The remaining six women did not conceive after etretinate therapy. The age of isotretinoin-exposed women was significantly lower than of their matched controls (25.2 ⫾ 6.7 years vs. 28.9 ⫾ 5.1 years, p ⫽ 0.03) (Table 1). They were also younger than women contacting Motherisk for other exposures and indications (29.9 ⫾ 3 years, p ⬍ 0.01). Nine of the isotretinoin-exposed women (34.6%) were less than 20 years of age (which we defined as adolescent), compared to only one woman (3.8%) in the matched control group ( p ⫽ 0.014). Women exposed to isotretinoin were more advanced in their pregnancy when they first contacted Motherisk than their matched

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Table 1 Comparison of Demographic Characteristics and Secondary Exposure Patterns Between Isotretinoin-Exposed Women and a Matched Control Group Counseled by the Motherisk Program in Toronto

Mean age at first consultation Number of adolescents (ⱕ20 years) Marital status Single Married Data not available Ethnic background White Black Oriental Persian East Indian Data not available Mean gestational age (wks) at first consultation Referral to Motherisk Physician Self Number of alcoholic drinks/day 0 ⱕ1 1–2 Data not available Mean number of cigarettes/day among admitted smokers Mean socioeconomic (SE) index (0, lowest 100, highest) Mean gravidity Mean parity Mean number of previous therapeutic abortions Mean number of previous spontaneous abortions a

Isotretinoin cases (n ⫽ 26)

Matched controls (n ⫽ 26)

p value

25.2 ⫾ 6.7 9

28.9 ⫾ 5.1 1

P ⫽ 0.03 P ⫽ 0.014

11 12 3

8 18 —

NS a

22 3 1 — — — 10.2 ⫾ 8

18 0 1 1 2 4 6 ⫾ 4.2

NS

P ⫽ 0.01

20 6

21 5

NS

15 6 — 5 1.3 ⫾ 4.4

17 7 2 — 3.6 ⫾ 7.3

NS

NS

44.3 ⫾ 16.1

43.9 ⫾ 23.6

NS

⫾ ⫾ ⫾ ⫾

NS NS NS NS

1.7 0.5 0.1 0.2

⫾ ⫾ ⫾ ⫾

1.5 0.6 0.4 0.7

1.9 0.6 0.2 0.4

1.4 0.7 0.4 0.7

NS: P value ⬎ 0.05; mean ⫾ SD.

controls (10.1 ⫾ 8 weeks versus 6 ⫾ 4.2 weeks, p ⫽ 0.01). The two groups did not differ in their ethnic or marital status distributions, obstetrical or gestational histories, or in their use of cigarettes or alcohol (Table 1). Of the 26 isotretinoin-exposed women, 10 (38.5%) did not use any method of contraception during therapy, 6 (23.1%) failed their method of contraception (3 experienced condom failure, 2 failed the oral contraceptive pill, and the partner of 1 patient experienced failure of a vasectomy), and 2 women (8%) elected to stop their method of birth control and continue isotretinoin therapy. Only 8 women (30.8%) used some method of contraception (4 oral contraceptive pills, 3 abstinence, and 1 rhythm) during therapy.

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One might submit that those patients who used birth control were those who knew the drug was teratogenic. This, in fact, is not the case. Twenty of the 26 women using isotretinoin (77%) acknowledged receiving some warning about the drug’s teratogenic potential and the consequent need for effective birth control during therapy. Two women stated that they did not remember receiving such information, one refused to answer this question, and for three cases, data were not available because contact was made with a physician not responsible for the original isotretinoin prescription, not the patient herself. In the worst-case scenario, if we combined the 10 who used no birth control, the 6 who failed the method, and the 2 who discontinued the birth control and assumed that in each case the patient conceived during therapy, we potentially might have observed 18 cases of fetal isotretinoin exposure. Of these 18, only 1 (5.5%) saw all components of the PPP; the remainder were counseled with only single components of the program. Conversely, of the 8 who used birth control, 5 (62.5%) saw all components of the PPP; the remainder were counseled with only single components. These ratios are statistically significant (5.5% versus 62.5%, p ⫽ 0.004) and the clinical significance is clear. Of women who received etretinate, 100% acknowledged receiving some warning about fetal risk consequent to in utero exposure to etretinate.

DISCUSSION Our study focused on the patterns of use of the PPP for isotretinoin and etretinate and the pattern of contraception use in those women who voluntarily contacted the Motherisk Program. We are aware that we are contacted by women who use effective contraception during retinoid therapy and that those women who do ultimately contact us may not represent all retinoid users. Similarly, the frequency of contraception failure in our study is likely not representative of true failure statistics for all retinoid users. However, we feel that our preliminary results have identified an extremely important public health issue. Fetal exposure to isotretinoin cannot be eliminated and will, in fact, continue to occur in those patients who do not use contraception and in those who experience method failure. Physicians prescribing retinoids need to be aware that this is a clinical area of concern. More aggressive contraception counseling and perhaps, rigorous follow-up may be warranted for these patients. More than 38% of the isotretinoin-exposed patients did not use any form of contraception during isotretinoin therapy despite admitting that they were informed about serious fetal risks. While this figure may, at the outset, reflect a selection bias, there is a populationbased study that has reported alarmingly similar numbers. Using 1988 data from the Saskatchewan Database, which records all prescriptions of isotretinoin, Hogan et al. (7) observed that 35% of all women prescribed isotretinoin in that province did not use contraceptive measure even though the drug was known to be teratogenic at that time. Similarly, Lammer (2) has found in a retrospective analysis that 33% of U.S. women on isotretinoin therapy did not use concurrent contraception. Of this same group, 18% failed their method of contraception. The higher prevalence of young women in our group may explain the higher rate of contraception failure, and ineffective contraception in sexually active adolescents may explain the study rise in teen pregnancies (8). Our figure for contraception failure is not entirely surprising, because a large proportion of these women did not use a method with a low failure rate. Barrier methods have high failure rates (spermicides up to 12%, condoms to 6%, intrauterine devices up to

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2.6%), when compared to oral contraceptive steroids (up to 2.6%), female sterilization (up to 0.6%), injectable depomedroxyprogesterone (0.3%), or implanted Norplant capsules (0.04%) (9–11). Pregnancy during isotretinoin therapy is counseled as an unwanted event by physicians and may be a possible factor contributing to contraception failure in our patients. This issue has been addressed by Grady and colleagues (11), who demonstrated that 4% of women seeking to prevent an unwanted pregnancy failed their method of birth control compared to 8.3% of those who sought to delay a wanted pregnancy. Our data suggest that young women are at a higher risk for unwanted fetal exposure to isotretinoin, and this trend may be consistent with the higher trend of unplanned pregnancies in adolescents in general. Hence, any strategy that aims to prevent pregnancy during isotretinoin therapy will need to address the unique difficulties in assuring effective contraception in young women. Women exposed to isotretinoin are likely to seek advice from a counseling service at more advanced stages of pregnancy than women exposed inadvertently to other medications during pregnancy. Assuming these patients have truly been warned by the prescribing physician, one may speculate that in addition to the unplanned nature of these pregnancies, denial, fear, and guilt may play a role in delaying appropriate steps by these pregnant women. It may also be argued that young women suffering from severe, cystic acne may represent a unique group, with long-standing difficulties in body image and sexuality. However, more studies are needed in order to prove that these characteristics have an impact on their approach to contraception. To reduce the chance of fetal exposure to isotretinoin, some countries have restricted dispensing of the drug to men only or prescription writing ability to dermatologists only (12). In Canada, however, the manufacturer has opted to structure the educational process of female patients who will receive isotretinoin. Our data indicate that merely informing women about the enormous teratogenic risk of isotretinoin is not sufficient to modify their sexual behavior toward using effective contraception. Although more than 75% of the isotretinoin-exposed women were warned a priori about the fetal risks associated with in utero exposure, 38% elected to use no contraceptive measures, and almost 25% experienced method failure with no second method being used as backup in case the first failed. We have observed that adherence to instructed contraceptive use tended to increase in women who were counseled with more components of the PPP for isotretinoin as compared with those who saw less of the package; only one woman who saw the whole program used no contraception. Ensuring better physician use of the PPP may help to decrease fetal exposure to retinoids; however, definitive conclusions will require more experience. Beyond the specific impact of gestational exposure to isotretinoin and etretinate, experience from current medical and regulatory initiatives that aim to prevent fetal damage from these drugs will help in crystallizing societal approaches to future, unique molecules that may be fetotoxic. Thalidomide, which was banned in 1961, is now used in groups of women with leprosy, who receive a monthly supply following injection of a systemic contraceptive hormone (13). The risk of contraception failure in sexually active women may prompt the necessity for more careful use and prescription of retinoids and the consideration of monthly prescription refills subsequent only to injection of a birth control agent. Society is painfully divided in its attitudes toward abortion. Presently, in Western countries, three babies are born for every aborted fetus (14). In young women who accept abortion as an option, early counseling after gestational exposure to retinoids is crucial. Our present data indicate that isotretinoin-exposed women tend to seek advice later than women exposed to other medications, thus shortening the period available for informed decisions. For those who do not accept abortion under any circumstances, an even stronger

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emphasis should be focused on well-counseled, stringent use of contraception. The current PPP does not address the woman’s and family’s attitudes to a pregnancy termination in case of fetal exposure to retinoids, despite this being a crucial consideration. This may reflect an unwillingness to confront a controversial and thorny issue, yet for such a preventative program to succeed, incorporation of this important determinant of pregnancy outcome should be considered. In summary, analysis of contraception use during isotretinoin therapy in patients contacting Motherisk reveals that an alarmingly high percentage of women do not use any contraception, and a similarly large group have failed their method despite their having been informed about the fetal risks. Our study shows that this group tends to be young and includes a high number of adolescents, which may suggest that preventative measures must address the special problems associated with unplanned pregnancies in this population of female patients. Our data demonstrate reasonable use of the PPP for isotretinoin in this first years of use and document a trend toward less inappropriate use of contraception in those patients who were counseled with the entire PPP, although larger numbers will be necessary to confirm this observation. ACKNOWLEDGMENT This work was supported by Hoffmann-La Roche Ltd. REFERENCES 1. Kamm JJ. Toxicology, carcinogenicity and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982; 6:652–659. 2. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837–841. 3. Pastuszak AL, Koren G. The retinoid pregnancy prevention program. In: Koren G, ed. Retinoids in Clinical Practice: The Risk-Benefit Ratio. New York: Marcel Dekker, 1993; pp 147–175. 4. Koren G, Feldman Y, Shear N. Motherisk—a new approach to antenatal counselling of drug/ chemical exposure. Vet Hum Toxicol 1986; 28:563–565. 5. Koren G, Pellegrini E. The Motherisk program. Drug Protocol 1990; 5:23–32. 6. Blishen BR, Carroll WK. Sex differences in a socioeconomic index for occupations in Canada. Can Rev Soc Anth 1978; 15:352–371. 7. Hogan DJ, Strand LM. Lane PR. Isotretinoin therapy for acne: a population-based study. Can Med Assoc J 1988; 138:47–50. 8. Russel JK. Sexual activity and its consequences in the teenager. Clin Obstet Gynecol 1974; 1:683–698. 9. Mishell DR. Contraception. N Engl J Med 1989; 320:777–787. 10. Sophocles AM, Brozovich EM. Birth control failure among patients with unwanted pregnancies: 1982–1984. J Fam Pract 1986; 22:45–48. 11. Grady WR, Hirsch MB, Keen N, Vaughan B. Contraceptive failure and continuation among married women in the United States, 1970–1975. Stud Fam Plann 1983; 14:9–19. 12. Lancaster PAL. Teratogenicity of isotretinoin. Lancet 1988; 1:1255. 13. Lane PR, Hogan DJ, Moreland AA. Making the use of isotretinoin safer. Can Med Assoc J 1989; 141:376. 14. Koren G, Bologa M, Pastuszak A. The way women perceive tertogenic risk: the decision to terminate pregnancy. In: Koren G ed. Maternal-Fetal Toxicology: A clinician’s Guide. New York: Marcel Dekker 1990, pp 373–381.

13 Drugs and Breast-Feeding Anna Taddio and Shinya Ito The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A woman who is breast-feeding her 2-month-old infant asks you if she can use fluoxetine during breast-feeding. What would you advise her to do?

INTRODUCTION This chapter reviews the safety of commonly used medications in lactating ambulatorycare patients. These medications include antibiotics, analgesics, antihypertensives, and many others. Breast-feeding mothers may require drug therapy and must make informed decisions about the safety of possible drug consumption by their nursing infants. We hope to provide nursing mothers and their health care providers with some general guidelines for these situations. The mother’s decision to breast-feed during drug therapy should be based on a reasonable understanding of any risks to her infant. The choice to avoid breastfeeding during drug therapy should be made where there is an unacceptable risk to the baby. In many cases, mothers may continue to breast-feed while on drug therapy with little risk to the child. In some situations of short-term courses of drug therapy, a mother may wish to suspend breastfeeding temporarily. It is not known how many women stop breast-feeding due to their concern for drugs in their breast milk. The use of medication, however, is believed to contribute to a mother’s choice to bottle-feed. Other factors that affect this decision are the mother’s parity, education level, social class, psychosocial factors, and socioeconomic class. The type of delivery, and the presence of illness in mother or baby are also contributory factors (1,2). Studies have shown that drug use in the postpartum period is high. One study reviewed medication use in 970 postpartum women in Norway in 1980. According to medical records, almost 98% of these women were breast-feeding when discharged from hospital. Ninety percent received at least one drug during the early postnatal period. The most frequently used drugs were analgesics (mainly codeine and dextropopoxyphene), hypnotics (mainly nitrazepam), and methylergometrine or ergometrine (3). A similar study examined medication use in 2004 postpartum women in Northern Ireland in 1982. Of these mothers, 33% were breast-feeding at the time of discharge from

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hospital. More than 99% of all postpartum women received at least one drug during the first week after delivery. The drugs used encompassed the following drug classes; antibiotics, analgesics, psychotropics, antiepileptics, gastrointestinal drugs, cardiovascular drugs, antihistamines, steroids, hematinics and vitamins, and miscellaneous drugs. The most commonly prescribed medications included iron and vitamin preparations and analgesics. The pattern of prescribing was not much different between breast- or bottle-feeding mothers except for sedative and iron and vitamin use. The mothers that did not breast-feed used sedatives and iron/vitamin preparations more often (4). The use of medication by breast-feeding women implies that nursing infants may be exposed to the medication through ingestion of breast milk. The magnitude of the risk to the baby from this practice determines the drug’s safety, and it must be evaluated in each patient’s case. To assist in this decision, this review summarizes determinants of drug excretion into milk and the methods used to estimate a nursing infant’s dose or exposure. An extensive summary of data obtained from selected studies on drug excretion into milk is provided. Some conclusions are drawn regarding the safety of these medications during lactation. The health professional reading this chapter should note that we do not recommend the use of any drug without the advice that all nursing infants be monitored for any adverse effects during maternal drug therapy. The intensity of this monitoring will vary with the potential risk and with the mother’s own concerns.

BACKGROUND Impact of Breast-Feeding on Infant Health The most recent statement by the American Academy of Pediatrics states that breastfeeding is the optimal mode of nutrition for infants in the first 12 months of life (5). The benefits of using human milk for infant feeding are improved infant nutrition, health, immune function, development, and intellectual performance (5). Breast-feeding has benefits for mothers, families, and society also. These include improved health, psychological, social, economic, and environmental benefits (5). Despite the overwhelming evidence of the advantages of breast-feeding, relatively few women breast-feed their infants for as long as 12 months (5). Many factors lead women to discontinue breastfeeding their infants prematurely; one is maternal use of medications. The benefits of breast-feeding should be considered whenever medications are required by nursing women, for, in many cases, breast-feeding need not be interrupted during maternal drug use. Breast-Milk Production Breast milk is synthesized in the mammary tissue. The alveolar cells make up the functional units of this gland and are responsible for secreting newly formed milk. A lactating breast can be compared to a cluster of grapes, where each grape consists of a cluster of alveolar cells and a central lumen (6). Capillaries surround the alveolar cells (7). These cells discharge milk products into the lumen, where they are transported to the duct system. The ducts meet in channels of increasing size until the nipple is reached (6). The process of lactogenesis is under the control of many hormones; principal among these are estrogen, progesterone, prolactin, and oxytocin. Estrogen and progesterone are

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necessary for the maturation of the mammary gland during pregnancy. These hormones are secreted under the control of the pituitary and placental follicle stimulating hormone (FSH) as well as luteotropic hormone (LH). They have an inhibitory effect on milk production. At the end of pregnancy, the alveolar cells are not completely developed and milk production is relatively slow. Just prior to parturition, the levels of estrogen and progesterone decrease rapidly. The inhibitory effect of these hormones on prolactin are thereby removed (8). Prolactin is the major stimulus for milk production and secretion, and it is released from the pituitary gland under the stimulus of infant suckling (9). Regular milk production is stimulated by the actual nursing period by the infant and continues after the nursing episode. Breast emptying during nursing is prompted by oxytocin, which promotes the contraction of the myoepithelial cells surrounding the alveoli and ducts and causes the ‘‘milk ejection reflex’’ (8). Other supportive hormones include insulin, cortisol, thyroidparathyroid hormone, and growth hormone (10).

Composition of Breast Milk Breast milk contains water, proteins, electrolytes, lipids, carbohydrates (mainly lactose), vitamins, minerals, and immune factors. Its composition changes over time during the course of lactation, which can be divided into three periods according to these changes. The first milk or colostrum, produced by a lactating mother is formed in the first 5 days postpartum. Transitional milk is produced after colostrum. Mature milk follows transitional milk, approximately 2 to 3 weeks postpartum (11). Mature milk contains higher concentrations of lactose and fat than colostrum does, but its protein and immunoglobulin content is lower (12). Water constitutes about 88% of mature milk, while lactose, lipids, protein, and mineral constituents make up 7, 4, 1, and 0.2%, respectively (13). Although the overall composition of mature milk is not thought to vary significantly (14), concentrations of lipid, fat-soluble, and water-soluble vitamins in milk do change according to the mother’s nutrient intake (15). There is a correlation between blood flow and milk production (16). Milk volume is usually low during the first 2 days postpartum but increases rapidly and levels off by 5 days (17). Milk yields reach approximately 800 mL/day or more by 6 months (17). The average daily intake by infants is variable and may determine milk yield (18). The average pH of milk is lower than that of plasma. Morriss (19) has shown that the average pH of milk also changes with time; it is 7.45 in colostrum and 7.0–7.1 for transitional and mature milk. The pH gradually increases during lactation until it reaches 7.4 at 10 months. Milk composition varies throughout the day. There is diurnal variation in fat content, the highest fat levels being found in the morning (20–22). Infants will generally feed 10–15 minutes on each breast, and milk composition is variable during that time. The hindmilk contains more fat than foremilk (21). The lipid content of mature milk also increases with time (23). The differences between milk from premature and term deliveries have been summarized by Anderson (24). Mother’s milk from early lactation in preterm deliveries is higher in fat and protein, lower in lactose, and more varied in its composition compared with milk from mothers with full-term babies. Many of the differences between preterm and term milk, however, become less prevalent as the mother continues to nurse. Drugs ingested by nursing mothers are not known to affect the maturation or pH of milk. They may, however, affect the quantity of milk produced or its composition.

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Bromocriptine, metoclopramide, and oral contraceptives represent a few examples of such drugs. The implications of the use of these medications are discussed later in this chapter.

DRUG EXCRETION INTO BREAST MILK Determinants of Infant Exposure Drugs taken by lactating women may be present in their infants through their consumption of breast milk. The extent of this exposure will depend on the pharmacokinetic properties of the drug in the child and mother. Breast physiology, milk composition, and infant suckling pattern also determine the extent of drug exposure in the infant. Infant Drug Handling There are differences between infants and adults in each of these factors: drug absorption, drug distribution, drug metabolism, and drug excretion. In a review of these factors, Besunder (25) concluded that neonatal gastric acid secretion and gastric emptying are both decreased compared to those in adults; the values for total body water of a newborns are higher than those for adults; fat content is lower, proportionally, than in adults; there is decreased protein binding in neonatal plasma; and there is decreased oxidative metabolism of drugs at birth. The capacity of this metabolizing pathway, however, increases in the first few weeks of life and supersedes adult capacity in childhood. The infant’s capacity for drug conjugation and glucuronidation of drugs is lower at birth. Sulfation, however, is relatively well developed in the newborn (26). Kidney blood flow, glomerular filtration, and tubular function are all reduced in the neonatal period. The infant’s capacity does not reach adult levels until approximately 6 months (25). The decreased clearance rate in neonates has been used to provide a summary of drugs incompatible with breast-feeding based on likely infant plasma levels achieved during maternal therapy (27). The susceptibility of an infant to adverse effects from drugs also depends on the pharmacokinetic characteristics of the drug and the sensitivity of the infant. Adverse reactions can be divided into two groups; those that are dose-related and reflect the pharmacological actions of the drug and those that are idiosyncratic reactions. Many of the adverse reactions reported in breast-fed infants consuming drugs via milk are dose-related, where relatively large doses of the drug have been delivered to the infant via breast milk. The rest of the reports reflect an exaggerated response to the agent by the infant. Idiosyncratic reactions are not dose-related, and it is often difficult to quantify the risk of such reactions occurring. Fortunately, they are not common in breast-fed infants. Summary of the Literature Regarding Drug Excretion in Breast Milk and the M/P Ratio Drugs must pass from maternal mammary capillaries to the alveolar cells before they can be transferred into milk. During this process, drugs must cross a series of membrane barriers (6). Drug molecules may pass through membranes in two ways—passive diffusion and active transport. Lipid-soluble drugs may dissolve in the lipid phase of the membrane and diffuse through it. Water-soluble drugs may diffuse through water-filled pores. Carrier proteins may also transport drugs across membranes (28). The rate of drug passage de-

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pends on the degree of ionization of the drug, lipid solubility, size, and concentration gradient (28). A drug transferred into milk may exist in association with the various milk components (29), such as the aqueous layer, the proteins, or fat. The protein-bound portion of a drug is not available for transfer into milk. Thus, a drug that is highly bound to maternal plasma protein may not appear in breast milk to as great an extent as a drug that is not protein-bound. Propranolol and warfarin are examples of highly protein-bound drugs that do not cross into breast milk in appreciable amounts. The milk-to-plasma ratio (M/P ratio) is a ratio of the concentration of a drug achieved in milk compared to maternal plasma. It is utilized as an estimate of the dose of a drug delivered in milk as a function of the amount in maternal plasma. Different models have been described to explain and predict how drugs are transferred into breast milk (30); however, a two-compartment model is usually sufficient to describe drug transfer in milk. It assumes a central compartment and a peripheral compartment that includes milk. In this model, there is a time dependency of the M/P ratio as a function of distribution characteristics. A method for deriving other mammary models has been described (31). Drug diffusion between plasma and milk is a dynamic and reversible process. Thus, most drugs are not permanently ‘‘trapped’’ in milk. For nursing mothers, this implies that they need not ‘‘pump and dump’’ milk in an attempt to promote drug elimination. This practice may be better suited for other purposes, such as alleviating the pain from engorged breasts or maintaining an adequate milk flow. Numerous clinical trials have measured the M/P ratios of different drugs. The values from these trials have provided health professionals with some measurements as a basis for assessing the safety of drug usage during breast-feeding. However, some reported values have questionable validity because they were obtained from studies with imperfect designs. Namely, investigators have often failed to assure steady-state conditions, to measure metabolites, to account for infant suckling pattern, or to study an adequate number of patients. This topic has been reviewed by Wilson (30); a summary is provided. Many trials report an M/P ratio obtained from only one simultaneously obtained milk and plasma drug level. Clearly, if the M/P ratio varies with time, this will not produce an accurate estimate of the amount of drug the infant may consume. The M/P ratio assumes that a constant ratio is maintained between the maternal plasma drug level and the milk drug level. For drugs in which the plasma and milk concentrations parallel each other over time, the M/P ratio is ideally calculated by taking the area under the curve (AUC) time-course profile in milk and plasma and equating these values in a ratio. One of the basic assumptions for calculating an accurate M/P ratio is that the mother is at steady state. This is because drugs may accumulate in breast milk as a function of dosing. The M/P ratio calculated before steady state is achieved may be an underestimate of the M/P ratio at steady state. Another factor that is overlooked in calculating the infant dose from drugs in breast milk is the contribution of metabolites with additional pharmacological activity (i.e., active metabolites). Metabolites may be formed in the maternal circulation or in breast tissue and transferred to the infant via breast milk. The M/P ratio of drug metabolites is not always measured. Case reports that measure metabolites offer valuable information on the overall transfer of a drug in breast milk. However, one of the pitfalls of many case reports is that they provide sparse details of the analytical methods used to achieve this. The effect of infant suckling on the M/P ratio is not always known. Clinical trials often do not incorporate infant feeding between measurements. It is known that a long

182

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feeding time is associated with an increase in the percentage of lipid in the milk. Thus, for lipid-soluble drugs, the M/P ratio may increase throughout a feeding interval, and this may not be detected in the trial. The calculation of an M/P ratio may also vary depending on the type of milk sample obtained. Some trials analyze the first few drops of milk expressed, while others average the amount collected over an entire feeding interval. The M/P ratio may vary according to the maturity of the milk as well. Trials should report the exact stage of lactation when drug analyses were made. Finally, many of the trials involving measurement of drugs in breast milk utilize small sample sizes. This may be due to factors such as insufficient number of women taking medications while breast-feeding, difficulty in retrieving consent and meeting study criteria, unavailability of assay methods, and perhaps a perception that drug consumption by infants through breast milk is negligible. Results often show considerable variability within and between subjects. It is clear that conclusions drawn from such studies cannot be extrapolated to all lactating women with a measurable degree of certainty. Estimating M/P Ratios and Drug Excretion into Breast Milk Studies of drug transfer into milk are not available for many agents, and the M/P ratio is now known. Another method, however, can be employed to estimate a nursing infant’s drug consumption. It involves calculating an M/P ratio from information known about the physicochemical properties of the drug. Much research has been done on drug transfer into milk in animal species. The principles of these findings are often used to estimate the M/P ratios of drugs if they are otherwise unavailable. Animal studies of drug transfer into milk have shown that the distribution of drugs between maternal plasma and milk can partially be explained using pH partition theory (32–35). Drug transfer occurs by passive diffusion of the un-ionized species; the degree of ionization at plasma pH determining the amount available for diffusion into milk. This can be determined using the pH partition theory (36) and the pKa of the drug: un-ionized ionized ionized Basic drugs: pk a ⫽ pH ⫹ log un-ionized Acidic drugs: pk a ⫽ pH ⫹ log

(1)

Because the pH of milk is generally lower than that of plasma, the concentration that an electrolyte achieves in milk will depend on the pK a of the drug. When the M/P ratio has not been measured, the milk-to-plasma ultrafiltrate ratio (M u /Pu ) (36) may be calculated instead by using the Henderson-Hasselbalch equation. This ratio describes drug partitioning into ultrafiltrate fluids devoid of lipids or proteins. For acidic drugs: M u /Pu ⫽ For basic drugs: M u /Pu ⫽

1 ⫹ 10(pH m ⫺ pKa ) 1 ⫹ 10(pHp

⫺ pK a )

1 ⫹ 10(pK a ⫺ pH m) 1 ⫹ 10

(2)

(pK a ⫺ pH p )

where pH p ⫽ pH of plasma, pH m ⫽ pH of milk. As most drugs are weak acids or weak bases, they will partition into breast milk according to their degree of ionization in the two mediums. Most acids are present in

Drugs and Breast-Feeding

183

dissociated and undissociated forms in milk and plasma. Since only the undissociated form can pass from plasma to milk, an equilibrium is established across the mammary membrane and the concentration of the undissociated drug is equal in both ultrafiltrates. However, since the plasma pH is slightly higher, a larger portion of drug will be present in plasma than milk in the dissociated state. Thus the M u /Pu ratio is less than 1. The situation is reversed for weak bases. Bases exist in dissociated and undissociated forms in plasma and milk. Due to the lower pH in milk, a larger portion of drug will be ionized. Thus, the drug concentration in the milk ultrafiltrate will be higher than in the plasma and weak bases can achieve higher concentrations in the milk ultrafiltrate than in the plasma. This phenomenon is called ion trapping. Un-ionized drugs will have M u /Pu ratios of approximately 1. The amount of drug available to cross into milk is dependent on protein-binding. This is because only the unbound portion is able to diffuse into milk. Binding to milk proteins may also occur, and predictions of M/P ratios without considering protein-binding may mislead conclusions (37). The Henderson-Hasselbalch equation can be modified to allow for correction of protein-binding of drugs in plasma and milk. The calculated milkto-plasma ratio then reflects the ratio of drugs in skim milk to plasma (M skim /P) (38). In this case, the milk is devoid of lipid constituents. M skim M u plasma f u ⫽ ⫻ P Pu milk f u

(3)

where f u ⫽ 1 ⫺ fraction protein-bound. Milk also contains other constituents that can alter drug concentration, such as lipids. Atkinson and collegues (39) have designed a detailed model accounting for drug octanol : water partition coefficient (or lipophilicity) and plasma protein-binding. This model thus estimates a whole milk to plasma ratio (M/P) instead of a M u /Pu or M skim /P ratio. The specific model is: For basic drugs: ln M/P ⫽ 0.025 ⫹ 2.3 ln(M u /Pu ) ⫹ 0.9 ln(Fup ) ⫹ 0.5 ln K For acidic drugs: ln M/P ⫽ ⫺0.405 ⫹ 9.4 ln(M u /Pu ) ⫺ 0.7 ln(Fup ) ⫺ 1.5 ln K where K ⫽ (0.955/f um ) ⫹ (0.045 ⫻ milk: lipid Papp ), f up ⫽ fraction of drug unbound in plasma (1 ⫺ plasma protein-binding), Papp ⫽ apparent partition coefficient at pH 7.2. An explanation of the derivation and use of the model is found in the cited paper. As mentioned, experimentally or theoretically derived M/P ratios are used to estimate the amount of drug excretion in milk. For example, the drug concentration in milk (C m ) can be calculated as follows: C m ⫽ M/P ⫻ C ss

(4)

where C ss is the average maternal plasma level at steady state, which is usually obtained from reference texts. If it is not known, the C ss can be estimated using the following wellknown equation: C ss ⫽

R⫻F CL

(5)

where R ⫽ dose rate, F ⫽ bioavailability, CL ⫽ clearance. These variables are also obtained from reference texts.

184

Taddio and Ito

Once the C m is calculated, it can then be used to estimate infant drug exposure. This is done by estimating the volume of milk (Vm ) that is ingested by a breast-feeding infant per day. An average value of 150 mL/kg/day (29) is often used. The following equation can then be used to calculate the infant dosage (D inf ) per unit time (29). D inf ⫽ C m ⫻ Vm

(6)

In addition to this, one can compare the infant dose with the maternal dose or with the therapeutic dose of the drug in infants. The former option involves calculating the percentage of maternal dose on a mg/kg basis, or the fraction of the dose that the infant receives (Finf ). It is obtained in the following way: Finf ⫽

D inf ⫻ 100 maternal dose

(7)

Another approach used to estimate infant drug exposure takes into account the M/P ratio and the clearance of the drug by the infant. The formula calculates the infant exposure index (40), which is defined as the percentage of the infant’s therapeutic dose per body weight that would be ingested through breast milk. The formula is: Exposure index (%) ⫽ (A ⫻ M/P) / Cl i

(8)

where A is a coefficient (10 mL/min/kg) representing milk intake ⫻ 100, M/P is the milk-to-plasma drug concentration ratio, and Cl i is the clearance of the infant. When Cl i is unknown, then the adult Cl is used as an estimate of Cl i . It is apparent from this formula that drugs with a high Cl i (even in the presence of high M/P) result in relatively low infant exposure. Drugs with low Cl i and low M/P will result in significant infant exposure. These calculations have been used by many investigators to estimate the drug consumption of nursing infants. It should be noted, however, that they are simply estimates of infant exposure to drugs through breast milk. The values obtained by these equations are not sufficient to estimate risk to the infant. Other variables will affect the risk-benefit analysis for drug exposure during breast-feeding. These include the pharmacology of the drug, the presence of active metabolites, the dose and length of therapy, the disposition of the drug in infants, infant age and clinical status, quantity of milk consumed, utilization of the drug in pediatric medicine, and possible effects of the drug on lactation. Most importantly, the probability of developing adverse reactions must be considered when risk is assessed. Breast-feeding mothers should not be encouraged to take medications unless it is necessary. When drug therapy is required during lactation, the safest in a therapeutic class should be chosen and the lowest dose that will achieve the therapeutic goal should be used. If the milk-plasma drug profile has been clearly defined, mothers can also tailor their dose times to avoid peak milk levels during infant feedings. Information Sources on Drugs and Lactation There are many reviews on the topic of drug excretion in breast milk. The most extensive review is from the World Health Organization (WHO) Working Group. In the text Drugs and Human Lactation (41), the WHO Working Group reviews breast physiology,

Drugs and Breast-Feeding

185

mechanisms of drug excretion in milk, clinical trials, and case reports involving drugs and breast milk. They also make recommendations on the safety of the drugs that are reviewed. Another source of information is the text Drugs in Pregnancy and Lactation (42). Here some of the findings from clinical trials and case reports are summarized. The recommendations of the American Academy of Pediatrics (AAP) Committee on drugs are also given; the AAP publishes a summary of drugs considered compatible with breastfeeding (43). Guidelines for studies on drug passage into milk have also been developed by the WHO Working Group (41). They address factors such as sample size of study, drug assay methods, and general study design. Clinical trials of drug excretion in milk are difficult to conduct and the case report makes up much of the information that is available in this area. A brief discussion of the clinical usefulness of case reports is therefore warranted. Obviously, case reports often provide information that is otherwise unavailable. They identify possible adverse effects of drugs from exposure through breast milk. For example, acetaminophen is generally regarded as safe during lactation. However, Matheson (44) reported on a 2-month-old infant who developed a rash after maternal ingestion of acetaminophen. Upon rechallenge at a later date, a similar type of rash developed. The milk concentrations found were similar to those previously reported. Accordingly, it is apparent from this case report that recognizing potential drug-related reactions is important during breast-feeding. Case reports can also verify that some drugs whose safety is suspect may indeed cause side effects in the breast-feeding neonate. For example, Atkinson (27) recommended that atenolol be avoided by nursing mothers with infants below 44 weeks postconceptual age. He based his recommendation on the estimated infant concentrations that would be achieved. Countering this concern, atenolol has been studied in puerperium lactating women without adverse effects. In a case report, however, Schmimmel (45) reported a neonate who suffered from signs of β-adrenergic blockade while her mother was taking atenolol. This was the first report of toxic effects caused by atenolol through breast-feeding and it lends credibility to the models that predicted it could occur. Case reports are often simpler to produce than a clinical trial; only 1 patient may be involved and the time committment may be proportionately smaller. Results are also rapidly available to the scientific community because the analysis of one patient is shorter than for more patients. Case reports may also be useful in introducing analytical methods that can be used by others to analyze drugs in breast milk. The potential disadvantage of case reports is that the events they describe may be interpreted by health professionals as common phenomena. It must be remembered that a single case report does not reflect the risk or safety from drug exposure for all nursing infants. In addition, it does not always prove a cause-and-effect relationship between drug exposure and effect. The information should be extrapolated to other settings with extreme caution. Whenever possible, it is best to incorporate the case report into an overall risk assessment together with other available clinical data. This includes information such as investigations of other available treatment modalities, consideration of infant age and clinical status, and observations of the baby’s breastfeeding pattern. Table 1, which includes data obtained from clinical trials and case reports, shows a summary of the excretion of selected drugs in milk. Recommendations on the safety of selected drugs during nursing follows thereafter.

Summary of Data Obtained from Studies of Drugs in Breast Milk Max. Finf

Standard adult dose

2–22 months

0.91

4.15

325–650 mg q4–6h

SD

2 months

1.02

1.28

4

SD

2–8 months

1.1

1.85

119 120

3 1

SD SD

? 7 weeks

— 0.40 (0.45)

1.58 1.29 (1.35)

as above

1

SD

13 weeks

121

2

MD

8–72 hours

0.59 (0.61) —

122

5

MD

1 day

1.47 (1.5) 0.61 (1.27) 1.57 (2.2)

123

5

SD

⬎1 month

—

6.0

122

5

MD

1 day

—

0.65 (0.89)

Yes

124

1

MD

3 weeks

—

2.25

Yes

125

6

MD

Postcesarean

—

10.17

Ref.

No. pts.

Dose

Analgesics Acetaminophen

117

11

SD

44

1

118

Meperidine

Morphine

Oxycodone

Lactation stage

M/P

M/S

t 1/2 (h)

t max (h)

BF

Comments

2.3

1–2

Yes

No adverse reaction in infants Acetaminophen and metabolite not detected in urine of infants (limit of detection 0.5 µg/mL) Case report of infant rash on two occasions No metabolites detected in milk (limit of detection 100 ng/mL)

Yes 1.24

10–60 mg q4–6h

0.76 2.16

No

2.7 2.5

2 1

No No

Yes 50–150 mg q3–4h

1.17

? Yes

5–30 mg q4h PO

5 mg q6h

2.45

3.4

?

?

M/P morphine ⫽ 2.46 ( ) ⫽ including active metabolite morphine ( ) ⫽ including active metabolite morphine ( ) ⫽ including active metabolite normeperidine Intravenous infusion Neurobehavioral depression observed in neonates during 3rd day of maternal therapy ( ) ⫽ including active metabolite normeperidine Epidural/intramuscular/ intravenous injection Intravenous infusion No adverse effects in neonates ( ) ⫽ including metabolite morphine-3-glucuronide No adverse reaction in neonate Neonatal plasma level 4 ng/mL Maternal dose unspecified; calculation based on 5 mg q6h Peak milk level 226 ng/mL

Taddio and Ito

Mean Finf

Drug

Codeine

186

Table 1

Anti-infectives Acyclovir

1

MD

4 months

0.77

1.17

Amoxicillin

127 128 129

1 1 6

MD MD SD

1 year 7 months 3 days

0.94 1.22 0.08

1.28 1.45 0.23

Ampicillin

130

10

MD

?

—

0.75

Cephalexin

131 132 129

2–3 6 6

SD MD SD

5–7 days 1–8 days 3 days

0.05 0.19 0.06

0.072 1.17 0.15

Cefadroxil

131 129

2–3 6

SD SD

5–7 days 3 days

0.13 0.16

0.29 0.43

Chloramphenicol

131 133

2–3 5

SD MD

5–7 days First week

— 1.88

0.18 5.23

as above 5 134 4 as above 5 131 2–3 135 1

MD SD MD SD SD

Puereperium 4 days 1 week 5–7 days 17 days

1.94 0.56 0.71 1.38 —

3.63 1.49 2.28 1.51 1.08

Ciprofloxacin

Clindamycin

136

1

MD

3 months

1.76

—

137 138

10 5

MD MD

? 1–2 weeks

0.91 —

2.27 6.2

139 131 140

2 2–3 1

MD SD MD

? 5–7 days 1–5 days

0.93 0.81 —

1.35 1.44 —

200 mg tid– 200 mg 5x/day

Yes

0.6–4.1

3.24

2.8

0.013–0.043

250–500 mg q8h 250–500 mg q6h

4–5

? Yes ?

0.23

Yes

250–1000 mg q6h

0.008–0.14

4–5

? 5 of 6 ?

500–1000 mg bid

0.009–0.019

6–7

? ? ? ?

50 mg/kg/ day divided q6h

0.6 0.47–0.59

1.8

1.4

250–750 mg q12h

1.6–2.14

2

No adverse reactions in infant

No difference in monitored parameters in infants compared with control group Administered as pivampicillin

Chemical method of analysis used measures antimicrobially effective fraction along with ineffective metabolites

? ? ? ? No Yes

150–450 mg q6h

One infant urine sample contained 1.08 µg/mL

Drugs and Breast-Feeding

126

One milk level reported Infant serum level below detection limit (0.03 µg/mL)

? No ? ? Yes

187

Intravenous therapy No milk levels obtained Report of neonatal bloody stools, but neonate previously treated with gentamicin and ampicillin

Table 1

Continued Dose

Cloxacillin

131

2–3

SD

5–7 days

0.072

Erythromycin Fluconazole

131 141

2–3 1

SD MD

5–7 days 8 days, 20 days

0.4 —

0.504 16.8

142

1

SD

12 weeks

12.5/day a

17.6/day a

Isoniazid

143

1

SD

?

Ketoconazole Metronidazole

144 145

1 12

MD MD

146

11

as above

147

Lactation stage

Max. Finf

Standard adult dose

0.144

250–500 mg q6h 250 mg qid 100–200 mg daily

10.0 (12.2)

5–10 mg/kg/ day

1 month 1 week

0.4 9.0 (13.2)

1.4 11.64 (15.9)

20 mg daily 250 mg bid– 750 mg tid

MD

First month

8.55 (11.7)

4

MD

First month

10.8 (13.4)

13.5 (18.2)

3

SD

6–14 weeks

2.78

5.04

M/S

t 1/2 (h)

t max (h)

BF ?

0.9 0.75

—

18.3 (24)

M/P

26.9

? ?

30

No

5.9

3

No

0.91

Yes Yes

1

Yes

1

Yes

2–4

No

Comments Intramuscular injection

a

Dose calculation based on infant consumption on a daily basis due to fluconazole’s long half-life in milk Peak acetylisoniazid milk level 5 h postdose; milk half-life 13.5 h ( ) ⫽ including metabolite acetylisoniazid Neonatal stool changes and Candida isolated in more cases than controls; no serious adverse reactions in neonates Neonatal plasma levels 1.27–2.41 µg/mL; metabolite levels 1.1– 2.41 µg/mL (in 7 neonates) M/P metabolite ⫽ 0.77 ( ) ⫽ including active hydroxymetabolite No adverse reactions in neonates Neonatal plasma metronidazole level 0.3–1.4 µg/mL; metabolite level 0.1–0.8 µg/mL M/P hydroxymetabolite ⫽ 1.2 ( ) ⫽ including active hydroxymetabolite No adverse reactions in neonates Neonatal plasma metronidazole level 0.6–4.9 µg/mL; metabolite level 0.4–2.3 µg/mL M/P hydroxymetabolite ⫽ 1.2

Taddio and Ito

No. pts.

188

Mean Finf

Ref.

Drug

148 149

13 1

SD MD

3–8 days 2 weeks

150

9

MD

151

?

Ofloxacin

152 as above 137

Penicillin

0.04 —

0.12 —

1000 mg qid

?

—

1.13

50–100 mg qid

MD

1–4 days

—

—

3 3 10

MD MD MD

2–5 days 2–5 days ?

— — 1.46

4.2 6.54 2.71

153

7

SD

2–5 days

—

0.054

Penicillin V

154

18

SD

?

0.04

0.21

Sulfamethoxazole

155

50

MD

First 10 days

2.0–2.5

—

Sulfisoxazole

156

6

MD

?

—

—

Tetracycline

157

5

MD

?

0.51

1.16

Trimethoprim

131 155

2–3 50

SD MD

5–7 days First 10 days

0.88 3.75–5.51

1.44 —

Vancomycin

158

1

MD

Puerperium

5.7

—

Nitrofurantoin

0.061

No Yes

0.27–0.31

No No

200–400 mg q12h 1–10 million units per day divided q4– 6h 125–500 mg q6–8h

400–1000 mg q12h 1000 mg qid

2.2 2.3 0.98–1.66

1–8

0.1 7.2

2–8

Intramuscular injection

14 infants 0.52 mg/L detected in urine of one infant; undetectable in another infant tested 3 infants with looser stools Yes 1 of 6

Yes

1.25

None detected in 20 milk samples (detection limit 2 µg/mL)

No No ? ?

250–500 mg q6h

A mean of 0.45% of the 24-h maternal dose was recovered in milk over a 48-h period (including metabolite) Detected in urine of the breastfeeding infant M/S N-acetyl sulfisoxazole ⫽ 0.22; milk half-life 8.9 h No adverse reactions in infants Infants’ serum ⬍0.07 mg/L

? Yes ?

Intravenous therapy Single milk level obtained 4 h postdose

189

80–160 mg q12h 125–500 mg q6–8h PO

2

0.06

Case report of hemolytic anemia in neonate negative for G6PD deficiency

Drugs and Breast-Feeding

Nalidixic acid

190

Table 1

Continued Max. Finf

2–30 days

3.0 (4.3)

3.32 (5.27)

MD

3–28 days

2.44 (2.97)

4.5 (5.0)

19

MD

2–35 days

2.72 (4.35)

3.83 (6.4)

162

1

MD

5 weeks

2.07

—

163

3

MD

2 days–5 weeks

3.78 (5.48)

4.66 (7.41)

164

?

MD

3–32 days

—

—

0.39

?

165

?

MD

?

—

—

0.41

?

166

1

MD

3 weeks

—

—

Ref.

No. pts.

Dose

Anticonvulsants Carbamazepine

159

1

MD

160

4

161

Lactation stage

Standard adult dose

M/P

M/S

10–20 mg/ kg/day

0.39

0.36

t 1/2 (h)

t max (h)

BF

Comments

Yes

No adverse reaction in infant Infant serum level 1.1–1.8 mg/L Mother also taking phenytoin ( ) ⫽ including active metabolite 10,11-epoxide Steady-state serum level in neonates 1.0 µg/mL Neonatal sedation and hyperexcitability noted M/S 10,11-epoxide ⫽ 0.49 ( ) ⫽ including 10,11-epoxide No abnormalities noted in breast-fed infants Neonatal serum levels ⬍1.5 µg/mL in 3 tested neonates M/P 10,11-epoxide ⫽ 0.53 ( ) ⫽ including 10,11-epoxide One milk level obtained No adverse reaction in infant Mother also taking primidone No adverse reaction in infants Infant plasma level 0–1.8 µg/mL M/P 10,11-epoxide ⫽ 1.05 ( ) ⫽ including 10,11-epoxide Mean milk level 1.9 µg/mL (0.8–3.8 µg/mL) Mean milk level 1.8 µg/mL (0.5–3.8 µg/mL) Neonatal cholestatic hepatitis after exposure throughout pregnancy and lactation

Yes

?

Yes

0.6

Yes

Yes

Taddio and Ito

Mean Finf

Drug

Phenobarbital

Phenytoin

167

1

MD

3–5 days

164

?

MD

3–32 days

168

1

MD

3 days–5 months

68.6

99

169

5

MD

3–28 days

51.2

81.3

165

?

MD

?

43.2

164

?

MD

3–32 days

170

6

MD

1–3 months

164

?

MD

165

?

171

172

48.9

53.8

—

—

297

1000–1500 mg/day

0.94

No

0.79

?

0.8

30–100 mg/ day

Yes

0.86

Yes

0.36

?

0.46

?

—

—

4.8

8.8 (9.84)

3–32 days

—

—

0.18

?

MD

?

—

—

0.19

?

1

MD

1 week

0.58

0.68

2

MD

1–33 days

4.8

7.8

100 mg tid

Yes

0.13

0.45

Yes

Yes

Mean milk level 21.3 µg/mL (18–24 µg/mL) No adverse reaction in infant Peak infant plasma level 29.5 mg/L 4 of 6 breast-feeding neonates hyperexcitable or sedated; 5 of these mothers taking additional antiepileptics Neonatal serum levels 15–40 µg/mL in 5 breast-fed neonates Maternal dose unspecified; calculation based on 100 mg/ day Mean milk level 4.8 µg/mL (0–33 µg/mL) Mean milk level 10.4 µg/mL (0.5–33 µg/mL) No adverse reactions in infants 2 of 6 infants with measurable levels of 0.12 and 0.18 µg/mL ( ) ⫽ including conjugated and unconjugated 4-OH phenytoin Mean milk level 0.8 µg/mL (0.5–1.4 µg/mL) Mean milk level 0.7 µg/mL (0–2.2 µg/mL) 5 infants breastfed nursing did not affect the elimination of phenytoin from exposure in utero No adverse reactions in infants

Drugs and Breast-Feeding

Ethosuximide

191

Continued

Drug Primidone

Valproic acid

Max. Finf

3–32 days

—

—

MD

?

—

?

MD

First month

—

174

4

MD

4–27 days

175

1

MD

176 177 178

11 1 6

MD MD MD

No. pts.

Dose

164

?

MD

165

?

173

Standard adult dose

M/P

t 1/2 (h)

t max (h)

BF

Comments

0.81

?

7.47–9.96

0.71

?

—

0.72

Yes

8.49 (18.3)

21.2 (37.8)

0.72

Yes

5–29 days

2.88

4.06

Mean milk level 2.3 µg/mL (0.5–6.7 µg/mL) Maternal dose unspecified; calculation based on standard adult dose Mean milk level 2.1 µg/mL (0–8.3 µg/mL) Withdrawal reaction in 1 of 6 infants breast-fed Peak neonatal serum level in 2 neonates tested; primidone, phenobarbital, PEMA levels 2.5, 13, and 1.4 µg/mL, respectively M/S metabolite phenobarbital ⫽ 0.36 M/S metabolite PEMA ⫽ 0.64 2 of 5 breast-fed neonates with poor feeding for first 5 days of life Serum levels of 1 neonate; primidone, phenobarbital, PEMA 0.8–1, 1.5–3, and 0.5–0.6 µg/mL, respectively M/S phenobarbital ⫽ 0.41 M/S PEMA ⫽ 0.76 ( ) ⫽ including metabolites phenobarbital and PEMA No adverse reaction in infant Undetected in infant serum at 1 month

3–6 days 62–130 h 3–82 days

1.22 0.58 1.12 (1.25)

3.8 0.85 6.98 (7.63)

Lactation stage

250 mg tid– qid

M/S

Yes

15–60 mg/ kg/day divided tid 0.05 0.01–0.02 0.027

? ? Yes

M/S 3-keto metabolite ⫽ 0.074 ( ) ⫽ including 3-keto metabolite; other metabolites not detected (⬍0.1 µg/mL)

Taddio and Ito

Mean Finf

Ref.

192

Table 1

1

MD

3 months

180

1

MD

4–6 months

1.06 (1.89)

1.2 (2.1)

181

1

MD

6–8 weeks

1.29 (1.79)

1.36 (1.89)

Clomipramine

182

1

MD

4–35 days

2.4

3.75

Desipramine

183

1

MD

10 weeks

0.84 (1.74)

1.38 (3.0)

Doxepin

184

1

MD

1–4 months

0.38 (1.09)

—

185

1

MD

8 weeks

0.19 (0.29)

0.31 (0.43)

Antidepressants Amitriptyline

50–150 mg/ day

Yes

Infant thrombocytopenia purpura, anemia and reticulocytosis after exposure throughout pregnancy and lactation; infant serum valproic acid 6.6 µg/mL

Yes

No adverse reaction in infant Infant serum amitriptyline ⬍5 ng/mL; nortriptyline ⬍15 ng/mL ( ) ⫽ including active metabolite nortriptyline Infant plasma levels below limit of detection 10 ng/mL ( ) ⫽ including active metabolite nortriptyline No adverse reaction in infant

Yes

75–150 mg/ day 75–150 mg/ day

0.76–1.62

75–150 mg/ day

1.08–1.66

Yes Yes

Yes

Yes

193

No adverse reaction in infant Infant plasma desipramine ⬍1 ng/mL; hydroxydesipramine ⬍5 ng/mL ( ) ⫽ including metabolite 2-hydroxydesipramine No adverse reaction in infant Infant plasma doxepin ⬍5 µg/L; desmethyldoxepin 15 µg/L M/P desmethyldoxepin ⫽ 1.02–1.53 ( ) ⫽ including metabolite Ndesmethyldoxepin Case report of infant sleepiness Infant serum doxepin 3 µg/L; desmethyldoxepin 58 and 66 µg/L on 2 occasions ( ) ⫽ including metabolite Ndesmethyldoxepin

Drugs and Breast-Feeding

179

194

Table 1

Continued Max. Finf

20–747 days

3.1 (6.5)

6.77 (17.18)

MD

5 months

1.3 (3.17)

—

Yes

1

MD

17 weeks

1.89 (3.35)

3.02 (5.36)

Yes

189

1

MD

14 weeks

0.65

—

190

1

MD

6 weeks

0.07 (0.19)

0.13 (0.29)

191

2

MD

1 month

—

1.64 (4.97)

192

1

MD

6–7 days

1.3

2.9

Sertraline

193 as above

1 1

MD MD

3 weeks 3 weeks

— 0.24

— 0.39

Trazodone

194

6

SD

3–8 months

0.27

0.43

Zopiclone

195 196

3 12

SD SD

? 2–6 days

0.5 0.26

1.27 1.37

No. pts.

Dose

186

10

MD

187

1

188

Fluvoxamin Imipramine

Fluoxetine

Nortriptyline

Lactation stage

Standard adult dose 20–40 mg/ day

M/P

M/S

t 1/2 (h)

0.88

t max (h)

BF

Comments

3

Yes

No adverse reactions in 11 infants ( ) includes active metabolite norfluoxetine Plasma fluoxetine and norfluoxetine ⬍1 ng/mL in 1 infant tested Urine fluoxetine 2–17 ng/mL in 4 of 5 infants tested Urine fluoxetine 11–13 ng/mL in 2 of 5 infants tested One milk level reported ( ) ⫽ including active metabolite norfluoxetine No adverse reaction in infant ( ) ⫽ including active metabolite norfluoxetine No adverse reaction in infant One milk level reported No adverse reaction in infant ( ) ⫽ including active metabolite desipramine M/P desipramine ⫽ 0.91 ( ) ⫽ including active metabolite desipramine No adverse reaction in infant; normal motor development at 4 months Infant serum ⬍10 ng/mL No adverse reactions in infant Infant serum ⬍0.5 ng/mL

Yes

100–200 mg/ day 75–150 mg/ day

30–100 mg/ day

50–200 mg/ day 150–400 mg/ day 7.5 mg prn

Yes

0.91

Yes

0.87–3.17

Yes

0.142 0.6 0.51

5.3

5–9

Yes Yes

2

No

2.4

? No

Taddio and Ito

Mean Finf

Ref.

Drug

6

SD

1–12 months

—

0.18 (0.34)

10 mg/day

1.2

198, 199

4

MD

5–12 months

(0.16)

(0.45)

60 mg q12h

(0.21)

200

3

SD

14 weeks–18 months

0.5

0.84

2.5 mg q4– 6h

0.5–0.56

?

Antihypertensives Acebutolol

201

3

MD

3–9 days

1.55 (5.31)

3.09 (8.07)

400–800 mg/ day

1.9–9.2

?

Atenolol

202

1

MD

1–6 weeks

19

25

50–200 mg/ day

2.9

203

7

MD

Puerperium

9.44

15.43

204 205

4 11

MD MD

4–12 days ?

9.8 6.39

25 —

206 45

5 1

MD MD

Puerperium 1 week

5.67 4.22

9.36 —

Captopril

207

11

MD

?

0.009

0.014

12.5–25 mg tid

Clonidine

208

9

MD

1–5 days

4.14

—

0.2–1.2 mg/ day divided qid

as above

9

MD

10–14 days

7.85

—

Yes

as above

9

MD

45–60 days

6.70

—

Yes

Terfenadine

Tripolidine

(14.2)

2

No

(4.3)

No

8

4.5 1.1–3.1

Yes

#? 2–6

Yes Yes

Yes Yes

3.8

No

Yes

Peak metabolite level 5.3 h postdose M/P metabolite ⫽ 0.8 ( ) ⫽ including active metabolite descarboethoxyloratadine ( ) ⫽ including carboxylic acid metabolite Terfenadine ⬍10 ng/mL

Hypotension, bradycardia in 1 neonate M/P diacetolol ⫽ 2.3–24.7 ( ) ⫽ including active metabolite diacetolol No adverse reaction in infant Infant plasma level, below detection, 10 ng/mL Serum level 0.07 mg/L in 1 neonate; no adverse reaction Infant plasma level ⬍3 µg/L No adverse reactions in infants Detected in urine of 3 tested infants No adverse reactions in infants One milk level reported Neonatal bradycardia, cyanosis Neonatal serum level 2010 ng/ mL on one occasion Several mothers nursed their infants during therapy with no adverse reports in infants M/B AUC ⫽ 0.031 Mean neonatal serum level 0.65 ng/mL Mean neonatal serum level 0.5 ng/mL Mean infant serum level 0.25 ng/mL

195

197

Drugs and Breast-Feeding

Antihistamines Loratadine

196

Table 1

Continued Max. Finf

Standard adult dose

0.69

0.83

3–45 days

—

—

30–60 mg q6–8h 2.5–40 mg/ day

SD

Puerperium

0.016 (0.03)

0.05 (0.07)

1

MD

8 weeks

—

0.8

213

25

MD

3 days

0.10

0.45

214

3

MD

6–9 days

0.30

0.59

215

1

MD

17 days

1.22

1.75

216

4

MD

30–60 hours

—

217

3

MD

1–8 weeks

—

0.09 (0.72) 1.19 (3.2)

218

8

MD

?

No. pts.

Dose

Diltiazem

209

1

MD

18 days

Enalapril

210

3

SD

211

5

Hydralazine

212

Labetolol

Methyldopa

Lactation stage

0.2 (0.51)

—

M/P

M/S

t 1/2 (h)

t max (h)

BF

Comments

No ?

0.005–0.043

No

Enalapril not measured; enalaprilat milk level ⬍0.2 ng/ mL Normal angiotensin-converting enzyme activity in milk M/S enalaprilat ⫽ 0.021–0.031 ( ) ⫽ including active metabolite enalaprilat

Yes

10–50 mg qid 200–600 mg bid

24 of 25 0.8–2.6

2–3

Yes

Yes

250 mg bid– 500 mg qid

? 0.19–0.34

Yes

0.46

Yes

No adverse reactions in neonates Neonatal plasma level above detection (21 µg/L) in 1 of 2 neonates tested No adverse reaction in neonate Neonatal serum level ⬍0.2 µg/mL ( ) ⫽ including conjugated (and free) methyldopa No adverse reactions in infants 1 of 3 infants with detectable plasma level of 0.09 µg/mL (detection limit 0.05 µg/mL) ( ) ⫽ including conjugated (and free) methyldopa Maternal dose unspecified; calculation based on 750 mg/ day ( ) ⫽ including conjugated (and free) methyldopa

Taddio and Ito

Mean Finf

Ref.

Drug

219

9

MD

?

220

8

MD

3–5 days

Minoxidil

203 204 221

3 3 1

MD MD MD

4–6 months 4–60 days 2 months

Nadolol

222

12

MD

Nifedipine

223

13

224

1.0

3.6

0.75–1.5

2.95–5.9

— 1.26 1.34 (1.54)

3.0 2.2 5.0 (5.41)

⬎1 month

4.1

5.0

MD

1–100 days

0.1

—

1

MD

?

—

0.53

225

1

MD

10 days

—

Nitrendipine

226

2

MD

⬎3 months

Oxprenolol

228

9

MD

3–6 days

0.1 (0.26) 0.45

1.04 (1.53) 0.25 (0.54) 1.5

Propranolol

229 230

12 3

MD MD

⬍4–⬎8 days First week

0.72 0.3 (1.0)

2.1 1.0 (2.0)

231 232 206

1 1 5

MD MD MD

2–3 months 3–6 days Puerperium

0.19 0.26 0.30

0.24 0.45 0.41

Sotalol

233

5

MD

First week

2.18

41.95

Timolol

234 235 229

1 1 11

MD MD MD

5, 105 days 5–7 days ⬍4–⬎8 days

— 21.8 1.1

23.6 28.1 3.3

50–100 mg bid

3.7

Yes

2.8

Yes 3.6

No Yes Yes

2–3.1 10–40 mg/ day 4.6

80–240 mg/ day 20 mg q12h

20 mg bid– 16 mg/day divided bid–tid

6

3.3

0.2–0.4

1

No

1

Yes

3–4

No

0.29 0.33–1.65

? ?

6.5

2.4–5.6 5–10 mg bid

Yes Yes Yes Yes

5.4

2.75–3.57 0.8

Sustained released nifedipine No adverse reactions in infants

( ) ⫽ including pyridine metabolite ( ) ⫽ including inactive pyridine metabolite

?

0.45

3

80–160 mg bid

Infant plasma level ⬍3 µg/L No adverse reaction in infant ( ) ⫽ including glucuronide metabolite

No Yes ⫽ 4

10–20 mg q8h

10–40 mg/ day 60–320 mg/ day divided tid

21.8

Peak neonatal plasma level 0.5–45 µg/L

Drugs and Breast-Feeding

Metoprolol

Yes No ?

M/P naphthoxylactic acid 0.19–0.42; milk half-life 4.2 h ( ) ⫽ including propranolol glucuronide and naphthoxylactic acid No adverse reaction in infant No adverse reaction in neonate No adverse reactions in neonates No adverse reactions in neonates No adverse reaction in infant

197

Continued

Drug Verapamil

Anti-inflammatory Acetylsalicylic acid

198

Table 1

Mean Finf

Max. Finf

3–5 days

0.09

0.14

MD

8 weeks

0.38 (0.51)

0.51 (0.68)

1 1

MD MD

13 days 3 months

0.55 0.10 (0.13)

0.91 0.30 (0.38)

120

1

SD

7 weeks

0.45

0.55

as above 240

1 1

SD MD

13 weeks 6 months

— 1.8–2.6

0.74 3.2–4.7

241

1

MD

9 weeks

—

—

Yes

242

1

MD

2 weeks

—

—

Yes

Ref.

No. pts.

Dose

236

1

MD

237

1

238 239

Lactation stage

Standard adult dose

M/P

M/S

t 1/2 (h)

t max (h)

0.23

80 mg tid– qid 0.64

Comments No adverse reaction in neonate Neonatal plasma level 2.1 ng/mL No adverse reaction in infant Infant plasma verapamil and norverapamil ⬍1 µg/L ( ) ⫽ including metabolite norverapamil

Yes

0.6

325–650 mg q4h antipyretic dose

BF Yes

4.29

2 1

No Yes

No

0.05

0.03–0.34 2.6–3.9 g/ day in divided doses–antiinflam. dose

Infant plasma verapamil and norverapamil ⬍1 µg/L Norverapamil peak milk level 2 h postdose; milk half-life 1.34 h; M/P ⫽ 0.16 ( ) ⫽ including metabolite norverapamil

0.04–0.08

3

Yes

Yes Maternal dose unspecified; calculation based on standard adult dose Peak milk level 1 mg/dL

Taddio and Ito

No milk levels obtained No adverse reaction in infant; infant serum level 0.47 mmol/L (infant 50% breastfed) No milk levels obtained Neonatal metabolite acidosis; serum salicylate level 24 mg/dL

243

6

SD

?

—

—

Flurbiprofen

244 245 246

12 10 1

MD SD MD

3–5 days ⬎1 month Mature milk

— — —

0.29 0.17 —

247

12

MD

3–5 days

—

—

248

16

MD

⬍10 days, 10 months

—

1.21

249

1

MD

4–6 days

—

—

Ketorolac

250

10

MD

2–6 days

—

0.18

Mefenamic acid

251

10

MD

2–4 days

0.2 (1.2)

0.79 (2.4)

250 mg q6h

Naproxen

252

1

MD

5 months

1.79

2.21

250 mg bid– qid

as above

1

MD

6 months

2.45

2.80

253 as above 254

1 1 4

MD MD MD

13 months 8 months 3—4.5 months

3.6 3.6 3.51

7.65 4.95 6.345

Ibuprofen

Indomethacin

Piroxicam

?

25–50 mg tid 50 mg q6h 0.019

3

400–800 mg q4–6h

No No Yes

? 25 mg bid– 200 mg/ day

Yes

0.37

Yes

10 mg qid

Yes

4

Mean infant level 0.08 µg/mL 1 hour after nursing ( ) ⫽ including metabolites

Yes Yes

0.01–0.03

Ibuprofen and major metabolites not detected in milk (limit of ibuprofen detection 0.5 µg/mL) No ibuprofen detected in milk (limit of detection 1 µg/mL) Rectal administration No adverse reactions in neonates; plasma levels in 6 of 7 neonates tested ⬍20 µg/L; level 47 µg/L in 1 neonate Neonatal seizures No milk or neonatal serum levels obtained

No

0.015– 0.037

20 mg/day

Intramuscular injection No drug detected in milk

Drugs and Breast-Feeding

Diclofenac

Yes No Yes

0.47 mg of naproxen and conjugated naproxen excreted by infant over 12 h after maternal dose of 375 mg (0.26% of cumulative maternal value) Not detected in infant serum No adverse reaction in infants Piroxicam and conjugate not detected in one infant’s urine

199

200

Table 1

Continued Max. Finf

—

0.44–2.94

6 weeks

0.15

—

MD

3–4 weeks

1.87

2.1

3 1 1

MD MD MD

? 1 month 5 days

3.72 0.12 16.6–33.3

9.60 0.17 —

261

4

MD

1–4 weeks

—

—

Yes

262

1

MD

0–10 weeks

—

27.02

Yes

263

1

MD

70 days

4.0

—

Yes

Ref.

No. pts.

Dose

Antipsychotics Chlorpromazine

255

4

MD

?

256

1

Md

257

1

258 259 260

Haloperidol

Perphenazine Lithium

Lactation stage

Standard adult dose

M/P

t 1/2 (h)

t max (h)

BF

Comments

10–50 mg tid–qid

2 of 4

Maternal dose unspecified; calculated based on standard adult dose Milk levels 7–98 ng/mL 1 of 2 breast-fed infants was drowsy and lethargic

0.5–2 mg bid–tid

No

M/S

Yes

2–8 mg tid 900 mg–1.2 g/day divided bid– qid (as carbonate)

0.7–1.1

? Yes Yes

No adverse reaction in infant; developmental milestones achieved at 6 months and 1 year 1.5 µg/L detected in infant’s urine No adverse reaction in infant Neonatal cyanosis, lethargy 0.6 mEq/L detected in infant plasma and in milk sample Infant exposed to lithium in utero Milk level range 0.16–0.56 mmol/L Infant serum level range 0.1– 0.3 mmol/L No adverse reaction in infant Infant serum level ⬍0.2 mmol/L throughout breastfeeding One milk level obtained No adverse reaction in infant; lithium level 0.04 mEq/L

Taddio and Ito

Mean Finf

Drug

Propylthiouracil

Anxiolytics Alprazolam

Clonazepam

Diazepam

264

1

MD

2–6 months

2.1

4.5

265 266 267

1 5 9

MD SD SD

? 2–6 weeks 1–8 months

7.17 — 0.32

11.52 1.34 —

268

1

SD

?

—

—

269

1

MD

7 days

—

—

270

8

SD

6–28 weeks

—

6.96/day b

271

1

MD

2–4 days

1.89

2.41

272

1

MD

3–14 days

—

—

273

1

MD

1 year

4.2 (7.36)

4.7 (8.6)

0.3–0.7

Yes

1.16 0.98

5–15 mg/day

1

50 mg bid– tid

? ? ?

No

Yes

0.25 mg bid– tid

0.36

8–10 mg/day divided tid 0.3

2 mg bid–10 mg qid

0.2

14.46

1.1

No

4

Yes Yes

Yes

Given as carbimazole No adverse effects in breastfeeding twins; methimazole plasma levels 0–156 ng/mL (peak level 2–4 h postdose) Given as carbimazole 1 infant breast-feeding while mother on long-term treatment showed no adverse effects 0.077% of a radioactive dose of propylthiouracil excreted in 500 mL of milk over 24 h

Drugs and Breast-Feeding

Antithyroid Methimazole

No levels obtained Neonatal restlessness and irritability; neonatal exposure in utero also b Dose calculation based on infant consumption on a daily basis due to alprazolam’s long milk half-life Alpha-hydroxy metabolite ⬍4 ng/mL Mother also taking phenytoin

201

Milk level range 11–13 ng/mL Infant neurodevelopmental exam normal at 5 months No adverse reaction in infant; low levels of metabolites detected in infant plasma M/P desmethyldiazepam ⫽ 0.13 M/P oxazepam ⫽ 0.10 M/P temazepam ⫽ 0.14 ( ) ⫽ including active metabolites n-desmethyldiazepam, oxazepam, temazepam

Continued Mean Finf

Max. Finf

2.76–4.6 (6.07– 10.12)

7.8–13.0 (14.8– 24.6)

No. pts.

Dose

Lactation stage

274

1

MD

1 week–3 months

275

4

MD

3–9 days

276

1

MD

8 days

—

—

Yes

277

3

MD

6 days

2.34 (3.9)

—

Yes

Lorazepam

278

1

MD

5 days

2.16 (6.1)

—

2–3 mg/day divided bid–qid

Yes

Midazolam

279

12

MD

2–7 days

—

—

15 mg prn

Yes

as above

2

SD

2–3 months

Nitrazepam

279

10

MD

2–7 days

0.06 (0.10) 2.52

0.11 (0.15) 3.60

Oxazepam

280

1

MD

⬎7 months

0.68

0.75

2.1 (5.4)

Standard adult dose

M/P

0.16

3.87 (11.5)

5–10 mg prn 10–15 mg tid–qid

M/S

t 1/2 (h)

BF

Comments

Yes

Normal infant development; infant sedation if feeding occurred within 8 h of maternal dose Infant diazepam level 0.7 ng/ mL and n-desmethyl-diazepam level 46 ng/mL at 32 days of age M/P n-desmethyldiazepam ⫽ 0.27; oxazepam not in milk ( ) ⫽ including n-desmethyldiazepam Neonatal lethargy and weight loss; urine positive for oxazepam No adverse reactions in infants Mean infant level on 2 occasions for diazepam 74 and 172 ng/mL; 31 and 243 ng/mL for n-desmethyl-diazepam Oxazepam not detected in any sample ( ) ⫽ including n-desmethyl-diazepam One milk level obtained No adverse reaction in neonate ( ) ⫽ including conjugated and free lorazepam Morning milk level after evening dose ⬍3 µg/L ( ) ⫽ including hydroxymidazolam Plasma level ⬍3 µg/L in 1 infant that was tested

Yes

0.15

?

0.27

Yes ?

Taddio and Ito

Ref.

Drug

t max (h)

202

Table 1

10

MD

⬍15 days

—

1.31

Cardiovascular Amiodarone

282

1

MD

6–9 weeks

—

36.9 (51.5)

283

1

MD

2–3 days

—

284

1

MD

First month

5.67 (7.7)

8.1 (11.7) 8.21 (11.0)

285

3

MD

0–6 weeks

10.35 (15.3)

13.7 (21.8)

Bretylium

286

1

MD

First 4 months

Digoxin

287

2

MD

288 289

11 1

290

11

—

—

14 days

2.14

3.5

MD MD

3–7 days 7 days

2.3 2.28

— —

SD

?

—

—

30 mg HS

⬍0.2

200–600 mg/ day

Yes

No adverse reactions in neonates; plasma levels of temazepam and oxazepam below detection in 2 neonates that were tested Milk oxazepam levels ⬍5 µg/L for all patients

Yes

Infant amiodarone and desethylamiodarone plasma level at 9 weeks 0.4 mg/L and 0.15 mg/L, respectively ( ) ⫽ including metabolite desethylamiodarone ( ) ⫽ including metabolite desethylamiodarone No adverse reaction in infant Infant serum amiodarone level ⬍0.1 mg/L; desethylamiodarone ⬍0.05 mg/L ( ) ⫽ including metabolite desethylamiodarone One infant stopped breast-feeding due to hypothyroidism Desethylamiodarone M/P ⫽ 1.9 ( ) ⫽ including metabolite desethylamiodarone No milk levels obtained No adverse events in infant

No Yes

7.8

100 mg tid– 600 mg q6h 0.125–0.25 mg/day

Yes

Yes

4–6

0.8–0.9

0.59 0.9

Yes

No Yes

0.62

No

No adverse reaction in neonates; neonatal plasma levels ⬍0.1 ng/mL One milk level obtained Neonatal serum level 0.2 ng/mL Intravenous injection

203

281

Drugs and Breast-Feeding

Temazepam

204

Table 1

Continued Max. Finf

Standard adult dose

5.85 (10.7)

8.55 (15.8)

100–200 mg qid

2–16 days

2.75

3.05

MD

2 months

1.75

2.21

1

MD

5–7 days

3.70

4.92

294 295

11 1

MD MD

1–6 days 2 days, 6 weeks

3.7 1.1

7.0 1.2

Procainamide

296 297

1 1

MD MD

2–5 days 2 days

1.04 2.43 (4.0)

1.58 4.59 (6.84)

Propafenone

298

1

MD

3 days

Quinidine

299

1

MD

4–5 days

0.03 (0.08) 5.58

6.27

300–600 mg q8–12h (as sulfate)

Diuretics Acetazolamide

300

1

MD

10–11 days

1.53

1.89

250 mg daily–qid

Yes

Chlorothiazide

301

11

SD

⬎3 months

—

500–2000 mg/day

No

No. pts.

Dose

291

1

MD

4 days–1 month

292

1

MD

293

1

Flecainide

235

Mexiletine

Disopyramide

Lactation stage

⬍0.36

M/P

M/S

t 1/2 (h)

t max (h)

0.9

0.4

100–150 mg q12h

Comments

Yes

No adverse reaction in infant; infant plasma level 0.5 mg/L at 28 days M/P n-monodesalkyl metabolite ⫽ 5.6 ( ) ⫽ including n-monodesalkyl metabolite No adverse reaction in neonate; neonatal plasma level ⬍0.5 mg/L Infant disopyramide level 0.1– 0.14 mg/L

Yes

0.46–0.53

Yes

1.57–2.18

No

2.6–3.7

14.7 1.14–2

200–300 mg q8h

50 mg/kg/ day divided q3h– q6h 150 mg q8h

BF

1.45 4.3

3–6

No Yes

Yes Yes

No 0.71

No

No adverse reaction in infant; infant serum level ⬍0.05 mg/L M/P NAPA ⫽ 3.8 ( ) ⫽ including active metabolite NAPA ( ) ⫽ including metabolite 5OH-propafenone Administered as quinidine sulfate

No adverse reaction in neonate; neonatal plasma level 0.2– 0.6 µg/mL Milk levels ⬍ mg/L; calculation assumes milk level of 1 mg/L

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Mean Finf

Ref.

Drug

302

7

MD

3 days

Furosemide

303

120

MD

First week

Hydrochlorothiazide

304

1

MD

Spironolactone

305

1

Gastro-intestinal Cimetidine

306

6.66

15.5

?

25–100 mg/ day 20–40 mg bid

—

—

28 days

1.94

2.92

50–100 mg/ day

Yes

MD

17 days

0.84

1.15

25–200 mg/ day

Yes

1

MD

6 months

4.42

4.77

800–1200 mg/day

No

as above 307 308

1 12 10

SD SD MD

6 months 6–45 weeks 1–5 days

0.92 — 0.08

1.67 5.66 0.26

309

2

MD

3–6 days

0.08

—

Famotidine

310 as above 311

10 4 8

SD MD SD

2–8 days 1–3 months ?

0.006 0.07 —

0.01 — 0.32

Loperamide

312

6

MD

First 3 days

0.024

Metoclopramide

313

5

MD

1–3 weeks

3.3

0.07 (0.09) 4.7

18 10 3

MD SD MD

9–14 weeks 7–10 days 3–8 months

1.44 2.26 1.47

3.75

Nizatidine

as above 314 315

Ranitidine

316

6

SD

6–10 days

1.4

4.4

317

1

MD

54 days

4.86

8.6

Cisapride Domperidone

3.6

No

5.77 5–10 mg tid–qid 10 mg tid– qid

20–40 mg/ day 2 mg prn

2.5

3.3

0.045

Furosemide and fluid restriction successfully suppressed lactation No adverse reaction in neonate; neonatal blood level ⬍20 ng/mL No adverse reaction in neonate Canrenone levels measured; spironolactone levels not measured M/S canrenone ⫽ 0.51–0.72

No No No No No ? No

0.41–1.78

No Yes

5–10 mg tid–qid

150 mg/day bid 150 mg/day– bid

M/B ⫽ 0.06

Drugs and Breast-Feeding

Chlorthalidone

Yes ? ?

⬍2

?

1.92–6.7 5.5

No

205

6.8–23.8

( ) ⫽ including loperamide and loperamide oxide Metoclopramide detected in plasma from 1 of 5 neonates tested; peak level 20.9 ng/mL

206

Table 1

Continued Mean Finf

Max. Finf

Standard adult dose

—

—

800 mg–4000 mg/day

?

0.07 (7.5)

—

7, 11 days

0.03 (3.59) —

(4.27) —

Drug

Ref.

No. pts.

Dose

Miscellaneous 5-aminosalicylic acid

318

1

MD

6 weeks

319

1

MD

320

2

MD

Chloroquine

Lactation stage

3

SD

2–5 days

322

11

SD

?

6.6/day c

11.25/day c

Hydroxychloroquine

323 324

5 1

SD MD

2–2.5 months 9 months

4.71/day 2.81

11.91/day 3.67

Methylergometrine

325 326

1 8

MD MD

8 weeks 5 days

— 2.4

⬍0.05 3.38

M/S

t 1/2 (h)

t max (h)

Yes

Rectal administration Milk levels not reported Case report of watery diarrhea in infant One milk level reported M/P acety-5-ASA ⫽ 5.1 ( ) ⫽ including metabolite acetyl 5-ASA ( ) ⫽ including acetyl-5-ASA

Yes

0.13

Yes

6.6

0.2–0.4 mg q6-12h

Comments

0.27

No

500 mg/week 1.96–4.26 for malaria (as phosphate)

200–600 mg/ day arthritis (as sulfate)

BF

5.5

8.8 days

14.4

Yes

5.5 days

3

No Yes

No ?

Mean amount excreted in milk over 9 days was 0.19% of maternal dose M/P metabolite desethylchloroquine ⫽ 0.54–3.89 c Dose calculation based on infant consumption on a daily basis due to chloroquine’s long milk half-life 4 infants of 4 tested had positive urine samples for chloroquine and desethylchloroquine M/P desethylchloroquine ⫽ 1.5

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321

M/P

327

6

MD

3–152 days

328

1

SD

329

7

Pseudoephedrine

200

Sulphasalazine

Sumatriptan

—

4.51

?

0.51

—

Yes

SD

?

—

—

No

3

SD

14 weeks–18 months

1.6

2.6

330

12

MD

5–6 weeks

—

0.9 (11.1)

331

1

MD

4.5–6.5 months

332

8

MD

2–24 weeks

—

333

1

MD

2 months

—

—

334

5

SD

10.8–28.4 weeks

—

4.2

(2.25)

5–60 mg/day (prednisone)

60 mg qid prn 2.4 g/day divided qid

1

0.1–0.2

2.2–2.8

4.2–7

1–1.5

?

? Yes

(5.85)

Yes

1.42 (11.7)

Yes

Yes

4.9

2.2

2.6

No

Sulfasalazine milk level ⬍1 µg/mL in 26 of 31 samples M/S sulfapyridine ⫽ 0.4 ( ) ⫽ including metabolite sulfapyridine No sulfasalazine, 5-ASA, acetyl-5-ASA detected in milk No adverse reaction in infant; infant sulfapyridine and metabolites urine levels 3–4.1 µg/mL M/P sulfapyridine ⫽ 0.6–0.63 ( ) ⫽ including sulfapyridine and metabolites Sulfasalazine undetected in 6 of 7 milk samples and 6 of 8 infants (⬍1 mg/L); peak infant plasma sulfapyridine level 4.8 mg/L M/S sulfapyridine ⫽ 0.48 ( ) ⫽ including sulfasalazine and sulfapyridine Bloody diarrhea in infant; infant blood sulfapyridine level 5.3 µ/mL Mother found to be a poor acetylator Subcutaneous injection

207

100 mg PO (6 mg SQ ⫽ subcutaneous)

One milk level reported Prednisolone and prednisone measured Mean total recovery per 1 L of milk during 48 h from radiolabeled prednisolone was 0.14%

Drugs and Breast-Feeding

Prednisolone

Table 1

Continued

Theophylline

Warfarin

Mean Finf

Max. Finf

Standard adult dose

?

—

8.14–13.48

400–900 mg/ day PO divided bid

SD

9 months

—

2.82

13

MD

3–10 days

—

—

2

MD

?

—

—

Ref.

No. pts.

335

3

SD

336

1

337

338

Dose

Lactation stage

M/P

M/S

t 1/2 (h)

t max (h)

0.67

0.7

2–10 mg/day

1–3

BF

Comments

No

Intravenous injection

Yes

Agitation in infant; 5 other nursing infants with no adverse effects No adverse reactions in neonates Milk and neonatal plasma levels below limit of detection 25 ng/mL No adverse reactions in infants No warfarin detected in milk

7—Yes

Yes

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Drug

Note: This table reviews the findings of clinical trials of drugs taken during lactation. It is inevitable that some of the details sought by the reader will be missing. Readers are encouraged to review the individual research papers cited and other resources for additional information. Study design: All drugs were taken orally unless otherwise specified. Where data were unavailable, a question mark (?) appears. Ref ⫽ reference. No. ⫽ number of subjects (taken from the number of women donating milk samples for drug analysis or from the number of women whose data appear in the paper). MD ⫽ multiple dose, SD ⫽ single dose. Lactation stage: The period of lactation is specified. Whether the infant was nursing or not during maternal drug therapy is also noted (BF ⫽ breast-fed infants). The mothers donating milk samples for study analysis were not always the same mothers who nursed their infants during drug therapy. Dosage to infant: The percent maternal dose available to the infant (Finf ) was calculated as a percentage of the maternal dose in milligrams per kilogram. The following formula was used: Finf(%) ⫽

C m ⫻ Vm ⫻ 100 D

D inf (mg/kg/day) ⫽ Finf ⫻ standard adult daily dose/60 kg Other findings: M/P ⫽ milk-to-plasma ratio; M/S ⫽ milk-to-serum ratio, M/B ⫽ milk-to-blood ratio. These ratios have been derived from investigators in different ways (e.g., arithmetic mean, area under the curve). The t 1/2 ⫽ half-life in milk, t max ⫽ time to maximum drug concentration in milk. Comments: Other findings of the study are noted.

Taddio and Ito

where C m ⫽ milk concentration of drug, Vm ⫽ volume of milk ingested by infant (150 mL/kg/day for MD studies and 30 mL/kg/dose for SD studies) (41). It is assumed that an infant nurses five times daily during MD therapy and once during a SD study. Maternal dose: D is the maternal dose (mg/kg). A maternal weight of 60 kg was used to calculate infant exposure if maternal weight was not provided by the paper. The bioavailability of the drug was assumed to be 100%. Mean Finf ⫽ mean percentage of maternal dose obtained through milk. This value was calculated using the average milk concentration reported, or the arithmetic average calculated from data shown; arithmetic means were calculated using milk levels reported in the first 8–16 hours after dosing if appropriate. Max Finf ⫽ maximum percentage of maternal dose obtained through milk. This value was calculated using the highest milk level observed in one subject or the average maximum concentration achieved. Standard adult dose: The standard adult dose, taken from standard reference books (339, 340), is provided so that an infant’s dose (Dinf) may be estimated using the relationship:

Drugs and Breast-Feeding

209

THERAPEUTIC IMPLICATIONS OF DRUG EXCRETION IN BREAST MILK Assessing the Risk of Drug Exposure Through Breast Milk The dose of a drug ingested by an infant through breast milk provides an estimate of the risk to the infant. For most drugs that have been studied, the infant dose ingested through breastmilk is less than 5% of the maternal dose on a weight-adjusted basis (Finf ). Because the therapeutic dose is similar in both adults and children on a milligram-per-kilogram basis, the dose ingested by the infant will not be sufficient to exert a pharmacological effect. Occasionally, however, the Finf may approach the recognized infant therapeutic dose. In such cases, the clinician assumes that the risk for side effects is not negligible and may be similar to the risk of side effects for a drug given to the infant directly. For the convenience of risk assessment, drugs can be ranked and categorized according to the proportion of the maternal dose (41). However, care should be exercised when these data are used in clinical settings. First, the risk to the infant is not entirely proportional to the Finf . Even if the infant dose should be a small fraction of a maternal dose, potent pharmacologic actions or potential for severe side effects may make the drug incompatible with breast-feeding. In contrast, a drug that causes no known adverse effects may be compatible with breast-feeding even if the infant ingests close to a therapeutic dose via milk. Assessing potential risks is a crucial step in counseling a mother about whether to breast-feed or formula-feed while taking medication. The potential risks of developing adverse reactions in the breast-fed infants exposed to drugs in milk should be weighed against the risks associated with formula-feeding if the mother does not breast-feed. Bottlefeeding is associated with higher mortality rates for infants than breast-feeding. In industrialized countries, bottle-feeding is associated with mortality rates of 1 to 5 per 1000 live births. In developing countries, the mortality rate is 300 per 1000 live births (46). Furthermore, recent studies have shown associations between premature infants’ exposure to cow’s milk (which most infant formulas are based on) to immune system disorders such as insulin-dependent diabetes mellitus (47) and Crohn’s disease (48). While there appears to be a real risk associated with formula based on cow’s milk, virtually nothing is known about the probability of adverse reactions developing in infants of breast-feeding mothers on medications. When one assesses the risk associated with breast-feeding during maternal medication, any case report of adverse reactions in breast-fed infants should be considered. One should also bear in mind that the incidence of such events may well be extremely low. General guidelines have been proposed by Berlin (6) based on consistent findings from studies that have evaluated drug excretion in breast milk: 1. Most drugs (and environmental chemicals) are capable of crossing from plasma to milk. 2. The concentrations of drugs in milk parallel the levels achieved in plasma over a similar time course, and milk-to-plasma concentration ratios vary from 50– 100%. 3. Following a single maternal dose of a drug, the observed half-lives are similar for both plasma and milk. 4. The total amount of drug available for infant absorption is usually less than 1% of the maternal dose.

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5. 6.

There are few studies or reports based on steady state-maternal dosing. For most drugs, the risk of side effects in the infant can be assessed to be small or negligible.

In the Motherisk Program in Toronto, we have been prospectively collecting infant outcome data in a cohort of breast-fed infants whose mothers were on medications. Mothers initially contacted Motherisk seeking advice on the safety of drug consumption during breast-feeding. They had not yet started drug therapy at this time. Mothers were subsequently contacted for a follow-up interview (about 6 weeks after the initial consultation). The mothers who ingested drugs while breast-feeding were asked if their children experienced any adverse reactions during their drug therapy. This study included 838 motherinfant pairs and took place between 1985 and 1991. No major adverse events (defined as requiring medical attention) were identified. Overall, 11% of the mothers reported symptoms in the infants during their drug therapy. These symptoms did not require medical attention. Table 2 shows a partial list of the minor adverse effects on the breast-fed infants exposed to drugs commonly inquired about in our program. Long-term effects due to infants’ drug consumption in breast milk are not available. Studies of this nature are difficult to conduct. Large cohorts are necessary and patients must be followed for long periods of time.

REVIEW OF SELECTED DRUG CLASSES This section offers recommendations for the use of selected drugs (mostly taken from Table 1) and breast-feeding. Infant monitoring guidelines are also recommended.

Analgesics Acetaminophen is excreted into milk in small amounts. Narcotic analgesics such as codeine and morphine have also been detected in milk in small amounts. Therapeutic doses of codeine are generally considered safe to use. One recent case report found morphine plasma concentrations in the analgesic range in a 3-week-old infant whose mother was being tapered off high doses of morphine (see Table 1). No adverse effects were reported in this infant. Nursing infants, however, may be sensitive to the effects of narcotics and should be observed for signs of sedation or unexplained episodes of cyanosis and apnea during maternal therapy (49).

Anti-infectives Penicillin and cephalosporin antibiotics are considered safe to use while breast-feeding. Infants should be observed for allergic reactions. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency should not be exposed to sulfonamides, nalidixic acid, nitrofurantoin, or other agents capable of causing hemolysis. Sulfonamides should be avoided if newborn infants have jaundice because of a theoretical risk of displacement of bilirubin from binding sites and kernicterus. The use of metronidazole during lactation is controversial. Experimental studies have revealed that it has carcinogenic and mutagenic properties (50). However, human

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211

Table 2 Main Maternal Drug Exposures and Associated Minor Adverse Reactions in the Breast-Fed Infants (Data from Motherisk Cohort)

Drug

No. of mother– infant pairs

Antibiotic Amoxicillin 25 Erythromycin 17 Sulfamethoxazole ⫹ 12 trimethoprim Cloxacillin 10 Cephalexin 7 Nitrofurantoin 6 Ampicillin 5 Cefaclor 5 Analgesic/narcotic Acetaminophen 43 Acetaminophen ⫹ codeine 26 ⫹ caffeine Ibuprofen 21 Naproxen 20 Aspirin 15 Antihistamine Terfenadine 25 Diphenhydramine 12 Astemizole 10 Dimenhydrinate 7 Chlorpheniramine 5 Sedative/antidepressant/antiepileptic Carbamazepine 6 Alprazolam 5 Miscellaneous Oral contraceptive 16 Pseudoephedrine 10 5-Aminosalicylic acid 8 Prednisone (prednisolone) 6 Levothyroxine 5 Permethrin 5 Warfarin 5 a

Number of infants with reactions Diarrhea

Drowsiness

Irritability

Others

3 2 0

0 0 0

0 2 0

0 0 2a

2 2 2 1 1

0 0 0 0 0

0 0 0 0 0

0 0 1a 0 0

0 0

0 5

0 1

0 2a

0 0 0

0 2 0

0 0 0

0 1a 0

0 0 0 0 0

0 1 0 0 0

3 0 2 1 0

0 0 0 0 0

0 0

0 1

0 0

0 0

0 0 1 0 0 0 0

1 0 0 0 0 0 0

2 2 0 0 0 0 0

4a 0 0 0 0 0 0

Other reactions included poor feeding (two cases with sulfamethoxazole/trimethoprim), decreased milk volume (one with nitrofurantoin and three with oral contraceptives), constipation (two with acetaminophen ⫹ codeine, one with oral contraceptives), and vomiting (one with naproxen).

data have not substantiated the carcinogenic risk (51). Breast-feeding may be continued during metronidazole therapy. Close supervision of the nursing infant is warranted, since significant amounts may be present in milk and the infant may be at risk for adverse effects such as diarrhea. If a single dose of metronidazole has been prescribed, breastfeeding may be temporarily withheld for 12–24 hours while the drug is being excreted

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by the body. During this time period, the breasts can be emptied manually to alleviate engorgement and maintain milk flow. Ciprofloxacin and ofloxacin have been measured in milk in small amounts. According to the drug monograph, norfloxacin was not detected in the milk of lactating women after a single dose of 200 mg (52). The use of quinolones during breastfeeding, however, has not gained wide acceptance in the medical community. The quinolones were shown to cause cartilage damage in juvenile animals (53) and were subsequently not recommended for use in children, pregnant women, and nursing women. Many pediatric patients, however, have received quinolone antibiotics. The current published data on over 1000 pediatric patients treated with quinolones has revealed no documentation of unequivocal quinolone-induced arthropathy (54,55). Even though the risk for quinolone-induced arthropathy in the nursing infant is unknown, it is probably very low. Nevertheless, quinolones are not first-line therapy for most infections that nursing women may encounter; other antibiotics are generally preferred. If maternal therapy with a quinolone such as ciprofloxacin is warranted, the data suggest that the baby may continue to nurse. As a precaution, the infants should be monitored closely for signs of arthropathy (e.g., tenderness, stiffness). Infant exposure to acyclovir through breast milk is small. Topical use of acyclovir is compatable with breast-feeding. Oral administration is unlikely to expose the infant to significant plasma levels because of the low bioavailability of the drug. Chloramphenicol should be avoided because of risks of idiosyncratic reactions in the newborn, such as bone marrow suppression. The use of tetracycline during breastfeeding has not been documented to cause problems. However, there is some controversy regarding its use. Even though tetracycline crosses into breast milk in low amounts, its bioavailability in nursing infants may be low due to complexation with calcium or magnesium ions in milk. However the potential risk for tooth mottling in the breast-feeding infant due to tetracycline is unknown. The AAP has recommended that tetracycline is safe to use during lactation (43). In most cases, safer antimicrobials can be substituted for both chloramphenicol and tetracycline. One case report showed that isoniazid is excreted in large amounts in breast milk. Its use during lactation has not been recommended due to concerns for infant liver toxicity.

Anti-inflammatory Agents Salicylic acid has been shown to cross into breast milk in small amounts following maternal acetylsalicylic acid (ASA) ingestion. Occasional use of ASA is not likely to harm the infant. Chronic high-dose ASA therapy, however, has not been adequately studied. Inevitably, more salicylate will be present in milk and the infant may be at risk for salicylate toxicity (56). Other nonsteroidal anti-inflammatory drugs (NSAIDs)—such as diclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, ketorolac, and mefenamic acid—have been shown to be present in small amounts and are considered safe to use.

Antihypertensive Drugs The special need for antihypertensive therapy in postpartum women has promoted the study of this class of drugs.

Drugs and Breast-Feeding

213

The transfer of different β-adrenergic blockers into breast milk has been well studied. The primary determinant of such passage for this drug class is protein-binding (57). Drugs that are less lipophilic and less protein-bound, such as atenolol or sotalol, are present in higher quantities. Any infant’s exposure to these drugs will be further increased by poor elimination processes. For example, drug half-lives may be doubled or tripled for drugs excreted renally (58) in the postnatal period. Another consideration is that β-adrenergic blockers used throughout pregnancy may cause hypotension, bradycardia, and respiratory difficulties in newborns. Since a newborn’s heart rate is lowest in the first few days postpartum, the added use of these drugs may be worrisome, especially if the newborn is premature (58). Other antihypertensive agents—such as methyldopa, captopril, enalapril, nifedipine, diltiazem, and verapamil—have been measured in breast milk in small amounts. Adverse effects have not been reported and the use of these drugs is considered compatible with breast-feeding. Anticonvulsants The anticonvulsants carbamazepine, valproic acid, and phenytoin are excreted into breast milk in low amounts. There are case reports of hematological and hepatic adverse effects in infants during maternal use of valproic acid and carbamazepine, respectively. However, breast-feeding is generally considered compatible with their use. Phenobarbital, primidone, and ethosuximide, on the other hand, are excreted in much higher amounts, and infants may be exposed to nearly therapeutic doses. Phenobarbital is usually contraindicated during nursing (Table 3). Infants exposed to these medications via milk may be at risk for adverse effects such as lethargy, sedation, and poor feeding. They should be closely supervised. Infant anticonvulsant plasma concentration monitoring is also advisable. Antihistamines This class of drugs should not stop the nursing mother from breast-feeding. Antihistamines are present in many over-the-counter medications. Although quantitative data on the excre-

Table 3 Drugs Usually Contraindicated During Breast-Feeding Antineoplastics Bromocriptine a Ergotamine Gold Iodine-containing substances Lithium Oral contraceptives a Phenobarbital Radiopharmaceuticals Social drugs and drugs of abuse a

May decrease milk supply.

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tion of most antihistamines in milk are lacking, their use is generally considered safe during nursing. Specific data on drug excretion in milk is present for loratadine, terfenadine, and triprolidine, all of which have been measured in milk in small amounts. There is one case report in the literature of sedation and irritability in an infant following maternal ingestion of clemastine (59). The Motherisk cohort data includes 54 mother-infant pairs, with 7 (13%) mothers reporting minor adverse effects in their children (Table 1). Antihistamines may be used during lactation; however, infants should be monitored for potential adverse effects. Cardiovascular Drugs Infant consumption of digoxin, flecainide, procainamide, or mexiletine from breast milk is small. Amiodarone and disopyramide, however, are present in larger amounts, which may affect the infant. Whenever possible, drugs levels in breast milk and/or infant’s plasma should be monitored during maternal therapy. During amiodarone therapy, infant thyroid function tests should be monitored as well since amiodarone can cause hyper- or hypothyroidism. Diuretics Diuretics have been found in breast milk in low amounts. The theoretical concern that they may suppress lactation has been raised. However, lactogenesis itself has not be been shown to be influenced by fluid intake (60), and the impact of taking diuretics is unknown. Drugs Acting on the Central Nervous System Many puerperial women may require these medications to alleviate symptoms of depression, anxiety, or other psychiatric conditions. Most of the information available for these drugs, however, is in the form of case reports. Generalizations regarding ‘‘risk’’ are difficult to make. Case reports and cohort studies of various tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) measured in breast milk show that infant exposure is consistently low for drugs of this class. Breast-feeding may be continued during antidepressant use, keeping in mind that the effects of long-term exposure of these drugs on the developing central nervous system are not known. Similarly, excretion of some neuroleptics into breast milk has been studied. Only small amounts have been found, but potential long-term behavioral effects are unknown. Lithium therapy during breastfeeding warrants concern because the drug freely passes into breast milk and significant plasma levels have been detected in nursing infants (Table 2). Lithium is contraindicated by many health professionals during lactation because of this (Table 3). If a woman chooses to nurse during lithium therapy, however, infant plasma lithium levels should be monitored. Benzodiazepines should be used with caution by breast-feeding women. Metabolizing capacity of these drugs may be limited in the neonatal period and accumulation may occur. If benzodiazepine therapy is necessary, short-term treatment with a short-acting agent devoid of pharmacologically active metabolites, such as lorazepam or alprazolam, is preferable (61).

Drugs and Breast-Feeding

215

Thyroid and Antithyroid Drugs Levothyroxine is compatible with breast-feeding. Thyroid hormones cross into breast milk in low amounts. Their presence is not likely to affect the infant’s thyroid (62–65). Propylthiouracil crosses into breast milk in small amounts and is the antithyroid drug of choice during breast feeding. Infants have been safely breastfed on maternal doses of 50–300 mg/day (66). Thyroid function tests should be performed in the infant on a regular basis (67,68), if warranted, to monitor for toxicity. Gastrointestinal Drugs and Laxatives H 2-receptor blockers such as cimetidine and ranitidine should be used with caution by breast-feeding mothers. To date, adverse effects have not been reported in nursing infants, but the potential for inhibition of gastric acid secretion and enzyme metabolizing capability exist. Aluminum and magnesium salts are considered safe to use (69,70). Sucralfate is poorly absorbed from the gastrointestinal tract and is not likely to cause adverse effects in the nursing infant (70). Metoclopramide and domperidone are excreted into milk in small amounts. Both increase prolactin levels (71–73), and metoclopramide has increased milk production in women with faltering milk production (72–74). Several investigators studied the clinical effects on nursing infants after maternal ingestion of laxatives. Phenolphthalein (75) mineral oil, magnesia, and senna glycosides (76,77) have all been associated with normal infant bowel patterns after short-term maternal therapy. No harmful effects from docusate have been observed (78). Nonetheless, lactating women are generally advised to use drugs that are poorly absorbed from the gastrointestinal tract, such as psyllium or other bulk-forming agents, instead. Miscellaneous 5-Aminosalicylic acid and sulfasalazine can be used by the lactating mother. The infant should be monitored for adverse reactions, such as diarrhea. Chloroquine and hydroxychloroquine are both excreted in breast milk. Adverse effects have not been reported with their use. Once-weekly dosing of chloroquine for malaria is unlikely to expose the nursing infant to toxic amounts. There are no reports on the safety of daily chloroquine administration for arthritis. Since the milk half-life of chloroquine is approximately 1 week (Table 1), daily administration would inevitably lead to accumulation of the drug in milk. Prednisone and prednisolone have been detected in milk in small amounts. Breastfeeding need not be interrupted. Because systemic absorption following topical and inhalational steroids are usually not substantial, they are also safe to use during lactation. Theophylline is excreted in milk. Since clearance of theophylline is low in the neonatal period, close monitoring of the infant is necessary to detect adverse effects. Warfarin is highly protein-bound. Levels in milk have been consistently below detection limits and no adverse effects have been reported in nursing infants. Heparin therapy is also compatable with breast-feeding. It does not pass into milk (79). Topical Agents The excretion of many topically applied drugs into breast milk has not been studied. This fact does not, however, preclude their use in nursing women. For example, the excretion

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of inhalational β-adrenergic agonists (e.g., salbutamol) in breast milk have not been studied, but bioavailability of these agents is low. Breast-feeding during their use is considered safe. Similarly, ipratropium and sodium cromoglycate are unlikely to cause adverse effects. Many other topical agents (eyedrops, creams, ointments, etc.), with low bioavailability and a low order or toxicity may be used during the lactation period as well. Examples of these agents are lidocaine ointment, nystatin cream, or clotrimazole cream.

DRUGS USUALLY CONTRAINDICATED DURING BREAST-FEEDING Table 3 lists drugs commonly avoided during lactation. The following section reviews the reasons why these drugs are not used. Some drugs that fall into this category are discussed under ‘‘Review of Selected Drug Classes,’’ above. Antineoplastics The use of antineoplastic drugs is generally contraindicated during lactation. Even if the absolute dose the infant is exposed to is small, the possibility for immediate or long-term toxicity precludes breast-feeding during their use. Azathioprine and methotrexate are two of the more commonly used antineoplastic agents in ambulatory-care patients. Both have been measured in breast milk. The peak milk concentration of 6-mercaptopurine, the active metabolite of azathioprine, was 18 ng/mL in a woman taking 25 mg of azathioprine daily and 4.5 ng/mL in a woman taking 75 mg daily (80). There are three cases of infants breastfed during maternal azathioprine therapy without adverse effects (80,81). Methotrexate secretion in milk was measured in a patient receiving 22.5 mg daily. The peak milk methotrexate level was only 2.6 ng/mL and the highest M/P ratio was 0.08 (82). Based on this data, some have argued that methotrexate may be safe to use in rheumatic diseases (83), where it is administered only once weekly. Further study seems warranted. Lactating mothers requiring these medications should be well informed of the risks to the baby. If these drugs are used during lactation, the following parameters should be strictly monitored: milk drug levels, infant plasma drug levels, and infant hematological parameters. Radiopharmaceuticals The use of radiopharmaceuticals usually requires temporary cessation of breast-feeding; this is done to avoid infant exposure to excessive radioactivity. The time necessary before most radioactivity is excreted varies with the radioisotope used; reference texts or nuclear departments can be consulted for this information. While the mother is awaiting clearance of the isotope, she may use breast pumping to preserve nursing function. Since most diagnostic testing is planned in advance, mothers may express milk (and keep it frozen) before the procedure. This milk will be given to the baby during the time that it is not nursing. Ergot Alkaloids Bromocriptine, an ergot alkaloid, is contraindicated during breast-feeding. It possesses prolactin-suppressing activity and is used to prevent lactation (84,85). Ergotamine is

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avoided due to risks of milk suppression (86) and ergotism in the infant (87). Methylergonovine, however, is used to assist uterine involution. Short-term therapy with methylergonovine is not associated with adverse effects. Social Drugs and Drugs of Abuse Social drugs such as alcohol are not recommended for use during lactation. Ethanol freely distributes into milk and levels in milk are similar to those in plasma. Elimination from milk is also similar to elimination from blood (88,89). Occasional alcohol consumption exposes the nursing infant to small amounts of ethanol and is not considered harmful, but the infant may be at risk for sedation with higher doses (90). At higher doses, ethanol presents a risk to successful lactation also, as oxytocin release is blocked (91). Infant motor development is affected by maternal alcohol ingestion in a dose-dependent fashion (92). Interestingly, both alcoholic and nonalcoholic beer has been shown to increase prolactin secretion (93). In summary then, alcohol use should be limited during lactation. Smoking during lactation is also not recommended. A nursing mother should be encouraged to stop smoking, as there are well-documented health risks to herself and her nursing infant. Nicotine has been measured in milk (94). Cotinine, the major metabolite of nicotine, has also been measured in milk (95,96). In fact, infant urine cotinine levels have been correlated with cotinine levels in maternal breast milk (97). Maternal smoking has been linked to a higher incidence of respiratory tract infections in infants (97). Smoking has also been shown to have a negative effect on breastmilk production (98). Smoking may be a contributing factor to infant colic (99). In addition, infants may also be exposed to other chemicals from cigarette smoking, such as carcinogens. As such, passive smoking by the infant (100,101) may lead to long-term adverse effects. The use of ‘‘street drugs’’ by lactating women is contraindicated. The first concern should be that it may be difficult for nursing women using these drugs to care for their infants properly if they are experiencing an altered state of mind. Also, there exists the potential for drug exposure through breast milk (or passive smoking) and, therefore, adverse effects on the infant. These drugs are typically very potent, and smaller doses can have pharmacological effects. In a case report, cocaine and its metabolite were present in a mother’s milk after intranasal use and in the urine of her infant, who showed signs of cocaine toxicity (102). Phencyclidine has been detected in breast milk (103). THC (delta-9-tetrahydrocannabinol), considered to be the main psychoactive component of marijuana, is also excreted into breast milk (104). In a study of infant development after marijuana exposure during pregnancy and lactation, maternal use of marijuana in the first month postpartum was associated with lower motor development scores at 1 year of age in exposed infants compared to unexposed infants (105). Marijuana has also been shown to decrease plasma prolactin levels in women (106). Gold The use of gold therapy during breast-feeding is controversial. Variable milk levels have been reported and the extent of absorption by the infant is unknown. In one report, the mean milk level of aurothioglucose was 41 µg/L in a nursing woman receiving weekly injections of 50 mg. The M/S ratio was 0.01. The drug was not present in her infant’s serum or urine (limit of detection 5 ⫻ 10⫺7 mg/L). (107) In another report, sodium aurothio-

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malate given weekly at a dose of 25 mg produced maximum milk levels of 40 µg/L, and the infant’s urine contained 0.4 µg/L. The infant experienced transient facial edema, which could not be explained (108). The highest milk level reported in a woman receiving 10 mg of sodium aurothiomalate monthly was 93 µg/L. The M/S ratio varied from 0.02– 0.03. The infant plasma level was 51 µg/L; no adverse reactions were observed (109). Nursing infants may have continued exposure to gold long after a dose is given to the mother due to gold’s long half-life (approximately 1 week in serum) (107). Gold has also been shown to be excreted in increasing concentrations over time in milk (107,109). Infants who are nursing during maternal gold therapy should be monitored very closely for adverse effects. Iodine Drugs containing iodine (e.g., potassium iodide, povidone-iodine) are not recommended during breast-feeding. Iodine is transported into breast-milk and can result in iodine-induced goiter and hypothyroidism in the infant (110). Extensive topical administration and vaginal use of povidone-iodine by breast-feeding mothers has led to transient congenital hypothyroidism (111,112) and grossly elevated serum iodine levels in their infants (113). Oral Contraceptives Much controversy has surrounded the use of oral contraceptives during lactation. The topic has been extensively reviewed by Koetsawang (114), who concluded that combination estrogen and progestogen oral contraceptives, even low-dose, forms, can decrease milk yield. Progestogen-only contraceptives are associated with less changes. The World Health Organization (115) recently studied the effects of different types of contraception on milk and in nursing infants. They found that combined oral contraceptives caused slight changes in milk composition as well as a decrease in milk yield. Hormonal contraceptives, however, were not associated with any significant difference in infant weight, fat fold, or rate of discontinuation of breast-feeding by the mothers compared to a control group. Oral contraceptives are not recommended for use in early lactation or in nutritionally deficient mothers because the potential adverse effects on milk supply may be clinically significant in these women. Overall, progestogen-only contraceptives may be preferable. Initiation of oral contraceptives during nursing should be delayed. However, there is no consensus as to how long (116). Nursing prolongs amenorrhea in postpartum women; therefore oral contraceptives need not be started right away. Oral contraceptives should probably not begin until breast-feeding is fully established (approximately 6 weeks) or even later.

CONCLUSIONS Most drugs taken by breast-feeding women are excreted into breast milk and a determination of the risk to the infant must be made. For most drugs, risk assessment is made by considering the dose delivered to the infant from nursing. Other factors in risk assessment include considering the toxicity profile of the drug. The amount of drug consumed by the infant during nursing is usually less than 5% of the maternal dose (milligrams per kilogram). This small amount is tolerable without

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toxicity by most infants. Common sense dictates that even though many drugs may be taken safely during nursing, mothers should not be exposed to them unnecessarily. If maternal drug therapy is required, the specific agents used should be chosen with the consideration of minimizing any risks to the infant. In this way, interruption of breastfeeding is rarely justified. The following principles should be applied: the drug used should be appropriate for treating the mother’s condition, it should be unlikely to cause adverse effects in the infant, and finally, the infant should be monitored for potential adverse effects. Clinical Case Answer The woman should be told that fluoxetine and its active metabolite are excreted into milk and may be detected in infant urine. The baby should be observed for adverse effects.

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300. Soderman P, Hartvig P, Fagerlund C. Acetazolamide excretion into human breast milk. Br J Clin Pharmacol 1984; 17:599–600. 301. Werthmann MW, Krees SV. Excretion of chlorothiazide in human breast milk. J Pediatr 1972; 81:781–783. 302. Mulley BA, Parr GD, Pau WK, et al. Placental transfer of chlorthalidone and its elimination in maternal milk. Eur J Clin Pharmacol 1978; 13:129–131. 303. Cominos DC, Van der Walt A, Van Rooyen AJL. Suppression of postpartum lactation with furosemide. S Afr Med J 1976; 50:251–252. 304. Miller ME, Cohn RD, Burghart PH. Hydrochlorothiazide disposition in a mother and her breast-fed infant. J Pediatr 1982; 101:789–791. 305. Phelps DL, Karim A. Spironolactone: relationship between concentrations of dethioacetylated metabolite in human serum and milk. J Pharm Sci 1977; 66:1203. 306. Somogyi A, Gugler R. Cimetidine excretion into breast milk. Br J Clin Pharmacol 1979; 7: 627–629. 307. Oo CY, Kuhn RJ, Desai N, McNamara PJ. Active transport of cimetidine into human milk. Clin Pharmacol Ther 1995; 58:548–555. 308. Hofmeyr GJ, Sonnendecker EWW. Secretion of the gastrokinetic agent cisapride in human milk. Eur J Clin Pharmacol 1986; 30:735–736. 309. Hofmeyr GJ, van Iddekinge B. Domperidone and lactation. Lancet 1983; 1:647. 310. Hofmeyr GJ, van Iddekinge B, Blott JA. Domperidone: secretion in breast milk and effect on puerperal prolactin levels. Br J Obstet Gynaecol 1985; 92:141–144. 311. Courtney TP, Shaw RW, Cedar E, et al. Excretion of famotidine in breast milk. Br J Clin Pharmacol 1988; 26:639P. 312. Nikodem VC, Hofmeyr GJ. Secretion of the antidiarrhoeal agent loperamide oxide in breast milk. Eur J Clin Pharmacol 1992; 42:695–696. 313. Kauppila A, Arvela P, Koivisto M, et al. Metoclopramide and breast-feeding: transfer into milk and the newborn. Eur J Clin Pharmacol 1983; 25:819–823. 314. Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol 1980; 9:217–219. 315. Obermeyer BD, Bergstrom RF, Callaghan JT, et al. Secretion of nizatidine into human breast milk after single and multiple doses. Clin Pharmacol Ther 1990; 47:724–730. 316. Riley AJ, Crowley P, Harrison C. Transfer of ranitidine to biological fluids: milk and semen. In: Misiewicz JJ, Wormsley KG, eds. The Clinical Use of Ranitidine. Oxford, England: Medicine Publishing Foundation, 1981, pp 78–81. 317. Kearns GL, McConnell RF, Trang JM, et al. Appearance of ranitidine in breast milk following multiple dosing. Clin Pharm 1985; 4:322–324. 318. Nelis GF. Diarrhea due to 5-aminosalicylic acid in breast milk. Lancet 1989; 1:383. 319. Jenss H, Weber P, Hartmann F. 5-aminosalicylic acid and its metabolite in breast milk during lactation. Am J Gastroenterol 1990; 85:331. 320. Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet 1993; 342:618–619. 321. Edstein MD, Veenendaal JR, Newman K, et al. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol 1986; 22:733–735. 322. Ogunbona FA, Onyeji CO, Bolaji OO, et al. Excretion of chloroquine and desethylchloroquine in human milk. Br J Clin Pharmacol 1987; 23:473–476. 323. Ette EI, Essien EE, Ogonor JI, et al. Chloroquine in human milk. J Clin Pharmacol 1987; 27:499–502. 324. Nation RL, Hackett LP, Dusci LJ, et al. Excretion of hydroxychloroquine in human milk. Br J Clin Pharmacol 1984; 17:368–369. 325. Ostensen M, Brown ND, Chiang PK, et al. Hydroxychloroquine in human breast milk. Eur J Clin Pharmacol 1985; 28:357.

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326. Erkkola R, Kanto J, Allonen H, et al. Excretion of methylergometrine (methylergonovine) into the human breast milk. Int J Clin Pharmacol Biopharm 1978; 16:579–580. 327. Ost L, Wettrell G, Bjorkhem I, et al. Prednisolone excretion in human milk. J Pediatr 1985; 106:1008–1011. 328. Katz FH, Duncan BR. Entry of prednisone into human milk. N Engl J Med 1975; 293:1154. 329. McKenzie SA, Selley, JA, Agnew JE. Secretion of prednisolone into breast milk. Arch Dis Child 1975; 50:894–896. 330. Jarnerot G, Into-Malmberg M-B. Sulphasalazine treatment during breast feeding. Scand J Gastroenterol 1979; 14:869–871. 331. Berlin CM, Yaffe SJ. Disposition of salicylazosulfapyridine (azulfidine) and metabolites in human breast milk. Dev Pharmacol Ther 1980; 1:31–39. 332. Esbjorner E, Jarnerot G, Wranne L. Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatr Scand 1987; 76:137–142. 333. Branski D, Kerem E, Gross-Kieselstein E, et al. Bloody diarrhea-a possible complication of sulfasalazine transferred through human breast milk. J Pediatr Gastroenterol Nutr 1986; 5: 316–317. 334. Wojnar-Horton RE, Hackett LP, Yapp P, et al. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol 1996; 41:217–221. 335. Stec GP, Greenberger P, Ruo TI, et al. Kinetics of theophylline transfer to breast milk. Clin Pharmacol Ther 1980; 28:404–408. 336. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1976; 57:518– 520. 337. Orme M L’E, Lewis PJ, de Swiet M, et al. May mothers given warfarin breast-feed their infants? BMJ 1977; 1:1564–1565. 338. McKenna R, Cole ER, Vasan U. Is warfarin sodium contraindicated in the lactating mother? J Pedatr 1983; 103:325–327. 339. Krogh CME, ed. Compendium of Pharmaceuticals and Specialties. 31 st ed. Ottawa: Canadian Pharmaceutical Association, 1996. 340. McElvoy GK, Litvak K, Welsh OH, et al, eds. American Hospital Formulary Service Drug Information. Bethesda, MD: American Society of Hospital Pharmacists, 1992.

14 Poisoning in Pregnancy Milton Tenenbein University of Manitoba, Winnipeg, Manitoba, Canada

Clinical Case You attend a 16-year-old pregnant (12 weeks gestation) woman who had tried to commit suicide by taking 60 caplets of Tylenol (325 mg each). The patient, who weighs 50 kg, did not tell anyone about her action for 24 hours, but then became frightened by her continued vomiting. Her boyfriend did not suspect anything because ‘‘she had morning sickness anyway.’’ How should she be treated?

INTRODUCTION Exposure to drugs and chemicals can have an adverse effect on the outcome of a pregnancy. We generally consider low-level exposures (doses insufficient to harm the expectant mother), which we evaluate by the criteria of reproductive wastage and production of dysmorphic offspring. Very little attention has been paid to the issue of acute poisoning during pregnancy. In such situations there is potential risk for the mother as well as the fetus. The fetal and maternal risks are not necessarily equal. Extent of toxin exposure may be different on both sides of the placenta. Although most agents that are absorbed across the gastrointestinal epithelium freely traverse the placenta, some, such as iron, have specialized transplacental absorptive mechanisms (1,2). In a massive overdose situation, this mechanism may become a rate-limiting step, thus resulting in a relatively smaller fetal exposure. Conversely, some agents, such as salicylates, are present in higher concentrations in the fetus (3,4). Fetal metabolic pathways are often immature. While this may seem to put the fetus at greater risk, it can also be protective when, for example, toxicity is due to an intracellularly generated metabolite, not the ingestant itself. Acetaminophen is an example of such an agent. Because the mother is at risk, she often requires treatment. Does the presence of a conceptus demand modified therapy? Do interventions to manage poisoning—such as syrup of ipecac, hemodialysis, or specific antidotes—present a risk to the fetus? In some

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cases, a unique decision in the management of the acutely poisoned patient may be required: should a potentially viable fetus be delivered on an emergency basis to prevent damage or death? This chapter reviews the management of the poisoned expectant mother. Adverse effects to the neonate from drugs administered in therapeutic doses to the mother are discussed elsewhere in this book, as are teratogenesis and the fetal and neonatal effects of substance abuse. First, the epidemiology of acute poisonings during pregnancy is reviewed. Then we discuss the general management of the overdosed expectant mother and the management of various specific poisonings.

EPIDEMIOLOGY OF POISONING DURING PREGNANCY Most poisonings during pregnancy are suicidal gestures. However, in one large series of hospitalized poisoned pregnant patients, 14% of the cases were accidental (5). In this series of 162 patients, there were two maternal and four fetal deaths. This cohort, which was gleaned from a specialized unit for the treatment of intoxications, consisted of relatively serious cases. The occurrence of only four fetal deaths, a 2.5% rate, would seem to indicate a relative resistance to an acute toxic insult. If indeed this is so, it may help to explain the limited number of published cases of overdoses during pregnancy, since most patients do well. In a subsequent series by the same authors (6), 2 out of 559 women died. Of 213 fetuses in the first month of pregnancy, 111 ended in early loss, 3 in clinical miscarriage, 12 survived to delivery, 73 pregnancies were terminated, and one woman died. Pregnant women may threaten suicide to strengthen their case for a therapeutic abortion (7). Conversely, pregnancy provides a unique motivation for drug overdose (i.e., an attempt to induce an abortion). In Czeizel’s series, 8% overdosed for the express purpose of inducing an abortion, and 23% subsequently had a therapeutic abortion (5). Some agents are commonly considered as abortifacients. If overdose of quinine during pregnancy is encountered, one should strongly consider the possibility that an attempt was made to induce abortion (8). Historically, lead was often ingested to induce abortions (9), and from time to time various herbal remedies have been utilized for this purpose (10). Whitlock and Edwards, who reviewed pregnancy and attempted suicide (11), felt that the incidence of suicidal gestures among pregnant women was at least equal to that among nonpregnant women. These authors reported that 7% of all women making suicidal gestures are likely to be pregnant. Although pregnant women are less likely to kill themselves, suicide does account for 1% of all deaths during pregnancy, and pregnancy is an associated factor in 5% of all female suicides (11). In a later study by the same group, they reported that pregnant women trying to commit a suicide through an overdose tended to be of lower socioeconomic class than controls and were more likely to be unmarried (12). Rayburn et al. reviewed drug overdose during pregnancy in an ambulatory population (13). Their cohort was gleaned from the case records of a poison control center. In a 4-year period, 0.07% of all telephone consultations involved overdoses by pregnant women. Although the ingestants were similar to those of the general population, one notable difference was an increased frequency of ingestion of vitamins and iron, which constituted the second most common group of ingestants. This should not be surprising, since pregnant women are routinely placed on these supplements. However, it is worrisome because the management of iron overdose is complex enough without the presence of a fetus.

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Czeizel studied drug overdose and pregnancy from another perspective (14). He wondered whether the prior occurrence of an overdose adversely affects subsequent reproductive function. Happily he found that a severe overdose does not lead to decreased fertility, increased pregnancy wastage, or subsequent dysmorphology (14).

APPROACH TO THE POISONED PREGNANT PATIENT At the time of first contact with the poisoned woman, the fact that she is pregnant may not be disclosed by her or may not even known to her. Jones and colleagues describe an overdosed patient in whom ruptured ectopic pregnancy was missed for significant time because of the patient’s normal menstrual history. These authors very logically recommend that a pregnancy test should be performed in all women of reproductive age who present with poisoning or drug overdose (15). The general management of the pregnant patient who has taken an acute overdose should not differ from that of the nonpregnant individual. The proper approach is well described elsewhere (16) and includes acute stabilization (airway, breathing, circulation), history, physical examination, supportive care, nonspecific antipoison therapy (prevention of absorption, enhancement of elimination), and specific antipoison therapy (administration of an antidote). In addition to such routine management, fetal well-being must be monitored. Recently, the approach to preventing the absorption of ingested poisons has undergone reappraisal and modification. The time-honored interventions of ipecac-induced emesis and orogastric lavage have been questioned and administration of activated charcoal has become the primary gastrointestinal decontamination procedure (17–19). In addition to this change in the approach to the prevention of absorption of poisons, an additional procedure, whole-bowel irrigation with polyethylene glycol-electrolyte lavage solution, has been introduced as a new intervention (20). Its use in a pregnant patient has been reported (21). From the perspective of the management of the overdosed pregnant patient, the trend away from syrup of ipecac circumvents potential concerns regarding the teratogenic potential and safety of this drug during pregnancy. Unlike ipecac, activated charcoal is not absorbed; thus adverse effects on the fetus would not be expected. The risk to the fetus from the administration of most antidotes is unknown. The scant available information is discussed below in connection with the poison in question. These risks may manifest as teratogenesis or as acute fetal toxicity if the antidote has agonistic properties. An example of the latter situation is the administration of atropine for organophosphate pesticide poisoning. Since the transplacental delivery of the poison and the antidote may not be similar, although the mother’s atropine dose may be optimal, the fetus is at risk to receive a relative underdose or overdose of this antidote. The latter situation has been documented (22). Despite these potential fetal risks, the needs of the mother are paramount. If the indication for an antidote exists, the presence of a gravid uterus must not be considered to contraindicate its administration. A tragic case of a maternal death associated with the withholding of an antidote because of fears of teratogenicity has been published (23,24). In a prospective study, Czeizel reported that, after excluding heavy drinking resulting in fetal alcohol syndrome, the overall rate of congenital anomalies (9%) was not higher than among controls (25). Although there is very limited literature on most forms of therapy for poisoning during pregnancy, some experiences with hemodialysis have been published. There are

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at least three reports of the use of acute hemodialysis during pregnancy to treat acute drug overdose (26–28) as well as reviews of pregnancy in hemodialysis patients (29–31). Acute hemodialysis does not seem to have an adverse effect on the fetus. Although women on chronic hemodialysis have increased reproductive wastage, premature labors, and growthretarded newborns, these are more likely a consequence of their underlying renal disease.

ACETAMINOPHEN Published Experience After nutritional supplements, acetaminophen is the commonest drug taken by pregnant women (32). It has been documented as the drug that is most frequently taken in overdose during pregnancy (13), and the published experience of overdoses during pregnancy is greatest for this agent (Table 1) (33–43). Since acetaminophen crosses the placenta (44), the fetus is at potential risk. The first case was published in 1978 but was poorly documented. The overdose occurred during the first half of pregnancy and was not treated with specific antidote; the mother suffered severe hepatotoxicity: serum aspartate transaminase (AST) of 9550 IU/ L. The fetus survived, only to be therapeutically aborted 2 weeks later. Since there was no description of a pathological examination of the abortus, it is not known whether there was any fetal toxicity. Between 1982 and 1986, eight case reports were found. Byer et al. (34) described a 26-year-old, 36-week-pregnant woman who ingested 32.5 g of acetaminophen. Some 41/2 hours after the ingestion, her serum concentration was just barely into the potential toxicity section of the nomogram, than expected (16–24 hours after overdose), the hepatic microscopy supported acetaminophen toxicity. Thus, toxicity must be considered to be the probable cause for the fetal death. Two cases were described in 1986. Robertson et al. (40) described a 21-year-old 16-week-pregnant woman who ingested 36 g of acetaminophen. Her serum concentration was well into the toxic range of the nomogram. Because oral N-acetylcysteine was not tolerated, this antidote was administered intravenously. There was no maternal hepatotoxicity, and a normal newborn was delivered at term. The second patient, described by Ludmir et al. (41), was 16 weeks pregnant and had ingested 64 g of acetaminophen. Her serum concentrations were also well into the toxic range, and N-acetylcysteine therapy was begun at 20 hours after the overdose, at a time when it was unlikely to alter the course. This patient developed severe hepatotoxicity, from which she fully recovered. A premature labor and delivery resulted in a normal 32-week newborn that subsequently thrived. The largest experience of acetaminophen overdose during pregnancy was published in 1989 (42). In this multicenter study, complete data were available in 60 of 113 cases, and one of these is of particular interest: a stillborn fetus at 33 weeks gestation, with death having occurred 2 days after maternal overdose. The mother’s serum acetaminophen concentration was toxic by nomogram and she received a full oral course of N-acetylcysteine beginning 12 hours after acetaminophen ingestion. Significant hepatotoxicity occurred in the mother, who survived. The fetal serum acetaminophen concentration was grossly elevated, and at autopsy the fetus was found to have massive hepatonecrosis. This case is very similar to that of Haibach et al. (39), strengthening the hypothesis that the fetus is at greatest risk if the acetaminophen overdose occurs during the third trimester.

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Table 1

Acetaminophen Overdose During Pregnancy

Case

Gestation (weeks)

Potential maternal toxicity

1

20

Yes

No

Yes

na

2 3 4 5 6 7 8 9 10

36 29 38 18 36 28 16 16 33

Yes Yes Yes Yes No Yes Yes Yes Yes

Yes No Yes Yes, but late Yes No Yes Yes, but late Yes

No Yes No Yes No Yes No Yes Yes

6 weeks 16 h 17 h 23 weeks 7h na 24 weeks 16 weeks na

Full course of antidote

Maternal toxicity

Timing of delivery after overdose

Fetal outcome

Ref.

Survival; subsequent therapeutic abortion Normal Survival; no hepatotoxicity Survival; no hepatotoxicity Normal Survival; no hepatotoxicity Stillborn Normal Normal Stillborn

29 30 31 32 33 34 35 36 37 38

Note: na, not available.

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Riggs et al. (42) also attributed a first-trimester fetal loss to an acetaminophen overdose. However, the mother was also very seriously affected and she died. It was not determined whether the fetal loss was secondary to the mother’s critical condition or primary to fetal hepatotoxicity. Another large series describing 48 cases was published in 1990 (43). Details of individual cases are sketchy, making commentary difficult. Of interest, though, was the observation of no birth defects associated with first-trimester N-acetylcysteine therapy. Of the 10 cases summarized in Table 1, case 6 is of little interest because of negligible potential for toxicity. Cases, 1, 3, 5, 7, 9, and 10 all exhibited maternal hepatotoxicity. The two intrauterine deaths, cases 7 and 10, were due to third-trimester overdoses. The other four fetuses did well. Of these, only one was in the third trimester (case 3), and this baby was delivered 6 hours after the overdose. Thus, it would seem that maternal hepatotoxicity in the third trimester is a marker for potential fetal demise. However, the clinical usefulness of this association (if it exists at all) is quite limited, since both fetuses who died did so prior to or during the early development of maternal toxicity. Pharmacology and Toxicology Estimation of the fetal risk from a maternal acetaminophen overdose requires an understanding of the metabolism of this drug by the mature organism and the differences that may exist in the fetus. We discuss only briefly the metabolism of this drug, since it is well reviewed elsewhere (45). In therapeutic amounts, acetaminophen is largely excreted as urinary sulfates or glucuronides. A small amount is oxidized by the cytochrome P-450 mixed-function oxidase system. This produces a highly reactive metabolite that binds to hepatocellular macromolecules, producing hepatoxicity. This effect can be prevented by complexation with hepatic glutathione. In overdose situations, sulfation and glucuronidation become saturated, thus presenting an increased load to the cytochrome P-450 pathway. Hepatotoxicity ensues after glutathione has been depleted. Thus it is an intracellularly generated metabolite, not the parent acetaminophen, that produces toxicity. Administration of N-acetylcysteine is protective because it acts as a glutathione precursor (46). Therefore, for hepatotoxicity to occur, the fetal hepatocyte must have an active cytochrome P-450 system. Absent or decreased capacity for sulfation, glucuronidation, and glutathione generation would increase the risk of fetal liver damage. In general, cytochrome P-450, sulfation, and glutathione are present in human fetal livers but glucuronidation is not (47,48). Not surprisingly, the extent of the activities of these processes is poorly documented. It varies among xenobiotics and with gestational age. However, acetaminophen is one of the few drugs that has undergone human fetal metabolic studies (45). Hepatocytes were harvested from fetuses at 18–23 weeks gestation. Cytochrome P-450 activity, glutathione generation, and sulfation were demonstrated along with an absence of glucuronidation. Mean cytochrome P-450 activity was only 10% of adult values, with a linear increase occurring over the gestational period under study. Thus, degree of fetal risk from maternal acetaminophen ingestion would seem to correlate with gestational age. This suggestion is supported by the observation that the two fetal deaths (39,42) were third-trimester gestations. Treatment of Acetaminophen Overdose During Pregnancy The management of the pregnant woman with an acetaminophen overdose should not differ from that of the nonpregnant individual—that is, stabilization, supportive care, ap-

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propriate gastrointestinal decontamination, and specific therapy (N-acetylcysteine administration), ideally based on serum acetaminophen concentration determination. A recent study documents that N-acetylcysteine crosses the human placenta and achieves fetal concentrations well within those associated with antidote effects (9.4 ⫾ 1.3 µg/mL). There were no adverse effects among these babies (49). The safety of this antidote for the fetus has not been established, but preliminary information is encouraging (42). In any event, N-acetylcysteine should not be withheld if the mother is at risk, but it has been shown to have negligible transplacental passage in sheep (51). Since oral administration in humans produces significantly lower plasma concentrations (51), the intravenous route in the mother seems to be the logical choice for protection of her fetus. Also, the fetal delivery of N-acetylcysteine may be compromised after maternal oral administration because of first-pass hepatic uptake, particularly if the maternal liver is in a relatively glutathionedepleted state owing to the acetaminophen overdose. Furthermore, the oral route is often poorly tolerated because of vomiting (52). Nevertheless, the findings of Selden et al. (51) point to a poor fetal prognosis in significant third-trimester acetaminophen overdose. The limited data available support immediate delivery of a mature fetus for direct extrauterine N-acetylcysteine therapy if the maternal serum acetaminophen concentration is well into the toxic range by nomogram. If the risk for delivery is too great because of fetal immaturity, direct intrauterine cannulation of the umbilical vasculature for N-acetylcysteine administration could be considered. However, neither of these options is likely to be practical because of the length of time required for their organization and implementation.

SALICYLATES Published Experience Five reports of in utero salicylate intoxication in pregnant women were found. Three were due to an acute ingestion (53–55), whereas the other two were the result of subacute or chronic toxicity (51,52). There were two deaths, both in the acute group (48,50). Jackson (48), in 1948, described a woman in her eighth month of pregnancy who delivered a 2.7kg stillborn fetus 17 hours after an overdose of 200 g of acetylsalicylic acid. Although at autopsy tentorial tears and cerebral hemorrhage were found, there was ‘‘a high concentration of salicylate’’ in the cord blood, indicating at least that the fetus was alive prior to the overdose. Nevertheless, the contribution of salicylate toxicity to the fetal demise is unclear. Also, given the mother’s benign course, it is unlikely that she actually ingested 200 g of acetylsalicylic acid. In 1961 Earle (54) described a 3.5-kg neonate whose mother had ingested 15–18 g of acetylsalicylic acid 27 hours prior to delivery. At 20 hours of age, the baby was acidemic, with a salicylate concentration of 350 mg/L. One hour earlier, the mother’s concentrations had been 220 mg/L; it had been 380 mg/L 20 hours prior to delivery. An exchange transfusion resulted in removal of an estimated 135 mg of salicylate. Since this represents only 40 mg/kg and is equivalent to two-fifths of a tablet, it is difficult to ascribe benefit to this intervention. Mother and baby did well. Rejent and Baik described a woman in her eighth month of pregnancy who ingested 36.5 g of acetylsalicylic acid (55). She was manifesting salicylism, but the fetus was not felt to be in distress. However, 20 hours later, the baby was dead. The postmortem fetal serum salicylate concentration was 243 mg/L, with a brain concentration of 200 µg/g.

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Since the latter amount is similar to fatal brain concentrations in mice (56), it is likely that the fetal death was due to intrauterine salicylate toxicity. Lynd et al. (57) described a case of chronic intrauterine salicylism in a 2.6-kg male neonate who was irritable and feeding poorly at 36 hours of age. It was learned that his mother had self-medicated with undetermined amounts of salicylates throughout her ninth month. The baby was hyperpneic and hypertonic, and he appeared malnourished. His serum salicylate level was 310 mg/L at 36 hours. A concentration of 383 mg/L was found upon analysis of the cord blood. The baby was treated with induced diuresis and his condition improved. His irritability, hypertonia, poor feeding, and intrauterine malnutrition may have been due to the salicylism, but other causes such as maternal drug abuse were not conclusively ruled out. Ahlfors et al. (58) described a 3-kg 37-week female neonate delivered by cesarean section for fetal distress. Her mother had consumed 3 g of acetylsalicylic acid daily for a flulike illness for several days prior to delivery. Shortly after birth, tachypnea, a compensated metabolic acidosis, and a cord blood concentration of 473 mg/L were documented. An exchange transfusion at 21 hours had a negligible effect on the serum salicylate concentration, but the neonate gradually recovered. An interesting observation was that the salicylate displaced bilirubin from its albumin bindings sites, thus necessitating interventions to lower bilirubin concentrations so as to prevent kernicterus. Buck and colleagues (59) described a neonate in metabolic acidosis, tachypnea, and hypoglycemia born to a mother who had taken aspirin throughout pregnancy. The authors highlight the similarities between symptoms of neonatal sepsis and those of a toxic reaction to salicylates. The toxic effects of salicylates on the mother are well described elsewhere (60). Because lungs do not function in the fetus, stimulation of respiration is of no concern. However, the ability of salicylates to uncouple oxidative phosphorylation makes them a general cellular poison, with the brain in particular being a target organ because of its inability to compensate with anaerobic energy production. Hill’s work with mice supports central nervous system toxicity as the mechanism of death in salicylism (56). Unlike the case with acetaminophen, in salicylate poisoning the parent compound rather than the metabolite produces the toxicity, thus placing the fetus at risk. Several factors would seem to support the hypothesis that there may be a greater risk to the fetus than to the mother. Salicylate traverses the placenta and is found in higher concentrations in the fetus (3,4). The fetus has a lower arterial pH than the adult, making the blood-tointracellular pH gradient less. Since the drug is a weak acid, this lower gradient favors a relatively greater proportion of the fetal salicylate load entering the central nervous system. In addition, the fetus has less capacity to buffer the acidemic stress imposed by the salicylate and, relative to the mother, a reduced capacity to metabolize and excrete this toxin. Indeed, in at least three cases, paired newborn-maternal sera demonstrated salicylate persistence in the neonate (54,55,57). Treatment of Salicylate Overdose During Pregnancy The treatment of salicylate poisoning is supportive care (60). This includes patient stabilization; appropriate gastrointestinal decontamination; administration of fluid, electrolyte, and glucose; and—when indicated—an extracorporeal removal intervention. In pregnancy, it is hoped that the positive effects of these maneuvers will be reflected transplacentally. However, several of the previously described fetal factors (higher serum concentra-

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tions, larger proportion of salicylate in the brain, lower buffering capacity, and decreased salicylate metabolism) would somewhat negate such benefits. Therefore, when the fetus is potentially viable ex utero, consideration should be given to prompt delivery. This provides the opportunity for direct provision of care to the newborn.

IRON Published Experience Prenatal vitamins and iron have been documented as the second most common overdosed drug group during pregnancy (13). A series of 49 cases from the United Kingdom has been published (61). However, the vast majority were either nontoxic or negligibly toxic overdoses, and the retrospective nature of the review makes analysis difficult. We have managed five cases, and there are six other case reports in the literature (23,24,62–66). The most notable observation is that the fetus seems to fare better than the mother. The literature reports one overdose in the first trimester (62), two in the second (23,24,63), and three during the third (58–60). One case was nontoxic by serum iron concentration and deferoxamine challenge criteria (63). The only fetal death occurred as a spontaneous abortion in a 17-year-old girl who was seriously ill and subsequently died of the overdose (23,24). The other five babies did well, although two maternal deaths (65,66) occurred shortly after the delivery of neonates who showed no signs of iron toxicity. Three mothers were treated with deferoxamine (one in the second trimester and two in the third trimester), and these babies were normal. Two other cases occurred prior to deferoxamine availability and were treated with other chelators no longer used in iron poisoning (62,65). Both these babies did well. Three pregnancies were delivered within 36 hours of overdose, and the cord blood or early postpartum serum iron concentrations were in the normal range (64–66). The fetus that died and its placenta were examined histologically for evidence of iron toxicity and for the presence of increased iron. Neither was found (23,24). This is also true for the only other placenta that was examined (64). The pathophysiology of acute iron poisoning is well reviewed elsewhere (67,68). This can be a difficult poisoning to treat, and several aspects of its therapy are controversial (67). Major features of iron poisoning include gastrointestinal hemorrhage, shock, acidosis, hepatic failure, and coagulopathy. Death is usually the result of cardiovascular collapse or hepatic failure. Although the introduction of the specific iron chelator deferoxamine improved the prognosis, optimal use of this antidote has not been established. The well-being of a fetus presents an additional challenge to the management of an already complex problem. The passage of iron across cellular membranes and its transport throughout the body involve complex processes. Iron, in physiological conditions, exists in its oxidized (ferric) state. Since ferric iron is insoluble, the plasma protein transferrin is required for its transport. Iron traverses membranes by receptor-mediated endocytosis, which is an active, rapid, unidirectional process able to function against a concentration gradient. Transferrin is bound by its specific receptor and is then internalized by endocytosis. The iron is cleaved from the transferrin and retained, whereas the transferrin is returned as apotransferrin. This has been documented as the iron transport system across the human placenta (1,2). Therefore, only transferrin-bound iron would be eligible for transplacental passage. This is further supported by studies in pregnant ewes (Fig. 1). Despite massive induced hyperferremia, only a negligible amount of iron was passed to the fetus (69). Thus, unlike the case with other poisons discussed in this chapter, the placenta acts as a barrier to iron.

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Figure 1 Maternal and fetal serum iron concentrations in control- and deferoxamine-treated animals. Plotted values are mean ⫾ standard error. Ewes in both groups received intravenous iron as 2 mg/kg maternal body weight over the first 60 minutes. Ewes in the deferoxamine group then received intravenous deferoxamine mesylate as 50 mg/kg maternal body weight over 15 minutes. Open circles ⫽ control ewes; solid circles ⫽ control fetuses; open squares ⫽ deferoxamine ewes; solid squares ⫽ deferoxamine fetuses. (Reproduced by permission from Steven C. Curry, M.D.).

This would explain why the fetus seems to do better than the mother. This ‘‘placental block’’ is supported by lack of neonatal hyperferremia (64–66), lack of histological iron toxicity (23,24,64). and two maternal deaths despite survival of the offspring (65,66). Thus, it would seem that the risk to the fetus is not from the iron itself but is secondary to the induced pathophysiological derangements in the mother. The use of the specific iron chelator deferoxamine during pregnancy is of concern because the product monograph cites it as a proved animal teratogen. These studies have not be published but have been referred to as personal communications in two case reports (63,70). They were briefly described as the prolonged administration of very high doses to pregnant nonhyperferremic mice and rabbits during early gestation. This resulted in skeletal anomalies and decreased ossification in the offspring. Because deferoxamine is negligibly absorbed across the gastrointestinal tract and is a charged and relatively large molecule, it would not be expected to cross the placenta. Therefore, the adverse effects observed in the rodents would most likely be due to chelation of essential nutrients required for skeletal maturation. This would occur over periods of time more prolonged than would typify the treatment of an iron overdose. In addition, chelation of other nutrients would be less likely in a hyperferremic state.

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These speculations are supported by three case reports of deferoxamine therapy during pregnancy (70–72). In two of these, deferoxamine was administered for the first 16 and 19 weeks of pregnancy in thalassemic women (70,71). In the third case, a woman received two intramuscular injections during her 10th week. In no case was there evidence of teratogenesis. In the three published cases of iron overdose in pregnant women treated with deferoxamine, all the babies did well (63,64,66). However, these were second- and third-trimester pregnancies. Treatment of Iron Overdose During Pregnancy Management principles should follow those of the nonpregnant patient (67,68). The teratogenic risk of deferoxamine is probably overstated. Nevertheless, as in all situations, maternal well-being takes precedence over fetal concerns. The death of an iron-poisoned mother associated with the withholding of deferoxamine because of concern over teratogenesis was especially tragic (23,24). ORGANOPHOSPHATE PESTICIDES Published Experience At least five cases of organophosphate pesticide poisoning during pregnancy have been described (22,73–75), but two are of limited interest. One of the latter provides only the results of postmortem analysis of various maternal and fetal tissues from a 19-year-old girl who, in her fifth month of pregnancy, committed suicide by ingesting mecarbam (73). The authors demonstrated that this pesticide crosses the placenta and, at least in this maternal–fetal pair, was found in higher concentrations in the conceptus. The other is a 24year-old woman in her third month of pregnancy whose malathion overdose was successfully treated with atropine, obidoxime, and assisted ventilation (74). She underwent a therapeutic abortion 2 months later, and there was no description of the products of conception. Thus, all that can be concluded is that appropriate treatment of organophosphorus poisoning during early pregnancy can result in full recovery of the mother and maintenance of her pregnancy. Two others, a 22-year-old woman in her 36th week who overdosed with methamidophos and a 25-year-old in her 16th week poisoned with fenthion, were both appropriately managed with atropine, pralidoxime, and respiratory support (75). No abnormalities of pregnancy were described, and both women delivered normal babies at term. Thus, it is possible to successfully manage organophosphate poisoning in the second and third trimesters. Perhaps the most interesting is the case report of Weis et al. (22). Although this 21year-old female in her 34th–35th weeks of pregnancy never admitted to ingesting a pesticide, the rapid onset of a severe cholinergic syndrome, the absence of plasma and erythrocyte cholinesterase activity, and the dramatic response to large doses of atropine preclude any other diagnosis. However, the stress of spontaneous onset of labor early on, along with the atropine therapy, resulted in a fetal heart rate of 200 beats/min. An emergency cesarean section was done, resulting in the delivery of a small, floppy, depressed neonate. As in the mother, assisted ventilation and atropine infusions were required. Curiously, the mother seemed to have been more severely affected, since she had a longer requirement for assisted ventilation and atropine, her cholinesterases took longer to return to normal, and her therapeutic atropine dose was a toxic dose for the fetus in utero.

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The pathophysiology of acute organophosphate pesticide is well described elsewhere (76). Of interest is the occurrence of two delayed paralytic syndromes. The better known is a peripheral neuropathy involving the distal extremities (77). Onset is a few weeks after the acute phase and is separated from it by a period of recovery. Respiratory failure is not a feature, and at worse its occurrence could complicate subsequent labor and delivery. The second paralytic syndrome was described in 1987 as the ‘‘intermediate syndrome’’ (78). It consists of proximal muscle weakness, multiple cranial nerve palsies, and respiratory failure beginning within 24–96 hours after ingestion. There may not be an apparent period of recovery between onset and the acute phase. The occurrence of this syndrome along with its required therapeutic interventions represent a more serious risk to pregnancy. Interestingly, this intermediate syndrome occurred in three of the cases described above (74,75). Not surprisingly, little is known regarding the human transplacental passage of the many organophosphate pesticides. However, if maternal toxicity follows ingestion, transgastrointestinal epithelial passage has occurred, making fetal entry a result to be expected. This was confirmed for mecarbam (73). The amount passed on to the fetus relative to the maternal body burden would likely differ from compound to compound. Although mecarbam was found in higher concentration in the fetus (73), the more severe maternal course in the case of Weis et al. (20) suggests a relatively smaller fetal burden in that situation. Of additional concern is the possibility of innate differences in the sensitivity to organophosphates by maternal and fetal cholinesterase systems. Decreased activities of neonatal plasma and red cell cholinesterase ranging from 50–70% of adult values have been consistently documented (79–82). Therefore, increased fetal sensitivity to cholinesterase-inhibiting pesticides would be expected. These issues of relative placental passage and potentially differing fetal and maternal sensitivities are important because the chief antidote, atropine, has potent agonistic properties. Therefore, there is the potential for a therapeutic maternal atropine dose being either subtherapeutic or toxic for the fetus. Treatment of Organophosphate Insecticide Poisoning During Pregnancy The basic management in a pregnant woman should not differ from that for the nonpregnant patient. It includes appropriate life support and gastrointestinal decontamination, meticulous respiratory care, and the administration of atropine and pralidoxime (76). The fetus should be closely monitored. If the maternal condition is satisfactory but distress is documented in a potentially viable fetus, consideration should be given to immediate delivery to permit the initiation of therapy ex utero.

DIGITALIS Published Experience With the advent of specific antidotal therapy for digitalis poisoning (83), it is important to discuss poisoning in pregnancy with this drug. However, only one case could be located (84): a 26-year-old woman who during her seventh month of pregnancy ingested 8.9 mg of digitoxin, demonstrating clinical and electrocardiographic evidence of digitalis toxicity. Although the patient was quite ill, she did well with supportive care. On presentation, fetal heart tones were irregular, with a rate of 68 beats per minute and regular. Spontaneous

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labor on the fourth day produced a female weighing 2160 g, in poor condition, who died 3 days postpartum. An electrocardiogram at 15 minutes of age supported a digitalis effect on the neonate. Autopsy findings were consistent with prolonged intrauterine anoxia. Because this report goes back to 1960, documentation does not meet current standards. Notably absent are serum drug concentrations and sophisticated fetal monitoring data. Nevertheless, there is a strong case for intrauterine digitalis toxicity. Acute digitalis poisoning and its treatment with Fab antibody fragments is well described elsewhere (85). Therefore our discussion is limited to issues pertinent to this problem in pregnancy (the transplacental passage of these cardiac glycosides and of the Fab antidigoxin antibody fragments). Radioactive tracer studies have demonstrated transplacental passage of both digoxin (86) and digitoxin (87) in humans during the first half of pregnancy. This result is further supported by the practice of treating fetal tacharrhythmias with maternal digitalization. Nagashima et al. report three such cases (88). They demonstrated arrhythmia conversion and similar cord and maternal serum digoxin concentrations. They also cite several other similar case reports. Therefore, the fetus is at risk for cardiovascular dysfunction due to maternal cardiac glycoside overdose. Indeed, Sherman and Locke documented fetal bradycardia (84). Data on the transplacental passage of Fab antibody fragments are lacking. If this antidote does not cross the placenta, its administration to the mother would be of no direct benefit to the fetus. However, transplacental passage is likely, since these fragments are freely excreted in the urine. Nevertheless, a brief case report exploring the use of this agent in eclampsia suggests otherwise (89). This conclusion is questionable, however, since the fetal presence of the fragments was only indirectly inferred from measurements of an endogenous digitalis-like factor, and the maternal and newborn samples were not simultaneous. Treatment of Digitalis Poisoning During Pregnancy The management of the pregnant woman with an acute digitalis overdose should be based on the same principles advised for nonpregnant individuals (85)—namely, initial stabilization, appropriate gastrointestinal decontamination, measurement of serum electrolyte and digoxin concentrations, cardiac monitoring, and supportive care. In addition, fetal cardiac rhythm should be monitored [with fetal echocardiography (88) if available]. If there is maternal indication (hyperkalemia or life-threatening rhythm disturbances) for the administration of antidigoxin antibody fragment, this should be done even though its safety and efficacy for the fetus is unknown. Hopefully, coexistent fetal cardiac arrhythmias would be simultaneously corrected. If not, a second maternal dose should be considered. If still unsuccessful, a viable fetus could be delivered and the antidote administered directly. In the case of a previable fetus, intrauterine cannulation of the fetal vasculature for direct antidote administration and for possible fetal blood sampling could be considered. Another possibility, albeit seemingly unlikely, would be the occurrence of a fetal indication for antidotal therapy in a healthy mother. If this were to occur, the same approach would seem to be appropriate. CAMPHOR Published Experience Camphor ingestions have become a relative rarity, likely owing to concerted efforts to discourage the use of this substance. However, since at least four poisonings during pregnancy have been described (83–86), the topic is reviewed for historical interest.

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Weiss and Catalano (90) described a 26-year-old woman at term who ingested 60 mL of camphorated oil instead of castor oil. She had two seizures but delivered a normal baby, who had the obvious odor of camphor. Camphor was qualitatively demonstrated in the newborn’s blood. Riggs et al. (91) described a 40-year-old woman at term who also ingested 60 mL of camphorated oil instead of castor oil She too had a seizure. thirty-six hours later, she delivered a daughter in very poor condition, who died in 30 minutes. Since the course was complicated by preeclampsia, abruptio placentae with hemorrhage, and breech presentation, the contribution of camphor to the fetal demise is uncertain. Camphor was qualitatively demonstrated in the maternal blood, cord blood, and amniotic fluid and in the infant’s brain, liver, and kidneys. Blackmon and Curry (92) described a hospitalized 32-year-old woman in her third month of pregnancy with a threatened abortion who was given 45 mL of camphorated oil in error. Although the patient had four seizures, she carried to term, delivering a normal baby. Jacobziner and Raybin (93) mentioned in passing a 17-year-old pregnant girl who drank 60 mL of camphorated oil to induce an abortion. Although she recovered and her conceptus remained vital, further details were not given. Pharmacology, Toxicology, and Treatment Camphor is both a gastrointestinal irritant and a central nervous system stimulant. Acute symptoms include nausea, vomiting, abdominal pain, tremors, convulsions, and coma. In two of the cases above, placental passage was demonstrated (90,91). The extent of this phenomenon was not quantified. No adverse effects on the conceptus were detected in three of the four cases, and the contribution of camphor to the one postpartum newborn death is uncertain. There is no specific therapy for camphor poisoning.

LEAD Published Experience Aspects to be considered in the discussion of lead exposure during pregnancy include spontaneous abortion, teratogenesis, symptoms and signs of toxicity in the mother or infant, and neurodevelopmental sequelae in the offspring. In keeping with the mandate of this chapter, we discuss only maternal and fetal toxicity. Five such case reports were located (94–99). In two of these, only the mothers demonstrated clinical toxicity (94– 96), whereas in three others toxicity developed only in the offspring during early infancy (97–99). Two other cases of significantly increased maternal and fetal lead burdens are reviewed, even though the mother-child pairs had no evidence of clinical toxicity (100,101). In 1964 Angle and McIntyre described a woman in her eighth month of pregnancy who complained of fatigue and abdominal pain (94). She had been exposed to the fumes of burning battery casings for the preceding 2 months, and her blood lead concentration was 240 µg/dL. The patient was treated with parenteral calcium disodium edentate (EDTA) for 1 week. Four weeks later she delivered a normal male. Cord blood lead concentration was reported as less than 60 µg/dL. However, the polarographic methodology used in this assay is questionable because of its low sensitivity. The other example of maternal toxicity is a 17-year-old girl who presented in her eighth month of pregnancy with abdominal pain, paresthesias in her feet, calf pain, gingival lead lines, and moderate anemia. She had been eating plaster chips from her apartment walls during her pregnancy. Blood lead and amniotic fluid lead concentrations were 86 and 90 µg/dL, respectively.

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The patient was treated with a 3-day course of EDTA. At delivery 8 days later, her blood lead had fallen to a near normal of 26 µg/dL, while the cord and amniotic fluid remained elevated at 79 and 86 µg/dL, respectively. There was no evidence of clinical toxicity in the neonate; however, skeletal radiographs demonstrated lead lines in the long bones. The baby was treated with a course of EDTA at 2 weeks and at 5 months of age, and her developmental evaluation was normal at 18 months. Three cases of fetal lead exposure presenting as toxicity in early infancy were located (97–99). The mothers were asymptomatic. Palmisano et al. (97) described a 2.5-monthold female infant with failure to thrive, hypertonic legs, spontaneous tremors, and hyperactive deep tendon reflexes; she had been born at term with a weight of 1900 g. The mother frequently drank illicit whiskey, which in this region was known to be contaminated by lead. No other sources of lead were found. Although there were no blood lead concentrations, increased lead burdens were documented in both mother and child by urinary excretion criteria. The infant received a 3-day course of EDTA. This baby’s intrauterine grown retardation, failure to thrive, and neurological abnormalities cannot solely be attributed to her fetal experience with lead because of the concomitant intrauterine alcohol exposure. However, the following two cases offer more convincing evidence that intrauterine lead acquisition produces toxicity during early infancy. Sensirivantana et al. (98) described a 2-month-old girl whose symptoms were seizures, anemia, basophilic stippling of red blood cells, skeletal lead lines, and brown nails. There had been a significant exposure to lead fumes during the 7th month of pregnancy because the mother had burned several electric motor rotors in a metal-salvaging operation. Pregnancy, labor, delivery, and neonatal course were otherwise unremarkable. Lead concentration in the maternal hair was markedly elevated, as was the baby’s blood concentration (113 µg/dL). Extremely high values were also found in the baby’s hair and nails (brown nails). The elevated hair (maternal and child) and nail values as well as the presence of skeletal lead lines support an intrauterine lead acquisition. The infant was treated with dimercaprol, EDTA, and d-penicillamine. The second case, described by Ghafour et al. (99), was a 36-hour-old neonate with seizures, opisthotonic posturing, and frequent spasms. Her blood lead concentrations were subsequently found to be elevated at 66 and 81 µg/dL at 12 and 17 days of age, with a maternal value of 76. The mother used lead-glazed cooking utensils and a lead-based eye cosmetic, both known to cause lead poisoning. She had a history of two miscarriages and two other children with neonatal seizures. This baby was treated with both dimercaprol and EDTA. In the other two reports of fetal lead exposure, both the mother and the baby were asymptomatic. Singh et al. (99) described a 20-year-old woman who sustained an acute lead exposure in the third trimester as a result of removing paint in her home. A blood lead concentration of 61 µg/dL was found, which declined to 39 at delivery, with cord blood level of 50. Ryu et al. (101) described a normal female neonate whose mother had worked for the preceding 3 years in a battery manufacturing plant. The mother’s blood lead concentration varied from a high of 57 µg/dL to 33 at delivery. Elevated concentrations were also documented in the cord blood and at 3 and 6 days of age. Pharmacology, Toxicology, and Treatment Lead serves no useful purpose in the body. It produces chronic rather than acute toxicity, and most individuals with increased body burdens are asymptomatic. Lead is a well-known reproductive toxin, producing spontaneous abortions, decreased fertility, and possible tera-

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togenesis. Exposure to lead during infancy can result in adverse neurodevelopmental sequelae, and it is speculated that the developing fetal nervous system may have an increased sensitivity. Maternal cord blood screening studies (102–104) as well as several of the case reports above demonstrate that lead crosses the placenta freely. However, it is unlikely that EDTA, the most commonly used lead chelator, enters the fetus. There has been only one well-documented case of EDTA therapy during pregnancy (95,96). Although the mother’s blood lead level declined from 86 to 26 µg/dL, the cord blood concentration remained elevated at 79, suggesting nonpassage of this chelator. Furthermore, human studies have demonstrated negligible penetration through the gastrointestinal epithelium, red blood cell membranes, and blood-brain barrier (105), making transplacental passage unlikely. There are no similar data for dimercaprol, but because it penetrates the central nervous system, fetal penetration would seem more likely. However, its use in adults is seldom indicated. Since dimercaprol must be given intramuscularly and is associated with several adverse effects, it is a poor candidate for maternal administration for fetal benefit. Dimercaptosuccinic acid (106), a new lead chelator that is structurally similar to dimercaprol and is given orally, seems to be the best choice. However, there is no reported experience with this drug during pregnancy. Even with a chelator exhibiting good fetal penetration, transplacental chelation would be difficult. Although chelators efficiently clear the blood, this compartment is refilled from tissue stores during the first few days after administration. Thus, prolonged courses would be required; this practice could deny the fetus essential trace elements. Thus, maternal indications would seem to be the only valid reason for the administration of lead chelators during pregnancy.

MISCELLANEOUS POISONINGS DURING PREGNANCY The following toxicants are discussed together because of limited experience with women who have ingested them during pregnancy. Arsenic Historically, organic arsenicals were used as antisyphilitics and antiparasitics. Iatrogenic toxicities were not uncommon; Kantor and Levin described one such case during pregnancy and cited others (107). Since other therapeutic agents have long since replaced these compounds, they are not discussed further. Two cases of acute inorganic arsenic poisonings during pregnancy were found (108,109). A 17-year-old girl in her seventh month of pregnancy ingested a rat poison containing arsenic trioxide (108). She received one dose of dimercaprol 24 hours after the ingestion; 3 days later, the patient spontaneously delivered an 1100-g female who died of hyaline membrane disease. High concentrations of arsenic were found in the infant’s liver, kidneys, and brain. The mother survived, although she required hemodialysis for renal failure in the postpartum period. A 30-year-old woman in her 28th week of pregnancy was poisoned with arsenic trioxide (109). She survived despite multiple organ failure and adult respiratory distress syndrome. Intrauterine death occurred during the fourth or fifth day after ingestion. Toxic concentrations of arsenic were found in the fetal liver, kidneys, stomach, and spleen.

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Both the foregoing cases show that inorganic arsenic freely crosses the placenta and that mother and fetus alike are at risk. Ideally, supportive and specific therapy should be effective for both patients. The management of arsenic poisoning is well reviewed elsewhere (110). The experience of Lugo et al. (108) regarding the safety of dimercaprol during pregnancy is not helpful, since only one dose was given during the third trimester and the baby died of hyaline membrane disease. Kantor and Levin (107) administered a course of dimercaprol to a woman in her 26th week of pregnancy (iatrogenic organic arsenic toxicity) and concluded that ‘‘it probably had no deleterious effect on the pregnancy.’’ However, dimercaptosuccinic acid, an orally effective analog of dimercaprol, is now available for the treatment of lead poisoning (106). It has been widely used elsewhere for arsenic poisoning and seems to be a better choice (111). However, there is no reported experience with this drug during pregnancy. Paraquat Overdose of the herbicide paraquat is associated with a very high mortality. Hemoperfusion, its touted intervention, is at best of questionable efficacy. The few described cases of paraquat poisoning during pregnancy reflect this dismal prognosis (112–114). Because of decreased substrate for the generation of free oxygen radicals, there is at least theoretical advantage for the fetus in the relatively hypoxic intrauterine milieu. And since hemoperfusion is of questionable value and technically difficult in the neonate, the argument for nonintervention of a potentially viable pregnancy is tenable unless fetal distress is present. Nutmeg The common spice nutmeg has anticholinergic properties and—being an halucinogen— is abused from time to time. A 29-year-old woman in her 30th week of pregnancy ingested a large amount of nutmeg secondary to a cooking error (115). She experienced mild to moderate anticholinergic syndrome. Fetal tachycardia (170 beats per minute) was documented, suggesting transplacental passage. The mother did well with supportive care and delivered a normal baby at term. Cyanide In recent animal studies, Curry and colleagues documented that coadministration of sodium thiosulfate with sodium nitroprosside to pregnant ewes prevented increases in fetal red cell cyanide concentrations. Their results suggest that coadministration of thiosulfate at doses currently in use in nonpregnant patients will prevent fetal as well as maternal cyanide toxicity (116). Quinine When quinine overdose occurs during pregnancy, the desire to induce an abortion should be suspected. Dannenberg et al. (8) described 4 such cases and reviewed 66 others. The maternal death rate was 16% and the abortion rate without maternal death was only 4%. In addition, at least 59% of the offspring had congenital anomalies. Therefore, quinine is of dubious efficacy as an abortifacient, has significant associations with maternal morbidity and mortality, and may be teratogenic.

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In overdose, quinine produces tinnitus, deafness, nausea, vomiting, vasodilation, visual impairment, and cardiac arrhythmias (117,118). Permanent visual disturbances and blindness are potential sequelae. Fatalities are usually due to cardiac toxicity. Treatment is nonspecific (general supportive measures and gastrointestinal decontamination as needed). From a theoretical perspective, acid diuresis would hasten the renal elimination of quinine and is often touted in the management of this poisoning. However, this intervention as well as dialysis and hemoperfusion have been shown to be ineffective (117). Since these are far from benign interventions, they should be avoided. Naphthalene Naphthalene poisoning during pregnancy has been reported twice (119,120). In both instances, the mothers were chronic mothball ingestors who presented at term with a hemolytic anemia. Hemolytic anemia and jaundice were found in both babies in the immediate postpartum period. Management of this problem should include the discontinuation of the ingestion of naphthalene and transfusion therapy of both mother and newborn as indicated. The latter should be monitored for hyperbilirubinemia and managed accordingly. It is conceivable that fetal anemia may be identified prior to term. In such instances, intrauterine transfusion should be considered. Hantson et al. (121) have described the first case of methanol poison in late pregnancy. The woman, who ingested 250–500 mL methanol at 38 weeks of gestation, developed initial concentrations of 230 mg/dL of methanol and 33.6 mg/dL of formate. Following normal gynecological examination and fetal monitoring, the poisoning was treated with ethanol, bicarbonate, and hemodialysis. At delivery 6 days later, both the mother and baby were in good health. Ciguatera Ciguatera is a fish-borne food poisoning characterized by gastrointestinal and neurological symptoms occurring within a few hours of ingestion (122). Two cases of ciguatera poisoning during pregnancy have been reported (123,124). One patient was in the early part of her second trimester (123). She had typical symptoms soon after ingestion, including increased fetal movements that persisted for a few hours. Her baby was normal at term and for the 10 months that he was followed thereafter. There were no neurological or muscular abnormalities. The other case involved a woman at term (124). She also developed typical symptoms soon after ingestion of the bad fish, and she experienced ‘‘bizarre,’’ ‘‘tumultuous’’ fetal movements for 24 hours. An elective cesarean section 2 days later produced a term male with left-sided facial palsy and possible myotonia of the hands. The liquor was meconium-stained, and a mild meconium aspiration syndrome was managed without assisted ventilation. In both instances assays of specimens from the fish confirmed ciguatera poisoning. The differences in the two newborns are probably a consequence of the timing of the fetal exposures. The treatment of this poisoning is symptomatic and supportive (123). Amanita Phalloides Poisoning during pregnancy with Amanita phalloides, a very toxic wild mushroom, has been briefly documented in a 21-year-old woman in her eighth month of pregnancy (125).

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Early in her course, both blood and amniotic fluid were sampled for the toxin. The former was positive and the latter negative. Two months later, a healthy baby without biochemical evidence of hepatotoxicity was born. Belliardo et al. (125) suggest that their negative amniotic fluid assay and the neonate’s lack of hepatotoxicity support nonpassage of the toxin across the placenta. More data are needed to support this claim. Poisonous Snake Bites Dunnihoo et al. (126) reviewed the literature on poisoning by members of the Crotalidae family (rattlesnakes, cottonmouths, and copperheads) during pregnancy. The venom of these reptiles has procoagulant activity. The authors described 30 cases in limited detail. The maternal mortality rate was 10%, and fetal wastage (intrauterine deaths plus spontaneous abortions) was 43%. There was no mention of antivenin therapy. Significant transplacental passage of this antidote would seem unlikely because of its high molecular weight. This, along with an apparent increase in risk for the fetus, prompts consideration of emergency delivery of a mature fetus in cases of severe maternal envenomation. However, this decision must be balanced against the risk this procedure presents to a mother with compromised coagulation. Clinical Case Answer This young woman has ingested acetaminophen in a toxic dose, where fatalities are not uncommon. She postponed treatment, thus substantially further increasing her risk for severe, or even fatal liver damage. Recent research suggests that N-acetylcysteine (NAC) therapy may have some efficacy even at this late stage. Her general status and especially liver function should be closely followed. In some institutions she may receive NAC even at this stage. Although the drug has been implicated in interrupting collagen formation in some babies, there is no clear-cut established causation. Available literature, although scarce, suggests that the fetus has an increased risk of liver damage and stillbirth. REFERENCES 1. Aisen P, Brown EB. The iron binding function of transferrin in iron metabolism. Semin Hematol 1977; 14:31–53. 2. Huebers HA, Finch CA. Transferrin. Physiologic behavior and clinical implications. Blood 1984; 64:763–767. 3. Garrettson LK, Procknal JA, Levy G. Fetal acquisition and neonatal elimination of a large amount of salicylate. Clin Pharmacol Ther 1975; 17:98–103. 4. Levy G, Procknal JA, Garrettson LK. Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium. Clin Pharmacol Ther 1975; 18:210–214. 5. Czeizel A, Szentesi I, Szekeres J, et al. Pregnancy outcome and health conditions of offspring of self-poisoned women. Acta Pediatr Hung 1984; 25:209–236. 6. Czeizel AE, Mosonyi A. Monitoring of early fetal development in women exposed to large doses of chemicals. Environ Mol Mutagen 1997; 30:240–244. 7. Sim M. Abortion and the psychiatrist. BMJ 1963; 2:145–148. 8. Dannenberg AL, Dorfman SF, Johnson J. Use of quinine for self-induced abortion. South Med J 1983; 76:846–849. 9. Hall A. The increasing use of lead as an abortifacient. BMJ 1905; 1:584–587.

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10. Gold J, Cates W Jr. Herbal abortifacients. JAMA 1980; 243:1365–1366. 11. Whitlock FA, Edwards JE. Pregnancy and attempted suicide. Comp Psychiatry 1968; 9:1– 12. 12. Lendvay A, Czeizel AE. A behavioral teratologic study on offspring of self poisoned pregnant women. Acta Paediatr Hung 1992; 32:347–349. 13. Rayburn W, Aronow R, Delancy B, Hogan MJ. Drug overdose during pregnancy: an overview from a metropolitan poison control center. Obstet Gynecol 1984; 64:611–614. 14. Czeizel A, Szentesi I, Molnar G. Lack of effect of self-poisoning on subsequent reproductive outcome. Mutat Res 1984; 127:175–182. 15. Jones JS, Dickerson K, Carlson S. Unrecognized pregnancy in the overdose or poisoned patient. Am J Emerg Med 19997; 15:538–541. 16. Kulig K. Initial management of ingestions of toxic substances. N Engl J Med 1992; 326: 1677–1681. 17. Kulig K, Bar-Or D, Cantrill SV, et al. Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985; 14:562–567. 18. Albertson TE, Derlet RW, Foulke GE, et al. Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989; 18:56–59. 19. Merigian KS, Woodard M, Hedges J Jr, et al. Prospective evaluation of gastric emptying in the self-poisoning patient. Am J Emerg Med 1990; 8:479–483. 20. Tenenbein M. Whole bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Med Toxicol 1988; 3:77–84. 21. Van Ameyde KJ, Tenenbein M. Whole bowel irrigation during pregnancy. Am J Obstet Gynecol 1989; 160:646–647. 22. Weis OF, Muller FO, Lyell H, et al. Materno-fetal cholinesterase inhibitor poisoning. Anesth Analg 1983; 62:233–235. 23. Strom RL, Schiller P, Seeds AF, ten Bensel R. Fatal iron poisoning in a pregnant female. Minn Med 1976; 59:483–489. 24. Manoguerra AS. Iron poisoning: report of a fatal case in an adult. Am J Hosp Pharm 1976; 33:1088–1090. 25. Czeizel AE, Tomcsik M, Timor L. Teratologic evaluation of 178 infants born to mothers who attempted suicide by drugs during pregnancy. Obstet Gynecol 1997; 90:195–201. 26. Theil GB, Richter RW, Powell MR, Doolan PD. Acute Dilantin poisoning. Neurology 1961; 11:138–142. 27. Kurtz GG, Michael UF, Morosi HJ, Vaamonde CA. Hemodialysis during pregnancy: report of a case of glutethimide poisoning complicated by acute renal failure. Arch Intern Med 1966; 118:30–32. 28. Vaziri ND, Kumar KP, Mirahmadi K, Rosen SM. Hemodialysis in treatment of acute chloral hydrate poisoning. South Med J 1977; 70:377–378. 29. Trebbin WM. Hemodialysis in pregnancy. JAMA 1979; 241:1811–1812. 30. Wing AJ, Brunner FP, Brynger H, et al. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynecol 1980; 87:839–845. 31. Hou S. Pregnancy in women requiring dialysis for renal failure. Am J Kidney Dis 1987; 368–373. 32. Rayburn W, Wible-Kant J, Bledsoe P. Changing trends in drug use during pregnancy. J Reprod Med 1982; 27:569–575. 33. Silverman JJ, Carithers RL Jr. Acetaminophen overdose. Am J Psychiatry 1978; 135:114– 115. 34. Byer AJ, Trayler TR, Semmer JR. Acetaminophen overdose in the third trimester of pregnancy. JAMA 1982; 247:3114–3115. 35. Lederman S, Fysh WJ, Tredger M, Gamsu HR. Neonatal paracetamol poisoning: treatment by exchange transfusion. Arch Dis Child 1983; 58:631–633.

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36. Ruthnum P, Goel KM. ABC of poisoning: paracetamol. BMJ 1984; 289:1538–1539. 37. Stokes IM. Paracetamol overdose in the second trimester of pregnancy. Br J Obstet Gynaecol 1984; 91:286–288. 38. Roberts I, Robinson MJ, Mughal MZ, et al. Paracetamol metabolites in the neonate following maternal overdose. Br J Clin Pharmacol 1984; 18:201–206. 39. Haibach H, Akhter JE, Muscato MS, et al. Acetaminophen overdose with fetal demise. Am J Clin Pathol 1984; 82:240–242. 40. Robertson RG, Van Cleave BL, Collins JJ Jr. Acetaminophen overdose in the second trimester of pregnancy. J Fam Pract 1986; 23:267–268. 41. Ludmir J, Main DM, Landon MB, Gabbe SG. Maternal acetaminophen overdose at 15 weeks of gestation. Obstet Gynecol 1986; 67:750–751. 42. Riggs BS, Bronstein AC, Kulig K, et al. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989; 74:247–253. 43. McElhatton PT, Sullivan GM, Volans GN, Fitzpatrick R. Paracetamol overdose during pregnancy: an analysis of the outcomes of cases referred to the Teratology Information Service of the National Poison Information Service. Hum Exp Toxicol 1990; 9:147–153. 44. Levy G, Garrettson LK, Soda DM. Evidence of placental transfer of acetaminophen. Pediatrics 1975; 55:895. 45. Jackson CH, MacDonald NC, Cornett JWD. Acetaminophen: a practical pharmacologic review. Can Med Assoc J 1984; 131:25–37. 46. Lauterberg BH, Corcoran GB, Mitchell JR. Mechanism of action of N-acetylcysteine in the protection against hepatotoxicity of acetaminophen in rats in vivo. J Clin Invest 1983; 71: 980–991. 47. Rane A, Tomson G. Prenatal and neonatal drug metabolism in man. Eur J Clin Pharmacol 1980; 18:9–15. 48. Perucca E. Drug metabolism in pregnancy, infancy and childhood. Pharmacol Ther 1987; 34:129–143. 49. Horowitz RS, Dart RC, Jarvie DR, et al. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Clin Toxicol 1997; 35:447–451. 50. Rollins DE, von Bahr C, Glaumann H, et al. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science 1979; 205:1414–1416. 51. Selden BS, Curry SC, Clark RF, et al. Transplacental transport of N-acetylcysteins in an ovine model. Ann Emerg Med 1991; 20:1069–1072. 52. Prescott LF. Treatment of severe acetaminophen poisoning with intravenous acetylcysteine. Arch Intern Med 1981; 141:386–389. 53. Jackson AV. Toxic effects of salicylate on the fetus and mother. J Pathol Bacteriol 1948; 60:587–593. 54. Earle R Jr. Congenital salicylate intoxication—report of a case. N Engl J Med 1961; 265: 1003–1004. 55. Rejent TA, Baik S. Fatal in utero salicylism. J Forens Sci 1985; 30:942–944. 56. Hill JB. Salicylate intoxication. N Engl J Med 1973; 288:1110–1113. 57. Lynd PA, Andreasen AC, Wyatt RJ. Intrauterine salicylate intoxication in a newborn. Clin Pediatr (Phil) 1976; 15:912–913. 58. Ahlfors CE, Shwer ML, Ford KW. Bilirubin-albumin binding in neonatal salicylate intoxication. Dev Pharmacol Ther 1982; 4:47–60. 59. Buck ML, Grebe TA, Bond GR. Toxic reaction to salicylate in a newborn infant: similarities to neonatal sepsis. J Pediatr 1993; 122:955–958. 60. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981; 141:364–369. 61. McElhatton PR, Roberts JC, Sullivan FM. The consequences of iron overdose and its treatment with desferrioxamine in pregnancy. Hum Exp Toxicol 1991; 10:251–259.

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88. Nagashima M, Asai T, Suzuki C, et al. Intrauterine supraventricular tacharrhythmias and transplacental digitalization. Arch Dis Child 1986; 61:996–1000. 89. Goodlin RC. Antidigoxin antibodies in eclampsia. N Engl J Med 1988; 318:518–519. 90. Weiss J, Catalano P. Camphorated oil intoxication during pregnancy. Pediatrics 1973; 52: 713–714. 91. Riggs J, Hamilton R, Hamel S, McCabe J. Camphorated oil intoxication in pregnancy. Obstet Gynecol 1965; 25:255–258. 92. Blackmon WP, Curry HB. Camphor poisoning: report of case occurring during pregnancy. J Fla Med Assoc 1957; 43:999–1000. 93. Jacobziner H, Raybin HW. Camphor poisoning. Arch Pediatr 1962; 79:28–30. 94. Angle CR, McIntire MS. Lead poisoning during pregnancy. Am J Dis Child 1964; 108:436–439. 95. Pearl M, Boxt LM. Radiographic findings in congenital lead poisoning. Radiology 1980; 136:83–84. 96. Timpo AE, Amin JS, Casalino MB, Yuceoglu AM. Congenital lead intoxication. J Pediatr 1979; 94:765–767. 97. Palmisano PA, Sneed RC, Cassady G. Untaxed whiskey and fetal lead exposure. J Pediatr 1969; 75:869–872. 98. Sensirivantana R, Supachadhiwong O, Phancharoen S, Mitrakul C. Neonatal lead poisoning. Clin Pediatr (Phil) 1983; 22:582–584. 99. Ghafour SY, Khuffash FA, Ibrahim HS, Reavey PC. Congenital lead intoxication with seizures due to prenatal exposure. Clin Pediatr (Phil) 1984; 23:282–283. 100. Singh N, Donovan CM, Hanshaw JB. Neonatal lead intoxication in a prenatally exposed infant. J Pediatr 1978; 93:1019–1021. 101. Ryu JE, Ziegler EE, Fomon SJ. Maternal lead exposure and blood lead concentration in infancy. J Pediatr 1978; 93:476–478. 102. Gershanik JJ, Brooks GG, Little JA. Blood lead values in pregnant women and their offspring. Am J Obstet Gynecol 1974; 119:508–511. 103. Zetterlund B, Winberg J, Lundgren G, Johansson G. Lead in umbilical cord blood correlated with the blood lead of the mother in areas of low, medium or high atmospheric pollution. Acta Paediatr Scand 1977; 66:169–175. 104. Angell NF, Lavery JP. The relationship of blood lead levels to obstetric outcome. Am J Obstet Gynecol 1982; 142:40–45. 105. Foreman H, Trujillo TT. The metabolism of C-14 labeled ethylenediaminetetra-acetic acid in human beings. J Lab Clin Med 1954; 43:566–571. 106. Graziano JH, Siris ES, LoIancono N, et al. 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985; 37:431–438. 107. Kantor HI, Levin PM. Arsenical encephalopathy in pregnancy with recovery. Am J Obstet Gynecol 1948; 56:370–374. 108. Lugo G, Cassady G, Palmisano P. Acute maternal arsenic intoxication with neonatal death. Am J Dis Child 1969; 117:328–330. 109. Bolliger CT, van Zijl P, Louw JA. Multiple organ failure with the adult respiratory distress syndrome in homicidal arsenic poisoning. Respiration 1992; 59:57–61. 110. Ellenhorn MJ, Barceloux DG. Arsenic. In: Medical Toxicology: Diagnosis and Treatment of Human Poisonings. New York: Elsevier, 1988, pp 1012–1016. 111. Aposhian HV. DMSA and DMPS—water-soluble antidotes for heavy metal poisoning. Annu Rev Pharmacol Toxicol 1983; 23:193–215. 112. Talbot AR, Fu CC. Paraquat intoxication during pregnancy: a report of 9 cases. Vet Hum Toxicol 1988; 30:12–17. 113. Fennelly JJ, Gallagher JT, Carroll RJ. Paraquat poisoning in a pregnant woman. BMJ 1968; 3:722–725. 114. Musson FA, Porter CA. Effect of ingestion of paraquat on a 20-week gestation fetus. Postgrad Med J 1982; 58:731–732.

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115. Lavy G. Nutmeg intoxication in pregnancy. J Reprod Med 1987; 32:63–64. 116. Curry SC, Carlton MW, Raschke RA. Prevention of fetal and maternal cyanide toxicity from nitroprusside with confusion of sodium thiosulfate in gravid ewe. Anesth Analg 1997; 84: 1121–1126. 117. Batemman DN, Blin PG, Woodhouse KW, et al. Pharmacokinetics and clinical toxicity of quinine overdose. Lack of efficacy of techniques intended to enhance elimination. Q J Med 1985; 54:125–131. 118. Dyson EH, Proudfoot AT, Prescott LF, Heyworth R. Death and blindness due to overdose of quinine. BMJ 1985; 291:31–33. 119. Anziulewicz JA, Dick HJ, Chiarulli EE. Transplacental naphthalene poisoning. Am J Obstet Gynecol 1959; 78:519–521. 120. Zinkham WH, Childs B. A defect of gluthathione metabolism in erythrocytes from patients with a naphthalene-induced hemolytic anemia. Pediatrics 1958; 22:461–471. 121. Hantson P, Lambermont JY, Mahieu P. Methanol poisoning during late pregnancy. J Clin Toxicol 1997; 35:187–191. 122. Gillespie NC, Lewis RJ, Pearn JH, et al. Ciguatera in Australia: occurrence, clinical features, pathophysiology and management. Med J Aust 1986; 145:584–590. 123. Senecal PE, Osterloh JD. Normal fetal outcome after maternal ciguateric toxin exposure in the second trimester. J Toxicol Clin Toxicol 1991; 29:473–478. 124. Pearn J, Harvey P, DeAmbrosis W, et al: Ciguatera and pregnancy. Med J Aust 1982; 1: 57–58. 125. Belliardo F, Massano G, Accomo S. Amatoxins do not cross the placental barrier. Lancet 1983; 1:1381. 126. Dunnihoo DR, Rush BM, Wise RB, et al. Snake bite poisoning in pregnant: a review of the literature. J Reprod Med 1992; 37:653–658.

15 Carbon Monoxide Poisoning During Pregnancy Benoit Bailey Hoˆpital Ste-Justine, Montreal, Quebec, Canada

INTRODUCTION Year after year, carbon monoxide accounts for many poisonings and fatalities worldwide. Its unique properties make it a potent silent killer. Sources of carbon monoxide include incomplete combustion of hydrocarbons and metabolism of methylene chloride. Carbon monoxide is not only dangerous to the adult but, as it easily crosses the placenta, may also endanger the fetus. Exposure to carbon monoxide during pregnancy can be caused by attempted suicide, accidents due to defective gas appliances or other sources, or in the workplace, such as firefighters or when workers are exposed to methylene chloride. Once carbon monoxide poisoning is recognized during pregnancy, not necessarily an easy task, physicians will be challenged by deciding if the pregnant patient should be treated, and if so, if she should received 100% oxygen by mask only or also hyperbaric oxygen. Upon disposition of such patients, the outcome of the pregnancy will also become a question for the mother, her family, and the physician. This chapter aims at helping to counsel women exposed to carbon monoxide during pregnancy.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATIONS Carbon monoxide is an odorless, colorless, tasteless, nonirritating gas that impairs oxygen delivery and utilization by different mechanisms, leading to cellular hypoxia. Carbon monoxide binds to hemoglobin 250 times more avidly than oxygen, causing a decrease in the amount of hemoglobin available to transport oxygen. The carboxyhemoglobins produced also impair the release of oxygen by increasing oxygen binding to hemoglobin: this leads to a shift in the oxyhemoglobin dissociation curve to the left (1). It also binds to cytochrome oxidase, thus impairing cellular respiration (1). Carbon monoxide poisoning during pregnancy is challenging. The gas readily crosses the placenta and tends to accumulate in the fetal blood because of its greater affinity for fetal hemoglobin than for adult hemoglobin; this causes fetal levels that are 10–15% higher than in the maternal blood (2,3). Also, because the fetal oxyhemoglobin 257

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curve lies further to the left than that of the adult, the fetus is even more affected by the shift to the left caused by carbon monoxide (2,3). Furthermore, the half-life of carboxyhemoglobin is increased in the fetus in comparison to adult: 7–9 hours versus 4–6 hours, respectively (2,3). Therefore, the fetus is exposed to a higher carbon monoxide level than the pregnant woman and for a longer period of time. In addition to the direct fetal effect of carbon monoxide, the mother’s carbon monoxide poisoning will decrease the oxygen content of the uterine artery, thus decreasing fetal oxygen delivery. This decrease oxygen content will also contribute to fetal hypoxia. Symptoms of carbon monoxide poisoning are often nonspecific and may be confused with those of other illnesses; a high degree of suspicion is needed. Patients with acute poisoning may present with nausea, vomiting, dizziness, and headache in the mild case. As the poisoning becomes more severe, various neurological and cardiac symptoms appear, leading to coma, myocardial depression, and death. Chronic carbon monoxide poisoning will be associated with nausea, vomiting, and headache followed by insidious intellectual deterioration and, in some patients, myocardial ischemia (1). Presentations in the pregnant woman will not differ. However, because of the facts previously discussed, carbon monoxide poisoning will represent a unique challenge.

ACUTE POISONING DURING PREGNANCY Most of the information on acute carbon monoxide poisoning during pregnancy comes from case reports or retrospective cases series (4–44). It is not surprising that most of these cases are the more serious poisonings in the mothers, with adverse outcomes in the infants. There is very limited information on mild poisoning during pregnancy, the most prevalent type of poisoning usually encountered according to the Toxic Exposure Surveillance System of the American Association of Poison Control Centers (45). Table 1 shows reported cases of carbon monoxide poisoning with clinical grading of central nervous system severity according to the New York Hyperbaric Group (46) and maternal and fetal outcomes that were evaluated with the original paper (4–25,43,44); some older and foreign-language literature could not be evaluated (26–42). Table 2 describes the clinical grading of the central nervous system (CNS) severity of the New York Hyperbaric Group (46). Grade of maternal carbon monoxide toxicity in relation to fetal outcome is summarized in Table 3. From the cases of carbon monoxide poisoning during pregnancy that could be retrieved in the literature (Table 1), it appears that published cases are evenly distributed between mild and severe cases and that the pregnancy outcome was worst when the mother suffered severe toxicity. Normal pregnancy outcome following either grade 4 or 5 carbon monoxide poisoning was published only once (44). However, because of the bias involved in reporting cases, this does not necessary reflect the reality. Abnormalities Induced by Carbon Monoxide Poisoning During Pregnancy Numerous animal models have demonstrated the adverse effects on the fetus of carbon monoxide poisoning during pregnancy: these include malformations, neurological dysfunction, decreased birth weight, and increased fetal death. Most of the abnormalities induced by carbon monoxide poisoning reported during human pregnancy are neurological

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dysfunctions or fetal deaths. Several neurological dysfunctions have been described in newborns that suffered carbon monoxide poisoning during pregnancy: hypotonia, hyporeflexia, difficulty swallowing and sucking, and seizure (13). Dysfunction described in infants and children have included mental and motor disabilities, seizures, microcephaly, hydrocephaly, tetraplegia, and involuntary movements (47,48). Furthermore, it is important to note that whenever postmortem examinations were done, there was evidence of lesions predominantly in the basal ganglia and the deeper layers of the gray matter (4). These lesions are similar to those caused by other hypoxic-ischemic injuries in children or animals (47), giving plausibility to the association of carbon monoxide poisoning during pregnancy and the observed neurological dysfunctions. Acute carbon monoxide poisoning has also been associated with various malformations of the upper and lower extremities (23,35,38,49), mongoloid-type malformations (21), and multiple abnormalities including low-set ears, oral cavity anomalies, and hypoplastic organ development (8,23) when exposure occurred in the first trimester. Definitive association between the carbon monoxide poisoning and the malformations is not possible because of the absence of a controlled study. However, because of the numbers of CNS dysfunctions described and the biological plausibility of the lesions, carbon monoxide can be considered a human teratogen—the term teratogen being use here in the broad sense and referring not only to morphologic malformations. However, the extent of the problem is difficult to appreciate from case series. Prospective Evaluation of Newborns Exposed to Carbon Monoxide Poisoning During Pregnancy There has been only one study aimed at evaluating prospectively the outcome of acute exposure to carbon monoxide during pregnancy (50). The Motherisk study collected and followed cases of carbon monoxide poisoning during pregnancy from different centers over a period of more than 3 years (50). When cases were identified and referred to Motherisk, participating physicians were sent a questionnaire to complete. Pregnant women were contacted and asked similar questions. The questionnaire explored the type and duration of carbon monoxide exposure, nature and severity of symptoms, time elapsed before treatment (if any), carboxyhemoglobin levels, and measurement of carbon monoxide in the air (50). The severity of the carbon monoxide exposure was graded according to the clinical grading system of the New York Hyperbaric Group of CNS severity poisoning (Table 2) (46). A second telephone contact was made to the mother a few weeks after the expected date of delivery to obtain data on the final course of pregnancy and birth. Thereafter, infants were followed up annually by telephone with a developmental questionnaire derived from the Denver Developmental Screening Test. Detailed, structured questions were asked of the mother by a developmental pediatrician (50). In all, 40 cases were collected: there were 3 twin births, one therapeutic abortion at 16 weeks gestation, and 4 pending births. Therefore, analysis was based on a total of 38 children. Exposures occurred in the first trimester in 12 cases and the second and third trimesters in 14 cases each. Table 4 summarizes cases for which a carboxyhemoglobin level was available. The outcome of pregnancy related to the severity of carbon monoxide poisoning was reported in 36 cases. All 31 women with grade 1 or 2 poisoning had a normal outcome. Of the 29 grade 1 cases, 19 had no treatment and 10 received high-flow 100% oxygen by mask. There were 2 grade 2 patients: one had no treatment while the second one had both high-flow 100% oxygen by mask and hyperbaric oxygen.

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Table 1

Case Report or Series of Carbon Monoxide Poisonings During Pregnancy and Maternal and Fetal Outcome According to Severity Mother

Timing w w w m m w w w m m w m m m

5.4 24.5 35 — — 2.8 23 9.6 — — 7 6.5 — —

Grade

Treatment

1 1 1 5 5 5 1 1 5 5 4 5 5 5

O2 O2 HBO — O2 O2 O2 O2 — — O2 — — —

Outcome D/C Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive

Outcome Short term Alive Alive Alive Alive Alive Died Alive Alive Alive Stillborn Stillborn Alive Alive Alive

Long term

Reference

Developmental delay (4 y) Normal 6 m Normal (2 m) Dead 7 d (T-21 ⫹ CF) Encephalopathy (5 m) 30 w gestation/multiple anomalies N/A N/A Encephalopathy (8 y) — — Developmental delay (13 m) Encephalopathy (4 y) Encephalopathy (7 y)

(10) (6) (43) (21) (23) (8) (8) (8) (22) (25) (14) (13) (21) (21)

Bailey

6 8 8 2 3 13 16 20 6 6 28 7 7 7

COHb

Infant

39 23.7 22.4 — — — — 5.3 47.2 52 5 — 6.3 — 32 — — — —

1 1 1⫹ 5 Dead 5 Dead 1 3 5 1⫹ 1⫹ 2 5 5 1⫹ 5 2 ?

O2 O2 HBO — — — — HBO HBO O2 O2 c/s HBO/C/S — O2 — O2 — —

Alive Alive Alive Alive Dead Alive Dead Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive

Alive Stillborn Alive Alive Stillborn Dead 13 h Stillborn Alive Alive Alive Stillborn Dead 24 d Alive Alive Stillborn Stillborn Stillborn Stillborn Stillborn

N/A — N/A Encephalopathy (3 y) — — — Normal 1 m Normal 6 m Normal (4 m) — — N/A Dead 10 d — — — — —

(8) (5) (11) (21) (20) (17) (19) (12) (9) (44) (8) (4) (7) (21) (8) (15) (16) (18) (24)

Carbon Monoxide Poisoning During Pregnancy

30 w 32 w 32 w 8m 8m 9m 9m 37 w 37 w 37 w 38 w 38 w 38 w 38 w 38 w 39 w Near term Term ?

Abbreviations: COHb ⫽ maximum carboxyhemoglobin level; D/C ⫽ maternal outcome at discharge from hospital; h ⫽ hour; w ⫽ week; m ⫽ month; y ⫽ year; C/S ⫽ cesarian section; O 2 ⫽ 100% oxygen by mask; HBO ⫽ hyperbaric oxygen treatment; N/A ⫽ not available; T-21 ⫽ trisomy 21; CF ⫽ cystic fibrosis.

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Table 2 Modified Clinical Grading of Central Nervous System Severity in Patients with Carbon Monoxide Poisoning Grade 1 Grade 1⫹ Grade 2 Grade 3 Grade 4 Grade 5

Alert, oriented. Symptoms include headache, dizziness, and nausea. As grade 1 but with a relative that was unconscious. Alert but with alterations in mental state, confusion, abnormal behavior. Symptoms more pronounced than grade 1. Not alert, disoriented, loss of recent memory, muscle weakness or incoordination. If intubated, responds to simple commands; if not, attention engaged easily. Very disoriented, depressed sensorium. Responses to simple commands limited and frequently inappropriate. Comatose; responds only to pain or no reaction.

Source: From Ref. 46

Adverse outcome occurred only after grade 4 or 5 poisoning—that is, in the more severe cases. There were 3 cases with grade 4 severity. Of these 3 cases, 2 had normal outcomes at 1 year of age after exposure at 27 and 28 weeks gestation with carboxyhemoglobin levels of 39 and 21% respectively: both were treated with hyperbaric oxygen. The third woman with grade 4 was exposed at 23 weeks gestation with a carboxyhemoglobin of 25%: she received high-flow 100% oxygen by mask for 2 hours. The delivery at term was uneventful except that the infant had an apneic spell immediately after birth. At 8 months, she had developmental delay diagnosed as secondary to cerebral palsy; computed tomography was compatible with postanoxic encephalopathy. The 2 cases with grade 5 severity had adverse outcomes. The first was stillborn at 29 weeks gestation; the mother was treated with high-flow 100% oxygen by mask because of a carboxyhemoglobin of 26%. The second woman had a fetal death at term. Grades 4 and 5 were associated with significantly worse pregnancy outcome compared with grades 1 and 2 ( p ⬍ 0.0001 by Fisher’s exact test). The authors concluded that pregnancy outcome following grades 4 and 5 poisoning in the study closely resembled that described in case reports (50). Moreover, despite limited numbers of patients in grades 4 and 5 (five in total), they noticed that two pregnant women treated with hyperbaric oxygen had normal outcomes and that three treated with high-flow 100% oxygen had adverse fetal outcomes. They also concluded that mild acciTable 3 Maternal Carbon Monoxide Toxicity Grade in Relation to Fetal Outcome

Maternal grade 1 1⫹ 2 3 4 5 ? Total

Outcome

No. of cases

Normal

CNS damage

Dead or stillborn

8 4 2 1 1 16 1 33

6 1 1 1 0 1 0 10

1 0 0 0 0 6 0 7

1 3 1 0 1 9 1 16

Sources: Data from Refs. 4–18, 21–23, 25, 43, 44.

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Table 4 Cases of Carbon Monoxide Poisoning During Pregnancy Prospectively Collected and Followed with Maternal and Fetal Outcome According to Severity Mother Timing

COhb

Grade

Treatment

D/C

Infant outcome

23 w 27 w 28 w 29 w 30 w — — — — — — —

25 39 21 26 14 40–50 18 14 6 2 2 1

4 4 4 4 2 5 1 1 1 1 1 1

O2 HBO HBO O2 O 2 ⫹ HBO O2 O2 — — — — —

Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive

Cerebral palsy Normal Normal Stillborn Normal TA Normal Normal Normal Normal Normal Normal

Abbreviations: COHb ⫽ maximum carboxyhemoglobin level; D/C ⫽ maternal outcome at discharge from hospital; TA ⫽ therapeutic abortion; w ⫽ week; O 2 ⫽ 100% oxygen by mask; HBO ⫽ hyperbaric oxygen treatment. Source: From Ref. 50.

dental poisoning likely would do no harm. Limitations of the study included the absence of control and the lack of proper neurobehavioral assessments in most cases that could have detected subtle CNS dysfunction. Also, because it is likely that the importance of fetal effect depends not only on maternal symptoms but also on duration of exposure, the amount of carbon monoxide to which the fetus is exposed and probably the stage of fetal development (9), the whole picture was not described even in that prospective study. Despite these limitations and the limited number of cases and considering the rarity of carbon monoxide poisoning during pregnancy, it is unlikely that more patients can be collected easily or in a better way. We can conclude from the Motherisk study and retrospective case reports that a normal infant outcome is more probable in mothers who did not have severe symptoms of carbon monoxide poisoning independent of the treatment used. Also, in the more severe cases, the Motherisk study suggests that treatment with hyperbaric oxygen may influence outcome. This suggestion, despite being believed by most clinicians, is not based on enough data to support it conclusively.

EFFECT OF HYPERBARIC OXYGEN ON PREGNANCY Hyperbaric oxygen is used routinely in the treatment of severe carbon monoxide poisoning in nonpregnant patients. It works based on the fact that it increases the arterial oxygen content by increasing the oxygen dissolved in the plasma and by increasing the removal of carbon monoxide from the blood and the intracellular cytochrome (9). The half-life of maternal carboxyhemoglobin is 320 minutes with an inspired oxygen fraction of 21%. Administration of 100% oxygen by mask decreases the maternal carboxyhemoglobin halflife to 80 minutes. The use of hyperbaric oxygen, with 100% oxygen at 3 atmospheres

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absolute (ATA), further decrease the maternal half-life to 23 minutes (48). The half-life of fetal carboxyhemoglobin is said to be 7–9 hours (2,3). If the mother receives 100% oxygen by mask, the half-life decreases to 3–4 hours (2,3). The fetal carboxyhemoglobin half-life during hyperbaric oxygen is not known. Safety of Hyperbaric Oxygen During Pregnancy The use of hyperbaric oxygen during pregnancy was initially controversial because of the possible adverse effects of hyperoxia on the fetus, including teratogenicity, retinopathy of prematurity, and cardiovascular effects (9). This controversy was further increased by conflicting evidence from animal studies (9). It appears that animal studies with adverse effects all used higher pressures or longer durations of hyperbaric oxygen than are normally used to treat nonpregnant patients; studies with standard treatment did not show any adverse effects of hyperbaric oxygen in animals (51). Some pregnant women poisoned by carbon monoxide during pregnancy and treated by hyperbaric oxygen have been described (7,9,11,12,43). Also, Elkharrat et al. published a prospective study that was part of a study aimed at evaluating the effect of normobaric (high-flow 100% oxygen) and hyperbaric oxygen in acute carbon monoxide poisoning (52,53). They reported on 44 women who knew they were pregnant at the time of the carbon monoxide poisoning and were treated because of their pregnancy with hyperbaric oxygen irrespective of the severity of the poisoning, age of the pregnancy, or carboxyhemoglobin levels (52). Hyperbaric oxygen was carried out for 2 hours, including 1 hour at 2 ATA. High-flow 100% oxygen was also given until hyperbaric oxygen was administered and then for up to 4 hours. Patients were seen 1 month after the poisoning and written reports were obtain from either the obstetrician or the pediatrician at the time of delivery. Of the 44 patients reported, 10 had suffered a loss of consciousness and 2 had coma (grade 4 or 5), while the remaining 32 patients had only gastrointestinal symptoms, headaches, and/or dizziness (grade 1). Thirty-five women were seen at 1 month after the poisoning: 24 were asymptomatic while 11 had moderate symptoms. The pregnancy outcome was available in 38 women: 32 had normal infants at birth. One woman delivered prematurely and one was induced before term. Two women had spontaneous abortions and one opted for therapeutic abortion for personal reasons. Finally, one woman delivered an infant with Down’s syndrome confirmed by karyotype; this child died at 6 days of age because of major cardiopulmonary defects (52). No further follow-up was attempted to evaluate the outcomes of these pregnancies. The authors concluded that hyperbaric oxygen appeared to be safe in pregnant women acutely intoxicated with carbon monoxide (52). In particular, it did not increase the risk of spontaneous abortion in general or in particular when performed early during the pregnancy. These results are further supported by studies from the former Soviet Union, where more than 700 pregnant women have been treated with hyperbaric oxygen for different etiologies (9). However, these studies were not available for review. From the Elkharat study (52) and the former Soviet Union experience, we can conclude that hyperbaric oxygen appears to be safe when use during pregnancy. Because of the limited studies available on the subject, a subtle adverse effect cannot be ruled out. Indications of Hyperbaric Oxygen for Carbon Monoxide Poisoning During Pregnancy If there are some data to suggest that hyperbaric oxygen is probably safe during pregnancy, there is no study that has evaluated the indication. Based on a review of the literature in

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1989, Van Hoesen et al, recommended the following for the treatment of pregnant patients poisoned by carbon monoxide (9). Hyperbaric oxygen should be administered if maternal carboxyhemoglobin is above 20% at any time during exposure, if the patient has suffered or demonstrates any neurological signs regardless of the carboxyhemoglobin level, or if signs of fetal distress are present in the form of fetal tachycardia, beat-to-beat variability, or late decelerations (9). When hyperbaric oxygen is not available, 100% oxygen should be administered by mask five times longer than for a nonpregnant patient. They also recommended that if the patient continues to demonstrate neurological signs or fetal distress is still present 12 hours after the initial treatment, additional hyperbaric oxygen treatment might be indicated. These recommendations are still in use despite the absence of formal validation. Any formal validation is unlikely to happen at this time in view of the wide acceptance that hyperbaric oxygen has in the treatment in pregnant women poisoned with carbon monoxide. Based on the results of the Motherisk study (50), these recommendations appear reasonable. But it is possible that many pregnant women have received hyperbaric oxygen without any benefit to their fetuses.

CHRONIC POISONING DURING PREGNANCY Chronic low-level carbon monoxide exposure and its effect on the fetus have been studied because of the importance and effect of maternal smoking on the pregnancy outcome and not because of poisoning from carbon monoxide. The infants born to women who smoke during pregnancy are known to have a higher risk of prematurity and lower-birth-weight as well as a greater risk of perinatal mortality (54). However, the precise role of carbon monoxide is not clear, since cigarettes contain other chemicals as well, including nicotine. There is no study in humans of the effect of low-level chronic exposure to a source of carbon monoxide other than cigarette smoking. It is therefore difficult to assess the effect of chronic carbon monoxide exposure on the fetus. Fortunately, situations where a defective gas appliance is responsible for carbon monoxide poisoning have become less common with the appearance of carbon monoxide detectors in the home (55). Because there is no information at this time, pregnant women with chronic carbon monoxide poisoning should be treated and counseled as if they had an acute poisoning. A ‘‘CHARGE’’ syndrome (ocular coloboma, heart defect, atresia or stenosis of choanae, retarded growth and development and CNS anomalies, genital hypoplasia, and ear anomalies and/or deafness) has been associated with chronic in utero exposure to carbon monoxide (56,57).

CONCLUSION There is no doubt that carbon monoxide is a teratogen throughout pregnancy. Multiple CNS abnormalities reported to date, despite reporting bias, and the biological plausibility of the observed dysfunction proves it. Its role as a teratogen during organogenesis—other than a CNS teratogen—is not clear. At this time, we do not know if carbon monoxide poisoning can cause malformations in humans. Adverse fetal and infant outcome appears to be linked to the severity of maternal symptoms in poisoning. Other factors may also be important but are not identified at the present time. Cases in which the mother exhibits only minor symptoms (GI symptoms, headache and dizziness) are likely to have good

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pregnancy outcome regardless of the use of 100% oxygen or hyperbaric oxygen. However, if 100% oxygen is used, it should be administered five times longer than in a nonpregnant patient. The role of hyperbaric oxygen in the treatment of severe carbon monoxide poisoning is clear. However, its effect on the outcome of pregnant patients with only minor symptoms is not known at present.

REFERENCES 1. Respiratory toxicology. In: Ellenhorn MJ, Schonwald S, Orgog G, Wasserberger J, eds. Ellenhorn’s Medical Toxicology, 2nd ed. Baltimore: Williams & Wilkins; 1997, pp. 1465–1474. 2. Longo LD. The biological effects of carbon monoxide on the pregnant women, fetus, and newborn infant. Am J Obstet Gynecol 1977; 129:69–103. 3. Hill EP, Hill JR, Power GG, Longo LD. Carbon monoxide exchanges between the human fetus and mother: a mathematical model. Am J Physiol 1977; 232:H311–H323. 4. Turpin JC, Escourolle E, Gray F, et al. Intoxication oxycarbone´e chez le foetus. Rev Neurol (Paris) 1978; 134:485–495. 5. Cramer CR. Fetal death due to accidental maternal carbon monoxide poisoning. Clin Toxicol 1982; 19:297–301. 6. Copel JA, Bowen F, Bolognese RJ. Carbon monoxide intoxication in early pregnancy. Obstet Gynecol 1992; 59:26S–28S. 7. Hollander DI, Nagey DA, Welch R, Pupkin M. Hyperbaric oxygen for the treatment of acute carbon monoxide poisoning in pregnancy. J Reprod Med 1987; 32:615–617. 8. Caravati EM, Adams CJ, Joyce SM, Schafer NC. Fetal toxicity associated with maternal carbon monoxide poisoning. Ann Emerg Med 1988; 17:714–717. 9. Van Hoesen KB, Camporesi EM, Moon RE, et al. Should hyperbaric oxygen be used to treat the pregnant patient for acute carbon monoxide poisoning? JAMA 1989; 261:1039–1043. 10. Woody RC, Brewster MA. Telencephalic dysgenesis associated with presumptive maternal carbon monoxide intoxication in the first trimester of pregnancy. Clin Toxicol 1990; 28:467– 475. 11. Brown DB, Mueller GL, Golich FC. Hyperbaric oxygen treatment for carbon monoxide poisoning in pregnancy: a case report. Aviat Space Environ Med 1992; 63:1011–1014. 12. Gabrielli A, Layon AL. Carbon monoxide intoxication during pregnancy: a case presentation and pathophysiologic discussion, with emphasis on molecular mechanisms. J Clin Anesth 1995; 7:82–87. 13. Beaudoing A, Gachon J, Butin LP, Bost M. Les conse´quences foe´tales de l’intoxication oxycarbone´e de la me`re. Pe´diatrie 1969; 24:539–553. 14. Farrow JR, Davis GJ, Roy TM, et al. Fetal death due to nonlethal maternal carbon monoxide poisoning. J Forens Sci 1990; 35:1448–1452. 15. Muller GL, Graham S. Intrauterine death of the fetus due to accidental carbon monoxide poisoning. N Engl J Med 1955; 252:1075–1078. 16. Tissier P. Asphyxie par le gaz d’e´clairage d’une femme au terme d’une grossesse. Obste´trique 1909; 14:911–914. 17. Schwedenberg TH. Leukoencephalopathy following carbon monoxide asphyxia. J Neuropathol Exp Neurol 1959; 18:597–608. 18. Burnod A, Maire G. Cause exceptionnelle de mort d’un foetus in ute´ro: intoxication de la me`re par oxyde de carbone. Bull Fe´d Soc Gyne´col Obstet 1956; 2:191–192. 19. Helpern M, Strassman G. Differenciation of fetal and adult human hemoglobin. Arch Pathol 1943; 35:776–782. 20. Balthazard V, Nicloux M. Intoxication mortelle oxycarbone´e chez une femme enceinte de huit mois. Arch Mens Obstet Gynecol 1913; 3:161–165.

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21. Beau A, Neimann N, Pierson M. Du roˆle de l’intoxication oxycarbone´e gravidique dans le gene`se des ence´phalopathies ne´o-natales. Arch Fr Pe´diatr 1956; 13:130–143. 22. Desclaux P, Soulairac A, Morlon C. Intoxication oxycarbone´e au cours d’une gestation, arrieration mentale conse´cutive. Arch Fr Pe´diatr 1951; 8:316–318. 23. Zourbas J. Ence´phalopathie conge´nitale avec troubles du tonus neuro-musculaire vraisemblablement conse´cutive a` une intoxication par l’oxyde de carbone. Arch Fr Pe´diatr 1947; 4:513– 515. 24. Goldstein DP. Carbon monoxide poisoning in pregnancy. Am J Obstet Gynecol 1965; 92: 526–528. 25. Phillips P. Carbon monoxide poisoning during pregnancy. BMJ 1924; 1:14–15. 26. Weiler G, Ribe M, Kloppel A. Zur akuten und subakuten fotalen CO-Intoxikation. Z Rechtsmed 1983; 90:191–197. 27. Weiler G, Ribe M, Kloppel A. Zur Bewertung der kindlichen Schadigung bei akuter COVergiftung der graviden Frau. Geburtsh Frauenheilk 1984; 44:744–748. 28. Bankl H, Jellinger K. Zentralnervose Schaden nach fetaler Kohlenoxydvergiftung. Beitr Pathol Anat 1967; 135:350–76. 29. Colmant HJ, Wever H. Prenatalee Kohlenoxydvergiftung mit Organtod des Zentralnervensystems. Arch Psychiatr Zeitschr Ges Neurol 1963; 204:271–287. 30. Csermely M. Uber die pathogenese des cerebrum polycysticum. In: Jacob H, ed. IV Internationaler Kongress fur Neuropathologie, Munich. Stuttgart; Thieme, 1962; pp. 44–48. 31. Hallerdoven J. Uber eine Kohlenoxydvergiftung im fettalehen mit Entwicklungsstrungen der Hirnrunde. Allg Zchr Psychiatr 1949; 124:289–298. 32. Maresh R. Uber einem Fall von Kohlenoxydgahadigung der Kinder in der Gebarmutter. Wien Klin Wochschr 1929; 79:454–456. 33. Neuburger F. Fall einer intra-uterine Hirnschadigung nach einer Leuchtgastervergiftung der Mutter. Beitr Gericht Med 1932; 13:85–95. 34. Solcher H. Uber einem Fall von uberstandener fataler Kohlenoxydvergiftung. J Hirnforsch 1957; 3:49–55. 35. Bette H. Extremitaten Missbildungen nach Leuchtgasvergiftung der Mutter, kasuistike Beitrag zur Missbildungsforschung. Munch Med Wochenschr 1957; 99:1246. 36. Brander T. Microcephalus und Tetraplegie bei einem Kinde nach Kohlenmonoxydvergiftung der mutter wahrend der Schwangerschaft. Acta Padiatr 1940; 28:123–132. 37. Breslau F. Intoxication zweier schangeren mit holzleuchtgas: Tod und vorzeitige Geburt eines Kindes. Monatsschr Geburtsk Frauenkrankh 1859; 13:449–456. 38. Corneli F. Contributo sperimentale all’azione teratogenica dell’ossido di carbonio nei mammiferi. Ortop Traumatol 1955; 23:261. 39. Debre R. Le´sions ce´re´brales par anoxie ne´o-natale. Arch Fr Pe´diatr 1955; 12:673. 40. Freund MB. Ein fall von abstaiben der Frucht in siebenten Schwangerschaftsmonate in folge von nur massiger Intoxication der mutter durch Kohlenoxydgas. Monatsschr Geburtsch Frauenkrankh 1859; 14:31–33. 41. Marchal C, Manciaux M, Neimann M. Les foetopathies d’origine toxique. Rev Praticien 1967; 4:155. 42. Martland HS, Martland HSJ. Placental barrier in carbon monoxide barbiturate and radium poisoning. Am J Surg 1950; 80:270–279. 43. Larcan A, Landes P, Vert P. Intoxication oxycarbone´e au 2e mois de grossesse sans anomalie ne´onatale. Bull Fe´d Socs Gyne´c Obstet Lang Fr 1969; 22:338–339. 44. Margulies JL. Acute carbon monoxide poisoning during pregnancy. Am J Emerg Med 1986; 4:516–579. 45. Litovitz TL, Smilkstein M, Felberg L, et al. 1996 annual report of the American Association of Poison centers Toxic Exposure Surveillance System. Am J Emerg Med 1997; 15:447–500. 46. Peirce EC, Kaufman H, Bensky WH, et al. A registry for carbon monoxide poisoning in New York City. Clin Toxicol 1988; 26:419–441.

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47. Ginsberg MD, Myers RE. Fetal brain injury after maternal carbon monoxide intoxication. Neurology 1976; 26:15–23. 48. Peterson JE, Steward RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health 1970; 21:165–171. 49. Ingalls TH, Philbrook FR. Monstrosities induced by hyperoxia. N Eng J Med 1958; 259:558– 560. 50. Koren G, Sharav T, Pastuszak A, et al. A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning during pregnancy. Reprod Toxicol 1991; 5: 397–403. 51. Hardy KR, Thom SR. Pathophysiology and treatment of carbon monoxide poisoning. Clin Toxicol 1994; 32:613–629. 52. Elkharrat D, Raphael JC, Korach JM, et al. Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intens Care Med 1991; 17:289–292. 53. Raphael JC, Elkharrat D, Jars-Guincestre MC, et al. Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989; 2:414–448. 54. De Haas JH. Parental smoking. Its effect on fetus and child health. Eur J Obstet Gynecol Reprod Biol 1975; 5:283–296. 55. Krenzelok EP, Roth R, Full R. Carbon monoxide: the silent killer with an audible solution. Am J Emerg Med 1996; 14:484–486. 56. Courtens W, Hennequin Y, Blum D, Vamos E. Charge association in a neonate exposed in utero to carbon monoxide. Birth Defects 1996; 30:407–412. 57. Hennequin Y, Blum D, Vamos E, et al. In utero carbon monoxide poisoning and multiple fetal abnormalities. Lancet 1993; 341:240.

16 Direct Drug Toxicity to the Fetus Orna Diav-Citrin The Hebrew University, Jerusalem, Israel

Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case One of your patients, a woman with chronic hypertension, is well controlled on captopril. In fact, after stormy years with β-adrenergic blockers, she is for the first time doing well. The patient finds out she is pregnant and would like to know whether she can stay on captopril. The fetal phase, from the end of the embryonic stage to term, is the period when growth and functional maturation of organs and systems already formed occur. Teratogen exposure in this period may adversely affect fetal growth (i.e., intrauterine growth restriction), the size of a specific organ, or the function of the organ rather than causing gross structural anomalies. The term fetal toxicity, rather than teratogenicity, is commonly used to describe such an effect. Fetal toxicity, unlike teratogenicity, is often predicted from the known pharmacological profile and toxicological effects of the agents involved. Fetal toxic effects may have a major impact on the morbidity and mortality of the neonate. In counseling pregnant women regarding drug exposure during pregnancy, it is important to address fetal toxic effects and estimate their risk. Table 1 reviews medicinal drugs that may cause direct fetal toxicity in humans and summarizes the evidence for the fetal toxic effect, with an attempt to estimate the rate of its occurrence. Whenever fetal toxic effects are based on case reports, they are used as a warning signal. In such cases, it is virtually impossible to give a true risk estimate because the denominator of the total number of exposed fetuses is unknown. Other chapters deal with drugs and substances of abuse and with neonatal withdrawal syndromes. The potential effect of psychoactive agents on the developing central nervous system, which belongs to the evolving field of behavioral teratology, is beyond the scope of this chapter. Clinical Case Answer Angiotensin-converting enzyme (ACE) inhibitors are potent antihypertensive drugs. Their use in the second and third trimesters of pregnancy has been associated with fetal toxicity, including intrauterine renal insufficiency. Neonatal hypotension, oliguria with renal failure, and hyperkalemia have been reported with the use of ACE inhibitors in late preg269

No.

270

Table 1

Direct Drug Toxicity to the Fetus Drug

1. Acebutolol

2. Acetaminophen

3. Acetazolamide

4. Acetohexamide

5. Albuterol

Fetal/neonatal toxic effects Lower mean birth weight than in neonates exposed, to pindolol; (higher than in those exposed to atenolol)

Neonatal apnea and hypotonia

Comments/recommendations Not known whether due to the degree of maternal hypertension, the potency of the drug, or a combination of these and other factors

Ref. 1

2

Neonates should be closely observed for signs of β-adrenergic blockade

3

C/R

Continuous maternal high daily dose

4

C/R 1/3

In an overdose situation Resolved after treatment

5 6

C/R

Oral hypoglycemics generally not recommended in pregnancy because of concerns regarding insufficient glycemic control Adverse reactions secondary to the cardiovascular and metabolic effects of the drug Effects more pronounced in diabetic patients Neonatal hypoglycemia should be prevented with adequate intake of glucose Direct adrenergic stimulation of the pituitary (?) Can be reversed with naloxone

7

C/R

8 9–14

15–19 20–21 22 23–24

Diav-Citrin and Koren

Transient hypoglycemia Lower blood pressure and heart rate than of similar infants exposed to methyldopa Polyhydramnios and fatal neonatal kidney disease in the newborn Fetal death with hepatic and renal toxicity Asymptomatic hypocalcemia, hypomagnesemia, and metabolic acidosis in the newborn Prolonged symptomatic hypoglycemia in the newborn Prolonged hypoglycemia and convulsions in the newborn Fetal tachycardia transient fetal atrial flutter Transient fetal hyperglycemia followed by hyperinsulinemia Higher growth hormone levels in cord blood

6. Alfentanil

Reported rate of occurrence

8. Ambenonium

Respiratory depression Transient sinusoidal fetal heart rate pattern Suppression of collagen-induced platelet aggregation Transient muscular weakness

9. Aminoglutethimide

Virilization

10. Amiodarone

11. Ammonium chloride 12. Amphetamine

13. Ampicillin

20% of newborns whose mothers were treated with choline-esterase inhibitors during pregnancy

May be caused by inhibition of adrenocortical function Not clinically significant

Prolonged QT interval Transient bradycardia Transient hypothyroidism Congenital hypothyroidism with goiter Transient asymptomatic hyperthyroidism Elevated serum iodine level IUGR

C/R C/R

Thyroid function tests recommended for newborns exposed to amiodarone in utero because of the high iodine content of the drug May be an effect of amiodarone, a result of the maternal disease or concurrent medications, or a combination of the above In large amounts near term Multifactorial: multidrug abuse, lifestyle, poor maternal health and antenatal care Due to the vasoconstrictive properties of the drug In an acute poisoning Maternal anaphylaxis

22 vs. 11% in not exposed

During the last 2 weeks of pregnancy, specific agents and doses not reported

Fetal acidosis IUGR Prematurity Cerebral injuries Intrauterine death Severe neonatal distress with neurologic sequelae Increased risk of retrolental fibroplasia in premature infants

No short-term neonatal adverse effects were observed Abnormal bleeding not reported Neonatal myasthenia may be caused by transplacental passage of anti-acetylcholine receptor immunoglobulin G antibodies, rather than a drug effect

25–32 33 34 35–36

37–38 39 40–41 44, 46, 48 45 41 42 43, 45

49–50 51 52 53 54 55 56

271

14. Antihistamines

17/40 (42.5%)

Direct Drug Toxicity to the Fetus

7. Alphaprodine

Table 1

Continued Drug

15. Aprotonin 16. Asparaginase

17. Aspirin

18. Atenolol

Decreased fibrinolytic activity Transient bone marrow hypoplasia in the newborn Chromosomal damage IUGR Increased perinatal mortality (stillbirths more than neonatal)

Reported rate of occurrence 2/7 C/R

Depressed platelet function In premature or low birth weight infants after full dose given near term Large doses

Immunosuppression

Chromosomal abberations

In combination with other antineoplastic agents Clinical significance not clear Some associated with antepartum hemorrhage, others may have been caused by closure of the ductus

Premature closure of the ductus arteriosus Decreased clotting ability Increased incidence of intracranial hemorrhage Toxic effects Congenital salicylate intoxication Depressed albumin-binding capacity IUGR Lower birth weight Persistent β-adrenergic blockade

IUGR

Comments/recommendations

Incidence of SGA: 20–40%

Ref. 57 58–63 64 65–67

68 69–76 77–80 81, 82 83, 84 85 86, 88

No increase in the incidence of 85 jaundice May be related to increased vascular resistance and is a function of length of drug exposure Newborns exposed near delivery should be 89, 94 closely observed during the first 24–48 hours for signs and symptoms of β-adrenergic blockade Dose reduction is recommended according 95, 97 to maternal leukocyte count at 32 weeks gestation to avoid neonatal leukopenia and thrombocytopenia Other potential contributors: underlying dis- 98–102 ease, (hypertension, vascular disease, and renal impairment), multiple medications Clinical significance unknown 103

Diav-Citrin and Koren

19. Azathioprine

Fetal/neonatal toxic effects

272

No.

Paralytic ileus

21. Betamethasone

Hypoglycemia Leukocytosis Transient constriction of the ductus arteriosus Transient decrease in glucocorticoid activity in the neonate Profound transient leukopenia with neutropenia and alopecia

22. Bleomycin

Two newborns

C/Rs Clinical significance not clear

C/R

Chromosomal aberrations 23. Bromides

24. Busulfan 25. Butorphanol

26. Caffeine

27. Calcitonin

IUGR Neonatal bromide intoxication (poor suck, weak cry, diminished Moro reflex, lethargy and hypotonia) IUGR Chromosomal aberrations Depressant effect Sinusoidal fetal heart rate pattern Low birth weight Tachyarrhythmias Premature atrial contraction Fine tremors Tachypnea

3 C/Rs

Rebounded and returned to normal in the first hours of life Other chemotherapeutic agents involved, by 12 weeks of age hair regrowth, at 1 year normal development except for moderate hearing loss In human marrow cells, significance to the fetus unknown Normal growth and development after several months

Clinical significance unknown 75% (38/51) vs. 13% (7/55) 25% vs. 1.7% 12.5% vs. 0 100% vs. 10.7% 25% vs. 3.5%

Clinical significance unknown

104 105 106, 107 108 109 110

111 112, 113 114–116

117, 118 119 120–122 123, 124

High consumption 125 Associated with maternal caffeine consump- 126 tion of more than 500 mg/day (n ⫽ 16) in comparison to offspring of women who used less than 250 mg/day (n ⫽ 56) of caffeine 127 Clinical significance unknown 128

273

Fetal behavioral and sleep pattern changes Marked increase of calcitonin concentrations in fetal serum at term

Exposure at term to chlorpromazine as well

Direct Drug Toxicity to the Fetus

20. Benztropine

No.

274

Table 1

Continued Drug

28. Camphor 29. Captopril

30. Carbamazepine

Fetal/neonatal toxic effects

31. Carbimazole 32. Chlorambucil

See methimazole Mutagenicity and carcinogenicity

33. Chloramphenicol

Low birth weight Cardiovascular collapse (‘‘gray-baby syndrome’’)

4 cases

C/R

Comments/recommendations

Ref.

Accidental ingestion

129–132

When used in the second and third trimesters of pregnancy. Speculated mechanism related to drug-induced oligohydramnios, causing a mechanical insult, combined with drug-induced fetal hypotension and decreased renal blood flow. In cases in which maternal disease requires captopril in late pregnancy, monitoring of amniotic fluid volume is advised during gestation as well as close observation of blood pressure and renal function in the neonate The levels were still within normal limits, questionable clinical significance Vitamin K prophylaxis advised to the mothers before the expected time of delivery Exposure during pregnancy and breastfeeding, resolved upon cessation of breast-feeding Converted in vivo to methimazole Not reported in newborns following in utero exposure

133

40% During the final stage of pregnancy

134 135–137

138

139–143 117 144

Diav-Citrin and Koren

Fetal toxicity and neonatal respiratory failure Oligohydramnios IUGR Renal dysplasia Intrauterine fetal death Fetal hypotension Neonatal anuria Renal failure Craniofacial deformations: hypocalvaria/ acalvaria Pulmonary hypoplasia Limb contractures Neonatal death Lower cord serum vitamin D levels compared to normal controls Neonatal vitamin K deficiency associated with early hemorrhagic disease of the newborn Transient cholestatic hepatitis

Reported rate of occurrence

35. Chloroquine

Marked depression of the infants (unresponsive, hypotonic, hypothermic and fed poorly) Cochleovestibular paresis

36. Chlorothiazide

Neonatal hypoglycemia

3 infants

Exposure within hours of delivery Hypotonicity persisted for up to a week

2 cases

2 cases 2 cases

Concern regarding cumulative ocular toxic- 146 ity of high doses used for rheumatological conditions if used for prolonged periods during pregnancy Newborns exposed to thiazide diuretics 147–150 near term should be observed for hypoglycemia as a result of maternal hyperglycemia Transfer of antiplatelet antibody demon148, 149, strated 151–155 150 157 156, 158 159

C/R

High doses, resolved within 3 weeks

160

2 cases

Doxepin coadministered in one Near term, may persist for months

104 161–165

4 cases

Near term, lasted for 4–6 days

166–168

Neonatal thrombocytopenia

37. Chlorpromazine

38. Chlorpropamide

Hemolytic anemia Hyponatremia Hypokalemia Fetal death attributed to maternal hemorrhagic pancreatitis Neonatal hypotonia, lethargy, depressed reflexes, and jaundice Paralytic lieus An extrapyramidal syndrome (tremors, hypertonia, spasticity, hyperactive reflexes) Prolonged neonatal symptomatic hypoglycemia secondary to hyperinsulinism Severe hypoglycemia Hyperbilirubinemia Polycythemia and hyperviscosity

145

Direct Drug Toxicity to the Fetus

34. Chlordiazepoxide

169 10/15 (67%) vs. 13/36 (36%) 4/15 (27%) vs. 1/36 (3.0%)

Generally, insulin provides better glycemic control and is the drug of choice for diabetes in pregnancy

275

Table 1

Drug

Fetal/neonatal toxic effects

Reported rate of occurrence

Fatal fetal subdural hematomas

C/R

40. Cimetidine 41. Cisplatin

Transient neonatal liver impairment Profound transient leukopenia with neutropenia and alopecia

C/R C/R

42. Clofazimine

Skin pigmentation at birth

43. Clonazepam

Neonatal apneic episodes with hypotonia and lethargy

44. Codeine 45. Coumarin derivatives

Neonatal respiratory depression CNS damage Hemorrhage IUGR Miscarriage Prematurity Stillbirth/neonatal death Pancytopenia Transient neonatal severe bone marrow hy- C/R poplasia Low birth weight 40% Chromosomal aberrations C/R

46. Cyclophosphamide

C/R

Comments/recommendations Possible result of vitamin K deficiency (caused by long-term use of high-dose cholestyramine), cholestasis, or both Exposure at term Other chemotherapeutic agents involved, by 12 weeks of age hair regrowth, at 1 year normal development except for moderate hearing loss (thought to be gentamicin- or cisplatin-related) In at least 3 infants, gradually resolved during a 1-year period Exposure throughout pregnancy and in breast-feeding Hypotonia resolved within 5 days, clinical apnea persisted for 10 days, for 10 weeks by follow-up pneumograms Use during labor Exposure in the second and/or third trimesters, probably caused by fetal or neonatal hemorrhage

Exposure to five other antineoplastics in the third trimester Combination chemotherapy including mercaptopurine and radiation Following administration of anticancer drugs during pregnancy Clinical significance unknown

Ref. 170

171 110

172, 173 174

175 176

177 58 117 64

Diav-Citrin and Koren

39. Cholestyramine

276

No.

Continued

C/R

Neonatal leukopenia Neonatal hypoglycemia and mild DIC IUGR

C/R C/R 8–45%

Chromosomal aberrations Pancytopenia

C/R

Low birth weight

40%

49. Dactinomycin

Low birth weight

40%

50. Danazol

Female pseudohermaphroditism

51. Dapsone

Neonatal hemolytic anemia Neonatal hyperbilirubinemia Anemia, hypoglycemia and electrolyte abnormalities Transient neutropenia at 2 months Severe transient bone marrow hypoplasia

⬃30–67% of female fetuses C/R C/R 1 case 2 cases C/R

Low birth weight

40%

53. Deferoxamine

Chromosomal aberrations Low neonatal iron levels

C/R

54. Dexamethasone

Neonatal leukocytosis

48. Cytarabine

52. Daunorubicin

May have been related to hydralazine concurrently administered to the mother Resolved spontaneously In the offspring of renal transplant patients, potentially multifactorial (maternal hypertension, renal function, immunosuppressive drugs, or a combination of the above) Clinical significance unknown Exposure in the third trimester, other neoplastics involved Following administration of anticancer drugs during pregnancy Following administration of anticancer drugs during pregnancy Exposure beyond 8 weeks gestation Spontaneously resolved within 10 days

Five other antineoplastic agents involved, thought to be secondary to mercaptopurine Following administration of anticancer drugs during pregnancy Clinical significance unknown In acute iron overdose at 34 weeks gestation White cell counts returned to normal in ⬃1 week

178 179 180 181

64, 182 177 117 117 183–192 193 194 195 196 58

117 64 197 198, 199

277

Neonatal thrombocytopenia

Direct Drug Toxicity to the Fetus

47. Cyclosporine

No.

278

Table 1

Continued Drug

55. Diatrizoate

57. Diazepam

58. Diazoxide

60. Digitalis 61. Dihydrocodeine bitartrate

Reported rate of occurrence

Clinical neonatal hypothyroidism

3/7

Biochemical neonatal hypothyroidism

6/7

‘‘Floppy infant’’ syndrome (hypotonia, lethargy, and sucking difficulties)

Altered neonatal thermogeneis Loss of beat-to-beat variability in fetal heart rate. Decreased fetal movements Transient fetal bradycardia

Newborn hyperglycemia Newborn alopecia, hypertrichosis, lanuginosa and decreased ossification of the wrist Cervical or vaginal structural changes Masculinization of the female infant Tumors of female and male reproductive systems Fetal intoxication and neonatal death Newborn respiratory depression

Comments/recommendations When administered by intra-amniotic injection with ethiodized oil Greater thyroid suppression, the longer the time interval between injection and delivery The frequency of newborn complications increases when doses exceed 30–40 mg or when diazepam is taken for long periods When administered in labor

After rapid drop in maternal blood pressure following intravenous bolus administration Following intravenous administration Following oral treatment during the last 19–69 days of pregnancy 22–58%

C/R

Ref. 200

201–204

205–208 209 210 211, 212

213, 214 215

180, 216– 218

Following maternal acute digitoxin overdose

219 220, 221, 175

Diav-Citrin and Koren

59. Diethylstilbestrol

Fetal/neonatal toxic effects

63. Docusate sodium

Fetal distress (i.e., bradycardia and loss of beat-to-beat variability) Neonatal hypomagnesemia

C/R

64. Doxepin

Paralytic ileus in a neonate

C/R

65. Enalapril

Oligohydramnios, IUGR, renal dysplasia, intrauterine fetal death, fetal hypotension, neonatal anuria, renal failure, craniofacial deformations, hypocalvaria/ acalvaria, pulmonary hypoplasia, limb contractures, neonatal death

66. Ephedrine

Increase in fetal heart rate and beat-tobeat variability Decrease in uterine blood flow and contribution to intrauterine anoxic insult resulting in neonatal death Abruptio placentae with resulting fetal death at 23 weeks

67. Epinephrine

68. Epoetin alfa

69. Ergotamine

C/R

C/R

Fetal death

C/R

Fetal distress

C/R

Possible result of uterine hyperstimulation

222

Chronic maternal overuse Resolved spontaneously Thought to be caused primarily by coadministered chlorpromazine When used in the second and third trimesters of pregnancy. Speculated mechanism related to drug-induced oligohydramnios, causing a mechanical insult, combined with drug-induced fetal hypotension and decreased renal blood flow. In cases in which maternal disease requires enalapril in late pregnancy, monitoring of amniotic fluid volume is advised during gestation, as well as close observation of blood pressure and renal function in the neonate When used to treat or prevent maternal hypotension following spinal anesthesia Following a large intravenous dose to reverse severe maternal hypotension secondary to anaphylaxis Erythropoietin could not be excluded as a contributing factor in a woman with severe hypertension and chronic renal failure Following acute overdose, in a suicide attempt at 35 weeks Accidental use of ergotamine and caffeine at 38 weeks

223 104 180

Direct Drug Toxicity to the Fetus

62. Dimenhydrinate

224–226 227

228

229 230

279

Table 1

Continued Drug

70. Esmolol

Fetal/neonatal toxic effects

Reported rate of occurrence C/R 2 cases

71. Ethacrynic acid

Ototoxicity observed in the newborn and mother

C/R

72. Ethosuximide 73. Etoposide

Spontaneous hemorrhage in the neonate Oligohydramnios, IUGR

C/R C/R

Anemia, leukopenia, and profound neutropenia and thrombocytopenia in the neonate

C/R

Marked leukopenia with neutropenia in the neonate on day 3 (10 days after in utero exposure to the chemotherapy), scalp hair loss and loss of lanugo at 10 days of age, moderate bilateral sensorineural hearing loss at 1 year follow-up

C/R

Resolved spontaneously by 60 hours of age Newborns exposed near delivery should be closely observed during the first 24– 48 hours for signs and symptoms of βadrenergic blockade Following the use during the third trimester Concomitant exposure to kanamycin Four cycles of chemotherapy consisting of etoposide and cisplatin given from 27 weeks’ gestation for dysgerminoma, initially treated surgically Normal hematological profile in the newborn Following combination chemotherapy consisting of two courses of etoposide, cytarabine, and daunorubicin given from 25 weeks’ gestation for acute myeloid leukemia Treated successfully; at 1 year of age blood counts were normal and treatment was stopped. Combination chemotherapy consisting of etoposide, cisplatin, and bleomycin given from 26 weeks’ gestation, the patient became profoundly neutropenic and developed septicemia By 12 weeks’ of age the infant had hair growth Aminoglycoside therapy also given to the mother and neonate

Ref. 231 232, 233

234

235 236

237

110

Diav-Citrin and Koren

Fetal bradycardia β-adrenergic blockade in the fetus and infant

Comments/recommendations

280

No.

Transient pronounced jaundice with elevated transaminases in the newborn

C/R

75. Fentanyl

Respiratory depression in the neonate Loss of fetal heart rate variability without causing fetal hypoxia

C/R

76. Flecainide

Loss of fetal heart rate variability and accelerations

C/R

Transient conjugated hyperbilirubinemia in the neonate

C/R

Cyanosis and jerking extremities in the newborn Minor extrapyramidal symptoms in the infant at 4 weeks of age

C/R

77. Fluorouracil 78. Fluphenazine

79. Gabapentin

C/R

Severe rhinorrhea and upper respiratory C/R distress at 8 hours of age, poor feeding, periodic vomiting, choreoathetoid movements, and intermittent arching of the body Jaundice and intermittent tremors that oc- C/R curred for about 5 days after birth

Following in utero exposure to etretinate, no other anomalies observed, resolved at 5 months follow-up Following epidural fentanyl during labor Was the only effect in a prospective study of 137 women receiving fentanyl in labor Following treatment of fetal supraventricular tachycardia during the third trimester Fetal heart rate returned to a reactive pattern 5 days after delivery Following successful treatment of fetal supraventricular tachycardia at 28 weeks’ gestation after a trial of digoxin and adenosine had failed Resolved at 2 months follow-up Following third-trimester exposure

238

239 240, 241

242

243

Direct Drug Toxicity to the Fetus

74. Etretinate

244

281

Following treatment in pregnancy with 245 fluphenazine decanoate injections every 3 weeks, readily responded to diphenhydramine, resolved at 2 months of age Following treatment with fluphenazine 246 throughout pregnancy for schizophrenia, symptoms improved with pseudoephedrine solution; rinorrhea and nasal congestion persisted for 3 months Following first-trimester exposure to lamo- 247 trigine in addition to administration of gabapentin before and throughout pregnancy; skin tags and ear anomalies also noted in the infant

Table 1

Drug

Fetal/neonatal toxic effects

Reported rate of occurrence

Neonatal hypoglycemia (blood glucose ⬍25 mg/dL)

4/15 (27%)

81. Hexamethonium

Paralytic ileus

3 cases

82. Hydralazine

Neonatal thrombocytopenia and bleeding

3 infants

Fetal premature atrial contractions

C/R

Lupus-like syndrome in the newborn, who died at 36 hours of age due to cardiac tamponade induced by pericardial effusion

C/R

Fetal distress

5/7 (71%)

83. Hydroxyprogesterone

Masculinization of the female fetus

This is seen 3.5 times more often than in newborns whose mothers were treated with insulin; in 1 newborn, the hypoglycemia persisted for more than 48 hours, insulin recommended when drug therapy indicated for diabetes The drug had been used in the treatment of preeclampsia and essential hypertension Daily exposure throughout the third trimester, may be related to severe maternal hypertension rather than to the drug Noted at 36 weeks gestational age, a week following the addition of hydralazine to the woman’s treatment with methyldopa, tachyarrhythmias not observed. The fetal arrhythmia resolved 24 hours after stopping hydralazine Treated with IV hydralazine during a 6day period in the 28th week of gestation for hypertension, IV methyldopa was administered on the sixth day of therapy, lupus-like syndrome developed in the mother on the fifth day of therapy and gradually resolved following discontinuation of hydralazine and delivery Associated with rapid uncontrolled decline in maternal blood pressure when given IV for hypertension

Ref. 248, 249

250, 251

252–254

255

256

257

258–260

Diav-Citrin and Koren

80. Glyburide

Comments/recommendations

282

No.

Continued

Decreased amniotic fluid volume Oligohydramnios

3/4 (75%) C/R of triplets 8/30 (27%) 3/61 (4.9%)

Low-normal amniotic fluid volume

4/61 (6.6%)

85. Idarubicin

Mild constriction of the ductus arteriosus (non-dose-related) Fetal death

C/R

86. Indomethacin

Reduction in the amniotic fluid volume

6/52 (11.5%)

Reduced fetal urine output Impaired renal function in preterm neonates Constriction of the fetal ductus arteriosus with or without tricuspid regurgitation

Periventricular leukomalacia in preterm neonates

In temporal relationship to therapy with ibuprofen Resolved on discontinuation of treatment, less than with indomethacin Resolved after discontinuation of ibuprofen, true oligohydramnios not observed Normal echocardiograms in all four cases within 1 week of discontinuing therapy Concomitant treatment with cytarabine for acute myeloblastic leukemia during the second trimester In preterm labor with intact membranes at gestational age of 32 weeks or less Usually transient

261 262 263 264 264 264 265

261, 263, 266–268 269 270

Ductal constriction is dependent on the 271–297, gestational age of the fetus, starting as 299, 300 early as 27 weeks and increasing markedly at 27–32 weeks, independent of fetal serum indomethacin levels; usually transient and reversible if therapy is stopped an adequate time prior to delivery

C/R

34% (26/76)

Most likely due to ductal constriction and shunting of the right ventricular outflow into the pulmonary vessels; Results in pulmonary arterial hypertrophy In one twin fetus after 28 days of indometha- 298 cin treatment, possibly due to ductal con- 301 striction, resolved completely within 48 hours of stopping the drug 302

283

Premature closure of the ductus arteriosus Primary pulmonary hypertension of the newborn, persistent fetal circulation after birth Neonatal death Unilateral pleural effusion

Used as a tocolytic agent

Direct Drug Toxicity to the Fetus

84. Ibuprofen

No.

284

Table 1

Continued Drug

Fetal/neonatal toxic effects

87. Insulin (bovine or porcine)

Fetal macrosomia

88. Iodides: Iodide or iodine-containing products Radioiodine

Hypothyroidism and goiter in the fetus and newborn, cardiomegaly

90. Isoproterenol

47% (21/46)

Partial or complete ablation of the fetal thy- Several C/Rs roid gland

Combined hypothyroidism and hypoparathyroidism Hemorrhagic disease of the newborn

An isolated late deceleration of 5 beats per minute in a fetus

Comments/recommendations Crosses the placenta as an insulin-antibody complex, the amount of transfer correlated with the amount of antiinsulin antibodies in the mother, high concentrations of animal insulin in cord blood were significantly associated with the development of fetal macrosomia. It is difficult to separate the effect of insulin from the mother’s glycemic control. Human insulin is the drug of choice for the control of diabetes mellitus in women who may become pregnant. When used for prolonged periods or close to term. Goiter may be large enough to cause tracheal compression and death The effect is dose-dependent (in the pregnancies terminating with a hypothyroid infant 131 I doses ranged from 10 to 225 mCi) and may occur only after 10 weeks gestation when the fetal thyroid begins concentrating iodine

C/R

303

304–309

310–316

317

C/R 2 cases

Ref.

Vitamin K supplementation of women taking the drug near term recommended prior to delivery for prevention Two minutes after the mother received 0.25 µg of the drug

318

319

Diav-Citrin and Koren

89. Isoniazid

Reported rate of occurrence

92. Kanamycin

93. Ketamine

94. Labetalol

Severe neonatal toxicity with respiratory depression and hypotension Hypotension Hypocalcemia Paralytic ileus Tachycardia Hypoglycemia Death ECG changes suggesting myocardial ischemia Ototoxicity: Deafness

C/R

Hearing impairment

2.3% (9/391)

89% 100% 33%

16% 6/9

Depression of the newborn Excessive neonatal muscle tone sometimes with apnea Newborn bradycardia

5 infants

Hypotension Mild transient hypotension in term newborns

1 infant 11 infants C/R

Neonatal hypoglycemia

19.1% (18/94) vs. 9.3% (9/97)

320, 321

Transient

323

The mother also experienced ototoxicity, ethacrinic acid also given during pregnancy In women who had received kanamycin, 50 mg/kg, for prolonged periods during pregnancy When used close to delivery for obstetrical anesthesia, transient dose-related toxicity, usually avoided with lower doses Bradycardia marked and persistent in one infant, all survived Delivered by C/S at 28 weeks’ gestation Other measures of β-adrenergic blockade did not differ when compared to matched controls The woman was also taking a thiazide diuretic Women were treated for mild preeclampsia presenting at 26–35 weeks’ gestation Newborns should be closely observed during the first 24–48 hours for signs and symptoms of α/β-adrenergic blockade if exposed close to delivery

234

320 322

324

325–335

336–341

285

Significantly more with IUGR after exposure to labetolol plus hospitalization compared with hospitalization alone

Rare if cord levels are less than 2 ng/mL, increased if cord blood serum levels exceeded 10 ng/mL When cord levels exceeded 10 ng/mL Not related to cord concentrations

Direct Drug Toxicity to the Fetus

91. Isoxsuprine

Continued

No.

Drug

95. Lidocaine

96. Lisinopril

286

Table 1

Fetal/neonatal toxic effects Abnormal fetal rhythm (tachycardia or bradycardia) Lower scores on tests of muscle strength and tone in newborns compared to controls CNS depression in the newborn (low Apgar scores) Chronic renal failure in the newborn Fatal hypocalvaria and chronic renal failure in the premature newborn

Severe oligohydramnios, IUGR, fetal distress, hypocalvaria, and persistent renal insufficiency Fetal calvarial hypoplasia ACE-inhibitor fetopathy 97. Lithium

50% (6/12)

Comments/recommendations Following paracervical block with lidocaine in 12 laboring women After continuous lumbar epidural blocks

Ref. 342 343

344 2 cases C/R

345–348 Fetal calvarial hypoplasia, open biopsy at 11 weeks of age showed extensive atrophy and loss of tubules with interstitial fibrosis

C/R

C/R See entries on captopril and enalapril for further details Most of the toxic effects self-limited (returning to normal within 2 weeks) Persisted for 2 months or longer

C/R

With high IV maternal doses The woman was also taking clozapine, resolved at 5 days of age

180, 349– 366

367, 368

Diav-Citrin and Koren

98. Lorazepam

Hypotonia, cyanosis, bradycardia, atrial flutter, T-wave inversion on ECG, cardiomegaly, thyroid depression with goiter, nephrogenic diabetes insipidus, polyhydramnios, shock, seizures, gastrointestinal bleeding, hepatomegaly, neonatal jaundice, stillbirth, fetal and newborn lithium intoxication ‘‘Floppy infant’’ syndrome Transient mild floppy infant syndrome

Reported rate of occurrence

Newborn depression and hypotonia

Series

Severe depression at birth

2 cases

Muscle contraction impairment Decreased gastrointestinal motility, ileus, hypotonia Cogenital rickets

Wide-spaced fontanelles and parietal bone thinning Fetal bradycardia 100. Medroxyprogesterone 101. Melphalan 102. Menadione

Ambiguous genitalia IUGR Marked hyperbilirubinemia and kernicterus in the newborn

103. Meperidine

Respiratory depression in the newborn

2/5

2/22 C/R

Especially in premature infants, phytonadione is considered the vitamin K of choice for administration during pregnancy Following exposure during labor, timeand dose-dependent Persisting for several days

105. Mercaptopurine

Myelosuppression Microangiopathic hemolytic anemia IUGR Chromosomal aberrations

2 cases C/R 40% C/R

369–375

376, 378

377 379 380–384

374 385 386 117 387–390

391, 392 393, 394

Mean decline in TcP O211.7 torr mean dura- 395 tion 4.6 minutes after injection Correlated with high fetal mepivacaine 396 blood levels after paracervical block 58, 177 After combination chemotherapy 397 Clinical significance unknown 117 64

287

Fetal bradycardia

Maternal hypothermia with maternal bradycardia

C/R

Impaired behavioral response and EEG changes in the neonate Transient decrease in oxygenation 104. Mepivacaine

Intrauterine hypoxia could not be ruled out as a potential cause or contributing factor Spontaneous remission in one infant, residual effects of anoxic encephalopathy in the second Up to 48 hours after birth Other drugs or maternal severe hypertension could have been the causes With long-term infusions of magnesium, probably due to sustained fetal hypocalcemia Effects returned to normal with time

Direct Drug Toxicity to the Fetus

99. Magnesium sulfate

No.

Continued Drug

106. Methadone 107. Methimazole/ carbimazole

108. Methotrexate

109. Methyldopa

110. Methylene blue

Fetal/neonatal toxic effects Neonatal hyperbilirubinemia Thrombocytosis Mild fetal hypothyroidism

Reported rate of occurrence

C/R

Hypothyroidism evident at 2 months of age Neonatal hypothyroidism with goiter Small goiters in the newborn Severe newborn myelosuppression

C/R

IUGR Chromosomal aberrations Mild reduction in neonatal systolic blood pressure in the first two days of life Transient neonatal nasal obstruction Newborn complications: hemolytic anemia, hyperbilirubinemia, methemoglobinemia, deep blue staining, intestinal obstruction Jejunal atresia

40% C/R 24 infants

Newborn respiratory depression

Respiratory depression on the day 1, hypoglycemia and jaundice on day 3

2 cases 2 cases 2 cases

Comments/recommendations In polydrug users Usually resolves spontaneously within a few days With subsequent mental retardation

In carbimazole-exposed newborns Concomitant administration of other antineoplastic agents Clinical significance unknown Reduction not clinically significant

Following intra-amniotic injection of methylene blue

In 19% (17/89) of twin pregnancies 19% (5/26)

When used in genetic amniocentesis in twins, possible mechanism: mesenteric vasoconstriction When used in combination with succinylcholine for rapid-sequence induction of anesthesia before cesarean section, higher proportion than the one found with thiopenthal When used before elective cesarean section

Ref. 398 399 400 401 402 403 58, 177 117 64 404 405 406–416

417, 418

419

420

Diav-Citrin and Koren

111. Midazolam

288

Table 1

Hypertrichosis Fetal death

114. Morphine

Respiratory newborn depression

115. Nadolol

IUGR, tachypnea, hypoglycemia, hypothermia, cardiorespiratory depression

C/R

116. Nalbuphine

Sinusoidal fetal heart rate pattern Fetal distress and neonatal respiratory depression Fatal respiratory failure in the newborn

C/R

117. Naloxone

2 cases C/R

C/R

118. Naproxen

Primary pulmonary hypertension of the 3 cases newborn with severe hypoxemia, coagulopathy, hyperbilirubinemia and impaired renal function

119. Nitroglycerin

Fetal heart changes (loss of beat-to-beat variability, late decelarations and bradycardia)

12

120. 121. 122. 123. 124.

Transient fetal bradycardia Masculinization of the female fetus Masculinization of the female fetus Neonatal urinary retention Neonatal hyperbilirubinemia ⫹/⫺ clinically significant jaundice Transient choreoathetosis

C/R 0.3–18.3% 25% (1/4) C/R

Nitroprusside Norethindrone Norethynodrel Nortriptyline Oral contraceptives

C/R

Less prominent at 2 months of age Following maternal poisoning in a suicide attempt at 31 weeks gestation When used in labor, more common than with meperidine Other possible contributing factors to some of the effects: concomitant administration of hydrochlorothiazide and maternal disease

421, 422 423 424, 425 426

427 428–432 When used at term to treat fetal heart rate baseline with low beat-to-beat variability Following exposure at 30 weeks for 2–6 days, attributed to prostaglandin inhibition, one infant died at 4 days of age and autopsy revealed a short and constricted ductus arteriosus Dose-dependent, following maternal IV treatment with nitroglycerin without volume expansion for severe pregnancy induced hypertension

433

Direct Drug Toxicity to the Fetus

112. Minoxidil 113. Misoprostol

434, 435

436, 437

438 439–442 439, 441 443 444 Resolved spontaneously

445

289

290

Table 1

Continued

No.

Drug

Fetal/neonatal toxic effects

Reported rate of occurrence

Fetal heart rate changes

126. Pentazocine 127. Phenazocine 128. Phenobarbital

Neonatal respiratory depression Neonatal respiratory depression Early hemorrhagic disease of the newborn

C/Rs

129. Phenytoin

Early hemorrhagic disease of the newborn

C/Rs

C/R

130. Pindolol

Neonatal hemorrhage secondary to thrombocytopenia Decrease in fetal heart rate

C/R

The woman used the nasal spray more frequently than the recommended dosage interval, speculated mechanism: α-adrenergic effect on the uterine vessels reducing the uterine blood flow and causing fetal hypoxia and bradycardia Following use during labor Following use during labor Probably as a result of induction of fetal microsomal enzymes that deplete the already low reserves of vitamin K, resulting in suppression of the vitamin K–dependent coagulation factors II, VII, IX, and X, vitamin K prophylaxis recommended prior to delivery. Probably as a result of induction of fetal microsomal enzymes that deplete the already low reserves of vitamin K, resulting in suppression of the vitamin K–dependent coagulation factors II, VII, IX, and X, vitamin K prophylaxis recommended prior to delivery

Ref. 446

447, 448 449, 450 451–460

451–454, 456, 458– 467

468 When compared before and after therapy in women with pregnancy induced hypertension in the third trimester

469

Diav-Citrin and Koren

125. Oxymetazoline

Comments/recommendations

Stillbirth

C/R

132. Prednisone/ prednisolone

Immunosuppression in the newborn

C/R

Stillbirth

Overactivity, tremors, jitteriness

23.5% (8/34) vs. 3% (1/34) in controls C/R

Hemorrhagic disease of the newborn

C/Rs

133. Primidone

134. Promazine

Neonatal hyperbilirubinemia

135. Promethazine

Neonatal respiratory depression Transient and behavioral and EEG changes

Small case series 100% (28/28)

Impaired platelet aggregation in the newborn

88.9% (16/18)

Podophyllum poisoning following topical administration of 7.5 mL of 25% podophyllum resin to florid vulval warts Following exposure to high doses of prednisone and azathioprine throughout gestation, resolved at 15 weeks of age Attributed to failure of placental function, controls had similar diagnoses

470

Malformed newborn, died at 3 weeks of age Probably as a result of induction of fetal microsomal enzymes that deplete the already low reserves of vitamin K, resulting in suppression of the vitamin K–dependent coagulation factors II, VII, IX, and X, vitamin K prophylaxis recommended prior to delivery From exposure to 100 mg or more during labor, mean bilirubin significantly higher in 317 exposed neonates compared to 272 controls

472, 473

Most women (27/28) received a combination of meperidine with promethazine or phenobarbital, persisted for less than 3 days

95

471

452, 454– 457

Direct Drug Toxicity to the Fetus

131. Podophyllum

474

475 476

477, 478

291

No.

Continued Drug

136. Propofol

137. Propranolol

Fetal/neonatal toxic effects Neonatal changes: Low Apgar scores Hypotonia Somnolence Irritability IUGR Hypoglycemia Bradycardia Respiratory depression Hyperbilirubinemia Polycythemia Thrombocytopenia Hyperirritability Hypocalcemia with convulsions Coagulopathy Respiratory depression Prematurity

Reported rate of occurrence

Comments/recommendations Following use in cesarean section

Ref. 479

5/20 1/20 5/20 14% 10% 7% 4% 4% 1% 0.6% 0.6% 0.6% 80% (4/5) 33% (3/9)

Transient fetal bradycardia 20% (2/10) Mild fetal hypothyroidism Fetal goiter

12% (29/241)

Newborn goiter with tracheal compression

2 cases

Clinical hypothyroidism with mental and physical delay in development Neonatal hepatitis

2 cases C/R

From analysis of 23 reports involving 167 180, 480– live-born infants exposed chronically to 501 propranolol in utero. Other possible factors that may have caused these effects or contributed are maternal disease, concomitant medications, or a combination of those factors. Newborn exposed to propranolol near delivery should be closely observed in the first 24–48 hours for signs and symptoms of β-adrenergic blockade 502 When given IV prior to cesarean section When administered for pregnancy-induced 503 hypertension 504 For dysfunctional labor When used close to term, resolves sponta- 505 neously within a few days 180 Usually smaller than iodide-induced goiters Resulted in death in one case and moder506, 507 ate respiratory distress in the second One of the infants also exposed to high 508, 509 doses of iodide during gestation 510 Resolved spontaneously

Diav-Citrin and Koren

138. Propylthiouracil

292

Table 1

Intrauterine and infantile convulsions

140. Quinidine 141. Quinine

Neonatal thrombocytopenia Auditory and optic nerve damage

142. Reserpine

Neonatal thrombocytopenic purpura Neonatal hemolytic anemia Nasal discharge, cyanosis, lethargy, and poor feeding in the newborn Hemorrhagic disease of the newborn

143. Rifampicin 144. Ritodrine

High doses of pyridoxine early in gestation presumably altered the normal metabolism of pyridoxine leading to intractable seizures in the newborn 0.9% (2/234) Usually in potentially toxic doses as an abortifacient N ⫽ 12 3 cases

Fetal and neonatal complications: Tachycardia Neonatal cardiac arrhythmias Disproportionate septal hypertrophy

145. Scopolamine

Prophylacic vitamin K is recommended prior to delivery

515 516–520 521 522 523 318 524–535

Following in utero exposure to ritodrine for 2 weeks or longer As a result of transient fetal hyperglycemia followed by hyperinsulinemia; more common following intravenous administration Following severe maternal ketoacidosis

Newborn hypoglycemia

Fetal death Neonatal hyperbilirubinemia Transient decrease in the glomerular filtration rate in the newborn Fetal tachycardia, decreased heart rate variability, and decreased deceleration of heart rate Newborn toxicity (fever, tachycardia, lethargy)

In G6PD deficient newborns From use near term

511–514

Direct Drug Toxicity to the Fetus

139. Pyridoxine

Noted between 12–36 hours of age, clinical significance unknown When administered at term

C/R

Reversed following treatment with physostigmine

536–538

539

293

Table 1

Continued Drug

Fetal/neonatal toxic effects

Reported rate of occurrence

146. Sotalol

Fetal bradycardia

5/6

147. Streptomycin

Ototoxicity (cochlear and vestibular)

3 C/Rs

148. Sulfonamides

Jaundice Hemolytic anemia

149. Sulindac 150. Tamoxifen 151. Terbutaline

Transient fetal tachycardia Neonatal hypoglycemia Myocardial necrosis in a newborn Cardiovascular decompensation

Yellow-gold fluorescence in the mineralized structures of a fetal skeleton Permanent yellow-brown discoloration of teeth

Lasting up to 24 hours, newborns exposed near delivery should be closely observed during the first 24–48 hours for signs and symptoms of β-adrenergic blockade From exposure to long-term high doses in late pregnancy When given close to delivery In the one case involving the fetus, resulting in hydrops fetalis and stillbirth

Ref. 540

541–543 544–549 544, 545, 549

550, 551 C/R

Following exposure during the first 20 weeks of pregnancy

C/R In 3 of a quadruplet pregnancy

C/R

Possibly due to downregulation of fetal βadrenergic receptors leading to decreased myocardial function and reduced cardiac output Following exposure prior to delivery Due to the chelating ability of the drug, forms a complex with calcium orthophosphate and becomes incorporated into bones and teeth undergoing calcification, effect on deciduous or permanent teeth depends on timing of exposure in pregnancy

552 553–556 557, 558 559 560

561 562–577

Diav-Citrin and Koren

152. Tetracyclines

Transient constriction of the fetal ductus arteriosus Ambiguous genitalia in a female newborn

3 cases (2 newborns and 1 fetus)

Comments/recommendations

294

No.

Transient tachycardia, irritability, and vom- 3 cases iting in the newborn

154. Thioguanine

Intrauterine fetal death

2 cases

IUGR Neonatal thrombocytopenia IUGR Neonatal hyperbilirubinemia Liver toxicity Neonatal afibrinogenemia with fatal hemorrhage Transient hyperglycinemia Fetal and neonatal distress Transient fetal bradycardia

40% C/R

155. Tolbutamide 156. Valproic acid

157. Vancomycin

158. Vinblastine 159. Vincristine 160. Zidovudine

IUGR IUGR IUGR Anemia

More likely to occur when maternal serum levels at term are in the high therapeutic range or above After antineoplastic therapy with thioguanine and other agents at 15 weeks’ gestation Persisted for ⬃2 weeks

3 cases 3 cases C/R

Causal relationship uncertain May be fatal

2 cases 43% (6/14) C/R

No adverse effects seen in the newborns

40% 40% 4% (2/45) 19% (6/31)

1 g IV dose was given in 3 minutes an hour before delivery, causing maternal hypotension

Difference in hemoglobin between exposed and unexposed infants was 1 g/ dL, occurring at 3 weeks of age, with similar values by 12 weeks of age

578–580

581, 582

117 583 180 583–586 586, 587 588

Direct Drug Toxicity to the Fetus

153. Theophylline

589 590 591

117 117 592 592, 593

C/R ⫽ case reports; IUGR ⫽ intrauterine growth retardation; SGA ⫽ small for gestational age; CNS ⫽ central nervous system; DIC ⫽ disseminated intravascular coagulation; ACE ⫽ angiotensin-converting enzyme; ECG ⫽ electrocardiogram.

295

296

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nancy. Complications of oligohydramnios (i.e., fetal limb contractures, lung hypoplasia, and craniofacial anomalies), prematurity, intrauterine growth restriction, and fetal death have also been reported with the use of these agents late in pregnancy. The adverse effects are related to the hemodynamic effects of ACE inhibitors on the fetus. These adverse effects are termed ACE-inhibitor fetopathy. The teratogenic risk with first-trimester exposure to these agents appears to be low. These agents are frequently used in women of reproductive age due to their efficacy and few side effects. This woman should be offered reassurance of unlikely first-trimester effects and may benefit from a review the fetopathy associated with the use of these agents during late pregnancy (494–596). Based on the adverse effects reported in the literature, she should discontinue the captopril, if possible. An alternative antihypertensive regimen should be substituted for the drug prior to her entry into the second trimester if drug therapy is required during pregnancy. In cases where all other options have been exhausted and captopril is required to treat the maternal disease, careful monitoring of maternal and fetal renal function is prudent. Serial sonograms are important for assessment of fetal growth and amniotic fluid volume. This should be followed by close observation of renal function and blood pressure in the newborn.

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514. Bejsovec MIR, Kulenda Z, Ponca E. Familial intrauterine convulsions in pyridoxine dependency. Arch Dis Child 1967; 42:201–207. 515. Domula VM, Weissach G, Lenk H. Uber die Auswirkung medicamentoser Behandlung in der Schwangerschaft auf das Gerennungspotential des Neugeborenen. Zentralbl Gynaekol 1977; 99:473–479. 516. Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs. New York: American Elsevier, 1976, pp 140–143. 517. Robinson GC, Brummitt JR, Miller JR. Hearing loss in infants and preschool children: II. Etiological Considerations. Pediatrics 1963; 32:115–124. 518. West RA. Effect of quinine upon auditory nerve. Am J Obstet Gynecol 1938; 36:241– 248. 519. McKinna AJ. Quinine induced hupoplasia of the optic nerve. Can J Ophthalmol 1966; 1: 261–264. 520. Morgon A, Charachon D, Brinquier N. Disorders of the auditory apparatus caused by embryopathy or fetopathy: prophylaxis and treatment. Acta Otolaryngol (Stockh) 1971; 291(suppl):5. 521. Mauer MA, DeVaux W, Lahey ME. Neonatal and maternal thrombocytopenic purpura due to quinine. Pediatrics 1957; 19:84–87. 522. Glass L, Rajegowda BK, Bowne E, Evans HE. Exposure to quinine and jaundice in a glucose6-phosphate dehydrogenase-deficient newborn infant. Pediatrics 1973; 82:734–735. 523. Budnick IS, Leikin S, Hoeck LE. Effect in the newborn infant to reserpine administration ante partum. Am J Dis Child 1955; 90:286–289. 524. Barden TP, Peter JB, Merkatz IR. Ritodrine hydrochloride: a betamimetic agent for use in preterm labor: I. Pharmacology, clinical history, administration, side effects, and safety. Obstet Gynecol 1980; 56:1–6. 525. Ritodrine for inhibition of preterm labor. Med Lett Drugs Ther 1980; 22:89–90. 526. Finkelstein BW. Ritodrine (Yutopar, Merrell Dow Pharmaceuticals Inc.). Drug Intell Clin Pharm 1981; 15:425–433. 527. Brosset P, Ronayette D, Pierre MC, et al. Cardiac complications of ritodrine in mother and baby. Lancet 1982; 1:1468. 528. Hermansen MC, Johnson GL. Neonatal supraventricular tachycardia following prolonged maternal ritodrine administration. Am J Obstet Gynecol 1984; 149:798–799. 529. Beitzke A, Winter R, Zach M, Grubbauer HM. Kongenitales Vorhofflattern mit Hydrops fetalis durch mutterliche Tokolytikamedikation. Klin Paediatr 1979; 191:410–417. 530. Nuchpuckdee P, Brodsky N, Porat R, Hurt H. Ventricular septal thickness and cardiac function in neonates after in utero ritodrine exposure. J Pediatr 1986; 109:687–691. 531. Leake RD, Hobel CJ, Oh W, et al. A controlled, prospective study of the effects of ritodrine hydrochloride for premature labor (abstr). Clin Res 1980; 28:90A. 532. Kazzi NJ, Gross TL, Kazzi GM, Williams TG. Neonatal complications following in utero exposure to intravenous ritodrine. Acta Obstet Gynecol Scand 1987; 66:65–69. 533. Schilthuis MS, Aarnoudse JG. Fetal death associated with severe ritodrine induced ketoacidosis. Lancet 1980; 1:1145. 534. Huisjes HJ, Touwen BCL. Neonatal outcome after treatment with ritodrine: a controlled study. Am J Obstet Gynecol 1983; 147:250–253. 535. Hansen NB, Oh W, LaRochelle F, Stonestreet BS. Effects of maternal ritodrine administration on neonatal renal function. J Pediatr 1983; 103:774–780. 536. Shenker L. Clinical experience with fetal heart rate monitoring of one thousand patients in labor. Am J Obstet Gynecol 1973; 115:1111–1116. 537. Boehm FH, Growdon JH Jr. The effects of scopolamine on fetal heart rate baseline variability. Am J Obstet Gynecol 1974; 120:1099–1104. 538. Ayromlooi J, Tobias M, Berg P. The effects of scopolamine and ancillary analgesics upon the fetal heart rate recording. J Reprod Med 1980; 25:323–326. 539. Evens RP, Leopold JC. Scopolamine toxicity in a newborn. Pediatrics 1980; 56:245–248.

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540. O’Hare MF, Murnaghan GA, Russell CJ, et al. Sotalol as a hypotensive agent in pregnancy. Br J Obstet Gynaecol 1980; 87:814–820. 541. Leroux M. Existe-t-il une surdite congenitale acquise due a la streptomycine? Ann Otolaryngol 1950; 67:194–196. 542. Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs. New York: Excerpta Medica, 1976, p 130. 543. Donald PR, Sellars SL. Streptomycin ototoxicity in the unborn child. S Afr Med J 1981; 60: 316–318. 544. Heckel GP. Chemotherapy during pregnancy: danger of fetal injury from sulfanilamide and its derivatives. JAMA 1941; 117:1314–1316. 545. Ginzler AM, Cherner C. Toxic manifestations in the newborn infant following placental transmission of sulfanilamide: with a report of 2 cases simulating erythroblastosis fetalis. Am J Obstet Gynecol 1942; 44:46–55. 546. Lucey JF, Driscoll TJ Jr. Hazard to newborn infants of administration of long-acting sulfonamides to pregnant women. Pediatrics 1959; 24:498–499. 547. Kantor HI, Sutherland DA, Leonard JT, et al. Effect on bilirubin metabolism in the newborn of sulfisoxazole administration to the mother. Obstet Gynecol 1961; 17:494–500. 548. Dunn PM. The possible relationship between the maternal administration of sulphamethoxypyridazine and hyperbilirubinaemia in the newborn. J Obstet Gynaecol Br Commonw 1964; 71:128–131. 549. Perkins RP. Hydrops fetalis and stillbirth in a male glucose-6-phosphate dehydrogenasedeficient fetus possibly due to maternal ingestion of sulfisoxazole. Am J Obstet Gynecol 1971; 111:379–381. 550. Kramer W, Saade G, Belfort M, et al. Randomized double-blind study comparing sulindac to terbutaline: fetal cardiovascular effects (abstr). Am J Obstet Gynecol 1996; 174:326. 551. Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 1995; 173:20–25. 552. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 1997; 350:183. 553. Haller DL. The use of terbutaline for premature labor. Drug Intell Clin Pharm 1980; 14: 757–764. 554. Andersson KE, Bengtsson LP, Gustafson I, Ingermarsson I. The relaxing effect of terbutaline on the human uterus during term labor. Am J Obstet Gynecol 1975; 121:602–609. 555. Ingermarsson I. Effect of terbutaline on premature labor: a double-blind placebo-controlled study. Am J Obstet Gynecol 1976; 125:520–524. 556. Ravindran R, Viegas OJ, Padilla LM, LaBlonde P. Anesthetic considerations in pregnant patients receiving terbutaline therapy. Anesth Analg (Cleve) 1980; 59:391–392. 557. Epstein MF, Nicholls RN, Stubblefield PG. Neonatal hypoglycemia after beta-sympathomimetic tocolytic therapy. J Pediatr 1979; 94:449–453. 558. Westgren M, Carlsson C, Lindholm T, et al. Continuous maternal glucose measurements and fetal glucose and insulin levels after administration of terbutaline in term labor. Acta Obstet Gynecol Scand 1982; 108(suppl):63–65. 559. Fletcher SE, Fyfe DA, Case CL, et al. Myocardial necrosis in a newborn after long-term maternal subcutaneous terbutaline infusion for suppression of preterm labor. Am J Obstet Gynecol 1991; 165:1401–1404. 560. Thorkelsson T, Loughead JL. Long-term subcutaneous terbutaline tocolysis: report of possible neonatal toxicity. J Perinatol 1991; 11:235–238. 561. Cohlan SQ, Bevelander G, Bross S. Effect of tetracycline on bone growth in the ptremature infant. Antimicrob Agents Chemother 1961; 340–347. 562. Harcourt JK, Johnson NW, Storey E. In vivo incorporation of tetracycline in the teeth of man. Arch Oral Biol 1962; 7:431–437.

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563. Rendle-Short TJ. Tetracycline in teeth and bone. Lancet 1962; 1:1188. 564. Douglas AC. The deposition of tetracycline in human nails and teeth: a complication of long term treatment. Br J Dis Chest 1963; 57:44–47. 565. Kutscher AH, Zegarelli EV, Tovell HM, Hochberg B. Discoloration of teeth induced by tetracycline. JAMA 1963; 184:586–587. 566. Kline AH, Blattner RJ, Lunin M. Transplacental effect of tetracyclines on teeth. JAMA 1964; 188:178–180. 567. Macaulay JC, Lestyna JA. Preliminary observations on the prenatal administration of demethylchlortetracycline HCl. Pediatrics 1964; 34:423–424. 568. Stewart DJ. The effects of tetracyclines upon the dentition. Br J Dermatol 1964; 76:374– 378. 569. Swallow JN. Discoloration of primary dentition after maternal tetracycline ingestion in pregnancy. Lancet 1964; 2:611–612. 570. Porter PJ, Sweeney EA, Golan H, Kass EH. Controlled study of the effect of prenatal tetracycline on primary dentition. Antimicrob Agents Chemother 1965; 5:668–671. 571. Toaff R, Ravid R. Tetracyclines and the teeth. Lancet 1966; 2:281–282. 572. Kutscher AH, Zegarelli EV, Tovell HM, et al. Discoloration of deciduous teeth induced by administrations of tetracycline antepartum. Am J Obstet Gynecol 1966; 96:291–292. 573. Brearley LJ, Stragis AA, Storey E. Tetracycline-induced tooth changes: Part 1. Prevalence in preschool children. Med J Aust 1968; 2:653–658. 574. Brearley LJ, Storey E. Tetracycline-induced tooth changes: Part 2. Prevalence, localization and nature of staining in extracted deciduous teeth. Med J Aust 1968; 2:714–719. 575. Baker KL, Storey E. Tetracycline-induced tooth changes: Part 3. Incidence in extracted first permanent molar teeth. Med J Aust 1970; 1:109–113. 576. Anthony JR. Effect on deciduous and permanent teeth of tetracycline deposition in utero. Postgrad Med 1970; 48:165–168. 577. Genot MT, Golan HP, Porter PJ, Kass EH. Effect of administration of tetracycline in pregnancy on the primary dentition of the offspring. J Oral Med 1970; 25:75–79. 578. Arwood LL, Dasta JF, Friedman C. Placental transfer of theophylline: two case reports. Pediatrics 1979; 63:844–846. 579. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate. Lancet 1977; 1:910. 580. Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982; 247:786–788. 581. O’Donnell R, Costigan C, O’Connell LG. Two cases of acute leukaemia in pregnancy. Acta Haematol 1979; 61:298–300. 582. Volkenandt M, Buchner T, Hiddemann W, Van De Loo J. Acute leukaemia during pregnancy. Lancet 1987; 2:1521–1522. 583. Schiff D, Aranda J, Stern L. Neonatal thrombocytopenia and congenital malformation associated with administration of tolbutamide to the mother. J Pediatr 1970; 77:457–458. 584. Nau H, Rating D, Koch S, et al. Valproic acid and its metabolites: placental transfer, neonatal pharmacokinetics, transfer via mother’s milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981; 219:768–777. 585. Bantz EW. Valproic acid and congenital malformations: a case report. Clin Pediar 1984; 23: 353–354. 586. Legius E, Jaeken J, Eggermont E. Sodium valproate, pregnancy, and infantile fatal liver failure. Lancet 1987; 2:1518–1519. 587. Felding I, Rane A. Congenital liver damage after treatment of mother with valproic acid and phenytoin? Acta Paediatr Scand 1984; 73:656–658. 588. Majer RV, Green PJ. Neonatal afibrinogenaemia due to sodium valproate. Lancet 1987; 2: 740–741. 589. Simila S, von Wendt L, Hartikainen-Sorri A-L, et al. Sodium valproate, pregnancy, and neonatal hyperglycinaemia. Arch Dis Child 1979; 54:985–986.

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590. Jager-Roman E, Deichi A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 1986; 108:997–1004. 591. Hill LM. Fetal distress secondary to vancomycin-induced maternal hypotension. Am J Obstet Gynecol 1985; 153:74–75. 592. Sperling RS, Stratton P, O’Sullivan MJ, et al. A survey of zidovudine use in pregnant women with human immunodeficiency virus infection. N Engl J Med 1992; 326:857–861. 593. Connor EM, Sperling RS, Gelber R, et al. for the Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173–1180. 594. Pryde PG, Sedman AB, Nugent CE, Barr M. Angiotensin converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993; 3:1575–1582. 595. Barr M. Teratogen update: angiotensin converting enzyme inhibitors. Teratology 1994; 50: 399–409. 596. Mastrobattista JM. Angiotensin converting inhibitors in pregnancy. Semin Perinatol 1997; 21:124–134.

17 The Approach to the Mother on Nonmedicinal and Chemical Use in Pregnancy Joyce F. Schneiderman The Addiction Research Foundation and The University of Toronto, Toronto, Ontario, Canada

Clinical Case One of your pregnant patients admits to having used narcotic opioids for several years. She wishes very much to discontinue this addiction pattern but does not know how. How should she be treated?

INTRODUCTION Nonmedical drug use can be defined as the taking of any psychoactive drug in the absence of a clearly defined medical indication (1). People ingest many chemicals to modify mood: as part of a social or recreational activity, as part of a lifestyle, or to self-medicate. Drugs are widely available in modern society. Alcohol, caffeine, and nicotine are so commonly used that they are not always considered to be drugs. Prescription drugs, like narcotics and benzodiazepines, may be obtained through a physician or other sources. Illicit drugs— whose purity, dose, and sometimes even the substance itself are unknown—include narcotics, stimulants, cannabinoids, and hallucinogens. This chapter focuses on the management of women who use psychoactive drugs during pregnancy; it covers advice appropriate to the woman who plans to discontinue her drug use and discusses the care of the drug abuser who will require intensive treatment and support in a specialized setting. Neonatal withdrawal and drug use during breastfeeding are discussed in Chapters 8 and 13. Detailed discussion of drug abuse treatment and of the teratogenicity of psychoactive drugs is beyond the scope of this chapter. Women of childbearing age have been increasing their nonmedical drug use over the last two decades (2–5). This increase and the thalidomide tragedy have fueled a concern for the effects of drugs on pregnancy. Recreational drug users and drug-dependent women may appear unconcerned about health risks to themselves, but they, too, usually wish to spare their unborn children from risks associated with drug use.

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Our experience at the Motherisk Clinic in Toronto suggests that many women and their primary care physicians overestimate the risk of drugs to the fetus (6). Some women will consider therapeutic abortion, often on the recommendation of their doctor, fearing a major teratogenic effect. It is therefore extremely important to provide accurate information on the known risks of maternal drug taking. There is no evidence that the father’s drug and alcohol consumption directly influences the outcome of pregnancy. His use may nonetheless be a marker for other factors contributing to increased risk. Concerns that previous drug use in either parent, particularly of hallucinogens and cannabinoids, may lead to an adverse outcome based on permanent chromosomal damage are unwarranted. In the 1990s, it is rare to find a woman drug abuser who uses only one drug or even one drug class. The synergistic effects of drug interactions on the fetus remain largely unknown. An adverse outcome may be related to drug exposure at a critical period in gestation, to maximal drug level obtained, to cumulative exposure, or to a combination of these and other factors. The outcome of pregnancy in the alcohol- or drug-dependent woman depends on more than just her drug-taking behavior. The pharmacological effects are often compounded by lack of prenatal care, higher risk for other complications of pregnancy, cigarette smoking, and poor diet. The outcome in women of the inner-city drug subculture cannot be extrapolated to the woman who has used a substance one or several times socially or to the one who has received a short course of parenteral narcotics in the treatment of an acute medical or surgical illness prior to knowledge of the pregnancy. Neurobehavioral abnormalities have been reported in neonates of drug-using mothers (7); alcohol (8), marijuana (9), methadone (10), and cocaine (11) have been among the substances implicated. However, it is not possible to separate the contribution of prenatal drug exposure from the effects of persistent drug levels at birth, withdrawal symptoms, difficulties with mother-infant bonding, and continued drug exposure if the mother is breast-feeding. Data on long-term sequelae of prenatal drug use are limited, and results must be interpreted in light of the frequently suboptimal postnatal environment. General Guidelines for Clinical Management Because pregnancy is usually diagnosed at 6–8 weeks after the last menstrual period, it is important to consider the woman’s usual drug-taking behavior. Confirmation of pregnancy may be further delayed in the drug abuser because the menstrual cycle is often irregular, and prolonged amenorrhea is common in this population. If early symptoms of pregnancy—such as nausea, cramps, and fatigue—are attributed to drug withdrawal, they may prompt an increase in drug use. For the woman presenting early in pregnancy and motivated to discontinue her drug use, a single counseling session addressing the adverse effects on pregnancy outcome if drug use is not curtailed may be sufficient. Even the problem user with some social stability can be managed by the primary care physician as an outpatient with a tailored detoxification regimen (see below) and a short course of weekly or biweekly counseling. If the patient is unsuccessful in following through on this plan after a 2-week trial or if she is severely drug-dependent and in crisis, referral for specialized alcohol and drug treatment services is indicated. The initial approach to the woman with a significant alcohol or drug problem should

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include a complete medical and obstetrical assessment. The drug history is part of data collection and should be taken in a nonjudgmental manner. Use of alcohol, tobacco, caffeine, over-the-counter drugs, prescription medications, and illicit substances should be asked about specifically in each case, including drug names, dose, route, timing in relation to conception, adverse reactions, and symptoms of overdose and withdrawal. Familiarity with street names and local availability of illicit drugs is helpful. A detailed psychosocial history provides the information on the patient’s attitude about the pregnancy, the involvement of the baby’s father, the condition of other children, and the current housing, financial, employment, and legal situations necessary to plan treatment. The physical examination should screen for associated medical problems, such as trauma, hepatitis, abscesses, and sexually transmitted diseases. Urine toxicology for alcohol, benzodiazepines, barbiturates, cannabinoids, narcotics, and stimulants should be done at the first visit and repeated regularly throughout the pregnancy. An ultrasound examination is useful to establish gestational age and to assess fetal morphology. For women who are ambivalent about discontinuing drug use, this procedure may have therapeutic benefit (12). By making the pregnancy more ‘‘real,’’ it may be possible to increase the commitment of such a woman to ensuring the best possible outcome for her child. Women with a long history of alcohol- and drug-related problems will usually require inpatient detoxification or methadone maintenance substitution. Prenatal care should be integrated with drug treatment. A multidisciplinary staff team comprising a physician, nurse, social worker, addiction counselor, and dietitian is useful for case management. These patients can be difficult and time-consuming to treat. A consistent approach by all team members is crucial so that the patient receives a clear message. The individual patient’s situation will dictate the need for a residential treatment program or outpatient individual or group counseling. If a spouse or partner who also has a drug problem is involved, every attempt should be made to facilitate his treatment. Liaison with Alcoholics Anonymous, Narcotics Anonymous, and other voluntary self-help groups is valuable. The ideal situation assumes a motivated patient presenting early in pregnancy and the availability of resources to provide intensive treatment if necessary. In many cases, prenatal care is sporadic at best, and crisis intervention (medical or psychosocial) may be the only treatment accepted. Each contact with the patient should be taken as an opportunity to engage her in ongoing care. At present, there is little to offer the woman who refuses treatment, but with sensitive handling she may ultimately comply voluntarily with a treatment plan. In Ontario, the Children’s Aid Society will not intervene until after the birth of the child. This is also the case for child protection agencies in most other jurisdictions. If the woman presents before 12 weeks of gestation and wishes to consider a therapeutic abortion, this should be discussed if applicable laws permit, but this option should not be recommended as a standard practice. The clinician’s personal views on the use of illicit substances and alcohol should not be allowed to interfere with forming a therapeutic alliance with the patient. The pregnant substance-abusing patient is generally ambivalent about seeking treatment and responds best to a nonthreatening approach. She should be provided with specific objective information on the known effects of her drug use on the pregnancy, and she should be encouraged to stop all use in the context of ensuring the best possible fetal outcome. After the birth, mother and child should be followed closely. Postnatal care should include supportive counseling, contraception counseling, visits from a public health nurse, and training in parenting skills.

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ILLICIT SUBSTANCES AND INTRAVENOUS DRUG ABUSE The lifestyle of women using intravenous drugs plays a very important part in the formulation of the treatment plan. If they and their children remain in the drug-using community, they are not likely to abstain. Furthermore, pregnancy does not guarantee protection from the high incidence of physical violence these women experience (13). Exchange of sexual favors for drugs, in addition to prostitution, puts these women at high risk for sexually transmitted diseases. Sharing unsterilized needles puts them at risk both for hepatitis B and HIV infections. With prenatal screening and immunization as required, perinatal transmission of hepatitis B can now largely be prevented. Women account for 7% of AIDS cases in the United States (14–16). More than half these women are intravenous drug users (17), and over 80% are of childbearing age. The incidence of perinatal transmission of AIDS is still uncertain. Friedland and Klein estimate a rate of roughly 40–50% based on information available in 1987 (16). Infants retain maternal antibody to a median age of 10 months (18) and must be monitored for the development of symptoms of AIDS. Prevention must be based on education and counseling of all intravenous drug users and their sexual partners. Routine screening for HIV in this population is controversial. Instead, serological testing should be offered to any high-risk woman contemplating a pregnancy. Contraceptive counseling is mandatory in any woman known to be HIV-positive.

Individual Drugs Alcohol Most women are aware that heavy drinking in pregnancy can harm the fetus. The fetal alcohol syndrome (FAS), first described by Smith and Jones in 1973, is now generally accepted to occur in the offspring of alcoholic women—that is, women who drink at least six standard drinks per day throughout the first trimester [one standard drink ⫽ 12 oz beer ⫽ 5 oz wine ⫽ 1.5 oz liquor, or approximately 15 g (0.5 oz) absolute alcohol]. The signs of FAS are prenatal and postnatal growth retardation, central nervous system dysfunction (often including mental retardation), facial dysmorphology, and many other congenital abnormalities (19–24). A proposed minimum criterion for the diagnosis of FAS recommends that at least two of the following be present: microcephaly (head circumference less than the third percentile), microphthalmia and/or short palpebral fissures, poorly developed philtrum, thin upper lip, and flattening of the maxillary area in addition to growth and neurological abnormalities (25). The fetal alcohol syndrome has been estimated to occur in between one and two live births per 1000 in the general population and is a major preventable cause of mental retardation. An incidence of greater than 40% has been reported in alcoholic women. However, prospectively collected data suggest a true incidence closer to 2.5% (26). On long-term follow-up, FAS children display lack of catch-up growth, attentional deficits, mental retardation, and dysmorphic features. With time, some improvement in all these areas occurs owing to biological maturation, but the children manifest poor school performance, which is independent of environment (27). Other adverse fetal outcomes in heavy drinkers include increased spontaneous abortions (26), premature placental separation, stillbirth, low birth weight (28), and congenital malformations (29). Drinking by the father in the month prior to conception has been

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associated with decreased birth weight (30), but—as indicated above—this finding does not necessarily represent causality. The data on women drinking less than six drinks per day are more difficult to interpret. Studies may rely on retrospective self-reports, use averaged amounts throughout the pregnancy, and employ varying definitions for moderate drinking. At drinking levels greater than two drinks per day, a partial FAS not meeting the minimal criteria, termed fetal alcohol effects, has been described. No such effects have been reported when consumption is less than two drinks per day (31). A prospective study examining firsttrimester alcohol use evaluated congenital malformations by chart review, including 32,409 patients drinking two or fewer drinks per day. There was no significant increase in malformations between the group drinking up to two drinks and abstainers (32). Another study of more than 12,000 pregnancies showed an increase in abruptio placentae but no other adverse outcome associated with an intake of less than two drinks per day (33). There is no known safe lower limit for alcohol consumption in pregnancy, and many authorities recommend complete abstinence on this basis. Clearly, this is the most conservative approach. If all women of childbearing age were to abstain from alcohol, presumably FAS would disappear. The absence of risk is, of course, very difficult to demonstrate scientifically. Pregnancy should not be a time for undue restriction of lifestyle, and most women do drink. Even women who plan to abstain during pregnancy usually continue their customary drinking pattern until they confirm they are pregnant. The mother of an infant with an unrelated congenital abnormality should not have to bear the guilt of thinking that her minimal alcohol intake was responsible. Rosett and Weiner conclude that there is no measurable risk from consuming less than 1 oz absolute alcohol (two standard drinks) per day (34). A Canadian committee has recommended abstinence ‘‘or at least to limit consumption to less than 4 drinks per week’’ (35). Setting reasonable goals for moderation may enhance clinical credibility and compliance while fairly emphasizing the hazards of heavy drinking. Alcohol consumption in the month preceding recognition of pregnancy most accurately reflects early postconception drinking. Even among the heaviest drinkers, more than 50% of women spontaneously decrease their intake at the diagnosis of pregnancy (36). The social drinker also markedly decreases her drinking, often citing distaste, lack of appeal, or adverse physiological effects (37). In the heavy social drinker or physically dependent woman, detoxification should occur as early as possible, and complete abstinence should be the only treatment goal considered. For a woman who is drinking more than 80 g per day, a gradual reduction over 3–4 days is preferable (34). Intensive supportive counseling should be available during detoxification and throughout the pregnancy. If the woman uses other drugs, has a medical illness, or seems unlikely to be successful as an outpatient because of prior failure or current circumstances, inpatient admission should be arranged. We have successfully used a diazepam-loading regimen in women requiring hospitalization and pharmacological treatment of alcohol withdrawal (38). The long half-life of diazepam offers a ‘‘pharmacological taper,’’ so that the patient usually does not require further drug after the first day of admission. This regimen is well tolerated by the pregnant woman, allowing early initiation of a global treatment plan instead of focusing on withdrawal symptomatology. Disulfiram interferes with the intermediary metabolism of ethanol. The alcohol-disulfiram reaction is believed to be due to accumulation of acetaldehyde, and this pharmacological effect has been used as an adjunct in the treatment of alcohol dependence. Since

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the efficacy of disulfiram is unproven and the potential for a severe reaction and teratogenic effect must be considered, this drug is contraindicated in the woman who is pregnant or planning a pregnancy (39). The woman taking disulfiram who has an unplanned pregnancy should be counseled with respect to the reported associations of teratogenesis. One series of five cases reported on spontaneous abortion and two cases of clubfoot (40). Another group described two case reports of infants with limb reduction (41). Isolated case reports do not necessarily mean teratogenesis; therefore therapeutic abortion should not routinely be recommended. A detailed ultrasound examination may be helpful. Narcotics Heroin use is associated with decreased birth weight and a higher incidence of medical— primarily infectious—and obstetrical complications. Narcotics do not appear to be teratogenic in humans (42). Infants of narcotic-dependent women are at risk for neonatal withdrawal (43) and sudden infant death syndrome (44). Although total abstinence seems preferable, this is often not realistically feasible. Pregnant women recently detoxified from narcotics have the same high rate of recidivism as nonpregnant addict (45,46). Rapid detoxification has been associated with fetal distress and death (47,48). Methadone maintenance has been the treatment of choice for the heroin addict (49). Pharmacologically, methadone suppresses withdrawal symptoms; in high enough doses, it will block opioid effects. It provides a constant drug level rather than the wide fluctuations that occur with illicit intravenous use, thus avoiding fetal risks from overdose or withdrawal. In addition to decreasing illicit use, methadone maintenance provides a framework for ongoing, often daily contact with a treatment facility and institution of counseling and prenatal care. With methadone maintenance, fetal outcome improves and birth weights increase, albeit less than those in matched non-drug-using controls. Kandall et al. (50) report mean birth weights of 2490 g in heroin-abusing mothers, 2961 g in methadone-maintained mothers, and 3176 g in controls. Birth weight correlates to the methadone dose (50); however, it is likely that other factors are responsible. For example, there may be less illicit use in women receiving high doses. A good outcome also correlates with the number of prenatal visits. A short initial hospitalization may provide the opportunity for prenatal assessment, treatment of concurrent medical problems, crisis intervention, introduction of the members of the multidisciplinary team, and stabilization on methadone (46). Ideally, the methadone dose should be carefully titrated to withdrawal symptoms, with special attention to lower abdominal cramping (which may reflect uterine irritability), so that the woman is on the lowest possible dose. With a starting dose of 10–20 mg and additional doses every 6–8 hours, the maintenance dose can be arrived at within 24–48 hours. In some programs, this is not feasible, and higher doses of 50–80 mg daily are chosen empirically. If a woman can be maintained on 20–25 mg daily, significant neonatal withdrawal usually does not occur (51,52). Areas outside major urban centers often lack methadone maintenance clinics. For the prescription abuser, or other highly motivated women with good community supports in such areas, a gradual outpatient detoxification with methadone or another narcotic can be undertaken over 1 to several weeks. This is most safety accomplished in the second trimester, when the risk of spontaneous abortion or precipitation of premature labor is lowest.

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What are the long-term effects of prenatal methadone exposure? Longitudinal studies of infants to age 2 have found mental and physical development to be well within the normal range, although some differences from controls were noted. When evaluated at ages 4 and 5, no differences were found from controls, but both groups had low scores, most likely an effect of low socioeconomic status (53,54). Accepting the difficulties of attempting to control for confounding variables, it appears that methadone in utero is one of the least important factors in the developmental outcome of these children. Cocaine and Other Stimulants The use of the stimulant cocaine increased rapidly in the past decade but now appears to have passed its peak. By 1986, nearly 40% of the U.S. population in the age range of 25–30 years had tried cocaine (55,56). Women of childbearing age are of particular concern because of the potential risk to the fetus. The first report of cocaine effects on pregnancy outcome appeared in 1985 (11). Spontaneous abortions, prematurity, and intrauterine growth retardation are increased in cocaine-using mothers. Labor may be precipitated following a large intravenous bolus of cocaine, and there is an increase in the incidence of abruptio placentae (57–60). Several infants have been reported with perinatal cerebral infarction (59). These adverse effects can be explained by the physiological alterations of acute cocaine intoxication. Since the first description of pregnancy outcome after cocaine use, scores of studies have been published; these are analyzed in Chapters 18 and 21. A withdrawal syndrome and neurobehavioral abnormalities have been described in a small number of infants of cocaine-using mothers; however, other drugs could not be ruled out (11). There does not appear to be an increase in the rate of major congenital abnormalities. Because of the small sample size, difficulty in controlling for other drug use, and differing inclusion criteria in all the reports above, these findings must be considered to be preliminary. Management of the mother depends on the extent of her drug use as well as concurrent medical and social problems. Many women can be managed as outpatients. Cocaine use often follows a cyclical pattern. Periods of abstinence of one to several weeks do not imply a less severe dependence, and counseling aimed at preventing relapse is crucial. Residential treatment should be made available to patients unable to abstain. Cocaine withdrawal consists of the ‘‘crash’’: several hours to days of depression, hypersomnolence, and hyperphagia, followed by a period of anergia and intense cocaine craving (56). No specific pharmacological therapy is required, since this syndrome does not appear to have any serious consequences to mother or fetus unless depression is severe enough to cause suicidal ideation. Heavy cocaine users often take central nervous system depressants such as alcohol and benzodiazepines for symptom relief during the crash phase and may have significant cross-dependence on these agents. A complete drug and alcohol history should be obtained to identify patients at risk for depressant withdrawal, since this information is not always volunteered. Amphetamines and other stimulants have a pharmacological profile similar to that of cocaine. Owing to restrictions on prescription use and limited illicit availability, the abuse of stimulants with the exception of cocaine is now a rarity. The Collaborative Perinatal Project found no evidence of teratogenesis with this class of drugs (61). Schardein, who reviewed the reports citing increased malformations, concluded that the evidence is

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generally negative (42). Clinically, the amphetamine-using mother presents in much the same way as the cocaine user and should be managed similarly (60,62). Cannabinoids The prevalence of marijuana use at the time of conception, which has been reported as 9–20% (9,63), varies with the population studied. More than half these women become abstainers during the first trimester. Although marijuana is not usually thought to be associated with a physical withdrawal syndrome, many regular users report irritability, sleep disturbance, and decreased appetite upon abrupt cessation (64). We have had a number of pregnant patients complain of severe nausea and vomiting on discontinuing marijuana smoking in the first trimester. This is consistent with the antiemetic effect of the cannabinoids. Several studies have reported a decrease in birth weight and an increase in the prevalence of small-for-gestational-age babies and preterm infants among marijuana users (65,66). This has not been a consistent finding; it is likely related to a wide range of intake. Wu et al. reported a nearly fivefold greater increment in the blood carboxyhemoglobin level and a threefold increase of inhaled tar with smoking of marijuana compared with tobacco cigarettes (67). Thus, effects similar to those in tobacco users would be expected in heavy marijuana users in addition to any effect from its active ingredient, ∆-9-tetrahydrocannabinol. Marijuana has not been associated with congenital abnormalities in humans. Fried found a doserelated association between marijuana smoking and alterations in visual responsiveness as well as increased tremors and startle reflexes in the newborn (9). Hallucinogens, Phencyclidine, and Solvents Prenatal exposure to lysergic acid diethylamide (LSD) has been implicated in an increased incidence of limb defects (68) and central nervous system and ocular abnormalities (42), but the evidence for teratogenic effects in humans is not convincing. With the widespread use of LSD in the 1970s, it is unlikely that a major teratogenic effect would have been missed. An early ultrasound examination is nonetheless recommended to rule out serious dysmorphogenesis. Phencyclidine (PCP) was used by 0.8% of pregnant patients in one study; 7.3% gave a history of past use (69). A single case report describes an infant born with abnormal appearance and behavior who subsequently developed a spastic quadriparesis (70). Chasnoff et al. described seven infants with sudden outbursts of agitation and rapid changes in the level of consciousness at birth but no congenital abnormalities (71). Recreational solvent abusers choose toluene-containing products preferentially. Toluene can be obtained in relatively pure form in a variety of readily available and inexpensive products, such as lacquer thinner and contact cement cleaner. Acute solvent intoxication is similar to that of alcohol; there is no significant withdrawal syndrome (72). With chronic use, a persistent encephalopathy may develop, characterized by signs of cortical and cerebellar dysfunction. This is at least partially reversible with abstinence (73). The evidence for teratogenicity from occupational exposure is inconclusive. Hersh reported three infants whose mothers regularly inhaled a toluene product throughout pregnancy. All the infants had microcephaly, central nervous system dysfunction, attention deficits, developmental delay, growth deficiency, and facial dysmorphology—a pattern quite similar to that of fetal alcohol syndrome (74). Users tend to have deprived backgrounds and

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limited social supports; inpatient treatment is usually indicated to initiate abstinence, but prognosis is generally poor. Withdrawal from hallucinogens, PCP, and solvents can usually be managed supportively. When severe agitation in the intoxication phase is unresponsive to reassurance, benzodiazepines can be administered. The acutely psychotic patient may require a neuroleptic; haloperidol, a butyrophenone, is usually better tolerated than the phenothiazines. Benzodiazepines Benzodiazepines are in widespread use therapeutically and are frequently consumed by polydrug abusers. Although isolated abuse of high doses of benzodiazepines is rate, it is not uncommon to find women who have been maintained on chronic therapeutic doses for many years. In 1975 two groups reported an increase in risk of cleft lip and palate with first-trimester exposure to benzodiazepines (75,76). A subsequent case-control study did not confirm this effect (77). The newer benzodiazepines have not been associated with specific abnormalities. Seven cases of a fetal benzodiazepine syndrome have been reported, but without adequate controls it is difficult to attribute a causative role (78). Given the high prevalence of benzodiazepine use, a human teratogenic effect is not likely to be large if it exists at all (79). A woman planning a pregnancy should be encouraged to discontinue her benzodiazepine use prior to conception (80). In counseling the woman with a history of first-trimester use, the clinician should provide a balanced summary of the reported effects. Although benzodiazepines are probably not teratogenic in humans, an ultrasound examination can be reassuring even if it does not guarantee the absence of abnormalities. A neonatal benzodiazepine abstinence syndrome has been reported (81), so detoxification should be advised regardless of the time during pregnancy at which the woman presents. Attempts at withdrawal are often unsuccessful when abrupt cessation leads to uncomfortable symptoms. In addition to anxiety and insomnia, these patients characteristically complain of sensory misperceptions and illusions as well as depersonalization. A tapering regimen with diazepam obviates the fluctuations in drug levels that occur with the shorter-acting benzodiazepines. A rough guideline for converting to an equivalent dose of diazepam is to assume that the largest unit dose available is equivalent to 10 mg diazepam per week with weekly outpatient supportive counseling (82). Abstinence can usually be achieved in 6–8 weeks. If outpatient detoxification is unsuccessful, a rapid diazepam taper may be tried in an inpatient unit. If abstinence cannot be achieved, the patient should be maintained on the lowest possible dose. Barbiturates and Hypnosedatives Owing to their limited availability, the barbiturates and nonbarbiturate hypnosedatives (chloral hydrate, glutethimide, meprobamate, methaqualone) are no longer commonly abused substances. Butalbital, available only as a proprietary combination with aspirin and caffeine with or without codeine (Fiorinal-C), is the only barbiturate we see frequently (83). Heinonen et al., in the Boston Collaborative Study, found little evidence for a teratogenic effect in this group of drugs (61). Because of the danger of a major withdrawal syndrome (tonic-clonic seizures and delirium), the pregnant woman ingesting more than 400 mg of barbiturate or equivalent daily should be admitted to the hospital for detoxification. Phenobarbital is the drug of choice, given either on a tapering schedule (84) or by an oral loading technique (85). A neonatal abstinence syndrome has been described.

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Tobacco Annual per capita cigarette consumption has decreased steadily in North America since 1973. However, the decrease has been much less in women than in men and the percentage of heavy smokers has increased, perhaps suggesting that many less severely dependent individuals have successfully quit (86). For married white women age 20 and over, the prevalence of smoking during pregnancy decreased from 40 to 25% between 1967 and 1980. This drop was greatest in women with high educational levels (87). The smoker is 80% more likely than the nonsmoker to have a spontaneous abortion and is 100% more likely to have a low-birth-weight infant (⬍2500 g). Cigarette smoking in pregnancy is associated with decreased birth weight by an average of 200 g. This effect is dose-dependent, is independent of other factors, and can be reversed by cessation of smoking in early pregnancy. Smoking during pregnancy leads to increased perinatal mortality, prematurity, placenta previa, and abruption (88,89). Although some studies have shown an increase in congenital malformations, most have not, and summing the data, we can say that tobacco smoking does not appear to cause human teratogenicity. Sexton and Hebel performed a randomized controlled study of an intensive smokingcessation intervention during pregnancy. Prior to randomization, both groups had decreased their mean number of cigarettes smoked by half and about 15% had quit. The reported quitting rate at 8 months of gestation was 20% for the control group and 43% for the treatment group (91). Use of a self-help booklet has been shown to increase smoking cessation in public health maternity clinics (92). Education and support to decrease smoking can be effective in patients who do not spontaneously change their smoking behavior at the onset of pregnancy (93) and may result in improved fetal outcome. Nicotine chewing gum, although a useful adjunct to smoking cessation therapy, should not be used in pregnancy. Caffeine The average intake of caffeine in pregnancy is 144 mg/day, or about one cup of filtered coffee or two cups of tea (94). Several studies have demonstrated little or no fetal effect of caffeine (95,96). Animal studies using high doses and some human studies reporting adverse outcome have led most clinicians to recommend caution in beverage caffeine consumption. Since many of the adverse physiological effects of caffeine do not occur at doses below 400 mg/day (97), it is reasonable to limit consumption to this level. SUMMARY The mood-altering drugs with the exception of alcohol and possibly organic solvents have not been documented to be major teratogens. Most have been associated with intrauterine growth retardation and a neonatal withdrawal syndrome at birth in infants of chronic, heavy users. In many women, a brief intervention consisting of education and support in the primary care setting can limit the morbidity of nonmedical drug use. A comprehensive prenatal program for drug-dependent women can help improve outcome in this high-risk population. Clinical Case Answer It is important to link this patient without delay with a program that specializes in addiction. Therapy should include all domains of life, since addiction cannot be effectively

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treated without accounting for its psychosocial aspects. Pharmacologically, most favorable experience comes from protocols using the long-acting opioid methadone. FURTHER READING Finnegan LP ed. Drug Dependence in Pregnancy: Clinical Management of Mother and Child. Washington, DC: National Institute on Drug Abuse, 1979. Lester BM ed. Prenatal drug exposure and child outcome. Clin Perinatol 1999; 26:1–250.

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18. Mok JQ, Guaguinto C, De Rossi A, et al. Infants born to mothers seropositive for human immunodeficiency virus. Lancet 1987; 1:1164–1168. 19. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999–1001. 20. Jones KL, Smith DW, Ulleland CN, et al. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1:1267–1271. 21. Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med 1978; 298:1063–1067. 22. Jones KL, Smith DW, Streissguth AP, Myrianthopoulos NC. Outcome in offspring of chronic alcoholic women. Lancet 1974; 1:1076–1078. 23. Hanson JW, Jones KL, Smith DW. Fetal alcohol syndrome: experience with 41 patients. JAMA 1976; 235:1458–1460. 24. Streissguth AP, Herman CS, Smith DW. Intelligence, behavior, and dysmorphogenesis in the fetal alcohol syndrome: a report on 20 patients. J Pediatr 1978; 92:363–367. 25. Rosett HL. A clinical perspective of the fetal alcohol syndrome. Alcohol Clin Exp Res 1980; 4:119–122. 26. Sokol RJ, Miller SI. Reed G. Alcohol abuse during pregnancy: an epidemiologic study. Alcohol Clin Exp Res 1980; 4:135–145. 27. Spohr HL, Steinhausen HC. Follow-up studies of children with fetal alcohol syndrome. Neuropediatrics 1987; 18:13–17. 28. Kaminski M, Rumeau-Rouquette C, Schwartz D. Alcohol consumption in pregnant women and the outcome of pregnancy. Alcohol Clin Exp Res 1978; 2:155–163. 29. Ouellette EM, Rosett HL, Rosman NP, Weiner L. Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Engl J Med 1977; 297:528–530. 30. Little RE, Sing CF. Association of father’s drinking and infant’s birth weight. N Engl J Med 1986; 314:1644–1645. 31. Hanson JW, Streissguth AP, Smith DW. The effects of moderate alcohol consumption during pregnancy on fetal growth and morphogenesis. J Pediatr 1978; 92:457–460. 32. Mills JL, Graubard BI. Is moderate drinking during pregnancy associated with an increased risk for malformations? Pediatrics 1987; 80:309–314. 33. Marbury MC, Linn S, Monson R, et al. The association of alcohol consumption with outcome of pregnancy. Am J Public Health 1983; 73:1165–1168. 34. Rosett HL, Weiner L. Alcohol and the Fetus: A Clinical Perspective. New York: Oxford University Press, 1984. 35. The effects of alcohol on the outcome of pregnancy. Bull Soc Obstet Gynaecol Can 1984; 6: 1–2. 36. Little RE, Streissguth AP. Drinking during pregnancy in alcoholic women. Alcohol Clin Exp Res 1978; 2:179–182. 37. Little RE, Schultz FA, Mandell W. Drinking during pregnancy. J Stud Alcohol 1976; 37:375– 379. 38. Sellers EM, Naranjo CA, Harrison M, et al. Diazepam loading: simplified treatment of alcohol withdrawal. Clin Pharmacol Ther 1983; 34:822–826. 39. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. Baltimore: Williams & Wilkins, 1986. 40. Favre-Tissot M, Delatour P. Psychopharmacologie et teratogenesis a propos du disulfirame: essai experimental. Ann Med Psychol 1965; 123:735–740. 41. Nora AH, Nora JJ, Blu J. Limb-reduction anomalies in infants born to disulfiram-treated alcoholic mothers. Lancet 1977; 2:664. 42. Schardein JL. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985. 43. Zelson C, Rubio E, Wasserman E. Neonatal narcotic addition: 10 year observation. Pediatrics 1971; 48:178–189. 44. Chavez CJ, Ostrea EM, Stryker JC, et al. Sudden infant death syndrome among infants of drug-dependent mothers. J Pediatr 1979; 95:407–409.

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45. Blinick G, Wallach RC, Jerez E. Pregnancy in narcotics addicts treated by medical withdrawal. Am J Obstet Gynecol 1969; 105:997–1003. 46. Finnegan LP, ed. Drug Dependence in Pregnancy: Clinical Management of Mother and Child. Washington, DC: National Institute on Drug Abuse, 1979. 47. Zuspan FP, Gumpel JA, Mejia-Zelaya A, et al. Fetal stress from methadone withdrawal. Am J Obstet Gynecol 1975; 122:43–46. 48. Rementeria JL, Nunag NN. Narcotic withdrawal in pregnancy: stillbirth incidence with a case report. Am J Obstet Gynecol 1973; 116:1152–1156. 49. Connaughton JF, Reeser D, Schut J, Finnegan LP. Perinatal addiction: outcome and management. Am J Obstet Gynecol 1977; 129:679–686. 50. Kandall SR, Albin S, Lowinson J, et al. Differential effects of maternal heroin and methadone use on birthweight. Pediatrics 1976; 58:681–685. 51. Ostrea EM, Chavez CJ, Strauss ME. A study of factors that influence the severity of neonatal narcotic withdrawal. J Pediatr 1976; 88:642–645. 52. Strauss ME, Andresko M, Stryker JC, Wardell JN. Relationship of neonatal withdrawal to maternal methadone dose. Am J Drug Alcohol Abuse 1976; 3:339–345. 53. Kaltenbach K, Finnegan LP. Perinatal and developmental outcome of infants exposed to methadone in utero. Neurotoxicol Teratol 1987; 9:311–313. 54. Kaltenbach K, Finnegan LP. Developmental outcome of children born to methadone maintained women: a review of longitudinal studies. Neurobehav Toxicol Teratol 1984; 6:271– 275. 55. Abelson HI, Miller JD. A decade of trends in cocaine use in the household population. Natl Inst Drug Abuse Res Monogr Ser 1985; 61:35–49. 56. Gawin FH, Ellinwood EH. Cocaine and other stimulants: actions, abuse, and treatment. N Engl J Med 1988; 318:1173–1182. 57. Madden JD, Payne TF, Miller S. Maternal cocaine abuse and effect on the newborn. Pediatrics 1986; 77:209–211. 58. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J Pediatr 1987; 110: 93–96. 59. Chasnoff IJ, Bussey ME, Savich R, Stack CM. Perinatal cerebral infarction and maternal cocaine use. J Pediatr 1986; 108:456–459. 60. Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates. J Pediatr 1986; 108:456–459. 61. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, CO: PSG Publishing, 1977. 62. Eriksson M, Larsson G, Winbladh B, Zetterstrom R. The influence of amphetamine addiction on pregnancy and the newborn infant. Acta Paediatr Scand 1978; 67:95–99. 63. Hatch EE, Bracken MB. Effect of marijuana use in pregnancy on fetal growth. Am J Epidemiol 1986; 124:986–993. 64. Hollister LE. Health aspects of cannabis. Pharmacol Rev 1985; 38:1–20. 65. Linn S, Schoenbaum SC, Monson RR, et al. The association of marijuana use with outcome of pregnancy. Am J Public Health 1983; 73:1161–1164. 66. Hingson R, Alpert JJ, Day N, et al. Effects of maternal drinking and marijuana use on fetal growth and development. Pediatrics 1982; 70:539–546. 67. Wu TC, Tashkin DP, Djahed B, Rose JE. Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med 1988; 318:347–351. 68. Long S. Does LSD induce chromosomal damage and malformations? A review of the literature. Teratology 1972; 6:75–90. 69. Golden NL, Kuhnert BR, Sokol RJ, et al. Phencyclidine use during pregnancy. Am J Obstet Gynecol 1984; 148:254–259. 70. Golden NL, Sokol RJ, Rubin IL. Angel dust: possible effects on the fetus. Pediatrics 1980; 65:18–20.

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71. Chasnoff IJ, Burns WJ, Hatcher RP, Burns KA. Phencyclidine: effects on the fetus and neonate. Dev Pharmacol Ther 1983; 6:404–408. 72. Hayden JW, Comstock EG, Comstock BS. The clinical toxicology of solvent abuse. Clin Toxicol 1976; 9:169–184. 73. King MD, Day RE, Oliver JS, et al. Solvent encephalopathy. BMJ 1981; 283:663–665. 74. Hersh JH, Podruch PE, Rogers G, Weisskopf B. Toluene embryopathy. J Pediatr 1985; 106: 922–927. 75. Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts. Lancet 1975; 2:498. 76. Safra MJ, Oakley GP. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 1975; 2:478–480. 77. Rosenberg L, Mitchell AA, Parsells JL, et al. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983; 309:1282–1285. 78. Laegrid L, Olegard R, Wahlstrom J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; 1:108–109. 79. Weber LWD. Benzodiazepines in pregnancy—academic debate or teratogenic risk? Biol Res Pregnancy 1985; 6:151–167. 80. Loudon JB. Psychotropic drugs. BMJ 1987; 294:167–169. 81. Romenteria JL, Bhatt K. Withdrawal symptoms in neonates from intrauterine exposure to diazepam. Pediatr Pharmacol 1977; 90:123–126. 82. Busto U, Sellers EM, Naranjo CA, et al. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med 1986; 315:854–859. 83. Devenyi P, Rideout J, Schneiderman J. Abuse of a commonly prescribed analgesic preparation. Can Med Assoc J 1985; 133:294–296. 84. Smith DE, Wesson DR. Phenobarbital technique for treatment of barbiturate dependence. Arch Gen Psychiatry 1971; 24:56–60. 85. Robinson GM, Sellers EM, Janecek E. Barbiturate and hypnosedative withdrawal by a multiple oral phenobarbital loading dose technique. Clin Pharmacol Ther 1981; 309:71–76. 86. Fielding JE. Smoking: health effects and control. N Engl J Med 1985; 313:491–498. 87. Kleinman JC, Kopstein A. Smoking during pregnancy, 1967–80. Am J Public Health 1987; 77:823–825. 88. Murphy JF, Mulcahy R. The effect of age, parity, and cigarette smoking on baby weight. Am J Obstet Gynecol 1971; 111:22–25. 89. Landesman-Dwyer S, Emanuel I. Smoking during pregnancy. Teratology 1979; 19:119–126. 90. Hebel JR, Nowicki P, Sexton M. The effect of antismoking intervention during pregnancy: an assessment of interactions with maternal characteristics. Am J Epidemiol 1985; 122:135– 148. 91. Sexton M, Hebel JR. A clinical trial of change in maternal smoking and its effect on birth weight. JAMA 1984; 251:911–915. 92. Windsor RA, Cutter G, Morris J, et al. The effectiveness of smoking cessation methods for smokers in public health maternity clinics: a randomized trial. Am J Public Health 1985; 75: 1389–1392. 93. Donovan JW. Randomized controlled trial of anti-smoking advice in pregnancy. Br J Prev Soc Med 1977; 31:6–12. 94. Morris MB, Weinstein L. Caffeine and the fetus—is trouble brewing? Am J Obstet Gynecol 1981; 140:607–610. 95. Rosenberg L, Mitchell AA, Shapiro S, Slone D. Selected birth defects in relation to caffeinecontaining beverages. JAMA 1982; 247:1429–1432. 96. Linn S, Schoenbaum SC, Monson RR, et al. No association between coffee consumption and adverse outcomes of pregnancy. N Engl J Med 1982; 306:141–145. 97. Curatolo PW, Robertson D. The health consequences of caffeine. Ann Intern Med 1983; 98: 641–653.

18 Maternal and Obstetrical Effects of Prenatal Drug Exposure Raafat Bishai and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Recent research on drug abuse during pregnancy has largely focused on fetal outcome, with very little attention to the biological and psychological effects on the mother. This review focuses on determinants of maternal health in drug-dependent women. These, directly or indirectly, are affecting fetal outcome, and careful attention to them is needed if one wishes to optimize perinatal outcome. Nonmedical drug use is defined as the use of any psychoactive drug in the absence of a clearly defined medical indication (23). While recreational drug users and drug-dependent women may appear unconvinced about health risk themselves, they, too, usually wish to spare their unborn children from risks associated with drug use (51). A Swedish study has shown that almost one-third of chemically dependent women succeeded in overcoming their addiction in early pregnancy once they realized that they were pregnant (12), indicating that pregnancy may, by itself, provide powerful motivation for women to overcome addiction. Another German study (50) documented that pregnancy and subsequent motherhood enhance and stabilize the motivation of the mother to quit drug consumption. The outcome of pregnancy in the drug-dependent woman depends on a complex of determinants far beyond the drug-taking behavior itself. The pharmacological effects of the abused substance are often compounded by suboptimal prenatal care, poor diet, higher risk for sexually transmitted diseases, and concomittant use of cigarettes and alcohol (51). Much of the research in this field comes from studies in women of the American innercity drug subculture, which may not be easily extrapolated to either women who have used a substance once or several times socially or to women who have received a short course of parenteral opioid in the treatment of an acute medical or surgical illness prior to the knowledge of the pregnancy (51). In this paper, we overview the published evidence on maternal complications in pregnancy as a result of drug dependence.

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A GENERAL VIEW ON MATERNAL COMPLICATIONS Silver and colleagues (53), have shown that drug-dependent women (DDW) have an increased incidence of medical and obstetrical complications; within the context of a family center, their study was undertaken to determine whether the DDW had normal patterns of labor and whether standard intrapartum management was appropriate. The study population included 336 women, of which 112 were DDW (72% of them receiving methadone maintenance). The comparison group of 224 non-drug-dependent women was matched for gravidity, parity, and socioeconomic background. The incidence of premature delivery, abruptio placentae, breech presentation, and intrauterine growth retardation, was significantly higher in the DDW. The average duration of the first, second, and third stages of labor were similar to the normal course of labor in the matched comparison group. Rates of complications during labor and cesarean section were not higher, but there were more than twice as many forceps deliveries, which correlated with a 40% increased use of epidural anesthesia. Of importance, the doses of analgesia and anesthesia needed for the DDW were in excess of those given to the control patients. Postpartum complications were common among the DDW, but most of them were secondary to the need to use subclavian intravenous lines due to the presence of sclerotic peripheral veins. These data suggest that high-risk prenatal management and careful monitoring in the intra- and postpartum periods—as well as the use of epidural anesthesia—usually prevents complications in DDW. Hawthorne and colleagues (20) have shown that patients tested positive for drugs of abuse weighed less, were older, were more prone not to seek prenatal care, and were more likely to deliver prematurely and have a growth-retarded infant than controls. Funkhouser et al. (16) have found that illicit drug use in pregnancy and socioeconomic status were negatively correlated with effective utilization of prenatal care. The following discussion focuses on the effects of specific drugs of abuse; however, it should be remembered that a woman rarely abuses one drug only, and it is very common for a cocaine-using mother, for example, also to consume alcohol, cigarettes, and marijuana. Any attempt to understand the clinical status of the mother must, therefore, address all exposures together.

Table 1 Maternal Complications That May Appear Among DrugDependent Women Poor antenatal care Preterm delivery Abruptio placentae Breech presentation Postpartum complications Sexually transmitted diseases Poor nutrition Psychiatric comorbidity Higher rates of prostitution

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DRUG-SPECIFIC COMPLICATIONS Cocaine The first report of cocaine effects on pregnancy outcome appeared in 1985 (6). The rates of spontaneous abortions, prematurity, and intrauterine growth retardation are increased among cocaine-using mothers. Labor may be precipitated following a large intravenous bolus of cocaine, a method often used by addicted mothers to induce labor, and there is an increase in the incidence of abruptio placentae (34,43). In a case-control study (38) of cocaine use in pregnancy, Miller and colleagues detected complications that occurred significantly more often among study patients—including vaginal bleeding, abruptio placentae, and premature rupture of the membranes— than among controls. Study patients were found to use prenatal care significantly less often (45 vs. 86%). Delaney and his group (8) have shown that women with recent cocaine use present with ruptured membranes at an earlier gestational age and may actually have a longer latency period than women who do not use cocaine. These results were corroborated by Kistin (28), who demonstrated higher risks than among smokers for prematurity, abruptio placentae, placenta previa, and prenatal death. Dinsmoor and colleagues suggested that preterm rupture of membranes associated with recent cocaine use is characterized by advanced cervical dilation at admission and a shorter latency period to labor and delivery (9). Singer et al. (54) concluded that maternal cocaine use predicts negative birth outcome directly as well as through obstetric risk factors of abortion history and less prenatal care. In a retrospective chart review (1), cocaine use (52% of the study group vs. 10% in the general population, p ⬍ 0.01) and HIV positivity (24% in the study group vs. 2% in the general population, p ⬍ 0.01), were significant risk factors for antepartum pneumonia. Moreover, Chan and colleagues (5) documented that cocaine use is a predisposing factor for pneumothorax during pregnancy, with spontaneous pneumothorax carrying a high risk of recurrence, possibly higher if associated with continued cocaine use. Jawahar et al. reported fatal complications in a pregnant woman who was an active cocaine abuser and developed an intestinal gangrene and multiorgan failure (24). Due to needle sharing as well as unplanned and unprotected sex with multiple partners, cocaine-using pregnant women have a higher risk of becoming infected with HIV. In an attempt to detect a biological cause for the high incidence of HIV and other sexually transmitted diseases among cocaine users during pregnancy, Hedstrom and colleagues tried to determine if cocaine suppresses mitogen-induced lymphocyte proliferation in pregnant women, but no such correlation was found in this study (22). Moen reported the case of a woman in her late pregnancy who experienced hepatic rupture associated with cocaine use. Liver damage may result from the potent vasoconstrictor property of cocaine, leading to vasospasm and ischemia (40). The use of cocaine in pregnancy can result in systemic and focal vasoconstriction and abnormal uterine contractions forceful enough to cause complete rupture of a gravid uterus along a previous vertical cesarean section scar, as reported by Mishra et al. (39). Adverse renal effects in pregnant cocaine-using women have been reported, characterized by hematuria, proteinuria, hemolytic anemia, thrombocytopenia, renal insufficiency, and pulmonary edema (4).

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Lampley and colleagues reported a case of a woman who developed abruptio placentae approximately 18 hours after using cocaine. Six hours later, a cesarean section was performed because of vaginal bleeding and fetal bradycardia. Oliguria was present from admission and persisted despite aggressive management. Serum CPK and urine myoglobin were both elevated. Hemodialysis was required for renal cortical necrosis. Rhabdomyolysis, as indicated by elevated CPK and the presence of myoglobin in the urine, suggested that myoglobinuria may contribute to the acute renal failure seen in cases of cocaineinduced abruptio placentae (30). As suggested by Towers and colleagues (60), cocaine exposure in pregnant women can present itself as preeclampsia. In attempting to better understand the pathophysiological changes induced by cocaine during gestation, Smith concluded that the drug may downregulate β-adrenergic receptors in human myometrium. This could result in a decreased capacity of the uterus to relax and, consequently, may predispose it to preterm labor (55). Erratic binge use of cocaine results in perinatal complications that may be as severe as those occurring with regular daily use. In women with erratic binging (variable in interval, duration, and amount) acute adverse effects (vaginal bleeding, abruptio placentae, still-births) were most prevalent, whereas in women who binge daily, chronic problems are more prominent (systemic infections, anemia, and low maternal weight) and significant (3). In an alerting message to family physicians who practice obstetrics, Fox summarized the potentially catastrophic maternal outcomes in cocaine-abusing pregnant women (15), including acute pulmonary edema, seizures, cardiac arrhythmia, and sudden death. In an attempt to understand the biological nature of the effects of cocaine in pregnancy, cardiovascular and neurological responses to cocaine during pregnancy are enhanced when compared with responses in nonpregnant subjects to the same dose per kilogram or to metabolites of crack cocaine (64). In addition, the placenta itself is a direct target organ for cocaine toxicity, and interaction of cocaine with specific placental proteins in the placenta may play an important role (17). Cocaine has been shown to inhibit specific transport of amino acids across the placenta; this is similar to the action of amphetamine. In a meta-analysis, we detected relatively few adverse reproductive effects associated with pregnancy exposure to cocaine, when the control groups were made up of polydrug users who did not use cocaine. This may indicate that other confounders, such as smoking and drinking, may contribute to adverse pregnancy outcome (33). For example, even placental abruption is not more common among cocaine users in this analysis as compared to polydrug (noncocaine) users.

Amphetamine Clinically, amphetamine-using mothers have been reported to present in much the same way as cocaine users and should probably be managed similarly (13,43). Elliott and Rees reported a case of a woman consuming amphetamine in late pregnancy who presented with confusion, agitation, and convulsions. Hypertension and proteinuria led to a diagnosis of eclampsia, for which a cesarean section was performed (10). Cardiovascular collapse during anesthesia for cesarean section has been reported in cases of chronic abuse (49,56), probably because chronic ingestion of amphetamine de-

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Table 2 Maternal Complications That May Appear Among Cocaine- and AmphetamineAbusing Pregnant Women Vaginal bleeding Abruptio placentae Placenta praevia Premature rupture of membranes Abortions Poor antenatal care Pneumothorax Pneumonia Malnutrition Seizures (25,41) Sexually transmitted diseases Psychiatric comorbidity History of sexual and psychological abuse

pletes catecholamine in adrenergic neurons, thus impairing the response to sympathomimetics and inhibiting the stress response. A cohort study of pregnant patients using prescribed or illicit amphetamine (52 and 237 patients, respectively) did not detect an increased incidence of placental abruption. It is possible that studies that detect an increased incidence of abruptio placentae include large numbers of patients who use multiple substances, including cocaine (25). It has been postulated that the human placenta is a direct target organ for amphetamine toxicity, as is the case with cocaine. Ramamoorthy and colleagues have showed that amphetamine and methamphetamine are potent competitive inhibitors of the placental norepinephrine transporter and, to a lesser extent, of the placental serotonin transporter. It is possible that increased levels of these vasoactive monoamines in the intervillous space may explain the clinical findings, which include maternal hypertension, fetal growth retardation, decreased uteroplacental blood flow, premature labor, and abruptio placentae (46). Opioids Among heroin-addicted women, the obstetric complications seen most frequently included premature labor, breech presentation, premature rupture of membranes, and toxemia (57). The more frequently noticed medical complications were anemia, syphilis, and infectious hepatitis, although maternal deaths are very rare. Many of these complications could be at least partially explained on the basis of no or inadequate prenatal care. Only one-quarter of the patients had registered in a prenatal clinic, and more than half of this small group did so only in the last trimester. The average number of clinic visits was less than one per patient. The average length of observed labor was considerably shortened, and many patients delivered their babies within 3 hours, with more than half having their babies in less than 7 hours. Most patients delayed coming to the hospital until they felt they were ready for delivery, partially in order to avoid a long labor without access to the opioids and thus also withdrawal. As a result of this delay, deliveries at home, in the ambulance, or on the

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stretcher were not uncommon. Appropriate counseling and reassurance that withdrawal will not happen with appropriate use of methadone, for example, may partially address this grim tendency. It has been suggested that pregnant patients on heroin may have increased uterine irritability (7), partially explaining the irregular progress of delivery. Ellwood and colleagues (11) conducted a retrospective analysis of the outcome of pregnancy among 174 women abusing opioids. The group was characterized by a high prevalence of previous obstetric and medical problems; the most common complications were preterm labor (24%) and anemia (12%). In another retrospective case-control study (31) carried out on 51 Chinese gravidas who had abused narcotics (mainly heroin) and who gave birth in a teaching hospital in Hong Kong, the major antenatal complications were late antenatal booking (average 28 weeks), prematurity (41%), antepartum hemorrhage (13.7%), and high prevalence of disease (23.5%). Of 51 pregnancies in addicted pregnant women (50 of them on heroin), 10 (20%) resulted in spontaneous abortion, 2 (4%) in extrauterine pregnancy, and 17 (36%) in preterm delivery (61). The apparently higher incidence of extrauterine pregnancy could be explained by the high incidence of previous salpingo-oophoritic disorders that frequently affect these subjects; moreover, the high incidence of miscarriages in the same subjects could have been due to their lifestyle and poor prenatal care or to an increased excitability of the myometrium. Preterm delivery and short labor seem to result from increased excitability of the myometrium, mainly during the period of drug craving, further emphasizing the need for appropriate replacement therapy. In a French study, lack of follow up, prematurity, short child stature, infections (notably with HIV) and the neonatal withdrawal syndrome (2) were commonly detected. The worse obstetric and prenatal outcomes have been encountered among HIV-seropositive drug addicts, and a positive correlation was found between the number of infectious episodes during pregnancy and the mean dose of opioid consumed daily, suggesting that regardless of the maternal serological status, opioid intake not only causes a further worsening of gestational and prenatal outcomes but also increases the mother’s susceptibility to infection (37). The study of Rodriguez et al. found that increased probability of a positive maternal HIV culture on delivery was significantly associated with prenatal use of hard drugs (48). In a study of a large obstetric service in Dallas (32), pregnancy outcome and health status of infants born to 24 heroin addicts were compared to those in a group of 100 unexposed women and their infants. Women who used heroin during pregnancy tended to use other substances (tobacco, alcohol, cocaine) more often than did controls. The frequency of preterm birth was increased significantly in women who abused heroin during pregnancy. Supraovulation and multiple births were found to be higher among opioidaddicted women, exposing them to the known hazards of this medical condition (47). In a retrospective Spanish study, the incidence of maternal syphilis, positivity to hepatitis B surface antigen, premature rupture of membranes, and abortions was significantly more common among heroin-addicted mothers (42). Data on the pre- and postnatal effects of pyribenzamine (‘‘Ts and blues’’) abuse in pregnancy were compared with those of a control group. Anemia, syphilis, hepatitis, and gonorrhea were more common among mothers abusing Ts and blues (62). Acute bacterial endocarditis, a fulminating disorder most often caused by Staphylococcus aureus, is uncommon in pregnancy. However, the frequency of this disease may

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Table 3 Maternal Complications That May Appear Among OpioidAbusing Pregnant Women Premature labor Premature rupture of membranes Breech presentation Antepartum hemorrhage Toxemia Poor antenatal care Anemia Uterine irritability Infections (HIV, hepatitis, syphilis)

be increasing due to increased intravenous drug abuse. Three cases were reported during pregnancy at Charity Hospital, New Orleans, and all three patients were intravenous drug abusers (44). Alcohol Although there is no known safe lower limit for alcohol consumption in pregnancy, two recent meta-analyses have failed to show increased risk of major malformations and perinatal complication in babies of social drinkers (less than one drink per day) (35,45). Abstinence is the most conservative approach. However, half of all pregnancies are unplanned and half of all pregnant women drink socially before being aware of their pregnancy. Hence, in about one-quarter of all pregnancies, the fetus is exposed to some alcohol (51). The results of our recent meta-analyses may be used to reassure such women. A study of more than 12,000 pregnancies showed an increase in rates of abruptio placentae but not in other adverse outcomes associated with an intake of less than two drinks per day (36), suggesting that only persistent and higher doses of ethanol increase obstetric risk in a clinically meaningful manner. Adverse outcomes in heavy drinkers include increased spontaneous abortions (59), premature placental separation (26), and, of course, the risks associated with alcoholrelated birth defects. It has been shown repeatedly that among alcoholic women, the risk of having a child with fetal alcohol syndrome (FAS) increases with gravidity, It appears that this risk is not due to increased drinking with age. Rather, it may be associated with increased maternal morbidity with longer drinking history, including hepatic, gastrointestinal, and neurological sequelae, to mention a few. Pregnancy complicated by pancreatitis may lead to substantial fetal and maternal morbidity and mortality. Among 30 women who developed pancreatitis during pregnancy, the etiology was gallstones in 22 patients, alcohol in 2 patients, and idiopathic in 6 patients (58). Organic Solvents Recreational abusers of solvents tend to choose toluene-containing products. Acute solvent effects resemble those of alcohol; however, there is no typical withdrawal syndrome (21).

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Table 4 Maternal Complications That May Appear Among SolventAbusing Pregnant Women Renal tubular acidosis Hypokalemia Cardiac dysrythmias Rhabdomyolosis Cortical and cerebellar dysfunction

With chronic use, a persistent encephalopathy, characterized by signs of cortical and cerebellar dysfunction may develop in the mother (27). In another study, abuse of toxic vapors during pregnancy was found to be associated with increased maternal and fetal morbidity. Toluene-induced renal tubular acidosis occurred in over half of these women and was clustered among long-duration abusers. The renal acidosis placed the mother at risk of hypokalemia, with associated cardiac dysrythmias and rhabdomyolosis (63). Cannabinoids Pregnant patients often complain of severe nausea and vomiting on discontinuing marijuana smoking in the first trimester. This is consistent with the antiemetic effect of the cannabinoids (51). We have interviewed women in the Motherisk Program who reported that one line of hash had a profound effect on their nausea and vomiting of pregnancy, better than that of prescription drugs. Wu et al. reported a nearly fivefold greater increment in the blood carboxyhemoglobin level and a threefold increase of inhaled tar with smoking marijuana when compared with regular cigarettes (65). Pregnant women with high serum levels of cannabinoids, phencyclidine and cocaine, exhibited significantly lower concentrations of folate and feritin than subjects with lower serum drug concentrations. High maternal serum concentrations of illicit drugs were associated with significant increase in leukocyte counts. In a study conducted by Shiono et al., to evaluate prospectively the effects of cocaine and marijuana use on pregnancy outcome, marijuana use was relatively common and was not associated with adverse pregnancy outcome (52). Similarly, in another prospective study of the effects of marijuana use in pregnancy, the rates of adverse effects were very infrequent, although infants born to cannabinoid users exhibited significantly more meconium staining (57 vs. 25% in nonusers). Significant differences in the duration of labor were also observed (18). Users of marijuana experienced slightly elevated rates of dysfunctional labor (43% vs. 35% in nonusers), precipitate labor (13% vs. 8%) and meconium staining (17% vs. 13%). Although these were not felt to be of clinical significance. (19).

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51. Schneiderman J. Nonmedical drug and chemical use in pregnancy. In: Koren G. ed. MaternalFetal Toxicology: A Clinician’s Guide, 2nd ed. New York: Marcel Dekker, 1994. 52. Shiono PH, Klebanoff MA, Nugent RP, et al. The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study. Am J Obstet Gynecol 1995; 172(1 pt 1):19–27. 53. Silver H, Wapner R, Loriz-Vega M, Finnegan LP. Addiction in pregnancy: high risk intrapartum management and outcome. J Perinatol 1987; 7(3):178–184. 54. Singer L, Arendt R, Song LY. Direct and indirect interactions of cocaine with childbirth outcomes. Arch Pediatr Adolesc Med 1994; 148(9):950–964. 55. Smith YR, Dombrowski MP, Leach KC, Hurd WW. Decrease in myometrial beta-adrenergic receptors with prenatal cocaine use. Obstet Gynecol 1995; 85(3):357–360. 56. Smith DS, Gutsche BB. Amphetamine abuse and obstetrical anesthesia. Anesth Analg 1980; 59:710–711. 57. Stone ML, Salerno LJ, Green M, Zelson C. Narcotic addiction in pregnancy. Am J Obstet Gynecol 1971; 109(5):716–723. 58. Swisher SG, Hunt KK, Schmit PJ, et al. Management of pancreatitis complicating pregnancy. Am Surg 1994; 60(10):759–762. 59. Sokol RJ, Miller SI, Reed G. Alcohol abuse during pregnancy: an epidemiologic study. Alcohol Clin. Exp Res 1980; 4:135–145. 60. Towers CV, Pircon RA, Nageotte MP, et al. Cocaine intoxication presenting as preeclampsia and eclampsia. Obstet Gynecol 1993; 81(4):545–547. 61. Volpe A, Correnti E, Grasso A, et al. Drug addiction during pregnancy. Biol Res Pregnancy Perinatol 1983; 493:137–138. 62. Von Almen WF II, Miller JM Jr. Ts and Blues in pregnancy. J Reprod Med 1986; 31(4):236– 239. 63. Wilkins-Haug L, Gabow PA. Toluene abuse during pregnancy: obstetric complications and perinatal outcomes. Obstet Gynecol 1991; 77(4):504–509. 64. Woods JR. Maternal and transplacental effects of cocaine. Ann NY Acad Sci 1998; 846:1– 11. 65. Wu TC, Tashkin DP, Djahed B, et al. Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med 1988; 318:347–351.

19 Neonatal Drug Withdrawal Syndromes James B. Besunder Metro Health Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio

Jeffrey L. Blumer Rainbow Babies and Children’s Hospital and Case Western Reserve University School of Medicine, Cleveland, Ohio

Clinical Case You are consulted about a baby who is suspected of having an opioid withdrawal syndrome: restlessness, intractable crying, diarrhea, vomiting, sweating, tremor, and poor feeding. The mother claims that although she is a heroin user, she has not been able to get any drug for several days. Neonatal urine test is negative, and the house staff suspects that the neonatal presentation is something other than drug withdrawal.

INTRODUCTION Drug abuse is a global problem within our society. As a result, the fetus, by passive addiction, has become an unfortunate victim of increasing maternal substance abuse. Although most pediatricians are acquainted with the neonatal narcotic withdrawal syndrome, substance withdrawal syndromes have now been described for many other classes of drugs, including sedative-hypnotics, stimulants, antidepressants, neuroleptics, antihistamines, and alcohol (1,2). The pediatrician, in particular, must be cognizant of the potential that signs or symptoms observed in a young infant may be the consequence of drug withdrawal. This chapter reviews drugs known to precipitate withdrawal syndromes in newborns, their clinical manifestations and therapy, and, when known, the mechanism for induction of the substance withdrawal syndrome.

OPIOIDS Although addiction to heroin and methadone is encountered most frequently, the narcotic withdrawal syndrome has also been described with propoxyphene (3–5), codeine (6,7), and the opiate agonist/antagonist pentazocine (8–10). A great deal is known about the 347

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short-term clinical effects of maternal opiate addiction on the newborn; however, many confounding variables such as polydrug abuse, improper nutrition, and socioeconomic factors obscure a description of their potential long-term effects. Mechanism of Opiate Withdrawal Evidence exists that at least part of the clinical manifestation of narcotic withdrawal results from α2-adrenergic supersensitivity in the locus ceruleus (LC) (11). Increased firing of neurons located in the LC of monkeys produces many of the central nervous system symptoms associated with narcotic withdrawal, including behavioral changes, increased wakefulness, and tremors (12,13). α2-Adrenergic receptors (14) as well as opiate receptors (15– 17) are located in the LC, and stimulation of these receptors by clonidine and morphine, respectively, inhibits activation of the LC in primates and rats (18,19). Hamburg and Tallman (20) demonstrated an increased number of α2-adrenergic receptors in rat brains following chronic morphine administration. In 1978 Aghajanian (21) observed similar depressant effects on LC neuronal firing by morphine and clonidine in rats, although the two drugs appeared to act at independent receptors within the LC. Initially, the administration of morphine markedly depressed LC-neuronal activation. However, tolerance developed rapidly, with normal firing rates observed after 4–5 days of daily morphine administration. Using a microiontophore technique, a withdrawal response (⬎ 100% activation of LC-neuronal firing) in tolerant rats was then observed with the direct application of the competitive opioid antagonist naloxone. When clonidine was applied to the LC neurons, inhibition of firing comparable to that observed with morphine alone was demonstrated. Finally, Aghajanian in the same set of experiments demonstrated that piperoxane, an α-adrenergic receptor antagonist, blocked clonidine, but not morphine-induced LC neuronal activation. Thus, these data suggest that stimulation of opiate and α2-adrenergic receptors inhibits in parallel, but not independently, activation of neurons in the LC. Withdrawal of opiates, possibly resulting from or potentiated by an increased number of unbound α2-adrenergic receptor sites, causes activation of neurons in the LC, leading to manifestations of the narcotic withdrawal syndrome. The effect of naloxone alone on LC neurons was not determined, however, and as a result, a direct effect of naloxone rather than induction of a narcotic withdrawal response cannot be excluded as a possible reason for the heightened activation of LC neurons following naloxone administration. These observations of Aghajanian (21) also offer a cellular basis for the efficacy of clonidine in suppressing some of the symptoms of opiate withdrawal. A spinal cord effect of opioid withdrawal may account for other symptoms of the withdrawal syndrome, such as hyperreflexia and hyperalgesia. Substance P (SP) is thought to be the neurotransmitter responsible for nocioceptive input into the spinal cord (22,23), and its release from the spinal cord is inhibited by opioids in rats and cats (24,25). Vacca et al. (26) observed an increase in SP concentrations in the dorsal horn of rat spinal cords following chronic morphine administration. Bergstrom et al. (27) reported similar findings in rats and suggested that release of accumulated SP or supersensitivity of postsynaptic SP receptors following opioid withdrawal is responsible for the hyperreflexia seen during the narcotic withdrawal syndrome. Bell and Jaffe (28), in a study evaluating dorsal and ventral root depolarization responses in neonatal rat spinal cords, provide evidence supporting a presynaptic mechanism of morphine withdrawal (i.e., presynaptic accumulation of SP and then release) rather than a postsynaptic mechanism. Of interest, Gintzler and

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Scalisi (29) demonstrated that morphine inhibits and SP induces non-cholinergic-mediated contraction of isolated guinea pig ileum. Further studies in the isolated guinea pig ileum strongly suggested that naloxone reversed the effects of morphine by releasing SP (29). Previously, Schulz and Herz (30) had shown that naloxone-precipitated enteric withdrawal from opiates is mediated, at least in part, by excitation of post-ganglionic cholinergic neurons with release of acetylcholine and activation of smooth muscle muscarinic receptors. Although these preliminary data on the neurohumoral effects of narcotic withdrawal are encouraging, further research in primates is needed to elucidate the mechanism of opiate withdrawal in human infants. Clinical Manifestations of Opiate Withdrawal Characteristics at Birth The incidence of premature birth among heroin-addicted women ranges from 17 to 30% (31–34). Zelson et al. (31) reported more than a twofold increase in premature deliveries over a 10-year period in 384 infants born to heroin-addicted mothers compared with the overall premature birthrate at their institution over the same time period. In contrast to heroin-addicted mothers, women enrolled in methadone treatment programs appear to be at only slightly increased risk of premature delivery. Newman et al. (35) reported a 7% incidence of deliveries prior to 8 months gestation in a large series of methadone-maintained women. Of interest, Olofsson et al. (32) observed younger mean gestational ages in infants whose mothers had been acutely withdrawn from methadone within a month of delivery compared with mothers who were maintained on methadone until the time of delivery. Low birth weight (⬍ 2500 g) is a common sequela among newborns of heroin addicts as well as the infants of women who use both heroin and methadone and women who enter methadone treatment programs during their third trimester (36–39). Naeye et al. (36) reviewed postmortem data in infants born to heroin addicts and demonstrated that growth retardation had been due mainly to a decreased number of cells in various organs, including the heart, pancreas, adrenal glands, spleen, thymus, and kidneys. Brain specimens were not available. Not all cases of growth retardation could be attributed to poor nutrition during pregnancy. Kandall et al. (37) reported mean birth weights of 2490 and 2535 g (mean gestational age of 38 weeks for both groups) among infants born to heroinand combined heroin- and methadone-addicted mothers, respectively, compared with a mean birth weight of 3176 g in the control group. Finnegan (38) identified a strong relationship between prenatal care and birth weight among infants born to heroin addicts. Birth weight under 2500 g was observed in 47.6% of infants born to drug-dependent women with no prenatal care compared with an 18.8% incidence for women with good prenatal care. By comparison, Finnegan reported a 20% incidence of low birth weight in a control group of nonaddicts who received no prenatal care. In contrast to the infants mentioned above, several investigators have observed higher birth weights among infants born to women addicted to methadone than to infants of heroin addicts (32,37,39,40). Kandall et al. (37) reported a mean birth weight of 2961 g (mean gestational age of 39.4 weeks) for 108 infants born to women who used methadone as their sole or major nacrotic during pregnancy compared with a mean birth weight of 2490 g (mean gestational age 38 weeks) for 61 infants born to heroin addicts. The effect of methadone on birth weight was independent of maternal age, race, or prenatal care. The same investigators also observed a direct relationship between methadone dose

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during the first trimester and birth weight in a subgroup of infants born to mothers registered in a methadone maintenance program where complete records of drug dosages and urinalyses were available. The investigators suggest that methadone may promote fetal growth during the first trimester in a dose-dependent fashion. Although methadoneaddicted women have larger babies than women addicted to heroin, both groups have an increased risk of delivering infants that are small for gestational age (SGA). Zelson et al. (39) reported incidence of SGA infants of 35 and 22% among babies born to heroin- and methadone-addicted women, respectively. Klenka (34) confirmed the high incidence of SGA infants born to heroin-addicted mothers when he described this finding in eight of 32 infants. On the other hand, Ostrea and Chavez (41) reported a lower incidence of 16.5% in 830 infants born to drug-dependent women. Head circumference and birth length are also significantly reduced among infants born to narcotic-addicted mothers compared with controls (42,43), although the incidence of head circumference below the 10th percentile did not differ between the two groups (42). A high incidence of low Apgar scores in infants born to narcotic addicts has also been reported by Olofsson et al. (32) and Ostrea and Chavez (42). Both groups of investigators found a 20% incidence of Apgar scores less than 7 at 1 minute, double the incidence observed by Ostrea and Chavez in their control infants. Ostrea and Chavez (41) also reported more than a two-fold greater incidence of low 5-minute Apgar scores (ⱕ6) in infants born to drug-dependent women compared with controls (7 vs. 3.2%). Infants born to heroin addicts appear to be less at risk of developing severe hyperbilirubinemia. In a prospective study, Nathenson et al. (44) reported significantly higher mean total bilirubin concentrations in control infants compared with infants born to heroinaddicted women during each of the first 3 days of life. Upon excluding factors predisposing infants to hyperbilirubinemia, such as hemolytic disease, the elevated bilirubin concentrations were found to be due mainly to an increase in the indirect fraction. The lower bilirubin concentrations observed in the heroin-addicted group most likely resulted from increased activity of bilirubin glucuronyl transferase. This effect of heroin has been demonstrated in animals (43). Marked hypertrophy of the smooth endoplasmic reticulum has been described in liver biopsies from heroin-addicted adults (45). Zelson et al. (31) reported the occurrence of jaundice in only 24 of 384 infants born to heroin-addicted mothers. Of these 24 infants, 6 had an ABO incompatibility and 1 was septic. In contrast, limited data are available on the incidence of hyperbilirubinemia among infants born to women maintained on methadone during pregnancy. Harper et al. (46) reported ‘‘clinical jaundice’’ in approximately half of their group of infants born to women in a methadone treatment program. However, only five of these infants had serum bilirubin concentrations exceeding 10 mg/dL, and all these babies had mild ABO incompatibilities. More data are required to ascertain the effect of methadone on serum bilirubin concentrations in newborn infants. Whether maternal narcotic addiction is associated with congenital defects is unknown. Zelson et al. (31) reported congenital abnormalities in only 4 of 384 infants born to heroin-addicted mothers. In contrast, the data of Ostrea and Chavez (41) reveal a statistically significant increased incidence of congenital malformations in their cohort of 830 newborns. Among the 37 infants with congenital defects, 20 (2.4%) had major malformations, including hydrocephalus, heart disease, and genitourinary tract abnormalities. Only 0.5% of their control population had major malformations. Harper et al. (46) reported

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congenital defects in 3 of 51 infants born to women maintained on methadone; however, only one would be considered a major malformation. Hyaline membrane disease (HMD) appears to occur less frequently among infants born to heroin addicts. Glass et al. (47) reported no cases of HMD in 33 premature infants born to heroin addicts compared with 26 cases in 123 premature infants born to nonaddicted mothers. The findings of this study are supported by the data generated by Gluck and Kulovich (48) and Taeusch et al. (49). Gluck and Kulovich reported mature lecithin/ sphingomyelin rations in fetuses of narcotic addicts at an earlier gestational age than would be expected in fetuses of nonaddicted women, whereas Taeusch and coworkers demonstrated accelerated lung maturation in fetal rabbits injected with heroin compared with fetal rabbits injected with saline. However, Ostrea and Chavez (41) observed no difference in the incidence of HMD between narcotic-addicted and control infants. In summary, in utero narcotic exposure may have profound effects on the developing fetus, effects that may increase perinatal morbidity and mortality. The birth characteristics of infants born to narcotic-addicted women are summarized in Table 1. Signs and Symptoms of Withdrawal Overt symptoms of narcotic withdrawal occur in 67–90% of infants born to narcoticaddicted women whether the additive drug is heroin or methadone (31–33,35,39,40, 46,50). Although the incidence of individual symptoms is similar between the heroin and methadone groups, infants born to methadone-addicted mothers appear to experience more symptoms (39) and the withdrawal syndrome appears to be more severe (39,40). Rahbar (40) reported moderate and severe symptoms associated with withdrawal in 50 and 18% of symptomatic infants, respectively, born to methadone-addicted women compared with 14 and 7% of infants born to heroin-addicted mothers. The severity (50,51) and possibly the duration of the withdrawal syndrome (32) have been shown to correlate directly with the amount of methadone but not heroin taken

Table 1 Birth Characteristics of Infants Born to NarcoticAddicted Women Characteristic Birth weight Premature infants (frequency) Small for gestational age Birth length Head circumference at birth 1-minute Apgar score ⬍7 (frequency) Hyperbilirubinemia (frequency) Congenital malformations a

Addictiona H⬍M⬍N H⬎M⬎N H⬎M⬎N H⫽M⬍N H⫽M⬍N H, M ⬎ N b H ⬍ Nc ⫾ H, M ⬎ N

H, Heroin; M, methadone; N, nonaddicted. Data comparing Apgar scores in infants born to heroin- and methadoneaddicted mothers are not available. c No data available evaluating the incidence of hyperbilirubinemia among infants born to methadone-addicted mothers. Source: Modified from Ref. 53. b

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during pregnancy. Ostrea and colleagues (51) observed a milder course among infants whose mothers took less than 20 mg/day of methadone during pregnancy. Olofsson et al. (32), in a similar study, reported withdrawal symptoms lasting longer than 5 days in 20 of 37 infants whose mothers were taking 20 mg or more per day of methadone at the time of delivery compared with 10 of 41 infants whose mothers took less than 20 mg/day. The onset of narcotic withdrawal symptoms varies tremendously from minutes after delivery to 1–2 weeks of age. However, the majority of infants will develop withdrawal symptoms by 48 hours of life (33,39,40,46). Methadone withdrawal, owing to its longer elimination half-life (t1/2β ) of approximately 35 hours (52), may be delayed compared with heroin but usually manifests itself within 48 hours (46). Harper et al. (46) reported the onset of withdrawal symptoms within 24 hours of birth in 42%, 48 hours in 73%, and 72 hours in 87% of symptomatic infants born to mothers in a methadone treatment program. Late-onset symptoms of withdrawal developed between 7 and 14 days of life in only 2% of these infants. The timing of the last maternal dose of narcotic with respect to birth also appears to influence the time to onset of symptoms (38,53). The neonatal narcotic withdrawal syndrome is characterized by signs and symptoms of central nervous system excitation, altered gastrointestinal function, respiratory distress, and vague autonomic symptoms. The signs and symptoms of withdrawal have been represented by the mnemonic withdrawal (1): W—wakefulness I —irritability T —tremulousness, temperature variation, tachypnea H —hyperactivity, high-pitched cry, hyperacusia, hyperreflexia, hypertonia D —diarrhea, diaphoresis, disorganized suck R —rub marks (excoriations of knees and face), respiratory distress, rhinorrhea A —apneic spells, autonomic dysfunction W—weight loss or failure to gain weight A —alkalosis (respiratory) L —lacrimation Other symptoms include hiccups, vomiting, stuffy nose, sneezing, yawning, photophobia, twitching, myoclonic jerks, opisthotonos, and seizures (1,53). Irritability is the most common manifestation of narcotic withdrawal, appearing in 45 to as many as 100% of symptomatic infants (31,33,39,50). Other symptoms that have been reported in more than half of symptomatic infants include tremors and hypertonicity (31,33,39,50). Vomiting occurs in one-quarter to one-third of infants. The frequency, if reported, of withdrawal manifestations is summarized in Table 2. Signs and symptoms of central nervous system hyperexcitability, such as irritability, restlessness, and tremors, appear early in the clinical course. Primitive reflexes, such as the Moro reflex, are exaggerated, as are deep tendon reflexes. Fist sucking is common and is reported in up to 80% of narcotic-addicted infants (51). Poor oral intake, regurgitation of feeds, vomiting, and diarrhea are frequently observed upon initiation of oral feedings (33). Feeding difficulties are most likely the result of an uncoordinated and ineffective sucking reflex (54,55). Excessive weight loss or the failure to gain weight, which is commonly observed in narcotic-addicted infants, is due to both poor caloric intake and to an increased tissue oxygen consumption (56). Abnormalities in ventilation also exist in infants whose mothers abuse narcotics. Glass et al. (57) reported tachypnea with a concomitant primary respiratory alkalosis in

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Table 2 Incidence of Withdrawal Manifestations in Symptomatic Infants Born to Narcotic-Addicted Womena Signs and symptoms

Percent with manifestation

Ref.

Irritability Tremors Hypertonicity Vomiting High-pitched cry Respiratory distressb Diarrhea Fever Convulsions Diaphoresis Yawning Sneezing Hiccups

45–100 65–86 20–86 8–37 17–45 9–30 7–22 6–16 3–21 6 3 ⬍1–65 ⬍1

31,33,39,50,51 31,33,39,50,51 31,39,50,51 31,39,50,51 31,39,50,51 31,33,39,50 31,50,51 31,33,39,50 31,32,39,50,61 31 31 31,51 31

a

Incidence is reported as percentage of infants with clinical manifestations, not as percentage of all infants born to narcotic-addicted women. b Respiratory distress due to etiologies other than hyaline membrane disease.

22 infants born to heroin addicts compared with 19 normal infants. Olsen and Lees (58) demonstrated a blunted ventilatory response to increasing concentrations of inspired carbon dioxide in 9 infants born to methadone addicts. This depressed response lasted for an average of 15 days but persisted for 31 days in one infant. Davidson et al. (59) reported abnormal sleeping ventilatory patterns in 27 infants born to substance-abusing mothers, many of whom abused opiates, compared with 43 control infants. These abnormalities included more frequent apneic episodes (ⱖ6 s), longer duration of apneic events, and more periodic breathing. The significance of these findings is presently unknown. Followup data have not disclosed a relationship in these infants between abnormal ventilatory patterns and future problems, such as the sudden infant death syndrome (SIDS) (60). Seizures have been reported in up to 21% of infants exhibiting narcotic withdrawal. The onset of seizure activity is usually delayed. Rosen and Pippenger (50) observed seizures in 5 of 18 symptomatic infants born to narcotic addicts. These infants developing seizures between the sixth and eighth days of life. Infants receiving paregoric for withdrawal symptoms had a significantly lower incidence of developing seizures than infants being treated with other drug combinations. These seizures were difficult to control with phenobarbital, diazepam, and paraldehyde alone, but responded to paregoric alone or in combination with diazepam or phenobarbital. Herzlinger et al. (61) reported the occurrence of seizures at a mean age of 10 days (range 3–34 days) in 18 narcotic-addicted infants. Seven infants experienced generalized seizures, seven myoclonic seizures, three had seizure activity manifested as automatisms (staring, blinking, lip smacking or abnormal sucking), and one infant exhibited multifocal clonic seizures. Paregoric was more effective than diazepam in controlling seizures. Interictal electroencephalograms (EEGs) were interpreted as normal in 12 of 13 infants in whom an EEG was obtained. Olofsson et al. (32), who found that seizures were statistically more frequent in infants with 1-minute Apgar scores below 7, inferred that birth asphyxia may predispose infants born to narcotic-addicted women to convulsions. In summary, seizures should be anticipated in infants born

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to narcotic-addicted mothers and should be treated with either paregoric or a parenteral narcotic agonist, such as morphine, until controlled. Maintenance therapy with paregoric appears to be effective in preventing the recurrence of seizures. The clinical course of the narcotic-addicted newborn can be extremely variable, ranging from only mild symptoms of brief duration to a crescendo in severity to intermittent symptomatology. A protracted clinical course with symptoms lasting 4–6 months has also been described (62). Wilson et al. (63) observed a biphasic course in 82% of symptomatic infants born to heroin-addicted mothers. These infants had an exacerbation or recurrence of symptoms upon discharge to the home environment. Symptoms included restlessness, agitation, tremors, wakefulness, hyperphagia, colic, and vomiting. These symptoms persisted for 3–6 months, and in some infants mandated resumption of therapy. Therefore, close outpatient follow-up to evaluate these infants for a recurrence of signs or symptoms of drug withdrawal is essential. Factors affecting the timing and severity of the withdrawal syndrome are summarized in Table 3. Although mortality from neonatal narcotic withdrawal approaches 0 with appropriate treatment, these infants may be at increased risk of dying from SIDS. Chavez et al. (64) compared the incidence of SIDS in 688 infants born to narcotic-addicted women with a control group of 388 randomly selected infants born to nonaddicted mothers of similar socioeconomic backgrounds. A fivefold increased incidence of SIDS (2.5 vs. 0.5%) was observed in the group of infants born to narcotic-addicted mothers. Of interest, more deaths were observed in infants who exhibited moderate to severe withdrawal compared with infants who manifested only minor or mild symptoms. The difference achieved significance at the p ⬍ 0.01 level. The mean age at the time of death was 9.2 weeks. Pierson et al. (65) also reported two confirmed and one possible case of SIDS among 14 infants whose mothers received methadone during pregnancy. Signs and symptoms of narcotic withdrawal resulting from maternal use of propoxyphene (3–5) codeine (6,7), and pentazocine (8–10) are similar and may be as severe as those described in heroin or methadone withdrawal. In these cases, the majority of infants manifested symptoms within the first 24 hours of life but were asympatomatic by 10 days of age. One infant developed seizures at 36 hours of life (4), and one infant died of SIDS at 14 weeks of age (10). Treatment Some infants exhibiting signs or symptoms of narcotic withdrawal can be effectively managed utilizing conservative measures such as holding, swaddling, minimal stimulation, and demand feedings using a hypercaloric formula (24 cal/oz). However, the majority of symptomatic infants require pharmacological therapy. Finnegan et al. (66) developed a neonatal narcotic abstinence scoring system in order to assess the severity of withdrawal

Table 3 Factors Influencing the Onset and Severity of the Neonatal Narcotic Withdrawal Syndrome Addictive drug used Drug dose during pregnancy and at time of delivery Timing of last dose prior to delivery Type and amount of analgesia/anesthesia given during labor

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and to guide therapy. They ranked 20 common symptoms of narcotic withdrawal, giving each symptom 1–5 points based on its clinical significance. The least significant symptoms, such as yawning, receive 1 point, whereas seizures receive 5 points (Table 4). This scoring system assumes that the greater the number of symptoms and the greater their severity, the higher the associated morbidity and mortality. According to Finnegan’s guidelines, babies are scored at birth and then hourly for 24 hours, every 2 hours during the second day of life, and every 4 hours thereafter. Infants with abstinence scores of 8 or more received pharmacotherapy, whereas those with scores less than 8 were treated conservatively. Finnegan and her coinvestigators then compared data from a group of 37 infants born to narcotic-addicted women prior to the development of the scoring system with a group of 37 infants born after the institution of the scoring system. The groups were similar with respect to severity of symptoms. Utilization of the scoring system not only increased the number of infants managed conservatively (46 vs. 30%), but also reduced the duration of pharmacological therapy from an average of 8–6 days. The mean length of hospitalization was also shortened from 21–15 days. Lipsitz (67) has developed a similar scoring system evaluating 11 signs and symptoms of narcotic withdrawal. This scoring system—while concentrating on the more common symptoms of withdrawal such as tremors, irritability, muscle tone, hyperreflexia, and tachypnea—does not emphasize several clinically important symptoms that may increase morbidity from narcotic withdrawal, such as vomiting, dehydration, seizures, and postprandial sleep. Although we feel the Lipsitz scoring system reliably identifies infants with a drug withdrawal syndrome, Finnegan’s scoring system is more detailed, has a greater emphasis on symptoms likely to correlate with morbidity and mortality, and therefore is better suited to quantify the severity of withdrawal and to guide pharmacological therapy. Also, to the best of our knowledge, the Lipsitz scoring system has not been rigorously evaluated as a means for identifying infants requiring pharmacotherapy or to guide ongoing therapy. Many drugs—including paregoric, tincture of opium, morphine, methadone, diazepam, chlorpromazine, phenobarbital, and clonidine—have been used to treat neonatal narcotic withdrawal (1,2,68). We discuss therapy with paregoric and phenobarbital in detail, since these drugs are the most popular agents used and represent the two important classes of compounds for treatment. Treatment with other drugs has been reviewed (1,2). Paregoric, a camphorated opium tincture, contains 0.4 mg/mL anhydrous morphine. Since the turn of the century it has been used successfully for the treatment of the neonatal narcotic withdrawal syndrome (69). The recommended dose for full-term infants is 0.2– 0.5 mL (0.08–0.20 mg anhydrous morphine) administered orally every 3–4 hours until symptoms are controlled (1). In general, we select our initial dose depending on the severity of withdrawal symptoms (Table 5). If no clinical improvement is observed within 4 hours after the initial dose, we increase the paregoric dose by 0.05 mL q4h until symptoms are controlled (Finnegan score ⱕ4). When the withdrawal score has remained stable for 48 hours the total daily dose may be tapered by 10% each day while maintaining the dosage interval constant. If symptoms recur, the dose should be increased to the previous dose which effectively controlled symptoms. Paregoric has the advantage of being a narcotic, so treatment should be more physiological than with nonnarcotic agents; and indeed, treated neonates have a more physiological sucking pattern, higher caloric intake, and more weight gain than infants treated with phenobarbital (55). Also, dosing of paregoric is easily titratable. Disadvantages of paregoric are mainly attributable to the other constituents present in the prepara-

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Table 4 Neonatal Narcotic Withdrawal Score Sign or symptom 1. High-pitched cry Intermittent Continuous 2. Postprandial sleep ⬍3 h ⬍2 h ⬍1 h 3. Moro reflex Hyperactive Markedly hyperactive 4. Tremors Mild when disturbed Marked when disturbed Mild when undisturbed Marked when undisturbed 5. Tone Increased Seizures 6. Frantic sucking of fists 7. Poor feeding 8. Vomiting Regurgitation Projectile 9. Stools Loose Watery 10. Dehydration 11. Frequent yawning 12. Sneezing 13. Nasal stuffiness 14. Sweating 15. Mottling 16. Fever 38–38°C ⬎38°C 17. Respiratory rate ⬎60 ⬎60 with retractions 18. Excoriation of nose 19. Excoriation of knees 20. Excoriation of toes Total maximum Source: From Ref. 66.

Possible score 2 3 1 2 3 2 3 1 2 3 4 2 5 1 2 2 3 2 3 2 1 1 1 1 1 1 2 1 2 1 1 1 40

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Table 5 Initial Paregoric Dose in Full-Term Infants Based on Withdrawal Score Withdrawal scorea ⬍ 8 8–10 11–13 14–16 ⱖ17 a b

Dose (mL) b None 0.2 0.3 0.4 0.5

Based on Finnegan Scoring System (66). See text for dosing interval and guidelines for chronic therapy.

tion. Camphor, a central nervous system (CNS) stimulant, is eliminated slowly owing to its high lipid solubility and dependence on glucoronidation for elimination. Paregoric also contains alcohol and anise oil, which may cause dependency (1). Benzoic acid, an oxidative metabolite of benzyl alcohol, is also present in paregoric: circumstantial, but not conclusive, evidence has linked benzyl alcohol, when administered in excessive doses, to the ‘‘gasping syndrome’’ described in premature infants (70–72). Our initial dosing recommendation for paregoric in premature infants is 0.05 mL/kg q4h with increments of 0.02 mL/kg q4h until symptoms are controlled. Although paregoric may be more physiological, phenobarbital and its analogs have also been employed successfully in the treatment of the neonatal narcotic withdrawal syndrome. Most physicians feel comfortable with using phenobarbital, which has the added advantage of mitigating symptoms referable to the central nervous system. Kundstadter et al., in 1958 (73), commented that when sedation is required, phenobarbital is a safer drug than an opiate. This belief is still held by many physicians today. However, phenobarbital will not relieve gastrointestinal symptoms, such as vomiting or diarrhea (69), and may cause significant CNS depression. Also, phenobarbital is not a suitable drug for dose titration owing to its prolonged elimination half-life. Other disadvantages of phenobarbital relate to other chemicals present in the formulation; the elixir contains alcohol, whereas the parenteral formulation contains propylene glycol, ethyl alcohol, and benzyl alcohol (1). Finally, there are no standard dosing guidelines for phenobarbital therapy, nor is the therapeutic serum concentration necessary to control withdrawal known. Two studies have compared the efficacy of treatment with paregoric and phenobarbital (74,75). Kandall et al. (74) prospectively randomized infants to receive paregoric or phenobarbital if their withdrawal score (modified Lipsitz scoring system) was 7 or greater or if any infant developed excessive severity of any sign. Serum phenobarbital concentrations were not monitored. The drugs were considered by the investigators to be comparable in their ability to control gastrointestinal, CNS, and autonomic symptoms. However, 7 of 62 infants receiving phenobarbital developed seizures, compared with none of 49 infants maintained on paregoric ( p ⬍ 0.025). Carin et al. (75) failed to demonstrate a difference in weight gain between infants treated with paregoric and those treated with phenobarbital. Paregoric-treated newborns received therapy for a longer period of time (median duration 22 days vs. 17 days) compared with phenobarbital-treated infants. This is most likely due to two factors: paregoric therapy was not discontinued until the daily dose had been weaned to 0.1 mL/kg, whereas once phenobarbital administration was stopped, effective

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serum concentrations were probably maintained for an extended period of time owing to the markedly prolonged t1/2β of phenobarbital. Carin’s study has several major flaws, which cast concerns on the validity of the data and conclusions. Among the mothers of infants treated with paregoric, 4 of 16 admitted to using heroin in addition to methadone, and 3 of 16 mothers used cocaine concomitantly. This is in contrast to the mothers whose infants were treated with phenobarbital, who had not used heroin or cocaine. Also, control of withdrawal symptoms and initial and subsequent withdrawal scores were not reported. Therefore, the severity of withdrawal was not controlled for in the treatment randomization process, nor was the efficacy of therapy in controlling withdrawal symptoms reported. In a more critical evaluation, Kaltenbach and Finnegan (76) demonstrated the superiority of paregoric in a study designed to determine whether there was a relation between pharmacotherapy and development outcome. Of 23 infants treated initially with paregoric, treatment was effective with this drug alone in 21. By comparison, only 17 of 36 infants were treated effectively with phenobarbital alone. The remaining 19 infants required the addition of paregoric to their phenobarbital regimen. Finnegan and Ehrlich (77) also reported that paregoric was more effective than phenobarbital or diazepam in controlling symptoms of narcotic withdrawal, whereas phenobarbital was more effective in controlling symptoms associated with nonopiate withdrawal. In summary, clinical manifestations occur in most infants of narcotic-addicted women. The Finnegan scoring system is a useful tool for assessing the severity of withdrawal and in guiding therapy. However, we would initiate pharmacological therapy with paregoric regardless of the infant’s withdrawal score if presenting symptoms included seizures, vomiting, or severe and persistent diarrhea resulting in weight loss or dehydration, or inability to sleep. Figure 1 outlines our treatment approach to infants of narcoticaddicted mothers. Outcome Interpreting follow-up data in infants born to narcotic-addicted mothers is very difficult owing to the paucity of studies, lack of adequate control populations, and the chaotic home environment into which these children are returned. Several studies have revealed marked behavioral abnormalities in narcotic-addicted infants (55,78–80). Strauss et al. (78) used the Brazelton Neonatal Behavioral Assessment Scale to evaluate 44 infants born to narcotic-addicted mothers. Testing was done during the first 48 hours of life. Addicted infants spend less time in an alert state and became less responsive to social and nonsocial stimuli over the first 2 days of life. The investigators suggested that this behavior may adversely affect development of infant-caregiver interaction patterns. This speculation is supported by a subsequent study by Kaltenbach et al. (79), who investigated the ability of the infants born to a narcotic-dependent mother to interact with their environment. These infants were evaluated on days 1 and 30 of life. All infants who would eventually require pharmacological therapy had a deficient interaction score on day 1. By day 30, only a subset of infants still receiving treatment demonstrated poor interaction skills. Interestingly, these were the infants whose mothers rarely visited them while hospitalized. The investigators theorized that poor interaction skills on day 1 may have alienated mothers, or conversely, maternal attention may have improved the infant’s interaction. Olofsson et al. (80) corroborated the data from these two studies. Of 72 infants born to narcotic addicts who were reinvestigated between 1 and 10 years

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Figure 1 Management approach for the infant born to a narcotic-addicted mother.

of life, 21% had moderate or severe psychomotor retardation primarily attributable to a deprivation syndrome. In addition, both Olofsson et al. (80) and Wilson et al. (63) observed hyperactive and aggressive behavior with a decreased attention span and lack of social inhibition in more than half of infants followed through infancy and early childhood. In contrast to the behavioral abnormalities described above, conflicting data regarding motor and mental development in infants of narcotic-addicted mothers have been reported. Rosen and Johnson (81) observed significantly lower mental and psychomotor developmental indices by the Bayley Scales of Infant Development at 12 and 18 months of age, though all scores were within normal limits. Lifschitz et al. (42) reported a higher incidence of low average and mildly retarded intellectual performance in children between 3 and 6 years of age who were born to narcotic-addicted mothers. Analysis of the data suggested that environmental and prenatal factors, not intrauterine exposure to narcotics, were responsible for the lower scores. By comparison, Wilson et al. (82) found no difference in mental or psychomotor developmental indices by the Bayley Scale at 9 months of age. Fine motor coordination was poorer, however, in infants born to narcotic addicts, supporting a similar observation by Rosen and Johnson (81). Finally, Kaltenbach and Finnegan found no evidence of impaired cognitive function in infants at 6 months of age (83), or in children between 3.5 and 4.5 years of age (84) who were born to narcoticaddicted women.

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Kaltenbach and Finnegan (76) reported no differences in mental development at 6 months of age between infants who demonstrated severe withdrawal symptoms at birth and those with mild symptoms not requiring pharmacological therapy. They suggest that appropriate therapeutic intervention may obviate adverse cognitive sequelae. However, prenatal or environmental factors were not analyzed. As stated previously, infants born to narcotic-addicted women have low measurements on mean birth weight, length, and head circumference. The growth curve in early infancy follows the percentiles noted at birth for these three parameters. However, after 4–6 months of age, some infants appear to have an accelerated growth pattern (62). Chasnoff et al. (62) followed the growth patterns of 15 infants whose mothers were maintained on a low dose of methadone (14 of 15 mothers received ⬍ 20 mg/day) during their third trimester of pregnancy. At birth and 4 months of age, the mean birth weight, length, and head circumference lay at the 10th, 10th, and 5th percentiles respectively. However, at 7.5 months, these infants lay at the 40th, 25–50th, and 25th percentiles, respectively. The excellent outcome for growth noted by Chasnoff et al. may be due to the low dose of methadone administered to the pregnant women. Olofsson et al. (80) demonstrated a correlation between maternal methadone dose and weight, height, and head circumference at a mean age of 3.5 years. Of mothers receiving less than 20 mg/day at birth, none of 33 infants were below the 10th percentile for weight, height, or head circumference, compared with 6 of 31 children whose mothers received 20 or more mg/day of methadone. Unfortunately, growth parameters at birth were not compared between the two groups. Overall, the heights of these children were statistically below the mean for age, a finding similar to those of Wilson et al. (85). While Lifschitz et al. (42) did not show impaired head growth, Rosen and Johnson (81) reported that head circumferences remained below the third percentile in 63% of infants followed up at 18 months of age whose head circumference at birth was below the third percentile. Wilson et al. (85) reported that 14% of heroin-exposed children had a head circumference below the third percentile when examined between 3 and 6 years of age. Again, the head circumference at birth was not reported. In summary, brain growth may be blunted long term subsequent to in utero narcotic exposure. Infants born to narcotic-addicted women may also be at increased risk of developing strabismus. Nelson et al. (86) and Rosen and Johnson (81) observed strabismus in 24 and 21% of narcotic-exposed infants, respectively, compared with a reported incidence of 2.8– 5.3% in the general population. Therefore, these infants should be evaluated for the presence of strabismus as part of their outpatient follow-up care. In summary, follow-up studies of narcotic-exposed infants have revealed significant behavioral abnormalities, but not long-term cognitive deficits.

STIMULANTS Adverse effects on the fetus and newborn attributable to maternal cocaine use during pregnancy are now being appreciated. It is not clear, however, whether infants of cocaineabusing mothers manifest symptoms from drug withdrawal. Madden et al. (87) reported no overt symptoms of withdrawal in eight infants whose mothers abused cocaine during pregnancy. Infants whose urine screens were positive for other abusive drugs were excluded from their study. Ryan et al. (88) recently compared three groups of infants; one group was born to mothers who used cocaine in addition to methadone and/or other drugs,

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another group of infants was born to mothers whose drug-use patterns were similar to those of the first group except they did not use cocaine, and the third group was a control population of non-drug-dependent women. The frequency of drug withdrawal symptoms was comparable between the cocaine/methadone- and methadone-exposed infants, implying that cocaine does not increase the risk of neonatal drug withdrawal. In contrast, other investigators have observed mild ‘‘withdrawal’’ syndromes consisting of abnormal sleep/wake patterns, poor feeding, irritability, tremulousness, hypertonia, and hyperreflexia (89–93). However, these symptoms are similar to those reported by Chasnoff et al. (94) in a 2-week-old cocaine-intoxicated infant. This child manifested symptoms for 48 to 72 hours. Cocaine should readily cross the placenta owing to its high lipid solubility. Since cocaine is primarily eliminated by hepatic metabolism and by plasma cholinesterases (95), which have low activity in the fetus and newborn (96), accumulation of cocaine in the fetus and subsequent toxic manifestations are not surprising. Owing to an expected slow elimination phase for cocaine by the fetus and newborn, we would anticipate withdrawal signs and symptoms to be delayed from birth if they occur at all. These pharmacokinetic/ pharmacodynamic predictions are supported by the data presented by Chasnoff et al. (97). These investigators reported the presence of cocaine or its metabolites in a newborn’s urine for at least 4 days after delivery. Therefore, we feel symptoms previously ascribed to ‘‘cocaine withdrawal’’ may in fact represent cocaine intoxication. Oro and Dixon (92) reported similar symptoms of CNS hyperexcitability among infants born to amphetamine-abusing mothers. However, some of these infants exhibited marked lethargy and required tube feedings when their hyperexcitable state subsided. This state of pronounced lethargy most likely represents a true withdrawal syndrome comparable to that observed during cocaine and methamphetamine withdrawal in adults (98). Other investigators have reported similar observations in infants born to mothers abusing amphetamines (99,100). Ramer (99), in 1974, reported the case of a full-term infant born to a mother using parenterally administered amphetamines during pregnancy. She was admitted to the maternity hospital 4 days prior to delivery. Episodes of diaphoresis, restlessness, and miotic pupils were observed in the newborn during the first day of life. By the third day of life, the infant was listless, with decreased muscle tone, and was observed to have a peculiar glassy-eyed stare. These symptoms abated by the ninth day of life. In summary, infants born to mothers abusing CNS stimulants may exhibit signs or symptoms of intoxication or withdrawal. As in the case of narcotic-addicted infants, the temporal relationship between the last maternal dose and delivery appears to be a major factor in the timing of neonatal symptoms and in determining whether the newborn manifests symptoms attributable to intoxication or withdrawal. Marked symptoms of CNS hyperexcitability can be controlled with the administration of benzodiazepines as needed (101), whereas withdrawal symptoms should be managed supportively. Although infants born to cocaine users may not manifest symptoms of drug withdrawal, cocaine clearly affects pregnancy and neonatal outcome adversely. Women who use cocaine during pregnancy are at increased risk for spontaneous abortion (88,89,102), premature labor (89), precipitous delivery (89), abruptio placentae (89,92,102), and meconium staining (89). Cocaine may also be teratogenic. Bingol et al. (103) reported a significantly higher congenital malformation rate in cocaine-using mothers compared with a non-drug-using control group. Affected infants presented with congenital heart disease or skeletal defects. Chasnoff et al. (104) observed genitourinary tract malformations in 3 of 23 infants born to women who only used cocaine during the first trimester of pregnancy,

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and in 6 of 52 infants whose mothers used cocaine throughout pregnancy. The genitourinary tract malformations included prune-belly syndrome (2), hydronephrosis (4), secondary hypospadias (2), and female pseudohermaphroditism (1). Two additional infants who were exposed to cocaine throughout pregnancy had ileal atresia. These clinical reports of the teratogenic potential of cocaine are supported by the work of Mahalik and coworkers (105), who described skeletal and genitourinary tract malformations in the offspring of gravid mice administered cocaine early in pregnancy. However, in none of these reports did a homogeneous pattern of malformations emerge, and the data should be interpreted cautiously. For example, during embryonic life the genitourinary system does not develop from one origin, and it is impossible to trace the malformations described above to one etiological factor. Although conflicting data initially appeared in the literature regarding the effect of maternal cocaine use on intrauterine growth (87,89,102), more recent investigations have observed a significant effect on growth (90,103,106). Bingol et al. (103) reported mean birth weight, length, and head circumference of 2276 g, 46.2 cm, and 32 cm in 50 fullterm infants born to women who abused only cocaine during pregnancy, whereas Fulroth et al. (90) discovered a 20% incidence of growth retardation and a 29% incidence of microcephaly in prenatally exposed infants. Most recently, Chasnoff et al. (104) reported lower mean birth weights, lengths, and head circumferences among term infants born to mothers who used cocaine throughout pregnancy compared with control infants. In contrast, no differences in intrauterine growth parameters existed between infants born to mothers who used cocaine only during the first trimester and control infants. Another adverse neurological outcome described in infants exposed in utero to cocaine is cerebral infarction. Chasnoff et al. (97) reported an infant with a right hemiparesis and right-sided focal seizures on the first day of life born to a mother who used excessive amounts of cocaine for 3 days prior to delivery. Computed tomography of the brain demonstrated a cerebral infarction within the distribution of the left middle cerebral artery, and a lumbar puncture revealed 1800 red blood cells and 5 white cells. The cerebrovascular accident may have resulted from intrauterine hypertension or hypotension due to the vasoconstrictor effects of cocaine on placental blood vessels. Furthermore, neurobehavioral effects similar to those observed in narcotic-exposed infants have been reported in infants born to cocaine users (90,91,102,104). Besides being more irritable, these infants demonstrate depressed interactive behavior and impaired responses to environmental stimuli. Chasnoff et al. (104), utilizing the Neonatal Behavioral Assessment Scale between 12 and 72 hours of life, observed significant deficiencies in orientation, motor ability, and state regulation among cocaine-exposed infants. In addition, Dixon et al. (91) observed very poor visual attention and abnormal flash-evoked visual potentials in 11 of 12 infants studied. Of concern are persistent visual disturbances at 4– 6 months of age, as revealed by preliminary data. Such neurobehavioral abnormalities may impede the establishment of appropriate caretaker-infant relationships. Abnormal (EEGs) featuring bursts of sharp wave-and-spike patterns and bursts of theta rhythm have also been seen in newborns of cocaine users (91,93). Doberczak et al. (93) reported an abnormal EEG during the first week of life in 17 of 38 infants studied. Although the EEG was still abnormal in 9 of 14 infants in whom the test was repeated between days 9 and 14 of life, all but one EEG had normalized by 3–12 months of age. These infants may also be at increased risk of SIDS (88,89). Chasnoff et al. (89) reviewed the histories of 66 cocaine-exposed infants born to women enrolled in perinatal drug programs in San Francisco or Chicago. Ten of these infants died of SIDS. This 15%

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incidence of SIDS is significantly greater than the risk previously reported for narcoticexposed infants and for the general population (64). In contrast, however, Bauchner et al. (106) did not detect an increased risk of SIDS among 175 infants exposed to cocaine in utero. In summary, cocaine intoxication should be anticipated in infants born to mothers abusing cocaine. Signs and symptoms of CNS hyperexcitability may persist for several days. Distinct neurobehavioral and EEG abnormalities have been attributed to in utero cocaine exposure. Long-term studies are required to determine whether these abnormalities will increase the infant’s risk for future developmental, cognitive, or behavioral sequelae.

SEDATIVE-HYPNOTICS Alcohol Jones et al. (107) first recognized malformations among eight infants born to alcoholic mothers and termed this pattern the fetal alcohol syndrome (FAS). Characteristic features of this syndrome include intrauterine growth retardation, slow postnatal growth, microcephaly, developmental delay, impaired intellectual performance, and craniofacial and musculoskeletal anomalies (107–109). Other reported abnormalities include cardiac defects (mostly septal defects), ear and external genitalia anomalies, and cutaneous anomalies such as hemangiomas, pigmented nevi, and hirsutism (108). Several of the functional and anatomical derangements observed in these infants most likely result from brain dysmorphogenesis. Jones and Smith (109) reported the results of an autopsy performed in one patient with FAS. Histopathology of the brain revealed small size, incomplete development of the cerebral cortex, agenesis of the corpus callosum, and disorganization of neural and glial elements. Although FAS is well recognized, symptoms of alcohol withdrawal in newborns have not been fully appreciated. Schaefer (110) published the first reported case of alcohol withdrawal in an infant born to an intoxicated American (Yukon) Indian woman. Symptoms appeared by 18–24 hours of life and included irritability, coarse tremors of the hands and feet, restlessness, sleepiness, and excessive crying. An ‘‘alcoholic fetor’’ was apparent up to 12 h of life. By the sixth day of life, the infant was still irritable and easily startled; however, other clinical manifestations had resolved. Since the report by Schaefer, other cases of alcohol withdrawal in neonates have been published (111,112). Central nervous system manifestations of alcohol withdrawal develop within 24 hour of birth and may include tremors, irritability, hypertonicity, muscle twitching, hyperventilation, hyperacusia, opisthotonos, and seizures (111,112). Gastrointestinal symptoms such as abdominal distention and vomiting are less frequent (111). Symptoms of alcohol withdrawal may be severe but appear to be of brief duration. Infants born to alcoholic mothers may be at a higher risk of seizures than narcotic-exposed infants; three of six newborns reported by Pierog et al. (111) and the neonate described by Nichols (112) developed seizures. Infants manifesting signs or symptoms of alcohol withdrawal require pharmacological intervention. The infants described above were treated with chlorpromazine or phenobarbital. Such interventions do not appear to be mechanistically based, and these drugs may not prove to be optimal therapy. Phenothiazines reduce the seizure threshold and thus may enhance the risk of seizures in these infants. Phenobarbital has been effective in adult cases of alcohol withdrawal, but it is not easily titrated. Our drug of choice is

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diazepam. Benzodiazepines demonstrate a cross-tolerance with alcohol and have a wider therapeutic index than phenothiazines or barbiturates (114). In adults, benzodiazepines are as effective as barbiturates in alleviating symptoms of alcohol withdrawal, and they can prevent withdrawal seizures (113). Several dosing regimens of diazepam have been used in adults (114). One such regimen, the diazepam-loading technique, appears to be both safe and effective (115). This technique relies on the slow clearance of diazepam and its active metabolites from the body. After effective loading with diazepam, the therapeutic effect usually persists longer than the duration of the withdrawal syndrome, obviating the need for additional pharmacological therapy. We would recommend administering 0.25 mg/kg IV of diazepam q2h until symptoms are controlled. Sellers et al. (115) reported successful responses to the diazepam-loading technique in a median time of 7.6 hour in 36 adults with acute alcohol withdrawal. Only three patients required therapy beyond 24 hours. In summary, alcohol withdrawal should be considered in the differential diagnosis of the irritable newborn, particularly when characteristic features of FAS are present. Signs and symptoms of neonatal alcohol withdrawal are remarkably similar to those observed in the neonatal narcotic withdrawal syndrome except that seizures may be more frequent in the former and gastrointestinal symptoms are more prevalent in the latter. Barbiturates Signs and symptoms of drug withdrawal have also been described in infants born to mothers receiving barbiturates (116–118). Desmond et al. (116) reported their observations on 15 infants born to mothers who either were addicted to barbiturates or were receiving phenobarbital for sedation, hypertension, or as part of an anticonvulsant regimen. Phenobarbital dosages ranged from 60 to 180 mg qd. Symptoms were similar to those observed in narcotic-exposed infants: all displayed hyperactivity, restlessness, disturbed sleep, and excessive crying, with the majority of infants also noted to be tremulous, hyperreflexic, and hyperphagic. Clinical manifestations of drug withdrawal appeared later in these infants compared with infants born to narcotic addicts. Most of the infants reported by Desmond et al. (116) became symptomatic toward the end of the first week of life, although the age at onset of barbiturate withdrawal was delayed up to 2 weeks in some infants. This delay should not be unexpected, considering the long t1/2β of barbiturates. Most infants were symptomatic for 2–6 weeks. Bleyer and Marshall (117) and Ostrea (118) also reported barbiturate withdrawal in infants born to mothers receiving secobarbital and butalbital, respectively. both these infants developed generalized seizures in addition to other symptoms of neuromuscular excitability. Infants demonstrating signs or symptoms of barbiturate withdrawal may be effectively treated with phenobarbital. Table 6 lists our indications for initiating therapy. We

Table 6 Indications for Initiating Pharmacological Therapy in Barbiturate Withdrawal Seizures Signs or symptoms interfering with normal caretaker–infant interactions, such as moderate to severe hyperactivity or irritability Poor feeding or failure to gain weight

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would administer a loading dose of 20 mg/kg IV or IM, and start maintenance therapy with 4 mg/kg/day IV or PO. Higher maintenance doses may be required to control symptoms (117). Serum phenobarbital concentrations should be monitored to avoid toxicity. When symptoms have been controlled for a week, we decrease the daily dose by 25% of the original dose every week. Benzodiazepines Symptoms indistinguishable from narcotic or barbiturate withdrawal, including seizures, have also been observed in infants born to mothers receiving therapeutic doses of chlordiazepoxide (119,120) and diazepam (121,122). The onset of symptoms may appear shortly after birth or be significantly delayed; Athinarayanan et al. (119) reported the onset of withdrawal at 21 days of age in twin infants born to a mother receiving 30 mg/day of chlordiazepoxide during pregnancy. Withdrawal symptoms persisted for long periods of time in several of these infants. We recommend initiating treatment of benzodiazepine withdrawal with 0.1 mg/kg diazepam q12h IV. More frequent dosing or larger doses may be required to control symptoms. When symptoms have been well controlled for approximately a week, we recommend weaning diazepam over 3–4 weeks by gradually reducing a given dose each day. Indications for initiating therapy are similar to those for barbiturate withdrawal (see Table 6). Case reports describing neonatal withdrawal from hydroxyzine (123), ethchlorvynol (124), and glutethimide (125) have also appeared in the literature. Although an abstinence syndrome from these agents would not be surprising, withdrawal from the concomitant use of phenobarbital, diazepam, and heroin, respectively, in these cases cannot be excluded. In summary, neonatal withdrawal from sedative hypnotics may occur and should be anticipated in infants born to mothers chronically receiving this class of drugs toward the end of pregnancy. Signs and symptoms of neuromuscular excitability predominate and may be delayed from birth in onset and may follow a protracted course. Treatment should be initiated when symptoms are life threatening or interfere with caretaker–infant interactions or when a potentially adverse effect on the growth of the infant is perceived.

MISCELLANEOUS DRUGS Other classes of drugs reported to be associated with a withdrawal syndrome in the newborn are tricyclic antidepressants (TCAs) (124–126) and phenothiazines (127). Webster (126) observed breathlessness, cyanosis, tachypnea, tachycardia, and irritability in a 1day-old infant born to a mother receiving desmethylimipramine during pregnancy. Gradual improvement in the infant’s condition was noted by 10 days of life. Eggermont (127) noted similar symptoms in three infants whose mothers took imipramine during pregnancy. Ben Musa and Smith (128) described an infant with hypothermia and jitteriness born to a mother receiving clomipramine. Symptoms were present by 12 h of life and persisted for 4 days. More data are required to permit us to appreciate the effect of maternally administered TCAs on the newborn and to decide whether these symptoms result from drug intoxication or drug withdrawal. O’Conner et al. (129), in 1981, reported an interesting case of late-onset neurological dysfunction in a 3-week-old infant born to a mother who had received intramuscular injec-

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tions of fluphenazine decanoate daily throughout her last two trimesters of pregnancy. The infant developed choreiform and dystonic movements, primarily of the upper extremities, associated with irritability, hypertonicity, and sleep disturbance. Diphenhydramine hydrochloride administration did little to alleviate the symptoms. The infant gradually improved and by 9 months of age was asymptomatic. This report illustrates a case of drug withdrawal following material administration of a high potency, long-acting phenothiazine. We feel that these symptoms may be analogous to a phenomenon known as withdrawal-emergent dyskinesias, a variant of tardive dyskinesias (130). This phenomenon most likely results from disuse supersensitivity of dopaminergic pathways in the brain. Treatment with phenothiazines may mask the dyskinesias. However, administration of phenothiazines or antimuscarinic agents may also worsen the underlying condition. Therefore, the aim of management should be supportive care with avoidance of neuroleptic and anticholinergic agents.

SUMMARY Neonatal drug withdrawal syndromes have been reported following chronic maternal administration of many classes of agents. Withdrawal from narcotics has been studied most intensely in newborns and is associated with both short- and long-term morbidity. Although infants born to mothers abusing stimulants may manifest symptoms of drug withdrawal, perinatal complications such as abruptio placentae and cerebrovascular accidents appear to be more worrisome. Neonatal withdrawal from sedative-hypnotics may also occur, with signs and symptoms of neuromuscular hyperexcitability predominating. Finally, the timing of the last maternal dose of a drug with respect to delivery as well as a given agent’s pharmacokinetic properties may influence the time to onset of a neonatal abstinence syndrome following delivery. Symptoms may be delayed from birth; they may be severe and life-threatening, and the clinical course may be protracted. Clinical Case Answer Drug withdrawal occurs when there is little or no drug in the system, therefore the negative neonatal urine test is consistent with the diagnosis. Although other diagnostic options must be carefully ruled out, the baby should benefit from oral paregoric acid treatment or other forms of sedation (e.g., phenobarbital). REFERENCES 1. Committee on Drugs. Neonatal drug withdrawal. Pediatrics 1983; 72:895–902. 2. Marx CM, Cloherty JP. Drug withdrawal. In: Manual of Neonatal Care, 2nd ed. Cloherty JP, Stark AR, eds. Boston: Little Brown, 1985, pp 17–28. 3. Tyson HK. Neonatal withdrawal symptoms associated with maternal abuse of propoxyphene hydrochloride. J Pediatr 1974; 85:684–685. 4. Klein RB, Blatman S, Little GA. Probable neonatal propoxyphene withdrawal: a case report. Pediatrics 1975; 55:882–884. 5. Quillan WW, Dunn CA. Neonatal drug withdrawal from propoxyphene. JAMA 1976; 235: 2128. 6. Mangurten HH. Neonatal codeine withdrawal in infants of nonaddicted mothers. Pediatrics 1980; 65:159–160.

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59. Davidson SL, Schuetz S, Krishna V, et al. Abnormal sleeping ventilatory pattern in infants of substance-abusing mothers. Am J Dis Child 1986; 140:1015–1020. 60. Checola RT, Prybylski D, Senie R, Kandall SR. Cardiorespiratory patterns in passively addicted (PA) neonates (abstr). Pediatr Res 1986; 20:345A. 61. Herzlinger RA, Kandall SR, Vaughan HG Jr. Neonatal seizures associated with narcotic withdrawal. J Pediatr 1977; 91:638–641. 62. Chasnoff IJ, Hatcher R, Burns WJ. Early growth patterns of methadone-addicted infants. Am J Dis Child 1980; 134:1049–1051. 63. Wilson GS, Desmond MM, Verniaud WM. Early development of infants of heroin-addicted mothers. Am J Dis Child 1973; 126:457–462. 64. Chavez CJ, Ostrea EM, STryker JC, Smialek Z. Sudden infant death syndrome among infants of drug dependent mothers. J Pediatr 1979; 95:407–409. 65. Pierson PS, Howard P, Kleber HD. Sudden deaths in infants born to methadone-maintained addicts. JAMA 1972; 220:1733–1734. 66. Finnegan LP, Kron RE, Connaughton JF Jr, Emich JP. A scoring system for evaluation and treatment of the neonatal abstinence syndrome: A new clinical and research tool. In: Morselli PL, Garattini S, Serini F, eds. Basic and Therapeutic Aspects of Perinatal Pharmacology New York: Raven Press, 1975, pp 139–153. 67. Lipsitz PJ. A proposed narcotic withdrawal score for use with newborn infants. Clin Pediatr 1975; 14:592–594. 68. Hoder EL, Leckman JF, Ehrenkranz R, et al. Clonidine in neonatal narcotic-abstinence syndrome (letter). N Engl J Med 1981; 305:1284. 69. Cobrink RW, Hood T Jr, Chusid E. The effect of maternal narcotic addiction on the newborn infant: review of literature and report of 22 cases. Pediatrics 1959; 24:288–304. 70. Brown WJ, Buist NRM. Cory Gipson HT, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit (letter). Lancet 1982; 1:1250. 71. Gershanik J, Boecler B, Ensley H, et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med 1982; 307:1384–1387. 72. Committee on Fetus and Newborn, Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics 1983; 72:356–358. 73. Kunstadter RH, Klein RI, Lundeen EC, et al. Narcotic withdrawal symptoms in newborn infants. JAMA 1958; 168:1008–1010. 74. Kandall SR, Koberczak TM, Mauer KR, et al. Opiate v. CNS depressant therapy in neonatal drug abstinence syndrome. Am J Dis Child 1983; 137:378–382. 75. Carin I, Glass L. Parekh A, et al. Neonatal methadone withdrawal: Effect of two treatment regimens. Am J Dis Child 1983; 137:1166–1169. 76. Kaltenbach K, Finnegan LP. Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol Teratol 1986; 8:353–355. 77. Finnegan LP, Ehrlich S. Maternal drug abuse during pregnancy and pharmacotherapy for neonatal abstinence syndrome (NAS). Pediatr Res (abstr). 1987; 21:234A. 78. Strauss ME, Lessen-Firestone JK, Starr RH, Ostrea EM. Behavior of narcotics-addicted newborns. Child Dev 1975; 46:887–893. 79. Kaltenbach K, Finnegan LP, Frankenfield M. Neonatal abstinence syndrome (NAS) and interactive behaviors at 1 and 30 days of life. Pediatr Res (abstr). 1981; 15:450. 80. Olofsson M, Buckley W, Andersen GE, Friis-Hansen B. Investigations of 89 children born by drug-dependent mothers: follow-up 1–10 years after birth. Acta Paediatr Scand 1983; 72: 407–410. 81. Rosen TS, Johnson HL. Children of methadone-maintained mothers: follow-up to 18 months of age. J Pediatr 1982; 101:192–196. 82. Wilson GS, Desmond MM, Wait RB. Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental and social implications. J Pediatr 1981; 98:716–722.

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83. Kaltenbach K, Finnegan LP. Perinatal and developmental outcome of infants exposed to methadone in utero. Neotoxicol Teratol 1987; 9:311–313. 84. Kaltenbach K, Finnegan LP. Children exposed to methadone in utero: cognitive ability in the preschool years (abstr). Pediatr Res 1987; 21:181A. 85. Wilson GS, McCreary R, Kean J, Baxter JC. The development of preschool children of heroin-addicted mothers: a controlled study. Pediatrics 1979; 63:135–141. 86. Nelson LB, Ehrlich S, Calhoun JH, et al. Occurrence of strabismus in infants born to drugdependent women. Am J Dis Child 1987; 141:175–178. 87. Madden JD, Payne TF, Miller S. Maternal cocaine abuse and effect on the newborn. Pediatrics 1986; 77:209–211. 88. Ryan L, Ehrlich S, Finnegan L. Cocaine abuse in pregnancy: effects on the fetus and newborn. Neurotoxicol Teratol 1987; 9:295–299. 89. Chasnoff IJ, Burns KA, Burns WJ. Cocaine use in pregnancy: perinatal morbidity and mortality. Neurotoxicol Teratol 1987; 9:291–293. 90. Fulroth RF, Phillips BL, Trueax RE, Durand DJ. Description of 72 infants exposed to cocaine prenatally (abstr). Pediatr Res 1987; 21:361A. 91. Dixon SD, Coen RW, Crutchfield S. Visual dysfunction in cocaine-exposed infants (abstr). Pediatr Res 1987; 21:359A. 92. Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates. J Pediatr 1987; 111:571–578. 93. Doberczak TM, Shanzer S, Senie RT, Randall SR. Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure. J Pediatr 1988; 113:354–358. 94. Chasnoff IJ, Lewis DE, Squires L. Cocaine intoxication in a breast-fed infant. Pediatrics 1987; 80:836–838. 95. Stewart DJ, Inaba T, Lucassen M, Kalow W. Cocaine metabolism: cocaine and norcocaine hydrolysis by liver and serum esterases. Clin Pharmacol Ther 1979; 25:464–468. 96. Echobichon DJ, Stephens DS. Perinatal development of human blood esterases. Clin Pharmacol Ther 1973; 14:41–47. 97. Chasnoff IJ, Bussey ME Savich R, Stack CM. Perinatal cerebral infarction and maternal cocaine use. J Pediatr 1986; 108:456–459. 98. Weiner N. Norepinephrine, epinephrine and the sympathomimetic amines. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. The Pharmacological Basis of Therapeutics, 7th ed. New York: Macmillan, 1985, pp 145–180. 99. Ramer CM. The case history of an infant born to an amphetamine-addicted mother. Clin Pediatr 1974; 13:596–597. 100. Eriksson M, Larsson G, Windlbadh B, Zetterstrom R. The influence of amphetamine addiction on pregnancy and the newborn infant. Acta Paediatr Scand 1978; 67:95–99. 101. Gay GR. You’ve come a long way baby! Coke time for the new American lady of the eighties. J Psychoactive Drugs 1981; 13:297–318. 102. Chasnoff IJ, Burns WJ, Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl J Med 1985; 313:666–669. 103. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J Pediatr 1987; 110: 93–96. 104. Chasnoff IJ, Griffith DR, MacGregor S, et al. Temporal patterns of cocaine use in pregnancy: perinatal outcome. JAMA 1989; 261:1741–1744. 105. Mahalik MP, Gautieri RF, Mann DE Jr. Teratogenic potential of cocaine hydrochloride in CF-1 mice. J Pharmacol Sci 1980; 69:703–706. 106. Bauchner H, Zuckerman B, McClain M, et al. Risk of sudden infant death syndrome among infants with in utero exposure to cocaine. J Pediatr 1988; 113:831–834. 107. Jones KL, Smith DW, Ulleland CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1:1267–1271.

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108. Hanson JW, Jones KL, Smith DW. Fetal alcohol syndrome: experience with 41 patients. JAMA 1976; 235:1458–1460. 109. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999–1001. 110. Schaefer O. Alcohol withdrawal syndrome in a newborn infant of a Yukon Indian mother. Can Med Assoc J 1962; 87:1333–1334. 111. Pierog S, Chandavasu O, Wexler I. Withdrawal symptoms in infants with the fetal alcohol syndrome. J Pediatr 1977; 90:630–633. 112. Nichols MM. Acute alcohol withdrawal syndrome in a newborn. Am J Dis Child 1967; 113: 714–715. 113. Devenyi P, Harrison ML. Prevention of alcohol withdrawal seizures with oral diazepam loading. Can Med Assoc J 1985; 132:798–800. 114. Sullivan JT, Sellers EM. Treating alcohol, barbiturate and benzodiazepine withdrawal. Rational Drug Therapy 1986; 20:1–8. 115. Sellers EM, Naranjo CA, Harrison M, et al. Diazepam loading: simplified treatment of alcohol withdrawal. Clin Pharmacol Ther 1983; 34:822–826. 116. Desmond MM, Schwanecke RP, Wilson GS, et al. Maternal barbiturate utilization and neonatal withdrawal symptomatology. J Pediatr 1972; 80:190–197. 117. Bleyer WA, Marshall RE. Barbiturate withdrawal syndrome in a passively addicted infant. JAMA 1972; 221:185–186. 118. Ostrea EM Jr. Neonatal withdrawal from intrauterine exposure to butalbital. Am J Obstet Gynecol 1982; 143:597–599. 119. Athinarayanan P, Pierog S, Nigam SK, Glass L. Chlordiazepoxide withdrawal in the neonate. Am J Obstet Gynecol 1976; 124:212–213. 120. Bitnum S. Possible effect of chlordiazepoxide on the fetus (letter). Can Med Assoc J 1969; 100:351. 121. Mazzi E. Possible neonatal diazepam withdrawal: a case report. Am J Obstet Gynecol 1977; 129:586–587. 122. Rementeria JL, Bhatt K. Withdrawal symptoms in neonates from intrauterine exposure to diazepam. J Pediatr 1977; 90:123–126. 123. Prenner BM. Neonatal withdrawal syndrome associated with hydroxyzine hydrochloride. Am J Dis Child 1977; 131:529–530. 124. Rumack BH, Walravens PA. Neonatal withdrawal following maternal ingestion of ethchlorvynol (Placidyl). Pediatrics 1973; 52:714–716. 125. Reveri M, Pyati SP, Pildes RS. Neonatal withdrawal symptoms associated with glutethimide (Doriden) addiction in the mother during pregnancy. Clin Pediatr 1977; 16:424–425. 126. Webster PAC. Withdrawal symptoms in neonates associated with maternal antidepressant therapy (letter). Lancet 1973; 2:318–319. 127. Eggermont E. Neonatal effects of maternal therapy with tricyclic antidepressant drugs (letter). Arch Dis Child 1980; 55:81. 128. Ben Musa A, Smith CS. Neonatal effects of maternal clomipramine therapy (letter). Arch Dis Child 1979; 54:405. 129. O’Conner M, Johnson GH, James DI. Intrauterine effects of phenothiazines. Med J Aust 1981; 1:416–417. 130. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. Gilman AG, Goodman LS, Rall TW, Murad F, eds. In: The Pharmacologic Basis of Therapeutics, 7th ed. New York: Macmillan, 1985, pp 387–445.

20 Current Management of the Neonatal Abstinence Syndrome: A Critical Analysis of the Evidence Jochen G. W. Theis and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Peter L. Selby St. Joseph’s Health Centre, Toronto, Ontario, Canada

Yazemir Ikizler The Addiction Research Foundation, Toronto, Ontario, Canada

INTRODUCTION Continuous or repeated fetal exposure to addicting drugs may lead to fetal drug dependence and after birth to the neonatal withdrawal or neonatal abstinence syndrome (NAS). While it is, of course, preferable to prevent NAS from occurring by reducing the incidence of maternal drug abuse, it needs to be acknowledged that prevention is not possible in many cases. Continuous fetal exposure to drugs of abuse is not uncommon. While a fraction of drug-using women discontinue the consumption after pregnancy has been diagnosed, others continue their use or consume replacements throughout pregnancy. A recent analysis estimated that during the period from 1988 to 1990 about 90,000 American women were discharged after parturation every year with a diagnosis of drug abuse, representing a rate of 2.2% of all women giving birth (1). NAS is most commonly observed after maternal use of opioids such as heroin (2,3), methadone (2,4,5), and even codeine (6,7), but it may also be observed after continuous fetal exposure to barbiturates (8), alcohol (9,10), or other psychoactive drugs with the potential to cause physical addiction (11,12). It is generally agreed that maternal heroin addiction during pregnancy should be treated by replacement with methadone which may be gradually reduced in dose (13,14). Abrupt withdrawal of opioids during pregnancy is not recommended because this may lead to major maternal withdrawal symptoms endangering both the mother and the fetus. Moreover, unplanned opiate withdrawal may lead to resumption of street opiate use or consumption of replacement drugs and may further disrupt prenatal care (15). The major drawback of methadone replacement therapy is that continuous fetal opioid exposure may often lead to NAS (16). From Biol Neonate 1997; 71:345–356. 373

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Table 1 Drugs Used to Treat NAS with Examples of Published Dosages Drug Phenobarbital Diazepam Chlorpromazine Paregoric Morphine Methadone Clonidine

Dosage 5–16 mg/kg/day q 8 h or loading dose: 16 mg/kg followed by 2–6 mg/kg/day 0.5–2.5 mg/kg/day q 8 h 2.8 mg/kg/day q 6 h 0.4–2.1 ml/kg/day q 3 h 1.6–6.4 ml/kg/day q 3 h 0.4–1.0 mg/kg/day 2–4 mg/day q 6 h 3–4 µg/kg/day

Citations Kandall et al. (29), 1983 Finnegan et al. (30), 1979 Herzlinger et al. (31), 1977 Kahn et al. (35), 1969 Kandall et al. (29), 1983 Herzlinger et al. (31), 1977 Pacifico et al. (27), 1989 Madden et al. (32), 1977 Hoder et al. (28), 1984

NAS is characterized by tremor, irritability, hypertonicity, high-pitched cry, vomiting and diarrhea, respiratory distress, sneezing, diaphoresis and fever, poor sucking and rarely convulsions (17,18). The onset of symptoms after continuous fetal exposure to opioids is usually observed within 48–72 hours after birth (16,19), and may be delayed after fetal exposure to barbiturates (20,21), or long-acting benzodiazepines (22). A more elaborate description of the signs and symptoms of NAS has been the topic of a number of reviews (12,18,23,24) and will thus not be discussed here in further details. Conservative comfort measures such as holding, swaddling, and minimal stimulation may be sufficient treatment if symptoms are mild and not progressing (12,18,21). However, it is generally agreed that more severe symptoms should be treated by adequate pharmacotherapy (12,18,24). It is important to realize that the aim of this pharmacotherapy should be to stabilize the neonate as far as physical dependence is concerned so that he or she can handle the other stresses of the newborn period (25). In addition to the suppression of tremors, hyperactivity, seizure activity, and other apparent symptoms, therapy should aim at restoring normal neonatal neurological patterns such as sleep and sucking. A number of different agents have been employed in order to achieve this aim, the ones most frequently cited are phenobarbital, opioids (mainly paregoric), chlorpromazine, diazepam, and more recently clonidine (26–35) (Table 1). Because these substances have very different modes of action, it should be expected that the desired effects and adverse effects may show marked differences depending on the agent employed. Nevertheless, in reviewing the literature, it appears that all of these agents are currently in use for the treatment of NAS. One of the most important changes in medicine during the late 1980s and the early 1990s has been the push toward evidence-based practice. It is more and more agreed that patient management and especially pharmacological therapy should be based on the available evidence with emphasis on data collected in well-controlled clinical trials (36). The aim of this article is to review and evaluate the evidence available in the present literature for the selection of agents effective in the treatment of NAS.

METHODS A literature review was performed for the years 1966 to April 1996 utilizing MEDLINE. To identify the articles dealing with the topic of NAS and its treatment, the following

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search pattern using medical subject headings (MESH) was employed: ‘‘neonatal abstinence syndrome’’ or ‘‘substance withdrawal syndrome’’ [limited to ‘‘newborn infant (birth to 1 month)’’]. This search pattern was necessary since the MESH ‘‘neonatal abstinence syndrome’’ was not used by MEDLINE before 1988 (37). Citations dealing with NAS and published before 1988 are identifiable by limiting the MESH ‘‘substance withdrawal syndrome’’ which includes the earlier MESH ‘‘drug withdrawal symptoms’’ to ‘‘newborn infant (birth to 1 month).’’ The resulting set of citations was combined using the operator ‘‘and’’ with the set of citations identified by the MESH combination ‘‘comparative study’’ or ‘‘evaluation studies.’’ The resulting set of citations and additionally the citations identified by the pattern ‘‘explode opioids’’ [limited to ‘‘newborn infant (birth to 1 month)’’] were screened by title MESH and, whenever available, abstract. Every citation that was thought to have any chance of containing data or original information about the treatment of NAS was obtained for evaluation. The references given in review articles about NAS written during the last 5 years and the references given in the articles obtained for information were further screened for any additional citations which may possibly identify subsequent studies comparing or evaluating the effectiveness of pharmacological treatment. The reports identified by this search were analysed regarding study design and outcome to identify a group of well-conducted studies which can serve as a basis for a metaanalysis. The analysis of study design addressed the following items: assignment criteria (random/nonrandom), number of neonates treated for NAS, blinding of observers regarding treatment or fetal exposure, methods to obtain and confirm fetal drug exposure, and measurements of outcome.

RESULTS ‘‘Neonatal abstinence syndrome’’ or ‘‘substance withdrawal syndrome’’ [limited to ‘‘newborn infant (birth to 1 month)’’] was a topic of 638 citations. When these citations were combined with the set of citations labeled with ‘‘evaluation studies’’ or ‘‘comparative study,’’ this number was reduced to 42 citations. Only 5 of these contained comparisons between medical treatments of the infant suffering from NAS. Of the 638 citations, 134 were labeled to deal with the therapy of NAS by having the abbreviations dt or th (dt meaning drug therapy, the standing for therapy) attached to the MESH headings ‘‘neonatal abstinence syndrome’’ or ‘‘substance withdrawal syndrome.’’ The vast majority of these articles, 129, do not contain original data about comparative trials of the treatment of NAS, 124 of these indicate this by not being labeled with the MESH ‘‘evaluation studies’’ or ‘‘comparative study.’’ This search strategy would have resulted in the same five citations found after the initial search. A total of 14 references containing clinical comparisons between drug treatments for NAS were identified by screening all initial 638 citations, the citations identified by the MESH search pattern ‘‘explode opioids’’ [limited to ‘‘newborn infant (birth to 1 month)’’] and hand searching the references stated in the obtained articles and recent review papers and chapters. The number of 14 identified citations may overestimate the number of independent studies since four studies published by the group of Finnegan et al. (38,39) in 1975 and Kron et al. (40,41) in 1975 and 1976 appear to be successive publications of results during validation and implication of their study design. It is not clear but likely that the results reported in these publications involve some of the same

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patients. Similarly, the report of Kaltenbach and Finnegan (23) (1986) mainly evaluating the developmental effects of NAS and its pharmacological treatment also contains data about the immediate effectiveness of the pharmacological treatment of NAS. These data are similar to the data presented by Finnegan and Michael (42) 2 years earlier. It is not clear whether the data dealing with the effectiveness of the pharmacological treatment differ between the studies or whether the results are based on the same patient population. Of these up to 14 comparative studies only 8 stated that treatments were assigned at random (29,32,35,38,39,42–44). Moreover, the methods of randomization employed in the majority of these 8 studies are not accepted as valid today. Observers and raters were not blinded in any of the studies regarding the type of treatment. Seven reports did not report how fetal exposure was verified (23,27,32,38–41), two studies relied on maternal history only (35,43), and five studies specified that maternal or fetal urine toxicology was performed to confirm fetal drug exposure (29,31,42,44,45). Main outcome measures varied widely. Incidence, prevalence, and control of a variety of symptoms were assessed clinically or with the help of neonatal abstinence scales. Objective nutritional sucking measures were the main outcome measure in four studies which appear to be related (38,39), while one study compared developmental progress at 6 months age (23). The studies are summarized in Table 2. Due to the many different therapy regimens employed, the large differences in outcome measures, and flaws in study design in the majority of the studies, no set of studies qualified for a combined statistical analysis in the form of a meta-analysis. Therefore, the studies were critically reviewed to highlight the methodological strengths and weaknesses and to extract and summarize the pertinent data. The drugs leading to NAS were most commonly opioids, although fetal exposure to multiple drugs was not excluded. The drugs evaluated in these 14 comparative studies were phenobarbital (in twelve of the studies), paregoric [eleven], diazepam [nine], chlorpromazine [one], morphine [one] and methadone [one]. In contrast to the other drugs, paregoric is a preparation containing a number of substances, most of them pharmacologically active: opium, benzoic acid, camphor, glycerin, and 44–46% alcohol. The preparation of paregoric was originated in 1715 (46) and has more recently been described as ‘a needlessly complex therapeutic survival of a former day (47). The composition of the formula has changed numerous times since its introduction into medicine (46) and still slightly differs between the United States and the British Pharmacopoeiae. None of the reports on its efficacy in NAS state the exact contents of the paregoric formulation used. When compared to pure opioids, it is questionable whether a cocktail of substances which includes a substantive amount of alcohol and the central stimulant camphor may in fact be of superior or equal value in the treatment of NAS. Nevertheless, paregoric was the opioid of choice in 11 of the 14 comparative studies. Only two comparative studies evaluated pure opioids in the treatment of NAS. Pacifico et al. (27) concluded that morphine alone was superior to the combination of phenobarbital and diazepam or to the combination of morphine, phenobarbital, and diazepam. In contrast, Madden et al. (32) found no statistical differences between treatments consisting of methadone, phenobarbital or diazepam. Unfortunately, the report by Pacifico et al. (27) contains too few details on its study design to be interpretable. In the study by Madden et al. (32) the decision to continue or to discontinue treatment was made purly on clinical grounds without the help of a standardized abstinence score. Nevertheless, length of treatment and hospital stay were the main outcome measures. Because these

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outcome measures may have been the result of decisions based on personal biases and other confounders, this report also has to be interpreted with caution. Phenobarbital was compared in different studies to chlorpromazine, paregoric, diazepam, and methadone. The study by Kahn et al. (35) comparing phenobarbital to chlorpromazine was the first after 1966 to comparatively evaluate pharmacological treatments for NAS. This study reported no significant differences in outcome after the treatment with either of the two drugs used in a short or long course. Outcome measure was assessment of irritability and tremors. Since phenobarbital and chlorpromazine both have sedating effects, the control of tremors and irritability may be achieved in a comparable way by either drug. Whether there were differences in the control of other symptoms of NAS such as sleep pattern or sucking and feeding performance was not evaluated. Moreover, fetal drug exposure was assessed by maternal history only. Almost one quarter of the neonates were born to mothers who were also fairly heavy drinkers, more than half of the neonates were born to heavy smokers, and only about one third of the mothers received antenatal care. These and other potential cofactors were not accounted for in the analysis of the data. It thus remains questionable whether the outcome would have been similar in a well-controlled study using objective or quantitative outcome measures. Phenobarbital was also compared to paregoric. Carin et al. (43) reported that phenobarbital treatment was necessary for an average of only 17 days compared to 22 days of treatment with paregoric. The authors acknowledged that this difference might have been due to the long elimination half-life of phenobarbital which prolongs its pharmacological action after the termination of the dose. There were also differences between the study groups which were not accounted for in the analysis: more than half of the infants receiving paregoric compared to only one-fifth of the infants treated with phenobarbital were exposed to multiple drugs of abuse in utero. In another study by Kandall et al. (29) comparing phenobarbital with paregoric, seizures were observed in 11% of the neonates treated with phenobarbital while no seizures were observed in the group of neonates treated with paregoric, this was statistically significant ( p ⬍ 0.025). Neonatal abstinence scores were not different between the two groups during treatment. In a study performed by Finnegan and Michael (42) paregoric successfully controlled withdrawal symptoms in 93% of the neonates exposed to narcotics in utero while phenobarbital and diazepam given at the highest dose were only successful in 50 and 0% of the treated neonates, respectively. In neonates exposed to multiple drugs in utero, phenobarbital was efficacious in the control of NAS symptoms in 89% of the infants while paregoric and diazepam were efficacious in 61 and 40%. The differences between paregoric and phenobarbital were significant in both comparisons. In a subsequent study by Finnegan and Ehrlich (44) utilizing the same study design, similar results were reported on a larger number of patients. In another study by Kaltenbach and Finnegan (23) focusing on the development after 6 months of life, no difference was seen among treatments with phenobarbital and paregoric. In the same study, it was reported that phenobarbital had been less efficacious in the control of NAS symptoms than paregoric but more efficient than diazepam. Important studies were performed by Finnegan et al. (38,39) and Kron et al. (40,41), who compared the rate and effectiveness of the nutritional sucking behavior of neonates suffering from NAS after fetal methadone exposure. While paregoric almost restored sucking measures to normal, phenobarbital had little effect compared to no pharmacological treatment. Diazepam worsened nutritive sucking behavior compared to no treatment or

Table 2

Clinical Studies Evaluating Drug Treatment for NAS Main outcome measurement

Phenobarbital, chlorpromazine Phenobarbital paregoric

Tremors, irritability

Phenobarbital, paregoric

Sucking measures

Phenobarbital, paregoric, diazepam, no therapy, normal control

Sucking measures

Phenobarbital, paregoric, diazepam, no therapy, normal control

Sucking measures

Paregoric, diazepam

Seizures

Paregoric, diazepam

Comparison of therapy not major aim of study

Sucking measures

No significant difference Paregoric ⬎ no treatment ⫽ phenobarbital Group 3: paregoric ⬎ no treatment ⬎ phenobarbital Paregoric ⬎ no treatment ⬎ phenobarbital ⬎ diazepam in restoring sucking pattern towards normal Normal control ⬎ paregoric ⬎ no treatment ⬎ phenobarbital ⬎ diazepam in restoring sucking pattern towards normal Incidence (p ⬍ 0.01) and control (p ⬍ 0.05) of seizures better with paregoric Convulsive activity occurred more often in the diazepam group (p ⬍ 0.01) No significant difference Paregoric 22 days, phenobarbital 17 days, p ⬍ 0.01

Assessment of main outcome

Maternal drug of abuse

Fetal exposure confirmed by. . .

Type of study

Neonates treated

Citation

Clinical observation

Heroin

History

Randomized

38

Objective measures with sucking instrument Objective measures with sucking instrument Objective measures with sucking instrument

Primarily methadone or heroin

Not stated

Randomized

38

Methadone or heroin

Not stated

Not randomized ⫹ randomized

26 ⫹ 38

Kron et al. (40), 1975

Methadone or heroin

Not stated

Assignment criteria not stated

39

Kron et al. (41), 1975

Objective measures with sucking instrument

Primarily methadone or heroin

Not stated

Assignment criteria not stated

26

Finnegan et al. (39), 1976

Clinical; in 72% of the patients with clinical seizures: EEG

Methadone, heroin and others

History, urine assays

Nonrandomized

60

Herzlinger et al. (31), 1977

Not mentioned

Heroin or methadone

Assignment criteria not stated

Clinical assessment not well standardized Neonatal abstinence scale developed by Finnegan et al. (38)

Mainly methadone and/or heroin

History, maternal and neonatal urine toxicology ‘when available’ Not stated

Maternal history

Methadone, 20–63% multidrug abusers

Kahn et al. (35), 1969 Finnegan et al. (38), 1975

132

Kendall et al (45), 1977

Randomized

51

Madden et al. (32), 1977

Randomized

31

Carin et al. (143), 1983

Theis et al.

Methadone, phenobar- Length of therapy rebital, diazepam quired, length of hospital stay Paregoric, phenobarDuration of necessary bital treatment

Result

378

Therapy regimen evaluated

Incidence of seizures; neonatal abstinence scores on days 3– 28

Paregoric, phenobarbital, diazepam,

Control of symptoms with highest dose of the agent employed

Paregoric, phenobarbital, diazepam, combination of above

Development after 6 months of life and control of symptoms

Morphine, phenobarbital ⫹ diazepam, morphine ⫹ phenobarbital ⫹ diazepam Paregoric, phenobarbital, diazepam

Daily average score on neonatal abstinence scale

Neonatal abstinence scale developed by Lipsitz (57) (modified)

Methadone, 52–61% multidrug abusers

History, urine toxicologic screening of mother and neonate

Randomized

111

Kandall et al. (29), 1983

Neonatal abstinence scale developed by Finnegan et al. (38)

Narcotic agents or multidrug abusers (analyzed separately)

Medical records, social data forms, urine toxicologies

Randomized unless clinically indicated

139

Finnegan et al. (42), 1984

Control of symptoms: not mentioned; development: Bayley Scale of Mental Development

Methadone polydrug abuse?

Not stated

Assignment criteria not stated

69

Kaltenbach and Finnegan (23), 1986

Neonatal abstinence scale developed by Finnegan et al. (38)

Heroin

Not stated

Assignment criteria not stated

25

Pacifico et al. (27), 1989

Medical records, social data forms, urine toxicologies Randomized

Randomized

Efficacy in opiate-ex- Days of treatment Narcotic agents or and days until synposed neonates: multidrug abusers dromes controlled; paregoric ⬎ pheno(analyzed sepatreatment and outbarbital ⬎ diazerately) pam efficiency in come dependent on scores on neonatal nonopiate-exposed abstinence scale deneonates: phenobarveloped by Finbital ⬎ diazepam ⬎ paregoric negan et al. (38)

176

Finnegan and Ehrlich (44), 1990

379

Days until abstinence symptoms controlled and days of treatment needed separated into neonates antenatally exposed to opiates, nonopiates, or both

Seizures occurring in 7 patients on phenobarbital and no patients on paregoric (p ⬍ 0.25); no difference in abstinence scores Success of treatment in: infants exposed in utero to opioids, paregoric 93%, phenobarbital 50%, diazepam 0%; infants exposed to multiple drugs: paregoric 61%, phenobarbital 89%, diazepam 40% Development: no difference between paregoric, phenobarbital and polytherapy; control of symptoms: paregoric 91%, phenobarbital 47%, diazepam 0% Morphine monotherapy better than polytherapy

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Paregoric, phenobarbital

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treatment with the other two agents. These studies are the only studies using a measure which is clearly objective (neonatal abstinence scores have a subjective component). However, the interpretation of the data regarding diazepam is hampered by the small numbers (five or six) of neonates assigned to this particular treatment. Diazepam was compared to paregoric in one study focusing on seizure activity as part of NAS. Herzlinger et al. (31) reported that paregoric was more effective in controlling and preventing seizures once they had occurred. However, it has to be noted that the patients were not randomized to different treatments and that the use of diazepam was discouraged during the second half of the study when concomitant treatment might have been improving. In a report by Kandall et al. (45), convulsive activity occurred more frequently when diazepam rather than camphorated opium tincture was used to treat NAS. However, neither methods of treatment assignments nor numbers regarding this outcome are given. A comparison between treatments was clearly not the major aim of this report.

DISCUSSION The available studies performed to date do not allow meaningful comparisons in the efficacy of paregoric, morphine, methadone, phenobarbital, chlorpromazine, and diazepam when used for the treatment of NAS. It may be possible to single out diazepam as an undesirable agent, since it may worsen nutritive sucking behavior and may provide less seizure control than opioids. Paregoric appears to be superior in restoring sucking behavior, but similar superiority was not generally demonstrated when the main outcome was the clinical withdrawal symptoms as assessed by neonatal abstinence scores. Whether this may also be representative for opioid preparations that do not contain camphor and alcohol remains unknown. Phenobarbital was shown in one study to be superior to paregoric in controlling NAS in a subgroup of neonates who had been exposed to multiple drugs in utero. However, when not discriminating subgroups of neonates with NAS or when evaluating the efficacy of phenobarbital in neonates exposed only to opiates, the results were controversial with a tendency towards achieving better control of NAS symptoms in neonates treated with paregoric. The efficacy of chlorpromazine has only been addressed in a single study dating back to 1969. This study, being by design not very discriminative, resulted in no differences between the treatment with chlorpromazine and phenobarbital. In spite of the nearly complete lack of proof of efficacy, chlorpromazine has remained in use for the treatment of NAS as documented by a number of reports published in the 1990s (48–50). The efficacy of clonidine in controlling symptoms of NAS has not been evaluated in comparative studies. In general, it has to be acknowledged that the data regarding the relative efficacy of the different pharmacological treatment options of NAS are weak. An attempt to use adult data as an additional source of information is of limited value. Adult opiate withdrawal differs from NAS because of the comparative lack of seizures and other life-threatening complications. Therefore, it is regarded safe for adults to be detoxified without pharmacotherapy. Sedating agents such as phenobarbital, diazepam and chlorpromazine are mainly used as adjacent symptomatic therapy to reduce the severe discomfort. Cocktails such as paregoric or tincture of opium do not even appear in the recent adult literature. However, the impact of substance withdrawal on the developing brain at its greatest adjustment to extrauterine life may not allow to compare it to adult substance withdrawal.

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Our analysis of available studies documents lack of strong evidence on the relative efficacy of different pharmacological regimens for the treatment of NAS. NAS, although often treated as one entity, cannot be regarded as a single pathological condition. It has been shown that the symptoms of NAS differ depending on the substances the fetus was exposed to. Neonates continuously exposed to alcohol in utero tend to have more seizures, opistotonos, and abdominal distention, while neonates exposed to opioids tend to have a high-pitched cry and suffer from sleeplessness and excessive but ineffective sucking (10). In contrast to opioids and alcohol, cocaine probably does not cause typical neonatal withdrawal symptoms (51). However, the drug or its metabolites are often still present in the neonate shortly after birth and may continue to have a toxic effect (52). These adverse effects may be confused with clinical signs of NAS. A study by Fulroth and Phillips (53) showed that neonates required treatment in less than half of the cases after fetal cocaine exposure compared to after fetal heroin exposure. When management was deemed necessary, the mean duration of treatment in cocaine-exposed neonates was only 2 days compared to 14 days in the heroin-exposed group. Clinical symptomatology thus may be different but is not pathognomonic; without a detailed and correct maternal history, the different etiologies cannot be distinguished with certainty. Unfortunately, maternal history is all too often an inaccurate source of information on drug abuse (54). In addition, polydrug abuse is common in the population of women taking illicit drugs during pregnancy. Utilization of modern analytical techniques such as meconium or neonatal hair analysis may allow better estimation of fetal drug exposure. Such knowledge, when built into the design of treatment trials of NAS, may allow for greater discrimination among treatment effects. Many confounders are often associated with pregnancies complicated by drug abuse. These include poor antenatal care, smoking, poverty, personal neglect, and poor health status. None of the existing studies evaluating the treatment of NAS have corrected for these confounders. Yet, during the last 10 years significant progress has been made in the quality of study design directed toward the evaluation of fetal exposure and outcome. Applying these standards to future studies on NAS is likely to allow clearer analysis of outcome measures. Careful assessment of outcome measures is a crucial element in controlled studies. NAS is a complex combination of clinical signs, which may respond differently to various pharmacological agents. While early studies assessed only tremor and irritability, a number of scoring scales have been developed, which range from simple indiscriminatory scales to very complex scales which assess a wide variety of symptoms (38,40,55–57). When selecting or developing a scale to monitor the pathology of NAS and the effectiveness of its treatment, it is important to understand the strengths and shortcomings of each of the scales. The most widely used and best validated scale today was developed by Finnegan et al. (38) and Kron et al. (40). However, even in this scale, sedation of a neonate suffering from NAS may lead to an improvement in scores. It is important to realize that the aim of treatment of NAS should also be to allow the neonate to adapt to and function in the extrauterine world. Utilizing other objective measures such as nutritive sucking measures or sleep pattern as additional independent endpoints may take this aim into account and may further discriminate between the effects of various modes of treatment. Neonates suffering from NAS deserve optimal care including the best possible pharmacological approach. Presently, good studies providing the evidence for the selection of the best pharmacotherapy for neonates with NAS are clearly missing. Centers caring for large numbers of neonates exposed to addicting drugs in utero should consider utilizing modern clinical epidemiological tools and up-to-date study design to produce the evidence

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needed to allow a rational choice between treatment modalities, and thus to lead to better future care of these neonates. REFERENCES 1. Dicker M, Leighton EA. Trends in the US prevalence of drug-using parturient women and drug-affected newborns, 1979 through 1990. Am J Publ Health 1994; 84:1433–1438. 2. Stimmel B, Goldberg J, Reisman A, et al. Fetal outcome in narcotic-dependent women: the importance of the type of maternal narcotic used. Am J Drug Alcohol Abuse 1982–83; 9: 383–395. 3. Zelson C, Kahn EJ, Neumann L, Polk G. Heroin withdrawal syndrome. J Pediatr 1970; 76: 483–484. 4. Doberczak TM, Kandall SR, Friedmann P. Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Obstet Gynecol 1993; 81:936– 940. 5. Newman RG, Bashkow S, Calko D. Results of 313 consecutive live births of infants delivered to patients in the New York City Methadone Maintenance Treatment Program. Am J Obstet Gynecol 1975; 121:233–237. 6. Mangurten HH, Benawra R. Neonatal codeine withdrawal in infants of nonaddicted mothers. Pediatrics 1980; 65:159–160. 7. Van Leeuwen G, Guthrie R, Stange F. Narcotic withdrawal reaction in a newborn infant due to codeine. Pediatrics 1965; 36:635–636. 8. Blumenthal I, Lindsay S. Neonatal barbiturate withdrawal. Postgrad Med J 1977; 53:157– 158. 9. Coles CD, Smith IE: Neonatal ethanol withdrawal: characteristics in clinically normal, nondysmorphic neonates. J Pediatr 1984; 105:445–451. 10. Robe LB, Gromisch DS, Iosub S. Symptoms of neonatal ethanol withdrawal. Curr Alcohol 1981; 8:485–493. 11. Auerbach JG, Hans SL, Marcus J, Maeir S. Maternal psychotropic medication and neonatal behavior. Neurotoxicol Teratol 1992; 14:399–406. 12. Levy M, Spino M. Neonatal withdrawal syndrome: Associated drugs and pharamacologic management. Pharmacotherapy 1993; 13:202–211. 13. Finnegan LP. Treatment issues for opioid-dependent women during the perinatal period. J Psychoactive Drugs 1991; 23:191–201. 14. Report of the Expert Advisory Committee on the use of drugs in the treatment of abuse and dependence to narcotic and controlled drugs. Can Med Assoc J 1990; 143:861–865. 15. Connaughton JF, Reeser D, Schut J, Finnegan LP. Perinatal addiction: Outcome and management. Am J Obstet Gynecol 1977; 129:679–686. 16. Zelson C, Lee SJ, Casalino M. Neonatal narcotic addiction. Comparative effects of maternal intake of heroin and methadone. N Engl J Med 1973; 289:1216–1220. 17. Harper RG, Solish G, Feingold E, et al. Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome. Am J Obstet Gynecol 1977; 129:417–424. 18. Finnegan LP, Kaltenbach K. Neonatal abstinence syndrome. In: Hoekelman RA, Friedman SB, Nelson NM, Seidel HM, eds. Primary Pediatric Care, 2nd ed. St. Louis: Mosby–Year Book, 1992, pp 1367–1378. 19. Desmond MM, Wilson GS. Neonatal abstinence syndrome. Recognition and diagnosis. Addict Dis 1975; 2:113–121. 20. Desmond M, Schwanecke R, Wilson G. et al. Maternal barbiturate utilization and neonatal withdrawal symptomatology. J Paediatr 1972; 80:190–197. 21. Blinick G, Wallach R, Jerez E, et al Drug addiction in pregnancy and in the neonate. Am J Obstet Gynecol 1976; 125:135–142.

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22. Sutton LR, Hinderliter SA. Diazepam abuse in pregnant women on methadone maintenance: implications for the neonate. Clin Pediatr 1990; 29:108–111. 23. Kaltenbach K, Finnegan LP. Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol Teratol 1986; 8:353–355. 24. Franck L, Vilardi J. Assessment and management of opioid withdrawal in ill neonates. Neonatal Network 1995; 14:39–48. 25. Kron RE, in round table discussion of Zelson C. Acute management of neonatal addiction. Addict Dis 1975; 2:159–168. 26. Wijburg FA, deKleine MJ, Fleury P, Soepatmi S. Morphine as an antiepileptic drug in neonatal abstinence syndrome. Acta Paediatr Scand 1991; 80:875–877. 27. Pacifico P, Nardelli E, Pantarotto MF. Neonatal heroin withdrawal syndrome: Evaluation of different pharmacological treatments. Pharmacol Res 1989; 21(suppl 1):63–64. 28. Hoder EL, Leckman JF. Clonidine treatment of neonatal narcotic abstinence syndrome. Psychiatry Res 1984; 13:243–251. 29. Kandall SR, Doberczak TM, Mauer KR, et al. Opiate v CNS depressant therapy in neonatal drug abstinence syndrome. Am J Dis Child 1983; 137:378–382. 30. Finnegan LP, Mitros TF, Hopkins LE. Management of neonatal narcotic abstinence utilizing a phenobarbital loading dose method. NIDA Res Monogr 1979; 27:247–253. 31. Herzlinger RA, Kandall SR, Vaughan HG Jr. Neonatal seizures associated with narcotic withdrawal. J Pediatr 1977; 91:638–641. 32. Madden JD, Chappel JN, Zuspan F, et al. Observation and treatment of neonatal narcotic withdrawal. Am J Obstet Gynecol 1977; 127:199–201. 33. Rosen M. Use of diazepam in neonatal narcotic withdrawal syndrome. Pediatrics 1972; 49: 314. 34. Nathenson G, Golden GS, Litt IF. Diazepam in the management of the neonatal narcotic withdrawal syndrome. Pediatrics 1971; 48:523–527. 35. Kahn EJ, Neumann LL, Polk GA. The course of the heroin withdrawal syndrome in newborn infants treated with phenobarbital or chlorpromazine. J Pediatr 1969; 75:495–500. 36. Evidence-Based Medicine Working Group. Evidence-based medicine. JAMA 1992; 268: 2420–2425. 37. Medical Subject Headings-Annotated Alphabetic List 1995. Bethesda, MD: National Library of Medicine, 1994. 38. Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: Assessment and management. Addict Dis 1975; 2:141–158. 39. Finnegan LP, Kron RE, Connaughton JF Jr, Emich JP: Assessment and treatment of abstinence in the infant of the drug-dependent mother. Int J Clin Pharmacol 1975; 12:19–32. 40. Kron RE, Litt M, Finnegan LP. Narcotic addiction in the newborn: differences in behavior generated by methadone and heroin. Int J Clin Pharmacol 1975; 12:63–69. 41. Kron RE, Litt M, Eng D, et al. Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior. J Pediatr 1976; 88:637–641. 42. Finnegan LP, Michael H. An evaluation of neonatal abstinence treatment modalities. NIDA Res Monogr 1984; 49:282–288. 43. Carin I, Glass L, Parekh A, et al. Neonatal methadone withdrawal. Effect of two treatment regimens. Am J Dis Child 1983; 137:1166–1169. 44. Finnegan LP, Ehrlich SM. Maternal drug abuse during pregnancy: Evaluation and pharmacotherapy for neonatal abstinence. In: Adler MW, Cowan A, eds. Modern Methods in Pharmacology. vol 6. Testing and Evaluation of Drugs of Abuse. New York: Wiley-Liss, 1990, pp 255– 263. 45. Kandall SR, Albin S, Gartner LM, et al. The narcotic-dependent mother: fetal and neonatal consequences. Early Hum Dev 1977; 1:159–169. 46. Osol A, Hoover E, eds. Remington’s Pharmaceutical Sciences, 15th ed. Easton, Mack, 1975, p 1037.

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21 Fetal Effects of Cocaine: An Updated Meta-Analysis Antonio Addis Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

Myla E. Moretti, Fayyazuddin Ahmed Syed, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION The high prevalence of cocaine use has become a major health concern during pregnancy. Cocaine crosses the human placenta with varying proportions absorbed by the placenta, suggesting that the placenta may offer a degree of protection to some fetuses after bolus administration (1). Cocaine is a CNS stimulant with effects thought to be due to its sypathomimetic-driven fetal, uterine, or maternal vasoconstriction and hypertension, leading to infarcts or hemorrhages at any time during gestation and in any structure. This may explain the variability of clinical effects attributed to cocaine use. A typical well-defined ‘‘fetal cocaine syndrome’’ has not been identified (2); however, exposure to cocaine during pregnancy has been associated with shorter gestation, premature delivery, abruptio placentae, and other maternal and neonatal adverse effects. In the past, congenital malformations of almost every system have been reported leading many clinicians to believe that the drug is teratogenic (3). Reports of fetal cocaine effects have been controversial, and it has been difficult to elucidate these effects, because interpretation of the results is hampered by the fact that cocaine use is commonly accompanied by confounding factors such as concomitant use of cigarettes and other recreational drugs, including heroin, cannabis, methadone, and others (4), all of which may affect pregnancy outcome by themselves. Our original systematic review and meta-analysis in 1991 (5) suggested that cocaine exposure during pregnancy is not a major risk for malformation (except for the genitourinary tract). When cocaine users were compared to women not consuming any drugs of abuse, a variety of risks emerged. Yet when we compared pregnancy and neonatal outcomes in children of cocaine consumers with those of polydrug consumers, the increased risk for most of the adverse outcomes was nullified. A major issue at that stage was the relatively small number of studies for each adverse endpoint. Since 1989 (the last year 385

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included in our previous meta-analysis), however, scores of studies on cocaine exposure during pregnancy have been published. Hence, the present meta-analysis has allowed us to separate the exposure data into several comparisons: (1) between all combinations of exposures that involve cocaine use during pregnancy (cocaine alone, polydrugs including cocaine, polydrugs not including cocaine) and (2) between the different methodologies used to determine exposure (urine analysis, maternal interview, chart review). The aim of this updated meta-analysis was to arrive at an overall quantitative estimate of the effect of cocaine use on pregnancy outcome and potential pregnancy complications, with a substantially increased power.

METHOD Data Sources The medical literature published between January 1989 and December 1997 was searched for papers dealing with the outcome of pregnancy following gestational cocaine exposure. The literature search was performed in the MEDLINE and EMBASE bibliographic databases. A search strategy using a combination of pregnancy or abnormalities drug induced and cocaine keywords (MeSH) were used. All references in the retrieved articles were screened for further papers. From all the references we excluded the non-English papers, comments, letters, editorials and reviews (Table 1). However, the references from these excluded publications were also scanned for other studies not quoted by the databases. All studies considered in the previous meta-analysis were retrieved and resubmitted to the inclusion or exclusion process. Study Selection Searches were reviewed or completed independently and in duplicate. Investigators were blinded as to the name of the journal, the authors of the paper, the hospital or site of the study, and the funding agency supporting the study. This blinding was accomplished by removing all identifying statements and titles prior to photocopying the papers for review

Table 1 Results of Search on Cocaine Use During Pregnancy Type of study

No.

Case reports/case series Letters Editorials Reviews and commentaries Studies not reporting fetal or pregnancy outcomes In vitro studies/placental perfusion Outcomes beyond the scope of this meta-analysis Studies without control group Cocaine users not separated from other drugs Studies included in the meta-analysis Total

80 43 22 87 127 40 54 19 12 33 517

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by another investigator. Without this identification, the prestige, reputation, or standards of the journal or author cannot interfere with the selection or analysis of articles. Although, theoretically, each journal has a type style that could identify it, the junior investigator who conducted blinding of the papers was not familiar with the different styles. The criteria for inclusion of papers in this analysis were human exposure to any amount of cocaine during any or all trimesters of pregnancy as evidenced by drug history or urine test and report of outcome of pregnancy or fetal development. Only case-control or cohort studies with at least one control group were included. Use of other drugs is common among cocaine users and was not an exclusion criterion. Case reports, reviews, editorials, and letters were excluded from the analysis but were retrieved and followed up for further papers. The ‘‘methods’’ section of each paper was evaluated using a scoring sheet, prepared a priori, which listed these inclusion criteria. Studies fulfilling all inclusion criteria were accepted for analysis. Successfully included studies were read and information was extracted using a standardized data extraction form. The information collected included the size and selection of cocaine and control groups; the pregnancy and fetal outcome measurements were studied. Studies were analyzed separately according to various exposure groups, namely: Pregnant women exposed to cocaine alone compared to drug-free controls Pregnant women exposed to cocaine plus other drugs compared to drug-free controls Pregnant women exposed to cocaine alone compared to cocaine plus other drugs Pregnant women exposed to cocaine alone versus other drug additions (and no cocaine) Pregnant women exposed to cocaine plus other drugs versus other drug addictions (and no cocaine) To avoid duplication of results, after data extraction, we examined data results of included studies with a cross analysis of author groups. The outcomes considered were related to maternal and neonatal health, namely: major malformations, low birth weight, prematurity, premature rupture of membranes (PROM), abruptio placentae, meconium, gestational age, head circumference, birth weight, and birth length. Studies examining only certain subtypes of malformations or studies with unspecified addictions were excluded from the analysis.

Data Analysis All controlled studies were pooled together to calculate the relative risk (RR) and 95% confidence interval (CI95%) using a random-effect model (6). For outcomes measured in a continuous scale (i.e., head circumference, birth weight, length, gestational age), weighted mean differences were calculated, also using, in this case, the random-effect model. Chi square tests for heterogeneity were also performed for all outcomes of interest in this analysis. Sensitivity analyses were performed on the study methodology (by excluding retrospective analysis) and according to the method used to identify cocaine users (by excluding studies that use chart review or maternal interview methodologies). This was done with the aim of assessing the impact of identification bias in the study population.

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RESULTS Over 600 scientific references were considered because they deal with the human effects of cocaine used during pregnancy, with an exponential growth in number of papers published in recent years. Of these, 517 studies were retrieved and, based on a review of their methods sections, only 36 studies met the inclusion criteria for this analysis. Three studies originally included (7–9) were excluded after a more detailed analysis. This was because they included groups with multiple exposure in more than 10% of cases and it was not possible to separate the different outcomes according to single or multiple exposures. Appendix A lists all the rejected studies from this analysis and the reasons for their rejection. The following were excluded: 80 case reports, 22 editorials, 43 letters, 87 reviews or commentaries, 127 studies without fetal or pregnancy outcomes, 40 in vitro studies or placental perfusions, 54 studies with outcomes not within the scope of this meta-analysis, 19 studies without a control group, and 12 studies where cocaine users had not been separated from users of other drugs. Table 2 highlights the characteristics of the 33 included studies. Exposure was mainly ascertained through urine or meconium analysis (73%) or by chart review and/or maternal interview (27% of the studies), while outcome was mainly confirmed using physician examination or record examination. The studies reported pregnancy and neonatal outcomes of 4184 women exposed to cocaine during pregnancy. Nineteen percent of these were also exposed to others drugs (i.e., heroin, methadone, marijuana). The outcomes were compared with 31,544 drug-free pregnancy controls and with 963 women exposed to other addictions but not cocaine. Major Malformations The teratogenic potential of cocaine was investigated in 16 (47%) of included studies (Fig. 1). Major malformations were those described by Heinonen et al. (10). Comparing women where cocaine was the only drug of abuse in pregnancy with drug-free controls, the pooled relative risk resulted significant (RR: 1.70, 95% CI 1.12–2.60). Six studies reported the number of malformed children after exposure during pregnancy to cocaine plus other addictions (heroin, marijuana, methadone, etc). The pooled relative risk was also significant in this case (RR: 2.10; 95% CI 1.42–3.09). The significance disappeared when the risk for major malformations was analyzed in women exposed to cocaine alone compared to women exposed to cocaine plus other addictions. When we used women exposed to polydrugs without cocaine as control, we were not able to identify any significant risk for major malformations in the women exposed to cocaine alone or to polydrugs with cocaine. A test for heterogeneity showed that all studies detected an effect size of similar magnitude and direction with the exception of the comparison between cocaine alone versus polydrugs with cocaine exposures. In this case, a single study was responsible for the heterogeneity (11). When that study was removed, the heterogeneity test was no longer significant. Low Birth Weight Of the included studies, 18 (54%) reported data on the number newborn with low birth weight after cocaine exposure (Fig. 2). The rate of low birth weight was defined as the number of live births weighing less than 2500 g. As in the previous analysis, mothers exposed to cocaine alone or to polydrugs with cocaine show a significant pooled relative risk of low birth weight when compared to a drug-free control (RR: 2.85, 95% CI 2.28–

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3.56 and 3.54, 95% CI 1.95–6.43, respectively). When we used as controls the mothers exposed to polydrugs with or without cocaine the significance disappeared. Results were homogeneous in three comparisons (cocaine alone versus polydrugs with and without cocaine and polydrugs with cocaine versus polydrugs without cocaine). The test for heterogeneity was positive in the first two comparisons with drug-free controls (cocaine alone and polydrugs with cocaine). However, in the comparison of cocaine plus polydrugs versus drug-free controls the heterogeneity was due to a single study (12). In the first comparison of cocaine alone versus drug free, the homogeneity resulted by using only prospective studies in which urine analysis was used to identify cocaine users.

Birth Weight Similar trends are shown with the data on the rate of low birth weight (Fig. 3). Use of cocaine during pregnancy (alone or with polydrugs) was associated with the risk of a weighted average birth weight reduction from 486 to 512 g. When pregnant women exposed to polydrugs with or without cocaine were used as controls, the significant birthweight reduction disappeared. Regarding the combinability of the included studies reporting birth weight after cocaine exposure, the comparisons of cocaine alone or with polydrugs versus drug-free control was homogeneous after the exclusion of outliers— Bingol (13) and Cohen (14) respectively. All other comparisons were homogeneous.

Birth Length Consistent with the data on birth weight, use of cocaine (alone or in combinations with polydrugs) during pregnancy is associated with the risk of a weighted average birth-length reduction from 2.20 to 2.65 cm (Fig. 4). Using as controls mothers exposed to polydrugs with or without cocaine, there was no difference in birth length of newborns exposed to cocaine (with or without polydrugs) during pregnancy. All comparisons were homogeneous with the exception of cocaine alone versus drug-free controls where one outlier (15) was excluded for homogeneity.

Prematurity Prematurity was defined as a live birth before 37 weeks of gestation (Fig. 5). Pregnant women exposed to cocaine alone or to cocaine plus polydrugs have a higher risk of preterm delivery (RR: 2.63 95% CI 2.13–3.26 and 3.19 95% CI 2.30–4.41, respectively) than do drug-free controls. A comparison of mothers exposed to cocaine alone versus polydrugs with cocaine or mothers with cocaine and polydrug exposure versus polydrugs without cocaine did not result in a significant risk for prematurity. When mothers exposed to cocaine alone were compared with the group of mothers exposed to polydrugs without cocaine, we noticed again a significant risk of prematurity (RR: 1.72 95% CI 1.19–2.52). All comparisons were homogeneous with the exception of the first comparison (cocaine alone versus drug-free control). This comparison became homogeneous when only prospective studies with identification of cocaine users by urine or meconium analysis were considered.

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Table 2

Characteristics of Studies Included in the Meta-analysis

Reference 1. Bateman, 1993 (16)

2. Bingol, 1987 (13)

3. Chasnoff, 1985 (17)

4. Chasnoff, 1987 (18)

Outcomes

Study type

Data collection

Cocaine alone (361) Drug free (387)

Cohort prospective

Urine analysis Chart review

Cocaine alone (50) Drug free (340) Polydrugs with Cocaine (110) Cocaine Alone (12) Drug free (15) Polydrugs with cocaine (12) Polydrugs no cocaine (15)

Cohort retrospective

Interview with the mother Chart review

Cohort prospective

Urine analysis

Polydrugs with cocaine (52) Polydrugs no cocaine (73)

Cohort prospective

Urine analysis Chart review

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Birth defects Low birth weight Prematurity Abruptio placentae Gestational age Head circumference Weight Length Birth defects Head circumference Weight Length Birth defects Abruptio placentae Head circumference Weight Length Birth defects Prematurity Abruptio placentae Meconium Weight Head circumference Length

Study groups (sample size)

6. Chavez, 1989 (20) 7. Chazotte, 1991 (21)

8. Cherukuri, 1988 (22)

9. Chouteau, 1988 (23) 10. Cohen, 1991 (14)

11. Eyler, 1994 (24)

Birth defects Low birth weight Prematurity Abruptio placentae Weight Head circumference Birth defects

Cohort prospective

Urine analysis

Cocaine alone (1063) Drug free (8326) Cocaine alone (42) Drug free (42)

Case control retrospective Cohort prospective

Chart review Interview with the mother Urine analysis

Cocaine alone (55) Drug free (55)

Cohort retrospective

Interview with the mother Chart review

Cocaine alone (124) Drug free (218) Cocaine alone (56) Drug free (166) Polydrugs with cocaine (27)

Cohort retrospective Cohort retrospective

Urine analysis

Cocaine alone (168) Drug free (168)

Cohort retrospective

Chart review

Urine analysis

391

Low birth weight Gestational age Weight Birth defects Low birth weight Prematurity PROM Abruptio placentae Meconium Gestational age Head circumference Weight Length Low birth weight Prematurity Low birth weight Prematurity Gestational age Weight Birth defects Low birth weight Prematurity Abruptio placentae Gestational age Weight

Cocaine alone (53) Drug free (40)

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5. Chasnoff, 1988 (19)

392

Table 2

Continued

Reference

Outcomes Prematurity Meconium

13. Galanter, 1992 (26)

PROMa Abruptio placentae Meconium Birth defects Low birth weight Prematurity PROM Abruptio placentae Head circumference Weight Length Birth defects Low birth weight Prematurity Abruptio placentae Meconium Head circumference Weight Length Weight

14. Gillogley, 1990 (27)

15. Hadeed, 1989 (28)

16. Isenberg, 1987 (29)

Cocaine alone (35) Drug free (1021) Polydrugs no cocaine (35) Polydrugs with cocaine (51) Polydrugs no cocaine (350)

Study type

Data collection

Cohort prospective

Urine analysis Chart review

Cohort prospective

Urine analysis

Cocaine alone (139) Drug free (293) Polydrugs with cocaine (35) Polydrugs no cocaine (125)

Cohort retrospective

Urine analysis Chart review

Cocaine alone (56) Drug free (56)

Cohort prospective

Urine analysis

Cocaine alone (13) Drug free (36)

Cohort prospective

Urine analysis

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12. Fulroth, 1989 (25)

Study groups (sample size)

18. Kelley, 1991 (15)

19. Kistin, 1996 (31)

20. Little, 1989 (32) 21. McCalla, 1991 (33)

22. MacGregor, 1987 (34)

23. Mastrogiannis, 1990 (35)

Low birth weight Prematurity PROM Abruptio placentae Meconium Gestational age Weight Low birth weight Prematurity Abruptio placentae Gestational age Head circumference Weight Length Birth defects Low birth weight Abruptio placenta Prematurity Birth defects Meconium PROM Abruptio placentae Low birth weight Prematurity Abruptio placenta Gestational age Weight Abruptio placentae PROM Meconium

Cocaine alone (63) Drug free (123) Polydrugs with cocaine (137) Polydrugs no cocaine (27)

Cohort retrospective

Chart review

Cocaine alone (30) Drug free (30)

Cohort retrospective

Chart review

Cocaine alone (64) Drug free (13,043)

Cohort retrospective

Urine analysis Chart review

Polydrugs with cocaine (53) Drug free (100) Cocaine alone (128) Drug free (983)

Cohort prospective Crosssectional study Cohort prospective

Interview with the mother Chart review Urine analysis

Cohort retrospective

Urine analysis

Cocaine alone (24) Drug free (70) Polydrugs with cocaine (46)

Cocaine alone (40) Drug free (46)

Fetal Effects of Cocaine

17. Keith, 1989 (30)

Chart review

393

394

Table 2

Continued

Reference 24. Matera, 1990 (36) 25. Nair, 1994 (37)

26. Neerhof, 1989 (11)

PROM Abruptio placentae Low birth weight Meconium 14 Weight Length Birth defects Prematurity Abruptio placentae Gestational age Head circumference Weight Low birth weight Low birth weight Prematurity Abruptio placentae Head circumference Weight Length

Study groups (sample size)

Study type

Data collection

Cocaine alone (51) Drug free (350) Polydrugs with cocaine (55) Polydrugs no cocaine (86)

Cohort prospective Cohort prospective

Urine analysis

Cocaine alone (113) Drug free (88) Polydrugs with cocaine (24)

Cohort prospective

Urine analysis

Polydrugs with cocaine (34) Drug free (590) Cocaine alone (21) Drug free (600)

Cohort prospective Cohort prospective

Interview with the mother

Meconium analysis

Meconium analysis

Addis et al.

27. Richardson, 1991 (12) 28. Rosengren, 1993 (38)

Outcomes

30. Singer, 1994 (40)

31. Sprauve, 1997 (41)

32. Stafford, 1994 (42) 33. Zuckerman, 1989 (43)

a

Prematurity Gestational age Head circumference Weight Length Low birth weight Prematurity Gestational age Weight Length Birth defect Low birth weight Prematurity Abruptio placentae Birth defects Birth defects Gestational age Head circumference Weight Length

Drug free (50) Polydrugs with cocaine (50) Polydrugs no cocaine (50)

Cohort prospective

Urine analysis Chart review

Cocaine alone (100) Drug free (100)

Cohort retrospective

Urine analysis Interview with the mother

Cocaine alone (483) Drug free (3158)

Cohort retrospective

Urine analysis

Cocaine alone (40) Drug free (40) Drug free (1010) Polydrugs with cocaine (114) Polydrugs no cocaine (202)

Cohort prospective Cohort prospective

Urine analysis

Fetal Effects of Cocaine

29. Ryan, 1987 (39)

Urine analysis Chart review

PROM ⫽ premature rupture of membranes.

395

396

Figure 1 Major malformations.

Addis et al.

Fetal Effects of Cocaine

Figure 2 Low birth weight.

397

Figure 3 Birth weight.

Fetal Effects of Cocaine

399

Figure 4 Birth length.

Gestational Age The analysis of a continuous variable like gestational age confirmed the findings on prematurity after cocaine exposure during pregnancy (Fig. 6). There was a significant reduction of the gestational age when we compare the mothers exposed to cocaine (alone or with other drugs) versus drug free control groups. Mothers using cocaine alone did not have a significant reduction of gestational age when compared with women exposed to polydrugs with cocaine. Similar results were found for polydrugs with cocaine exposure versus

Figure 5 Prematurity.

Fetal Effects of Cocaine

Figure 6 Gestational age.

401

402

Addis et al.

polydrugs without cocaine exposure. Of the included studies, only one reported the data on gestational age comparing women exposed to cocaine alone versus polydrugs without cocaine. After the exclusion of one outlier in the comparison of cocaine with polydrugs versus drug-free control, all comparisons were homogeneous.

Abruptio placentae Of the included studies, 19 reported data on abruptio placentae after cocaine exposure (Fig. 7). The risk for this pregnancy complication was significant when we considered the studies that compared mothers exposed to cocaine alone or in combination with other addictions versus drug-free controls or versus exposure to polydrugs but not cocaine. No risk of abruptio placentae was noted when we considered mothers exposed to cocaine alone versus women exposed to cocaine plus other drugs. The pooled risk for abruptio placentae was higher in studies comparing cocaine alone or with polydrugs versus polydrugs without cocaine. All comparisons were homogeneous.

Premature Rupture of Membranes (PROM) This analysis included 7 studies (Fig. 8). The pooled relative risk for PROM was significantly higher for pregnant women exposed to cocaine alone or with polydrugs compared to drug-free controls or to polydrugs but not cocaine. The only comparison not found to be significant was ‘‘cocaine alone versus polydrugs with cocaine.’’ In all comparisons, the test for heterogeneity showed that all studies detected an effect size of similar magnitude and direction.

Head Circumference Thirteen studies reported measurements of head circumference in children exposed to cocaine during pregnancy (Fig. 9). Cocaine use (alone or with polydrugs) during pregnancy was associated with a significant risk of reduction of head circumference in the newborns. Cocaine alone or with other addictions did not lead to a significant reduction of head circumference when compared to polydrug (but not cocaine) exposure. All these comparisons were found to be homogeneous. Only two studies had data eligible for the comparison between exposure to cocaine alone versus cocaine with polydrugs, which showed no significant reduction of head circumference. Finally, only one study reported data comparing head circumference after cocaine alone versus polydrugs with no cocaine. No significant risk was detected in this last comparison.

Sensitivity Analysis Both retrospective analyses and studies identifying exposure by maternal interview or chart extraction may result in bias as to the correct exposure type. For this reason the analysis was repeated, excluding, where possible, all retrospective studies and analyses

Figure 7 Abruptio placentae.

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Figure 8 Premature rupture of membranes.

where the identification of cocaine exposure was done by chart extraction or maternal interview. After the exclusions of those studies, the risk of major malformation was still significantly higher in mothers exposed to cocaine than in drug-free controls (RR: 1.09, 95% CI 1.09–4.93) but nonsignificant in the comparison of pregnancy with cocaine alone versus polydrugs without cocaine exposures. Using the same exclusion criteria, we recalculated the relative risk or weighted average of low birth weight (RR: 2.82, 95% CI 1.72–

Fetal Effects of Cocaine

405

Figure 9 Head circumference.

4.64), birth weight (weighted average: ⫺485g 95% CI ⫺550.8 to ⫺379.9 g), birth length (weighted average: ⫺2.18 cm 95% CI ⫺2.84 to ⫺1.52 cm), prematurity (RR: 2.44 95% CI 1.90–3.12), gestational age (weighted average: ⫺1.24 weeks, 95% CI ⫺1.61 to ⫺0.8 weeks), abruptio placentae (RR: 5.89 95% CI 1.90–3.12), PROM (RR: 1.58 95% CI 1– 2.51), and head circumference (weighted average ⫺1.7 cm 95% CI ⫺2.0 to ⫺1.35 cm) in women exposed to cocaine alone versus drug-free control. In none of these comparisons with cocaine versus drug-free controls did the significance disappear.

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DISCUSSION Because very large numbers of women in the reproductive age group consume cocaine, there are serious concerns regarding the long-term health of millions of children exposed in utero to this recreational drug (2). An issue widely recognized by researchers and clinicians is that, in addition to cocaine, many other risk factors occur and may adversely affect infants exposed in utero to cocaine. These include other drugs of abuse and cigarettes, alcohol, poor prenatal care, single motherhood, and poverty, to mention a few (2,4). Any attempt to separate the effects of cocaine from those of other drugs of abuse must therefore address the role of the various confounders. In our original meta-analysis, performed a decade ago (5), there was often insufficient statistical power to address differences between cocaine-exposed fetuses and controls. Because of the tremendous volume of research published during the last 10 years, we had the opportunity to address several important adverse effects that are widely attributed to cocaine. By separating studies into those where women were exposed mainly to cocaine, to cocaine plus other drugs, mostly to other drugs, or no drugs (who were drug-free), we have created a population-based control for many of the confounding factors mentioned above that are known to affect infants adversely. The rates of major malformations among children of cocaine users are significantly higher than among drug-free women. However, when these babies are compared to those exposed to other drugs of abuse, the effect size is nullified, strongly suggesting that the various confounders, also occurring in polydrug/no cocaine users, are responsible for this effect. An identical trend has emerged for other endpoints, including gestational age, birth weight, birth length, and head circumference as well as the rates of prematurity and low birth weight. The two adverse effects measured by this systematic review that are significantly associated with cocaine itself are the rates of abruptio placentae and premature rupture of membranes. In both cases, cocaine users had higher risks for these adverse events than women consuming other drugs of abuse. These results are different from those in our original analysis (5), where there was insufficient power to prove placental abruption as directly associated with cocaine. It is important to recognize that this analysis did not include reports of neurobehavioral endpoints, which are currently the focus of much research and clinical attention. A separate systematic review will be needed to address long-term brain development in these children.

Appendix A List of Rejected Studies and Reason for Rejection Case Reports/Case Series (80) Abramowicz, (1991)(3); Apple, (1990)(27); Bakht, (1990)(32); Beltran, (1995)(41); Brown, Jr., (1993)(50); Burkett, (1990)(57); Carlan, (1991)(63); Cohen, (1991)(91); Collins, (1989)(95); Deoliveira, (1991)(110); Dollberg, (1989)(121); Dominguez, (1991)(122); Evelyn, (1992)(138); Geggel, (1989)(160); George, (1995)(161); GieronKorthals, (1994)(163); Gomez-Anson, (1994)(171); Gonsoulin, (1990)(173); Good, (1992)(175); Greenfield, (1991)(183); Greenland, (1989)(184); Hall, (1992)(188); Hannig,

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(1991)(192); Harris, (1993)(196); Hepper, (1995)(205); Ho, (1994)(208); Hoeger, (1996)(209); Hoyme, (1990)(216); Hsu, (1992)(217); Iriye, (1994)(230); Iriye, (1995)(229); Jack, (1990)(232); Jasnosz, (1994)(238); Jawahar, (1997)(239); Johnson, (1995)(245); Kankirawatana, (1993)(254); Kapur, (1991)(255); Lampley (1996)(282); Lessick, (1991)(289); Lezcano, (1994)(293); Liu, (1992)(302); Martinez, (1994)(315); Meeker, (1990)(324); Mendelson, (1992)(325); Mercado, (1989)(326); Miller, (1990)(329); Mishra, (1995)(338); Mittleman, (1989b)(340); Moen, (1993)(341); Moriya, (1995)(348); Murphy, (1993)(352); Nolte, (1991)(367); Nyirjesy, (1993)(371); Okoruwa, (1995)(373); Ostrea, Jr., (1994)(375); Perlow, (1990)(380); Peters, (1992)(381); Porat, (1991)(387); Potter, (1994)(388); Rais-Bahrami, (1990)(394); Reznik, (1989)(400); Robin, (1994)(410); Sarpong, (1992)(427); Seballos, (1994)(432); Sheinbaum, (1992)(435); Sims, (1989)(442); Singer, (1995)(444); Skopp, (1997)(448); Spinazzola, (1992)(458); Spires, (1989)(459); Spital, (1991)(460); Streissguth, (1991)(468); Sturner, (1991)(469); Sumner, (1993)(471); Sztulman, (1990)(476); Thatcher, (1989)(478); Towers, (1993)(480); van den Anker, (1993)(489); Viscarello, (1992)(491); Wilson, (1993)(504). Editorials (22) Alexander, (1991)(13); Amoury, (1993)(15); Anonymous, (1990a)(20); Anonymous, (1991a)(23); Baxley, (1990)(36); Brouhard, (1994)(49); Chasnoff, (1989a)(71); Fantel, (1990)(141); Heagarty, (1990)(200); Howard, (1995)(214); Jentzen, (1993)(240); Jos, (1995)(247); Kearney, (1995)(259); Konkol, (1994a)(273); Lewis, (1989)(292); Lone, (1991)(303); Neuspiel, (1993b)(360); Nora, (1990)(368); Plessinger, (1993)(384); Salamy, (1990)(424); Tudehope, (1989)(482); Zuckerman, (1994)(515). Letters (43) Abdeljaber, (1990)(1); Ahmed, (1989)(7); Anonymous, (1990)(17); Bays, (1991)(37); Carraccio, (1994)(64); Chavkin, (1990)(80); Cottler, (1992)(102); DiGregorio, (1993)(116); Downing, (1991)(125); Fogarty, (1991)(146); Friedman, (1995)(153); Goldin, (1989)(169); Good, (1994)(174); Graham, (1989a)(178); Gratacos, (1993)(182); Hansen, (1990)(193); Herschman, (1991)(207); Hunt, (1990)(220); Jerome, (1995)(241); Kain, (1992)(249); Levy, (1993)(290); Maynard, (1990)(319); Miele, (1992)(328); Mittleman, (1989a)(339); Moore, (1993)(346); Morfesis, (1994)(347); Neuspiel, (1992a)(358); Neuspiel, (1992b)(362), Neuspiel, (1995)(361); Nucci, (1994)(369); Page, (1992)(377); Petrulis, (1992)(382); Racine, (1994)(393); Sackoff, (1992)(423); Shaw, (1991)(434); Sher, (1989)(437); Stephens, (1989)(464); Sugarman, (1995)(470);Tabor, (1990)(477); Thorp, Jr. (1991)(479); van den Anker, (1991)(487); van den Anker, (1992)(488);Yang, (1995)(508). Reviews and Commentaries (87) Abel, (1991)(2); Adams, (1990)(5); Anonymous, (1989a)(18); Anonymous, (1993)(25); Aronson, (1990)(29); Berger, (1990)(44); Brent, (1994)(48); Buehler, (1995)(54); Buehler, (1996)(55); Byrne, (1992)(60); Chan, (1997)(68); Chao, (1996)(69); Chasnoff, (1989b)(72); Chasnoff, (1993)(73); Chavkin, (1993)(81); Church, (1993)(88); Coles, (1992)(92); Coles, (1993)(93); Cornish, (1996)(101); Day, (1993a)(106); Day, (1993b)(107); Dixon, (1989)(118); Dow Edwards, (1991)(124); Dow-Edwards, (1993)(123); Dumas, (1992)(127); Dungy-Poythress, (1995)(128); Elhassani, (1990)(132);

408

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Ellen, (1993)(135); Fantel, (1993)(140); Ferner, (1993)(143); Finnegan, (1994)(145); Frank, (1993)(152); Garcia, (1990)(158); Gaskill, (1992)(159); Giacoia, (1990)(162); Gintautiene, (1990)(168); Goldstein, (1990)(170); Goodwin, (1990)(176); Grossman, (1993)(185); Horger, (1990)(211); Janke, (1990)(237); Johnson, (1992)(242); Kaltenbach, (1994)(251); Kandall, (1991)(252); Karmel, (1991)(257); Keller, (1993)(261); Kenner, (1997)(263); Khoury, (1991)(264); Klitsch, (1994)(270); Knisely, (1991)(272); Koren, (1989)(278); Koren, (1993)(275); Landry, (1996)(284); Lauder, (1991)(286); Lewis, (1991)(291); Litt, (1997)(299); Lunsford, (1995)(306); Lutiger, (1991)(307); Martin, (1992a)(312); Martin, (1992b)(313); Meyer, (1996)(327); Miller, (1994)(333); Miller, (1997)(330); Murphey, (1993)(351); Neuspiel, (1993a)(359); Ostrea, (1992)(374); Pokorni, (1996)(385); Richardson, (1993)(405); Richardson, (1996)(406); Ripple, (1992)(408); Rizk, (1996)(409); Sexson, (1993)(433); Shepard, (1993)(436); Slade, (1993)(449); Spear, (1993)(456); Sprauve, (1996)(461); Strauss, (1997)(467); Sun. (1997)(472); Swadi, (1993)(474); Szeto, (1991)(475); Warner, (1997)(494); Webster, (1993)(497); Westdorp, (1995)(502); Wightman, (1991)(503); Wootton, (1994)(507); Zuckerman, (1992)(514); Zuckerman, (1991)(512). Studies not reporting fetal or pregnancy outcomes (127) Abusada, (1993)(4); Alemi, (1996)(10); Alemi, (1996)(11); Alemi, (1996)(12); Amaro, (1990)(14); Anonymous, (1990c)(22); Anonymous, (1996)(26); Archie, (1997)(28); Ball, (1997)(33); Bauchner, (1990)(35); Behnke, (1997)(39); Bendersky, (1996)(42); Berenson, (1991)(43); Billman, (1996)(46); Browne, (1992)(52); Browne, (1994)(51); Brunader, (1991)(53); Burke, (1993)(56); Callahan, (1992)(62); Cartwright, (1991)(65); Casanova, (1994)(66); Chasnoff, (1990)(78); Charpentier, (1996)(70); Condie, (1989)(96); Cornelius, (1993)(99);Cornelius, (1994)(100); Czeizel, (1990)(105); de Feo, (1995)(108); DelaneyBlack, (1996)(109); DePetrillo, (1995)(111); DeVane, (1991)(113); DiGregorio, (1994)(117); Dudish, (1996)(126); Egelko, (1996)(131); Elk, (1994)(133); Elk, (1995)(134); Ellerbrock, (1995)(136); Emery, (1995)(137); Fetters, (1996)(144); Forman, (1992)(149); Forman, (1994)(147); Frank, (1992)(151); Galanter, (1992)(157); Gillmore, (1992)(165); Graham, (1989b)(180); Graham, (1991)(179); Grant, (1994)(181); Gomez, (1996)(172); Hall, (1996)(187); Hawley, (1995)(198); Heller, (1996)(202); Henderson, (1989)(203); Henderson, (1997)(204); Hurd, (1991)(222); Hurt, (1996)(223); Hurt, (1997a)(225); Hurt, (1997b)(226); Hutchins, (1997)(227); Ingersoll, (1996)(228); Jacobson, (1991)(234); Jacobson, (1996)(235); Jain, (1993)(236); Johnson, (1997)(244); Joyce, (1995)(248); Kain, (1995)(250); Karmel, (1996)(256); Killeen, (1995)(265); Klein, (1992)(268); Klein, (1994)(267); Kline, (1997)(269); Konkol, (1994b)(274); Koren, (1992a)(276); Koren, (1992b)(277); Koren, (1992c)(279); Land, (1990)(283); Lindsay, (1990)(297); Lanehart, (1994)(285); Lauria, (1997)(287); Lindsay, (1991)(295); Lindsay, (1992)(296); Lindsay, (1997)(294); Little, (1990)(300); Marques, (1993)(310); Martin, (1996)(311); Martinez Crespo, (1994)(314); Mayes, (1996)(318); McCalla, (1992)(322); McFarlin, (1996)(323); Miller, (1993)(334); Minkoff, (1990)(335); Moore, (1996)(345); Moriya, (1994)(349); Moser, (1993)(350); Napiorkowski, (1996)(355); Neuspiel, (1993c)(365); O’Connor, (1997)(372); Peeke, (1994)(378); Pelham, (1992)(379); Phibbs, (1991)(383); Polzin, (1991)(386); Quinn, (1992)(391); Reddin, (1991)(398); Regalado, (1996)(399); Richardson, (1996a)(406); Richardson, (1996b)(402); Rico, (1990)(407); Rodriguez, (1996)(414); Rogers, (1991)(416); Rosenkranz, (1990)(418); Ruiz, (1994)(420); Ryan, (1994)(422); Scafidi, (1996)(428); Schutzman, (1991)(431); Singer, (1997)(443); Smith, (1989)(453); Strano-Rossi, (1996)(466); Svikis, (1997)(473); Tron-

Fetal Effects of Cocaine

409

ick, (1996)(481); Ursitti, (1997)(483); Vega, (1997)(490); Wasserman, (1993)(495); Weeman, (1995)(498); Weese-Mayer, (1991)(499); Welch, (1993)(501); Wingert, (1994)(506); Zimmerman, (1994)(511); Zuckerman, (1989a)(513). In vitro studies/placenta perfusion (40) Ahmed, (1990)(9); Ahmed, (1991)(8); Bailey, (1994)(30); Bailey, (1996)(31); Cejtin, (1990)(67); Chiarotti, (1996)(85); Cook, (1996)(97); Dicke, (1993)(114); Dicke, (1994)(115); Gilbert, (1990)(164); Harker, (1994)(194); Hurd, (1993)(221); Johnson, (1996)(246); Krishna, (1993)(281); Malek, (1995)(309); Miller, (1996)(332); Mirochnick, (1997)(337); Monga, (1993)(343); Monga, (1994)(342); Moore, (1992)(344); Oyler, (1996)(376); Prasad, (1994)(389); Ramamoorthy, (1993a)(396); Ramamoorthy, (1993b)(397); Ramamoorthy, (1995)(395); Richards, (1990)(401); Roby, (1996)(411); Roe, (1990)(415); Saraf, (1995)(426); Schenker, (1993)(429); Simone, (1994b)(441); Simone, (1996)(438); Simone, (1997)(439); Smith, (1992)(452); Smith, (1995)(454); Sosnoff, (1996)(455); Sternfeld, (1997)(465); Wang, (1996)(493); Winecker, (1997)(505); Yelian, (1994)(510). Outcomes beyond the scope of this meta-analysis (54) Ahluwalia, (1992)(6); Anonymous, (1989b)(16); Anonymous, (1990b)(21); Anonymous, (1990d)(19); Anonymous, (1991b)(24); Bhushan, (1994)(45); Burkhead, (1995)(59); Calhoun, (1991)(61); Chen, (1991)(83); Chiu, (1990)(86); Cohen, (1991)(90); Cohen, (1994)(89); Coles, (1992)(94); Cordero, (1990)(98); Cotton, (1994)(103); Curry, (1995)(104); Dixon, (1989)(119); Durand, (1990)(129); Dusick, (1993)(130); Johnson, (1992)(243); Frank, (1990)(150); Fritz, (1993)(155); Gingras, (1994)(167); GottbrathFlaherty, (1995)(177); Handler, (1991)(189); Handler, (1994)(190); Hanlon-Lundberg, (1996)(191); Harris, (1992)(195); Harsham, (1994)(197); Hoskins, (1991)(213); Hume, Jr., (1994)(218); Hurt, (1995);(224); Jacobson, (1994)(233); Kandall, (1993)(253); Legido, (1992)(288); Lopez, (1995)(304); Lounsbury, (1989)(305); Miller, Jr., (1995)(331); Mirochnick, (1995)(336); Needlman, (1993)(356); Neuspiel, (1991)(363); Neuspiel, (1994)(364); Nulman, (1994)(370); Prichep, (1995)(390); Richardson, (1991)(403); Richardson, (1994)(404); Rodning, (1989)(412); Rodriguez, (1993)(413); Schneider, (1992)(430); Skolnick, (1990)(447); Singer, (1994)(446); van de Bor, (1990)(486); Wehbeh, (1995)(500); Yawn, (1994)(509). Studies without control group (19) Beeram, (1993)(38);Beltran, (1994)(40); Burkett, (1994)(58); Chasnoff, Fries, (1993)(154); Hofkosh, (1995)(210); Horn, (1992)(212); Howard, Hume, Jr., (1989)(219); Knight, (1994)(271); Kramer, (1990)(280); Link, McCalla, (1995)(320); Ney, (1990)(366); Racine, (1993)(392); Rosenstein, Slutsker, (1993)(450); Smit, (1994)(451); Weathers, (1993)(496).

(1989c)(77); (1995)(215); (1991)(298); (1990)(419);

Cocaine users not separated from other drugs (12) Doberczak, (1991)(120); Feldman, (1992)(142); Forman, (1993)(148); Handler, (1991)(189); Hawthorne, (1993)(199); Hernandez, (1992)(206); Kaye, (1989)(258); Nanda, (1990)(354); Samuels, (1993)(425); Spence, (1991)(457); van Baar, (1994)(485); Van Baar, (1990)(484).

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22 Pregnancy Outcome and Infant Development Following Gestational Cocaine Use by Social Cocaine Users in Toronto, Canada Karen Graham McMaster University, Hamilton, Ontario, Canada

Annette Feigenbaum, Irena Nulman, Rosanna Weksberg, Stan Ashby, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Thomas R. Einarson and Susan Goldberg The University of Toronto, Toronto, Ontario, Canada

Clinical Case A young woman in her first trimester of pregnancy used three lines of cocaine weekly before finding out she was pregnant. She discontinued her use of cocaine at 10 weeks of pregnancy. She wants to continue her pregnancy if the teratogenic risk is not high. How should she be counseled?

INTRODUCTION Recreational use of cocaine is increasing in Canada and the United States in all age and socioeconomic groups, with women aged 18–29 years showing the greatest rate of increase (1,2). Reports of the effects of cocaine on pregnancy outcome are becoming increasingly common. However, published studies have concentrated on populations of women who have used the drug frequently throughout pregnancy and had a variety of other risk factors related to use of other drugs, poor prenatal care, and low socioeconomic status. It is evident that these drug-dependent women are the minority of cocaine users, with the vast majority of users consuming the drug less than once monthly (1). Knowledge obtained from studies of drug-dependent women cannot be directly extrapolated to the pregnancies of women who use cocaine occasionally in early pregnancy and generally have few other

Reprinted with permission of Toronto University Press from Clin Invest Med 1992; 15:384–394. 433

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Table 1 Comparison of Social Cocaine Users and Cocaine-Dependent Women Social cocaine users Stop cocaine use when realize pregnant Rarely use other hard drugs Generally have good prenatal care Low incidence of sexually transmitted diseases Mixed socioeconomic status

Cocaine-dependent women Use cocaine throughout pregnancy (21) Frequently use other hard drugs (18) Poor prenatal care (19) High incidence of sexually transmitted diseases (19,21) Low socioeconomic status (18–21)

risk factors (Table 1). The reproductive risks of cocaine use among social cocaine users are unknown. If cocaine causes embryonic damage during the first trimester similar to other classical teratogens, then even a brief exposure during early pregnancy may adversely affect the unborn baby. Conversely, if the effects of cocaine are cumulative and longer exposure is needed to interfere with fetal development, a brief first-trimester exposure to the drug, as is the usually case among women who use the drug before finding themselves pregnant, may not be detrimental. This prospective study was designed to compare outcome of pregnancy and infant well-being following cocaine exposure during early pregnancy by social cocaine users to that of two control groups.

METHODS Subject Recruitment and Assessments All women participating in this study were recruited from among those attending the Motherisk Program in Toronto, Canada, between November 1985 and February 1989. The program is an antenatal service that counsels pregnant women and their physicians about concerns related to drug, chemical, and radiation exposure during pregnancy and lactation. The following protocol was approved by The Hospital for Sick Children’s Human Experimentation Review Committee. Social cocaine users, who were selected from all pregnant women admitting to cocaine use in early pregnancy, were defined as women who were not chemically dependent and stopped cocaine use soon after the discovery of pregnancy. Subjects were excluded if cocaine exposure occurred only before conception or continued after the Motherisk Clinic visit despite our recommendation to cease this drug use, or if there were other exposures or medical conditions thought to increase the risk for adverse outcome. Two control groups were chosen prospectively from among women attending the Motherisk Clinic during the study period and followed in a similar manner to the social cocaine users. One group consisted of women admitting the use during pregnancy of cannabis but not cocaine. This cannabis user control group was deemed necessary because many of the social cocaine users admitted using cannabis as well. Subjects were excluded if cannabis exposure occurred only before conception, or if medical conditions or additional exposures placed a given pregnancy at increased risk for adverse outcome. The second control group consisted of women who came to the clinic for exposures to compounds and environmental agents believed to be safe during pregnancy (e.g., oral penicil-

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lins, video display terminals, acetaminophen), and reported no exposure to cocaine, cannabis, or other illicit recreational drugs. Subjects were excluded from this recreational drugfree control group if they had medical conditions or additional exposures that placed the pregnancy at increased risk for adverse outcome. This group was matched to the social cocaine user group for maternal factors thought to influence pregnancy outcome or infant development, including marital status, cigarette and alcohol consumption, obstetric history, and ethnic background. Assessment of pregnancy course and infant development was conducted at three time points. During the initial interview in the Motherisk Clinic, early in pregnancy, a detailed history of known reproductive hazards was obtained from each woman, including medical, obstetric, and genetic background as well as a history of drug, chemical, and radiation exposure. The amount(s) of drug(s) used and the time period of exposure(s) were recorded based on the patient’s report. No urinalysis for cocaine or other drugs was routinely performed because these women voluntarily approached the clinic to inquire about their reproductive risks following cocaine exposure during early gestation. Second, by the time of the clinic appointment 1–2 weeks after discontinuing cocaine, urine is not likely to be positive, as verified by us in several cases. Details concerning time of exposure are critical for determining the temporal relation to conception; therefore, in addition to requesting details on last menstrual period, we performed an ultrasound examination if there were doubts about the gestational age. In addition, the women provided personal data about themselves and the father of the baby. Socioeconomic status was estimated using the occupational status titles and the scales of Blishen and Carroll for females (3) and of Blishen and McRoberts for males (4). Six to ten months after the expected date of confinement, the women were contacted and administered a standard telephone questionnaire. The course of pregnancy, labor and delivery, perinatal period, and the health and development of the infant were assessed. Developmental milestones were recorded and compared with the screening norms of the Denver Developmental Screening Test to identify any areas of developmental delay (5). The interviewer was not blinded to the gestational exposure of the subjects at this time, since follow-up stems from the initial intake form, filled out during the initial visit to the Motherisk Clinic. Obstetric and pediatric records were obtained from appropriate medical centers, and additional medical information was obtained for birth weight, head circumference, gestational age, Apgar scores, and perinatal complications. At approximately 18 months of age, infant developmental status was assessed during a visit of the mother and infant to the Motherisk Clinic, using the Bayley Scales of Infant Development (BSID) mental and psychomotor scales (MDI and PDI)(6) and the Vineland Adaptive Behavior Scales (7). At this visit, the interviewer was blinded to the in utero exposure of the child. Current marital status, occupations, and education levels of the prospective parents were obtained. Maternal IQ was assessed by the Raven’s Standard Progressive Matrices, a language- and culturally independent test (8). During this visit, a detailed physical examination of the infant was performed by one of two clinical geneticists, each of whom was blinded to the in utero exposure. Measurements of current weight were recorded and plotted on standard Tanner-Whitehouse charts (9). In addition, a general physical examination was performed to document any minor or major malformations. Family history and previous medical and surgical history were taken. Where possible, this history was verified by requesting records from the child’s primary care physician.

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Statistical Analysis Comparisons of continuous variables between the cocaine, cannabis, and recreational drug-free groups were performed using one-way analysis of variance (ANOVA). The Scheffe F test was used to identify differences between subsets. Noncontinuous variables measured at nominal level were compared individually using the chi-square test and those in a ranked order by Kruskal-Wallis one-way ANOVA followed by a Mann-Whitney U test when post-hoc analysis was required. Least-squares regression analysis was performed to investigate correlations between variables. Sample Size The primary endpoint in this study is the score of the Bayley Scales of Infant Development, which has a coefficient of variation (CV) between 10 and 15%. If one considers a large effect size (ⱖ 0.8 SD) to be clinically significant, then between 25 and 54 patients in each group would be required (the smaller number corresponds to 10% and the larger to 15%) (10). Substantially larger numbers would be required to reject the null hypothesis if medium or small effect sizes are considered to be clinically relevant. Because upon starting the study it was evident that between 20 and 30 babies exposed to cocaine would have completed the study within 3 years and because there were no previous studies on developmental effects of cocaine in social users, we decided to study all available children and subsequently to perform a power analysis to address the possibility of a type II error (see ‘‘Results’’).

RESULTS Maternal Demographic Characteristics Six percent (n ⫽ 51) of all women attending the Motherisk Clinic during the study period reported use of cocaine during or just prior to pregnancy. Fifty-one of them (89%) met our criteria for social cocaine users. Of these, nine relocated and were lost to follow-up, four had elective abortions, three refused to participate, two had spontaneous abortions, two were exposed to cocaine only before conception, and one infant was too young for follow-up. Hence the study group consisted of 30 social cocaine users who completed all assessments (Table 2). Table 2 Subject Exclusion in the Social Cocaine Users Group Number of subjects

Description

51 Social cocaine users attending the Motherisk Program ⫺9 Subject relocated and not found ⫺4 Elective abortion ⫺3 Refused to participate in follow-up ⫺2 Spontaneous abortion ⫺2 Preconception cocaine exposure only ⫺1 Infant too young for complete assessment 30 ⫽ Number of social cocaine users with complete assessment

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All subjects reported stopping cocaine use before coming to the Motherisk Clinic, soon after discovering that they were pregnant. Eighty-seven percent (n ⫽ 26) of the subjects used less than a total of 10 g of cocaine during early pregnancy; only four women used more than 10 g. Most women snorted cocaine as the sole route of drug intake (n ⫽ 24); intravenous cocaine use (n ⫽ 4) and smoking crack (n ⫽ 3) were less common. Cannabis use was common among social cocaine users, occurring in 50% (n ⫽ 15) of the cases. All women reported stopping cannabis use upon realizing that they were pregnant. Use of other psychoactive drugs, which occurred only to a small extent, included sedatives (n ⫽ 2), opioids (n ⫽ 2), lysergic acid diethylamide (LSD) (n ⫽ 1), amphetamines (n ⫽ 1), and psilocybin (n ⫽ 1). These drugs were used infrequently and were discontinued upon realization of pregnancy. Eight percent (n ⫽ 69) of the women attending the Motherisk Clinic reported use of cannabis just prior to and/or during pregnancy. Fifty-one of these women reported no cocaine use and were considered for inclusion in the cannabinoid control group. After 31 cases had been excluded for a variety of reasons, 20 cases were assessed completely (Table 3). Other drug use was uncommon among subjects in this group, with only four women reporting use of LSD. The second control group comprised 30 women reporting no exposure to any illicit drug during pregnancy. Upon starting the study, it was apparent that the social cocaine users and cannabinoid users had very high rates of single motherhood. Therefore, we matched the drug-free control group according to this parameter in addition to age, gravidity, parity, and amount of alcohol and cigarettes consumed. The women of the three groups were similar in age, marital status during pregnancy and at infant developmental testing, obstetric history, and ethnicity (Table 4). However, the social cocaine users used significantly more alcohol and cigarettes than the women of the recreational drug-free control group. The women were of similar socioeconomic status (SES), and at least 20% in each group either stayed at home with their children or attended school. The cocaine-using women had significantly fewer years of formal education than drug-free controls, although they were of similar IQ. Comparison of demographics of cohabitating male partners, who occasionally were not the fathers of the study infants, shows that these spouses of cocaine

Table 3 Number of subjects

Subject Exclusion in the Cannabinoid Control Group Description

69 Cannabis users attending the Motherisk Program ⫺18 Used cocaine as well ⫺6 Preconception exposure only ⫺6 Subject relocated and not found ⫺6 Elective abortion ⫺5 Spontaneous abortion ⫺3 Not pregnant at the time of Motherisk Clinic visit ⫺2 Exposure to known teratogens (phenytoin, isotretinoin) ⫺2 Refused to participate in follow-up ⫺1 Infant too young for complete assessment 20 ⫽ Number of cannabis users (cocaine-free) with complete assessment

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Table 4 Comparison of Maternal and Paternal Characteristics Between Groups Groups a Demographic variables Age, years (mean ⫾ SD) Single at first Motherisk visit, % Single at BSID, % Ethnic background, % Caucasian Black Oriental Gravidity Parity Elective abortion Spontaneous abortion SES, female, % student, housewife, unemployed unskilled skilled professionals SES, male, % student, unemployed unskilled skilled professionals Years of school female male Maternal IQ d Alcohol use (%) No use ⬍1 drink/day 1–2 drinks/day ⬎2 drinks/day ⬎5 drinks/day (binge) Cigarette usee No use ⬍1/2 ppd 1/2 to 1 ppd ⬎1 ppd

Social cocaine (n ⫽ 30)

Cannabis (n ⫽ 20)

Drug-free (n ⫽ 30)

p value

26.6 ⫾ 5.5 70.4

26.3 ⫾ 5.4 45

29.3 ⫾ 4.8 31

0.06* 0.10**

55

33.3

20

0.14**

100 0 0 1.6 0.2 0.3 0.1

⫾ ⫾ ⫾ ⫾

1 0.5 0.7 0.3

100 0 0 1.9 ⫾ 0.9 0.6 ⫾ 0.8 0.3 ⫾ 0.6 0

78.9 10.5 10.5 2 ⫾ 1.2 0.5 ⫾ 0.7 0.2 ⫾ 0.5 0.3 ⫾ 0.7

20

25

31

50 26.7 3.3

30 35 10

3.5 31 34.5

A 7.4 48.1 40.7 3.7 12.9 ⫾ 2.3 12.7 ⫾ 1.6 109.1 ⫾ 12.4 A 14.3 46.4 21.4 10.7 7.1 A 17.2 24.1 55.2 3.4

B

⬍0.005***

15.1 ⫾ 2.9 15.1 ⫾ 2.6 114.1 ⫾ 11.7 B 33.3 60 0 6.7 0 B 73.3 3.3 23.3 0

0.004b 0.004c 0.24* ⬍0.025***

A 20 20 40 20 10.4 ⫾ 4.4 12.8 ⫾ 2 109.1 ⫾ 25.2 A 25 50 20 5 0 A 35 25 40 0

0.73** 0.10** 0.10** 0.39* 0.14* 0.80* 0.12* ⬎0.05***

3.3 20 33.3 43.3

⬍0.005***

* ANOVA and post-hoc Scheffe F test if ANOVA significant at p ⬍ 0.05. ** Chi-square, significant at p ⬍ 0.05. *** Kruskal-Wallis (KW) test and post-hoc Mann-Whitney U test if KW is significant at p ⬍ 0.05. a Groups with different letters are significant at p ⬍ 0.05 (i.e., A and A, B and B are nonsignificant and represent different populations). b Cannabis and control group values differ at p ⬍ 0.05. c Social cannabis users and drug-free group values differ and cannabis and drug-free group values differ at p ⬍ 0.05. d One father in each group performed the Raven IQ test. e ppd ⫽ package per day.

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users were of significantly lower SES than those of the two control groups and had significantly fewer years of formal schooling than the spouses of the drug-free women. Pregnancy Outcome Table 5 presents pregnancy outcome variables for the three groups studied. There were no significant differences in mean pregnancy weight gain, incidence of emergency cesarean sections or forceps- or vacuum-assisted delivery, or meconium staining of the amnoitic fluid between the three groups. Similarly, there were no significant differences in gestational age at delivery or birth weight, or in incidences of prematurity or low birth weight. Apgar scores at 1 and 5 minutes were not significantly different between the groups. Three of the four cocaine users who used more than 10 g of cocaine delivered two premature infants and one normal gestational age infant, each weighing less than 2500 g. Apgar scores for the four infants in this subgroup were 7, 7 and 7, 9 for the two premature infants and 4, 7 and 6, 4 after an elective and emergency cesarean section for the third and fourth, respectively. Developmental Assessment Developmental milestones of the offspring of the social cocaine users were similar to those of offspring of cannabis users and recreational drug–free subjects (Table 6). In general, most children met all milestones within the normal range of time, as described by the Denver Developmental Screening Test (DDST) norms (5). Overall, 7 of 30 children of social cocaine users, 8 of 20 of the cannabis group, and 11 of 30 of the drug-free control group showed delay in attaining one milestone, being 2 or more standard deviations below

Table 5

Comparison of Obstetrical and Neonatal Information Groups

Obstetric and neonatal variables Pregnancy weight gain, kg Emergency cesarean section, % Forceps delivery, % Meconium staining, % Gestational age, weeks Premature delivery (⬍ 37 wk), % Birth weight, g Low birth weight (⬍ 2500 g), % Apgar score at 1 minute at 5 minutes a b

ANOVA. Chi-square.

Social cocaine (n ⫽ 30)

Cannabis (n ⫽ 20)

Drug-free (n ⫽ 30)

p value

17.3 ⫾ 7.6 6.9

16.4 ⫾ 5.5 0

15.9 ⫾ 5.6 7.1

0.73a 0.49b

10.7 12 39.4 ⫾ 3.3 6.7

21 15.4 39.6 ⫾ 1.5 0

10.7 17.6 39.5 ⫾ 3.3 6.7

0.56b 0.89b 0.97a 0.51b

3294.6 ⫾ 677.6 10

3523.4 ⫾ 377.8 0

3407.7 ⫾ 703.4 10.3

0.45a 0.4b

7.9 ⫾ 1.3 8.6 ⫾ 1.3

8.5 ⫾ 0.6 9.1 ⫾ 0.2

7.9 ⫾ 1.9 8.9 ⫾ 1

0.38a 0.36a

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Table 6 Developmental Assessment Comparisons Groups Developmental assessment Milestones, mean months ⫾ SDa 1st smiled (0–2 months) 1st lifted head (0–3 months) 1st sat unaided (4.5–7.5 months) 1st crawled (6–8.5 months) 1st stood unaided (9–13 months) 1st walked unaided (11–14 months) 1st work spoken (8.5–13.5) BSID, MDI (mean ⫾ SD) BSID, PDI (mean ⫾ SD) Vineland (mean ⫾ SD) Infant age at testing, months a b

Social cocaine (n ⫽ 30)

Cannabis (n ⫽ 20)

Drug-free (n ⫽ 30)

p valueb

1.2 1.5 5.9 7 9.7 11.7

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

0.6 0.8 1.3 1.8 1.7 1.8

1.2 1.8 6 7 8.2 11.4

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

0.4 1.2 1.0 1.6 2.1 2.8

1.4 2.2 6 7.2 9.2 11.9

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

0.8 1.3 1.2 1.5 1.8 2.1

0.47 0.13 0.97 0.80 0.06 0.78

9.3 110.1 100.1 98.4 20.2

⫾ ⫾ ⫾ ⫾ ⫾

2.3 13.8 20.8 10.9 4.2

11.5 111.6 106.4 96 19.2

⫾ ⫾ ⫾ ⫾ ⫾

4.4 17.6 16.3 7.7 2.4

10.9 109.0 103.8 96.7 19.8

⫾ ⫾ ⫾ ⫾ ⫾

2.7 16.5 12.4 9.4 3.0

0.07 0.86 0.42 0.65 0.56

Range given for each milestone is DDST range of normal values from 25th percentile to 95th percentile. ANOVA.

normal as determined during the standardization of the DDST. Three infants exposed to cocaine, three infants exposed to cannabis, and five drug-free infants were delayed in reaching two milestones. A comparison of infant development shows similar, and numerically almost identical, scores achieved on the mental and motor scales of the Bayley Scales of Infant Development and on the Vineland Adaptive Behavior Scales. The four infants of mothers using more than 10 g of cocaine attained normal developmental scores. In the three groups, the age at which developmental testing was performed was similar (Table 6). There was a

Figure 1

Influence of maternal IQ (Raven) on infant MDI scores for all 80 mother-infant pairs.

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Infant Abnormalities by Study Group

Study group Cocaine (n ⫽ 30)

Cannabis (n ⫽ 18) Drug-free (n ⫽ 29)

Abnormalities documented on examination or from history 1 1 1 1 1 1 1 2 1 1 1 1 1 2 2 5

Isolated unilateral 4th–5th finger syndactyly Ventral septal defect Functional ejection systolic murmur (ESM) Intrauterine growth retardation, bilateral hydroceles, phimosis Prematurity with patent ductus arteriosus Failure to thrive Intussusception Functional ESM Intrauterine growth retardation, premature thelarche Inguinal hernia (repair) Dislocated hip Brachycephaly, speech delay, fine motor incoordination Nonparalytic strabismus Small umbilical hernia Congenital torticollis Functional ESM

weak correlation between maternal IQ and infant scores on the Bayley Scales Mental Development Index (r ⫽ 0.22, p ⫽ 0.06, Fig. 1). Power analysis reveals that it would take thousands of cases to verify whether the 1–3 point differences in BSID scores reflect a true but marginal effect size. Such an endeavor cannot be undertaken; moreover, such a small difference in scores is within the margin of error of the test and is not believed to be clinically significant. Physical assessment at 1.5 years revealed no differences in numbers of malformations among the three groups (Table 7). Several children in each group had minor malformations such as epicanthic folds or relative hypertelorism but no other physical abnormalities. Review of growth parameters found no group having significant growth retardation. Four infants in the cocaine group, two in the cannabis group, and one in the recreationaldrug-free control group were not seen by the geneticists as a result of scheduling difficulties. Comparison of the children’s facial features, both at the follow-up visit and thereafter with the aid of photographs, did not reveal any characteristic or significant dysmorphic features in the cocaine group. In addition, there was no clinical evidence of fetal alcohol syndrome in any infant. Only one child in the cocaine group had mild abnormalities of the external genitourinary system (Table 7). There was no evidence in any child of a vascular disruption event. However, in the absence of any associated alterations in finger size or formation, the case of syndactyly present in one child in the cocaine group could be classified as a vascular disruption.

DISCUSSION Cocaine use by pregnant women has become a major health issue. To date all reports of effects of cocaine use in pregnancy have dealt with women who use large amounts of cocaine, often throughout pregnancy. These women commonly use other drugs and have

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poor prenatal care and nutrition, thus making it difficult to determine the independent effect of cocaine on their offspring. It is important to study social cocaine users who stop cocaine use early in pregnancy, because they more closely represent the majority of the cocaine-using population than do cocaine-dependent women. In Ontario, Canada, only 5% of those admitting long-term cocaine use report consuming the drug more than once per month (1). Thus, if social cocaine users expose their fetuses to the drug during embryogenesis, apparent adverse effects consequent to first-trimester cocaine use would suggest that cocaine has embryopathic potential. It is imperative that the risk of early cocaine exposure in pregnancy be determined so that proper, nonbiased counseling of women can be provided. It is our experience at the Motherisk Program in Toronto that without such information, pregnant social cocaine users often consider termination of pregnancy after extrapolation of information obtained from studies of cocaine-dependent women. The pregnant social cocaine user may learn about the adverse effects of cocaine on pregnancy from the lay media. Newspaper and magazine articles often make such unsubstantiated statements as ‘‘a single cocaine hit during pregnancy can cause lasting fetal damage’’ (11). The tendency to terminate pregnancy based on fear of unknown teratogenic risk was made evident following the Chernobyl radiation incident of 1985. It was estimated that 2500 otherwise wanted pregnancies were terminated in Greece and 100,000–200,000 in all of western Europe, because of scientifically unjustified fear of radiation teratogenicity. At the time, doctors could not allay fears because of lack of data on the degree of exposure and, therefore, on the real teratogenic risk (12). At Motherisk we rely on self-reporting of exposure to drugs and medications to determine the degree and timing of exposure. It is our experience that these women, who come to the clinic voluntarily and generally before 13 weeks of pregnancy, provide information honestly and to the best of their ability. Temporally then, their report is unlikely to be affected by recall bias. In selected cases, self-reporting was checked against hair accumulation of cocaine with very good correlation (13). A recognized problem when interviewing female cocaine users is that they often do not have detailed knowledge of the purity of cocaine they used. Based on seized drugs in Toronto in 1987, the Health Protection Branch of Health and Welfare Canada reported that cocaine in Toronto is over 90% pure (14). An important factor to consider when interpreting our results is that all women themselves requested the clinic visit because of anxiety about their drug use during pregnancy, and all agreed to participate in our follow-up program. In addition, we were able to locate these women over a 2-year period, which reflects a measure of stability in their lives. Therefore, these social cocaine users are a self-selected subset of the population who may be in a better position to provide stable home environments for their infants than the social cocaine users who did not come to our clinic or were lost to follow-up. A child’s home environment can influence mental and motor development and performance on standardized developmental tests (15). Because of the clinical nature of our program, this study could not be blinded during either the initial clinic interview or the telephone follow-up interview. We do not believe that this circumstance has led to any significant bias on the part of the interviewers, since the information collected during these interviews was mainly factual (age, marital status, number of previous pregnancies, drug use, neonatal information, etc.), leaving little room for interpretation. In addition, we verified the women’s reports by obtaining the medical records of the deliveries and for the offspring.

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The ethnic distribution and ages of women of our three study groups is representative of the distribution of pregnant women attending the Motherisk Program, where 93% were white and the mean age was 29.9 years (16). The social cocaine users in our study are of mixed SES, making this population different from the predominantly lower SES cocainedependent women previously studied (17–20). The women studied previously have additional risk factors, including use of other illicit drugs, increased rate of sexually transmitted diseases, and poor prenatal care, which may place the pregnancy at increased risk for complications. All women in our study received good medical care; most came to the Motherisk Clinic in early pregnancy, regularly visited a family doctor, and experienced satisfactory pregnancy weight gain. The 54% use of cannabis by the social cocaine users in our study is much higher than the 15% prevalence reported for females 18–29 and the 6% incidence reported for those 30–49 years on Ontario (1). This high cannabinoid use among cocaine users has been well described, as cannabinoids ‘‘smoothen’’ some of the undesirable effects of cocaine (20). Alcohol use was also greater among our population of social cocaine users than that reported among Ontario females aged 18–29 or 30–49 years (1) and significantly greater than among the two control groups in this study. Similarly, cigarette use was greater than among the recreational drug–free control subjects, making it impossible to match for these criteria. These additional drug exposures may potentially affect pregnancy outcome and fetal growth and development, hence are possible confounding variables. However, none of the women consumed alcohol in the teratogenic range (⬎ 2 drinks per day) for more than one week, and almost all stopped their cigarette use during the first trimester before effects on fetal growth are believed to occur. In addition, the cocaine group had fewer maternal and paternal years of schooling and lower parental SES; again, these demographic characteristics may potentially affect an infant’s ability to perform during developmental testing. That the outcome of infants of the social cocaine users was identical to that of the control infants ruled out major effects of first-trimester cocaine exposure. No differences were found in attainment of developmental milestones or mental and motor functioning as assessed by the Bayley Scales of Infant Development. This test is the most widely used screening tool for cognitive development during the preschool years and has been used to document the teratogenic effects of lead, alcohol, and methadone (21–23). However, longer follow-up is needed to rule out other potential behavioral effects that cannot be assessed at 1.5 years of life. Children exposed to cocaine in utero were not different from the control groups in incidence of obstetric complications or neonatal adverse effects. However, our sample size was calculated to address the primary endpoint (the Bayley Scale) and is not sufficient to address differences in obstetric or neonatal complications. Studies assessing development of infants exposed to cocaine have thus far dealt exclusively with the offspring of drug-dependent women. In one study, children exposed throughout pregnancy to a variety of psychoactive drugs including cocaine scored significantly lower than controls on the Bayley Scales PDI at 3 months and MDI at 6 months but were within normal limits on both scales by 24 months of age (24). The number of children exposed to cocaine alone or with other drugs was not specified, and the mean scores were not provided. A preliminary report of another study noted that six cocaineexposed infants tested at 6 months of age had Bayley Scales of Infant Development scores similar to matched controls reporting no drug use (25). The very small sample sizes of both these studies limit the validity of this information.

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Only one study has investigated cocaine use occurring in the first trimester of pregnancy. Chasnoff and coworkers compared outcome of pregnancy of 23 women using cocaine only in the first trimester to women using it throughout pregnancy, and to women not using cocaine, cannabis, or alcohol during pregnancy (19). First-trimester cocaine use was associated with an increased rate of abruptio placentae, genitourinary malformations, and neonatal behavioral impairment as compared to the drug-free control group. However, no long-term neurobehavioral assessment was reported on these patients, who were recruited from a drug rehabilitation center and appear to be very different from our social cocaine users. In summary, in a first study that follows cocaine-exposed infants of social cocaine users into their second year of life, the outcome of pregnancy appears to be within normal limits and identical to two control groups followed prospectively in a similar manner. That the cocaine-exposed infants had normal attainment of milestones and normal scores on their developmental assessment at 1.5 years of age suggests normal brain development. While all women should be encouraged to discontinue cocaine use during gestation, our data indicate that there is no evidence to support women’s fears that brief exposure to the drug in early pregnancy warrants termination of pregnancy. Clinical Case Answer Our study indicates that babies of mothers who used cocaine have a likelihood of achieving cognitive function comparable to that of the normal population. It will be important to rule out excessive drinking and smoking, which are commonly combined with cocaine use. ACKNOWLEDGMENT This work was supported by a grant from Health and Welfare Canada.

REFERENCES 1. Smart RG, Adlaf EM. Alcohol and Other Drug Use Among Ontario Adults, 1977–1987. Toronto, Ontario, Canada: Alcoholism and Drug Addiction Research Foundation, 1987, pp 33– 37. 2. Abelson HK, Miller JP. A decade of trends in cocaine use in the household population. NIDA Research Monograph Series 61. Washington, DC: Government Printing Office, 1985, pp 35– 49. 3. Blishen B, Carroll WK. Sex differences in a socioeconomic index for occupations in Canada. Can Rev Sociol Anthopol 1978; 15:352–371. 4. Blishen B, McRoberts H. A revised socioeconomic index for occupations in Canada. Can Rev Sociol Anthropol 1976; 13:71–79. 5. Frankenburg WK, Dodd JB, Fandal A. The Revised Denver Developmental Screening Test Manual. Denver: University of Colorado Press, 1970. 6. Bayley N. Bayley Scales of Infant Development. New York: Psychological Corporation, 1969. 7. Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behavior Scales. Minneapolis, MN: American Guidance Service, 1984. 8. Raven JC. Standard Progressive Matrices. London: HK Lewis, 1960.

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9. Tanner JM, Whitehouse RH, Takaishik M. Standards from birth to maturity for height, weight, height velocity and weight velocity. Arch Dis Child 1966; 41:613–635. 10. Snedecor GW, Cockran WG. Statistical Methods, 7th ed. Ames, IA: Iowa State University Press, 1980. 11. Babies injured for life by cocaine, study says. Toronto, Ontario, Canada: Globe & Mail. September 6, 1988. 12. Trichopoulos D, Zavitsanos X, Koutis C, et al. The victims of Chernobyl in Greece: induced abortions after the accident. BMJ 1987; 295:1100. 13. Forman R, Klein J, Graham K, et al. Cocaine accumulation in maternal and fetal hair: doseresponse characteristics. Life Sci 1992; 50;1333–1341. 14. Health Protection Branch, Ottawa, Canada, 1987 (unpublished). 15. Werner EE, Honzik MP, Smith RS. Prediction of intelligence and achievement at ten years from twenty months pediatric and psychological examinations. Child Dev 1968; 39:1063– 1075. 16. Koren G, Feldman Y, MacLeod SM. Motherisk II: the first year of counseling on drug, chemical, and radiation exposure in pregnancy. In: Koren G, ed. Maternal-Fetal Toxicology. A Clinician’s Guide. New York: Marcel Dekker, 1990, pp 383–402. 17. MacGregor SN, Keith LG, Chasnoff IJ, et al. Cocaine use during pregnancy: adverse perinatal outcome. Am J Obstet Gynecol 1987; 157:686–690. 18. Doberczak TM, Shanzer S, Senie RT, Kandall SR. Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure. J Pediatr 1988; 113:354–358. 19. Chasnoff IJ, Griffith DR, MacGregor S, et al. Temporal patterns of cocaine use in pregnancy: pregnancy outcome. JAMA 1989; 261:1741–1744. 20. Chasnoff IJ, Lewis DE, Griffith DR, Willey S. Cocaine and pregnancy: clinical and toxicological implications for the neonate. Clin Chem 1989; 35:1276–1278. 21. Bellinger D, Leviton A, Waternaux C, et al. Longitudinal analysis of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med 19878; 316:1037–1043. 22. O’Connor MF, Brill NF, Sigman M. Alcohol use in primiparous women older than 30 years of age: relation to infant development. Pediatrics 1986; 78:444–450. 23. Rosen T, Johnson HL. Children of methadone-maintained mothers: follow-up to 18 months of age. J Pediatr 1982; 101:192–196. 24. Chasnoff IJ, Schnoll SH. Consequences of cocaine and other drug use in pregnancy. In: Washton AM, Gold MS, eds. Cocaine: A Clinician’s Handbook. New York: Guildford Press, 1987, pp 241–251. 25. Eyler FD, Behnke M, Stewart NJ, Bucciarelli RL. Incidence and effects of cocaine use: Perinatal center experience. Pediatr Res 1988; 22:1468.

23 Long-Term Neurodevelopmental Risks in Children Exposed in Utero to Cocaine The Toronto Adoption Study Irena Nulman, Gideon Koren, Joanne Rovet, Rachel Greenbaum, and Michael Loebstein The Hospital for Sick Children, Toronto, Ontario, Canada

Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

THE COCAINE EPIDEMIC Cocaine is an alkaloid prepared from the leaves of the Erythroxylon coca plant. The most common modes of administration are the intranasal and inhalation routes; peak concentrations are achieved almost immediately with a mean elimination half-life of 1 hour. Cocaine is a powerful central nervous system stimulant and has the ability to increase heart rate, blood pressure, and body temperature. Subjects using cocaine experience euphoria, reduced fatigue, sexual stimulation, increased mental ability, and increased sociability. These characteristics account for the very wide recreational use of the drug and its addictive potential (3). The last two decades have seen a dramatic increase in the recreational use of cocaine. It is estimated that more than 10 million Americans currently use cocaine. As a rapid increase in use has occurred in women of child-bearing age, much concern has been expressed about the potential effects of the drug in pregnancy (4–8). Addiction Research Foundation reports revealed that during the last decade cocaine use in women of Ontario increased significantly (9); in young females aged 18–29, 11.5% reported use in 1987 compared to 3.5% in 1984 ( p ⬍ 0.05). Among all adults in Ontario, highest use is reported in Metropolitan Toronto (11%), whereas outside Toronto it is 5% or less (9).

From Ann NY Acad Sci 1998; 846; 306–313. 447

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EFFECTS OF COCAINE IN PREGNANCY Animal studies show that cocaine affects fetal growth and brain development. A study in pregnant mice showed increased eye and skeletal defects, whereas a study by Fantal and Marphail (10) using both rats and mice showed no increase in congenital abnormalities but only a reduction in fetal weight and increased resorption frequencies. Cocaine injections to the pregnant ewe (11), which decreased uterine blood flow and increased uterine vascular resistance, resulted in marked fetal hypoxemia, hypertension, and tachycardia. Because these effects on fetal heart rate and blood pressure were greater than those from direct cocaine administration to the fetus, it appears that adverse outcome is associated to a greater degree with changes in maternal uterine blood flow than with direct pharmacological effects on the fetus. Behavioral studies of animals exposed to cocaine in utero indicate increased motor activity and impaired learning (12). In most human reports published to date, subjects were typically poor, black, innercity addicted women. The first study linking maternal cocaine use with adverse neonatal outcome was reported from Chicago (8). These researchers found that cocaine exposure in utero was associated with significant depression of interactive behavior and a less effective organizational response to environmental stimuli, suggestive of effects on neurological integrity. In a more recent study on a different population by the same authors, growth parameters at birth were significantly altered by cocaine exposure, but catch-up occurs by 1 year of age (13). In a recent study conducted by us in Toronto, comparing 37 infants exposed to cocaine in utero to 563 unexposed infants, we found that the cocaine-exposed group had significantly lower birth weights. However, this difference was nullified after correction for maternal smoking, with babies exposed to cocaine, but not cigarette smoke, being similar to the unexposed controls. Of clinical importance, we also found that mothers using cocaine were significantly more likely to test positive for hepatitis B and the cocaineexposed infants needed resuscitative measures significantly more often (14). An early study of infants of mothers with a history and positive screen for cocaine showed no signs of teratogenicity (15). In a recent prospective study (16), the incidence of stillbirth was significantly higher in the group abusing cocaine near term, and all stillbirths were related to abruptio placentae. Birth weight, length, and head circumference were also significantly decreased in infants exposed to cocaine or cocaine plus other drugs, whereas the rate of congenital malformations was significantly higher in users of cocaine only than in the drug-free group. Several groups describe increased lethargy, irritability, tremulousness, hypertonicity, poorer social responsivity, and disorganized patterns of feeding and sleeping among cocaine-exposed infants (17,18). A recent study observed long-term neurological sequelae including rigidity and visual dysfunction (19). Respiratory pattern abnormalities have also been described (20), potentially explaining cocaine association with sudden infant death syndrome (21). Eisen et al. (22) showed that habituation was impaired in cocaine-exposed infants during the first week of life. However, a study of infants at 1 day and 1 month of age (23) failed to differentiate between cocaine-exposed and unexposed infants. Deficits in motor function and abnormal reflexes (24), have also been observed during the first month. Although studies of older children show that intrauterine cocaine exposure increases the risk of behavioral and social problems as well as intellectual impairment, they have not accounted for differences in parenting and other background variables. For example, a recent study (25) compared the environments of mothers who were drug users with that

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of mothers who were poor. Children of the former were more likely to be victims of emotional and physical neglect. Drug-abusing mothers were more depressed, had fewer resources, spent less time with their children, and moved more. The home environments were more chaotic; there were fewer toys, less adequate housing, poorer care, and less contact with fathers. In older children, mother-child interactions are atypical in cocaine-exposed children, reflecting an increased incidence of disorganized and insecure attachments (26,27) and the children show more immature and deviant play (28), more difficult temperaments, (23) and more behavior problems (29). Cognitively, poorer outcome has also been described, although the findings are not consistent across studies. Most studies employing the Bayley Scales of Infant Development have failed to detect differences between infants exposed to cocaine versus control group (17). Report of a 2-year follow-up (13) concluded that whereas cocaine-exposed infants differed from controls on the Bayley at 6 and 24 months, no differences were observed at 3, 12, or 18 months of age, the reason for which was not clear. Overall however, cocaine exposure was associated with increased risk of subnormal intelligence in about 15% of the children. The lack of consistent results on cognitive testing with young children does not necessarily signify that cocaine has had no effect on the developing brain. It is possible that deleterious effects on limbic, hypothalamic, and extrapyramidal systems will address themselves in domains other than global cognitive and perceptual-motor functions, as assessed by the Bayley. Although areas such as attention, emotional control, learning, memory, and language may be affected, infant tests may not be sufficiently sensitive to detect these subtle effects. On the other hand, assessment during infancy may precede the emergence of more advanced skills (25,29,30).

INTERACTION BETWEEN IN UTERO COCAINE EXPOSURE AND CRITICAL HEALTH DETERMINANTS The main problem in identifying the effects of in utero cocaine exposure on child neurodevelopment is the clustering of many other unfavorable health determinants in the same population. These include other reproductive risks taking place during pregnancy as well as a variety of determinants affecting the environment of the child postnatally. These health determinants are summarized in Table 1. Any attempt to address the role of cocaine on child neurodevelopment must therefore take into account the relationship and potential interaction among these determinants and cocaine itself. For example, many cocaine users also smoke cigarettes which increases by themselves the risk of prematurity and intrauterine growth retardation. We recently showed that the birth weight of children of cocaine users who do not smoke in pregnancy is only marginally different from the general population mean of 3400 g; those who were exposed to cigarettes alone were at a mean birth weight of 3200 g, yet when the mother consumed both cocaine and cigarettes, the average birth weight was 2800 g, implying a synergistic adverse relationship between cocaine and cigarettes (14). In a similar way, Singer and colleagues showed that maternal use of cocaine and alcohol in combination was the best predictor of fetal linear growth after controlling for prematurity (48).

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Table 1 Health Determinants Clustered in Cocaine-Using Women Determinant Maternal addiction Socioeconomic status Poverty Maternal education Maternal compliance/participation in intervention program Maternal infection Maternal STDa Maternal race (minority status) Maternal age Prenatal care Cigarette use Parity Psychiatric comorbidity Employment Time of exposure during pregnancy Dose of exposure Single motherhood Disruptive parenting (caretaking) Home environment Postnatal maternal bonding Prematurity Alcohol use a

Recent Reference Hofkosh et al. (31) Fetters et al. (32,33) Hurt et al. (32) Richardson et al. (34) Hofkosh et al. (31) Bunkhead et al. (35) Ball et al. (36) Hurt et al. (37) Bendersky et al. (38) Chazotte et al. (39) Kistin et al. (40) Bendersky (4) Killeen et al. (41) Bendersky et al. (38) Barton et al. (42) Sallee et al. (43) Ingersoll et al. (44) Ingersoll et al. (44) Howard et al. (45) Scafidi et al. (46) Jacobson et al. (47) Singer et al. (48)

STD ⫽ sexually transmitted disease.

Numerous studies have shown that postnatally, low socioeconomic status and especially poverty strongly predict children’s achievements in standard neurodevelopmental tests. When Hurt and colleagues recently compared early language development at 21/2 years of age among a cohort of children of low socioeconomic status exposed or unexposed to cocaine in utero no differences were noted between the subgroups in expressive or receptive language scores (32), suggesting that the effects of poverty are by far stronger than those of cocaine itself. Similar conclusion were reached by Fetters and Tronick (33) in a longitudinal study. Poor children have a higher likelihood of prenatal exposure to cocaine as compared to their non-poor peers; however, with or without cocaine exposure, children of poverty are more likely than their more advantaged peers to exhibit low birth weight, prematurity, malnutrition, anemia, and congenital infections (49). Maternal addiction leads to increased rates of poverty, disruptive home environment (45), and reduced parenting or caretaking skills (44) and is often associated with psychiatric comorbidity (45). Another aspect that must be addressed in establishing cocaine effects is the drug’s direct (primary) versus indirect (secondary) effects on neurodevelopment (19). Primary effects are those that are direct on brain development. Examples of secondary effects of cocaine are the strong association between drug exposure and either prematurity or increased risk of abruptio placentae, both of which may impair child development. Therefore, any attempt to address direct cocaine neurotoxicity must control for these adverse effects (47).

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An example of the complex interaction between health determinants in cocaineexposed children has been documented in a study by Chazotte et al. (39), showing that among cocaine-using pregnant women, those attending prenatal care had a significantly fewer low-birth-weight infants than did those who failed to attend prenatal care. In a similar manner, in substance-exposed infants whose mothers were receiving support services, developmental skills were not different from those of the general population. Based on all of the foregoing, it is generally accepted that the effects of cocaine on the fetus will not be related in a simple linear fashion to cocaine exposure per se but rather will reflect interactions of the drug with a variety of health determinants, both perinatally and postnatally. It is biologically plausible that the primary or secondary effects of cocaine itself on neurodevelopment may be overcome by the fetus/child because of tremendous brain plasticity and by providing that optimal environmental health determinants surround the child (49). Conversely, suboptimal or poor caretaking, socioeconomic status, etc. may render children susceptible to long-term developmental dysfunction.

THE TORONTO ADOPTION STUDY Because many of the health determinants placing children exposed in utero to cocaine at risk exert their effect postnatally, our ability to follow-up children after adoption into a typically middle-upper class environment should nullify these risks. These include the risks of poverty, broken family, disruptive parenting, low maternal education, addiction, and a variety of other determinants listed in Table 1. Similar research approaches are often used to separate genetic from environmental effects in addressing questions such as the etiology of alcoholism or schizophrenia. In trying to separate intrauterine cocaine insults from suboptimal postnatal home conditions, we carried out a study in children exposed in utero to cocaine who were given up for adoption soon after birth and were being raised by middle- to upper-class families. The aim of this approach was to answer directly the question of whether intrauterine exposure to cocaine by itself results in measurable effects on neurodevelopment. We studied all families referred to the Motherisk Program at The Hospital for Sick Children, Toronto, for counseling and follow-up after adopting children whose biologic mothers had used cocaine during pregnancy. At the initial visit none of the parents reported having perceived any physical or developmental abnormalities in their children, and in no case were such problems the reason prompting the consultation. Each adoptive mother was paired with the first woman in the Motherisk Program database who matched the index mother on socioeconomic class, IQ, and age of the child, to allow use of the same cognitive tests. Both IQ and socioeconomic class of the mothers strongly predict the home environment of the child. The matched control women attended the Motherisk Clinic during pregnancy for counseling regarding nonteratogenic exposures (e.g., penicillins, acetaminophen), and their children were tested with the same tests as those of the study children. The control women were identical to the adoptive mothers in IQ and socioeconomic class (as these were the matching variables); however, the former were significantly younger than the latter ( p ⬍ 0.0001). None of the biological mothers or control women reported heavy alcohol use during the pregnancy; however, three of the biologic mothers reported moderate alcohol use (up to 0.5 g/kg of ethanol per day).

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Table 2 Anthropometric Characteristics of Cocaine-Exposed and Control Children Group, Mean (and SEM) Cocaineexposed (n ⫽ 23)

Control (n ⫽ 23)

p value

2597 (200) 37.3 (0.8)

3415 (106) 40.1 (0.37)

0.005 0.002

Characteristic At birth Weight (g) Gestational age (weeks) At testing Age (months) Weight (kg) Percentile Height (cm) Percentile Head circumference (cm) Percentile

34.0 13.8 56.7 89.8 39.2 47.7 30.7

(3.3) (0.72) (7.6) (2.0) (6.2) (0.5) (7.0)

33.3 15.4 69.5 92.6 52.3 49.8 63.4

(2.5) (0.84) (6.6) (2.2) (7.1) (0.4) (6.6)

NS NS NS NS NS 0.002 0.001

Eighteen of the biological mothers reported having smoked cigarettes during pregnancy, whereas only one of the control women smoked ( p ⫽ 0.0001). All the biological mothers were reported to have used cocaine throughout pregnancy. None of the control women reported using alcohol or any recreational drug during pregnancy. The children exposed to cocaine had a significantly lower mean birth weight ( p ⫽ 0.005) and gestational age ( p ⫽ 0.002) than the control subjects (Table 2). At the time of testing, cocaine-exposed children were not different from control children in body weight or stature (both nominal and percentile for age). However, the former had a significantly smaller fronto-occipital head circumference than did the latter in both nominal values ( p ⫽ 0.002) and percentile for age ( p ⫽ 0.001) (Table 2). Nine of the cocaine-exposed children, compared with only two of the control children ( p ⬍ 0.01), had a head circumference under the 11th percentile for age and sex. Eight of the children exposed to cocaine were considered microcephalic. Cocaine-exposed children were eight times as likely as control children to be microcephalic (95% confidence interval 1.5–42.3). No differences were noted between the study and control groups in global IQ (Table 3). However, among the children tested with the McCarthy scales there was a trend toTable 3 Results of Cognitive and Language Testing in Cocaine-Exposed and Control Children Group: mean (and SEM) Variable Global IQ (Bayley and McCarthy scales) McCarthy global IQ

Cocaine-exposed n ⫽ 23 109

112

n ⫽ 11

(2.2)

NS

(2.0)

0.1

(0.18) (0.17)

0.003 0.001

n ⫽ 11 (4.8)

117

n ⫽ 23 0.4 ⫺0.58

p value

n ⫽ 23 (3.0)

107 Score on Reynell language test Verbal comprehension Expressive language

Control

n ⫽ 23 (0.19) (0.14)

1.2 0.4

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wards lower IQ in the cocaine-exposed group [107 (SEM 4.8) vs. 117 (SEM 2.0)] ( p ⫽ 0.1). No differences were found between the study and control groups in mean scores on the Bayley scales. Cocaine-exposed children had significantly lower scores than did the control children on both the verbal comprehension scale ( p ⫽ 0.003) and the expressive language scale ( p ⫽ 0.001) of the Reynell language test (Table 3). No correlation was noted between gestational age, birth weight, or moderate alcohol use and achievement on the cognitive or language tests or in percentile of head circumference at testing. ANCOVA failed to show effects of prematurity on head circumference or of prematurity and number of siblings in the home on IQ or achievement on the language tests. Our study, after controlling for the postnatal environment of children exposed in utero to cocaine, detected clinically significant language delay and a trend towards decreased IQ as measured in preschool children. These effects were not due to prematurity, which may be caused by cocaine. Because mothers using cocaine also smoke heavily and consume ethanol, it is impossible to separate the effects of cocaine from those of other chemicals. However, it is noteworthy that neither cigarette smoking nor moderate alcohol consumption has been associated with cognitive and language delay. It is possible, however, that a synergistic effect exists between cocaine and cigarettes or alcohol. For example, esterification of cocaine and ethanol results in the production of cocaethylene which is more neurotoxic than is either cocaine or ethanol. Further and longer studies of larger cohorts of adopted children exposed in utero to cocaine will help to better identify the risks on various domains of child neurodevelopment.

ACKNOWLEDGMENT This work was supported by a grant from Health Canada.

REFERENCES 1. Graham K, Feigenbaum A, Pastuszak A, et al. Pregnancy outcome and infant development following gestational cocaine use by social cocaine users in Toronto. Clin Invest Med 1992; 15:384–394. 2. Nulman I, Rovet J, Altman D, et al. Neurodevelopment of adopted children exposed in utero to cocaine. Can Med Assoc J 1994; 151:1591–1597. 3. Haddad LM. Cocaine. In: Haddad LM, Winchester JF, eds. Clinical Management of Poisoning and Drug Overdose. Philadelphia: Saunders, 1983, p 445. 4. Wallis C. Cocaine Babies. Time Magazine 1986; 127:50. 5. Szabo P. Cocaine babies differ significantly. The Journal 1987; April 1:4. 6. McConnell H. Women’s cocaine use is probably underestimated. The Journal 1986; Feb 1:3. 7. Neuspiel DR. Behavior in cocaine-exposed infants and children: association versus causality. Drugs and Alcohol Dependence. 1994:36:101–107. 8. Chasnoff IJ, Burns WJ, Schnoll SH, et al. Cocaine use in pregnancy. N Engl J Med 1985; 313:666–669. 9. Smart RG, Adlaf EM. Alcohol and other drug use among Ontario adults 1977–1987. Toronto: Addiction Research Foundation, 1987. 10. Fantel AG, Macphail BJ. The teratogenicity of cocaine. Teratology 1982; 26:17–19.

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11. Woods JR, Plessingey MA, Clark KE. Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987; 157:957–961. 12. Neuspiel D, Hamel SC, Hochberg E, et al. Maternal cocaine use and infant behavior. Neurotoxicol Teratol 1991; 13:229–233. 13. Chasnoff IJ, Bassey ME, Savicho R, et al. Perinatal cerebral infarction and maternal cocaine use. J Pediatr 1986; 108:456–459. 14. Forman R, Klein J, Meta D, et al. Maternal and neonatal characteristics following exposure to cocaine in Toronto. Reprod Toxicol 1993; 7:619–622. 15. Chasnoff IJ, Griffith DR, Freier C, et al. Cocaine/polydrug use in pregnancy: two-year followup. Pediatrics 1992; 89:284–189. 16. Bingol N, Fuchs M, Diaz V, et al. Teratogenicity of cocaine in humans. J Pediatr 1987; 110: 93–96. 17. Dixon SD, Bejar R. Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: incidence and clinical correlates. 1989; 115:770–778. 18. Singer LT, Garber R, Kliegman R. Neurobehavioral sequelae of fetal cocaine exposure. J Pediatr 1991; 119:667–676. 19. Volpe JY. Effect of cocaine on the fetus. N Engl J Med 1992; 327:399–407. 20. Chasnoff IJ, Hunt CE, Kletter R, et al. Prenatal cocaine exposure is associated with respiratory pattern abnormalities. Am J Dis Child 1989; 143:583–587. 21. Doberczak TM, Shanzer S, Senile RT, Kandall SR. Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure. J Pediatr 1988; 1134:354–358. 22. Eisen LN, Field TF, Bandstra SE, et al. Prenatal cocaine effects on neonatal stress behavior and performance on the Brazelton Scale. Pediatrics 1989; 13:229–233. 23. Woods NS, Eyler FD, Hehnke M, et al. Cocaine use in pregnancy; maternal depressive symptoms and infant neurobehavior over the first month. Infant Behav Dev 1993; 16:83–98. 24. Coles C, Platzman KA, Smith I, et al. Effects of cocaine and alcohol use in pregnancy on neonatal growth and neurobehavioral status. Neurotoxicol Teratol 1992; 14:23–33. 25. Fawley HTL. Children of the crack epidemic: the cognitive, language, and emotional development of preschool children of addicted mothers. Presented at the meeting of the Society of Research in Child Development, New Orleans, March 1993. 26. Rodning C, Beckwith L, Howard J. Characteristics of attachment organization and play organization in prenatally drug exposed toddlers. Dev Psychopathol 1989; 1:277–289. 27. Rodning C, Beckwith L, Howard J. Prenatal exposure to drugs: behavioral distortions reflecting CNS impairment. Neurotoxicity 1989; 10:629–634. 28. Beckwith L. Spontaneous play in two-year-olds born to substance-abusing mothers. Presented at the meeting of the Society for Research in Child Development, New Orleans, March 1993. Centers for Disease Control. MMWR 1993; 39:225–227. 29. Crawford SD. Developmental characteristics of prenatally drug exposed young children. Presented at the meeting of the Society for Research in Child Development, New Orleans, March 1993. 30. Ahl V. Classification of infants prenatally exposed to cocaine. Presented at the meeting of the Society for Research in Child Development, New Orleans, March 1993. 31. Hofkosh P, Pringle JL, Wald HP, et al. Early interaction between drug-involved mothers and infants. Arch Pediatr Adolesc Med 1995; 149:665–672. 32. Hurt H, Brodsky NL, Betancourt L, et al. Cocaine-exposed children: follow-up through 30 months. Pediatrics 1997; 130:310–312. 33. Fetters L, Tronick EZ. Neuromotor development of cocaine-exposed and control infants from birth to 15 months. Pediatrics 1996; 98:938–943. 34. Richardson GA, Hamel SC, Godschmidt L, et al. The effects of prenatal cocaine use on neurobehavioral status. Neurotoxicol Teratol 1996; 18:627–634. 35. Burkhead J, Ericksen JL, Blanco JD. Cocaine use in pregnancy and the risk of intraamniotic infection. Reprod Med 1995; 40:198–200.

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36. Ball SA, Schottenfeld RS. A fine factor model of personality of addiction, psychiatric and AIDS risk severity in pregnant and postpartum cocaine misusers. Subst Use Misuse 1997; 31: 25–41. 37. Hurt H, Brodsky NL, Betancourt L, et al. Cocaine exposed children: follow-up through 30 months. J Dev Behav Pediatr 1995; 16:25–35. 38. Bendersky M, Alessandri S, Gilbert P, et al. Characteristics of pregnant substance abusers in two cities in the northeast. Am J Drug Alcohol Abuse 1996; 22:349–362. 39. Chazotte C, Youchah J, Freda MC. Cocaine use during pregnancy and low birthweight: the impact of prenatal care treatment. Semin Perinatol 1995; 19:293–300. 40. Kistin N, Handler A, Davis F, Ferres C. Cocaine and cigarettes: a comparison of risks. Paediatr Perinat Epidemiol 1996; 10:269–278. 41. Killeen J, Brady KT, Thevos A. Addiction severity, psychopathy and treatment compliance in cocaine-dependent mothers. Addict Dis 1995; 14:75–84. 42. Barton SJ, Harrigan R, Tse AM. Prenatal cocaine exposure; implications for practice, policy development and needs for future research. J Perinatol 1995; 15:10–22. 43. Saller FR, Katinkaneni LP, McArthur PD, et al. Head growth in cocaine-exposed infants: relationship to neonate hair level. J Dev Behav Pediatr 1995; 16:77–81. 44. Ingersoll K, Dawson K, Haller D. Family functioning of perinatal substance abusers in treatment. J Psychoact Drugs 1996; 28:61–71. 45. Howard J, Beckwith L, Espinosa M, Tyler R. Development of infants born to cocaine abusing women: biologic/maternal influences. Neurotoxicol Teratol 1995; 17:403–411. 46. Scafidi FA, Field TU, Wheeder A, et al. Cocaine-exposed preterm neonates show behavioral and hormonal differences. Pediatrics 1996; 97:851–855. 47. Jacobson SW, Jacobson JL, Sokal RJ, et al. New evidence for neurobehavioral effects on in utero cocaine exposure. J Pediatr 1996; 129:581–590. 48. Singer L, Arendt R, Song LY, et al. Direct and indirect interactions of cocaine with childbirth outcomes. Arch Pediatr Adolesc Med 1994; 148:959–964. 49. Frank D, Bresnahan K, Zuckerman BS. Maternal cocaine use: impact on child health and development. Adv Pediatr 1993; 40:65–99.

24 Biological Markers of Intrauterine Exposure to Cocaine and Cigarette Smoking Gideon Koren, Julia Klein, Rachel Forman, and My-Khanh Phan The Hospital for Sick Children, Toronto, Ontario, Canada

Karen Graham McMaster University, Hamilton, Ontario, Canada

Clinical Case You suspect that a 4-day-old, 30 weeks’ gestation baby with grade III intracranial bleeding was exposed in utero to cocaine. The mother denies having used this drug, and the baby’s urine is negative. How would you proceed?

INTRODUCTION Almost all xenobiotics circulating in the maternal blood are capable of crossing to the fetus. Thirty years after the thalidomide disaster, only about thirty human teratogens have been identified, whereas a large number of compounds have not been documented to impose fetal risk when used as recommended (1). Even the most potent human teratogens, such as retinoids and thalidomide, adversely affect only some fetuses while sparing many others. This variability in response may stem from pharmacokinetic and/or pharmacodynamic differences. For most animal and human teratogens, dose-response curves can be documented, highlighting the importance of extent of fetal exposure to these compounds. However, in recognizing the extent of variability existing in systemic exposure to xenobiotics in adults (in terms of the area under the curve), one can imagine how much larger is the variability of fetal exposure to the same maternal dose by adding known interpatient differences in placental transport and fetal pharmacokinetics.

From Dev Pharmacol Ther 1993; 18:228–238.

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Consequently, any attempt to explain variability in fetal susceptibility to xenobiotics and their metabolites must incorporate a meaningful measurement of fetal exposure. The most widely used tool for estimation of fetal exposure is measurement of concentrations in umbilical blood in an effort to extrapolate to intrauterine events. However, this can be a useful tool only if the mother has continued her drug consumption, and when the elimination t1/2 of the compound in question is long enough. For example, measurement of umbilical carboxyhemoglobin (COHb) may reflect degree of fetal exposure to carbon monoxide. However, the elimination t1/2 of CO is around 5 hours in maternal serum and 2–3 times longer in the fetal circulation. Hence, if the mother has not smoked during the 10–15 hours of the delivery, the baby may have undetectable levels of COHb despite clinically significant exposure throughout pregnancy. The case of cocaine is even more problematic, because the elimination t1/2 of this compound is substantially shorter. In a search for biological markers for fetal exposure to xenobiotics, we have developed during the last few years hair tests for cocaine and its metabolite benzoylecgonine as well as for nicotine and its metabolite cotinine. In this review we wish to describe the rationale for this new approach, some of its technical aspects and, finally, its clinical relevance.

GESTATIONAL COCAINE USE Recently there has been an increasing use of cocaine in North America (2). In a variety of American inner cities the prevalence of cocaine use among young women has been estimated as high as 40% (3). The potential effects of cocaine on the fetus have raised serious concerns about the short- and long-term health of millions of children exposed in utero to the drug. To date, the role of cocaine in causing fetal pathology has not been established despite scores of studies comparing such babies to controls (4–14). Because cocaine users tend to be of lower socioeconomic status, maintain poorer prenatal care, and use other recreational drugs, alcohol, and cigarettes, it is almost impossible at present to verify whether cocaine is causing adverse health effects or is only associated with them (4). One of the main methodological problems in many of the studies addressing fetal effects of cocaine is in the ways cocaine use is ascertained. There is evidence that maternal reports are unreliable (15); similarly blood and urine tests are not sufficiently reliable due to the very short elimination half-life of cocaine.

CIGARETTE SMOKING IN PREGNANCY Cigarette smoking during gestation is associated with increased risks for low birth weight, prematurity, spontaneous abortions, perinatal mortality, and the sudden infant death syndrome (16–20). Moreover, during the last decade, evidence has been accumulated for long-term neurotoxicity affecting neurobehavioral development (21). Fetal concentrations of carboxyhemoglobin are generally higher than maternal levels due to higher affinity of fetal hemoglobin to carbon monoxide (22). Carbon monoxide decreases the amount of oxygen carried to cells but also affects intracellular processes by impairing cytochrome

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enzymes. In addition to carbon monoxide, other toxins are elicited by cigarette smoke, including nicotine, hydrogen cyanide, and benzopyrene.

HAIR AND MECONIUM AS BIOLOGICAL MARKERS FOR FETAL EXPOSURE During the last few years the use of hair (23) and meconium (24) has emerged as much more reliable due to the long-term accumulation of cocaine and its major metabolite benzoylecgonine (BZ). While meconium is available only during the first day of life, neonatal hair carries such information until it sheds at 3–4 months of age. Because neonatal hair grows during the last 3–4 months of pregnancy, measuring cocaine in neonatal hair reflects cocaine use by women who were aware of their pregnancy at the time of drug use. This information is of importance because in our experience many young women who counsel Motherisk in Toronto after they had used cocaine recreationally (and not as part of an addiction pattern) discontinue their habit once pregnancy is detected. Hence, accumulation of cocaine in neonatal hair may detect infants at high risk of being cared for by addicted mothers. There is evidence that maternal addiction put the baby at serious postnatal risks (25).

HAIR ACCUMULATION OF COCAINE: DOSE-RESPONSE STUDIES To establish the dose-response characteristics of cocaine deposition, the following experiments were carried out. We measured hair concentrations of BZ in adult women who voluntarily admitted cocaine use and recalled their consumption patterns (route of administration and dose). A 10-mg hair sample, corresponding to eight strands, was cut close to the scalp with scissors. In another three subjects there was a history of an abrupt change in cocaine use. Hair was sectioned to reflect the periods of different consumption, by assuming that adult hair grows at 1–1.5 cm/month. Table 1 shows the data on these three patients. Pregnant guinea pigs purchased from High Oaks (Ontario) were injected subcutaneously with cocaine (4% hydrochloride solution) at daily doses of 5, 7.5, 10, 15, and 20

Table 1

Detection of Changes in Cocaine Use Pattern Through Analysis of Hair

Patients

History

Hair sample (cm)

Patient 1

No cocaine use Frequent cocaine use No cocaine use Occasional cocaine use Heavy cocaine use Occasional cocaine use Occasional cocaine use

3–14 0–3 10–20 0–10 9–22 6–9 1.5–3

Patient 2 Patient 3

Time hair represents (months)

BZ (ng/mg hair)

3–14 0–3 10–20 0–10 9–22 6–9 1.5–3

0.056 6.350 0.191 0.527 14.575 6.424 3.641

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mg/kg/day between days 40 and 73 of gestation. The normal length of gestation is 66– 72 days. After delivery, pup and maternal hair was cut close to the skin at the back using fine scissors. Hair Analysis Extraction of BZ from hair samples and subsequent analysis followed a method standardized in our laboratory (23). Briefly, the hair was washed repeatedly with 100% ethanol, and 2-mg hair samples were sonicated with 1 mL methanol for 30 minutes and subsequently incubated overnight at 45°C. The next day, the methanol was pipetted off and the hair rinsed briefly with an additional 1 mL of methanol. After the methanol had been evaporated at 40°C under a stream of nitrogen, the samples were reconstituted with 0.1 mL phosphate-buffered saline (pH 7.5). For cocaine measurements Coat-A-Count for cocaine metabolite in urine (Diagnostic Products, Los Angeles) was used, but instead of the BZ standards provided with the kit, in-house cocaine hydrochloride standards (1–500 ng/mL) were used. The antiserum used in the method has a much higher affinity for cocaine than for BZ, subsequently the cross-reactivity with BZ is only 0.5%. The sensitivity of the assay is 0.5 ng/mL, which corresponds to 0.025 ng cocaine/mg hair. For the analysis of BZ in the extracts the Roche Abuscreen (Hoffmann-La Roche, Nutley, NJ) for cocaine metabolite in urine was used. The cross-reactivity with cocaine was found to be 4% and the sensitivity of the assay in 5 ng/mL, which corresponds to 0.25 ng BZ/mg hair. Results are expressed in nanograms of cocaine or BZ/mg hair. Correlation between daily dose of cocaine (in grams) consumed by the patients and hair concentrations of BZ was studied by least-squares regression analysis using the Statview 512 program on an Apple Macintosh personal computer. For these calculations we assumed a reported one line of cocaine to contain 100 mg of pure cocaine. This estimation is based on a recent analysis revealing that cocaine sold in Toronto is over 95% pure and contains very little adulteration. The correlation between daily dose of cocaine injected to the pups and neonatal hair concentrations was estimated by the above methodology. A total of eight hair samples from seven adults using cocaine, who volunteered complete history of their cocaine use, were analyzed. Two of these patients reported changes in daily amounts, and their hair was cut to reflect these changes by estimating hair growth of 1 cm per month. The concentrations of BZ ranged between 0.3 and 14.6 ng/mg of hair. There was a significant correlation between reported amounts of cocaine use and hair accumulation (r ⫽ 0.964, p ⬍ 0.01). We subsequently studied the relationship between the cocaine dose given to pregnant guinea pigs and the concentration of BZ in the dams’ and their pups’ furs. The lower detection limit in our laboratory is 1 ng/g hair. No detectable accumulation was measured in the pups’ hair at daily doses of 5 and 7.5 mg/kg, whereas with 10, 15, and 20 mg/kg/ day there was a linear correlation in the dams as well as in their pups (r ⫽ 0.867, p ⬍ 0.0250 dams; r ⫽ 0.889, p ⬍ 0.001 for pups). The same trend was observed when cocaine accumulation in the fur was measured at the daily dose of 15 and 20 mg/kg cocaine hydrochloride. We then converted the number of lines taken by the women to a daily dose per kilogram in order to compare the human to the animal data. In both species a dose-response curve could be documented. It appears that levels in the tested pregnant guinea pigs were lower than in women taking 10 or 15 mg/kg/day, but at 20 mg/kg/day the human and animal data were similar.

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MEASUREMENT OF NICOTINE AND COTININE IN MATERNAL AND FETAL HAIR Smoking and nonsmoking mothers were identified in two nurseries in Toronto. Detailed history of smoking habits was recorded, and all smoking mothers reported a steady number of cigarettes used daily. Hair samples were obtained by cutting five to seven hair shafts near the skull using fine scissors. The hair samples were washed with a detergent, rinsed with water, and dried in a warm (37°C) oven overnight. The following day 2–5 mg hair samples were weighed on an analytical balance and placed in a glass container with 1 mL of 0.6 N NaOH. The samples were digested overnight at 50°C. The following day the solutions were neutralized with 50–70 µL concentrated HCl, and 100 µL aliquots of the neutral solution were used to measure nicotine or cotinine by radioimmunoassay (RIA) as described by Langone et al. (26). The RIA materials were obtained from the Department of Biochemistry, Brandeis University, Waltham, Massachusetts. Both nicotine and cotinine assays use the same isogel Tris buffer (0.01 M Tris-HCl, 0.14 rM NaCl, 0.1% gelatin, pH 7.4), [3 H]-nicotine or [3 H]cotinine, the respective antiserum raised in rabbits and a goat antirabbit γ-globulin to separate the antibody-bound nicotine or cotinine from the free analyte. For quantification, nicotine standards (0.5–50 ng/mL) or cotinine standards (0.2–20 ng/mL) were used. Results were expressed as nanograms analyte per milligram of hair. The lowest sensitivity of the assay was 0.25 ng/mg hair for nicotine when 2 mg of hair was used, and 0.1 ng/mg hair for cotinine when 2 mg of hair was used. The crossreactivity of nicotine in the cotinine assay was 5.0% and that of cotinine in the nicotine assay was 2.0%. The other metabolites, which retain only one of the two ring systems (the pyridine or N-methyl-pyrolidine rings), did not exhibit any cross-reactivity with either assay. Pregnant women participating in the study smoked between 5 and 25 cigarettes/day (mean 18 ⫾ 8) during pregnancy. They had a mean of 21.3 ⫾ 18 ng/mg hair of nicotine and 6 ⫾ 9.2 of cotinine; the differences between the concentrations of the drug and its metabolite were significant ( p ⬍ 0.01). There was no correlation between the number of cigarettes smoked daily by the mothers and nicotine or cotinine concentrations in their hair. Babies of smokers had mean nicotine concentration of 6 ⫾ 9.2 ng/mg (range 0– 27.3) and cotinine of 2.1 ⫾ 3.7 ng/mg (range 0–12.2). There was no correlation between number of cigarettes smoked by the mothers and babies’ hair concentrations of nicotine or cotinine. Conversely, there was a significant correlation between maternal and neonatal concentration of nicotine (r ⫽ 0.78, p ⬍ 0.01 by least-square linear regression) and cotinine (r ⫽ 0.64, p ⬍ 0.05, Spearman’s correlation). Maternal concentration of nicotine was invariably higher than neonatal levels ( p ⬍ 0.01, Wilcoxon’s signed rank test). Conversely, concentrations of cotinine did not differ significantly between mothers and children. There were 11 pairs of nonsmoking mothers. Their mean hair concentrations of nicotine (0.9 ⫾ 0.8 ng/mg) and cotinine (0.3 ⫾ 0.5 ng/mg) were significantly lower than in smoking mothers ( p ⬍ 0.0001). Similarly, neonatal hair concentrations of nicotine (0.7 ⫾ 0.7 ng/mg) and cotinine (0.3 ⫾ 0.2 ng/mg) were significantly lower in babies of nonsmokers when compared to infants of smokers ( p ⬍ 0.001). Of the 11 pairs of nonsmokers, 4 mothers were passively exposed to cigarette smoking in the household during pregnancy. Their concentrations of nicotine (0.9 ⫾ 0.9) were

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not different from those not exposed (0.9 ⫾ 0.9 ng/mg). Conversely, cotinine concentrations in passive smoking mothers (0.6 ⫾ 0.7 ng/mg) were significantly higher than in those not exposed to any smoke (0 ⫾ 0 ng/mg) ( p ⬍ 0.02). Similar trends were observed in the babies of passive smokers having more cotinine (0.3 ⫾ 0.2 ng/mg) than in nonexposed ones (0.1 ⫾ 0.1 ng/mg; p ⬍ 0.05), with no differences in nicotine concentrations.

DISCUSSION The assessment of the reproductive toxicology of cocaine is complex. This drug is a potent vasoconstrictor and it also causes uterine contraction (4); both are mechanisms that may induce fetal damage. However, most women using cocaine have many other risk factors that may cause the reported adverse fetal effects. In a recent meta-analysis we have documented that while a variety of detrimental fetal effects can be associated with cocaine when addicted users are compared to middle-class nonusers, most of these effects are canceled out when women addicted to cocaine are compared to those addicted only to other drugs of abuse (Chap. 16). Meaningful estimation of fetal toxicity of cocaine must define the dose and time of fetal exposure, because human teratogens invariably follow dose- and time-response curves. A variety of xenobiotics may adversely affect the fetus at high doses, but not in lower doses. The toxicology of human teratogens may follow a dose-response pattern with or without threshold level. The time of exposure may be crucial with some teratogens (e.g., thalidomide), affecting the fetus only during organogenesis, whereas others (e.g., lead) may affect brain development throughout pregnancy (1). Several studies have revealed that maternal reports of cocaine use are very inaccurate, likely because admitting to drug abuse may result in legal action against women as well as child apprehension by child protection agencies. Similar to nutrients and other small molecules, drugs transfer into the growing hair shaft through the capillaries nourishing it. While the mechanisms governing drug transport into hair are not well understood, it is pharmaco-kinetically conceivable that systemic exposure to the drug, measured as the area under the concentration-time curve, will dictate the amount of the drug deposited in the hair. The present study reveals an excellent dose-response curve between the dose consumed in humans and animals and their hair concentrations of BZ. Similarly, there is very good correlation between maternal dose and fetal hair concentrations in animals. Recently, meconium has been proposed as an accurate reservoir of fetal exposure to cocaine (24); however, there are several limitations to meconium when compared to hair as a biological marker of intrauterine drug exposure. 1. 2.

3.

Meconium is available only during the first day of life, whereas hair will stay positive for several months. At present it is not clear how much cocaine in the meconium stems from swallowing of amniotic fluid versus enterohepatic circulation of the drug, and a doseresponse curve has not yet been established. Because hair grows constantly, deposition of cocaine into the shaft yields a rare opportunity to study the time of exposure. As shown in Table 1, sectioning of hair in adults who reported changes in use over time avidly reflects these patterns. Because most women’s hair is longer than 10 cm, it should reflect the whole length of gestation.

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The initial fetal hair (lanugo) sheds at 5–6 months of gestation, and the hair neonates are born with grew during the third trimester of pregnancy; therefore detection of cocaine in newborn hair reflects maternal use of the drug during the last 3 months of pregnancy. Here again, hair is capable of verifying time of exposure; negative neonatal hair may often confirm mothers’ reports of stopping cocaine use upon realizing that they were pregnant. Guinea pigs are optimal for these experiments because their pups are born with abundant fur which develops, as in humans, during the third trimester of pregnancy. While there are no reported cases of history of second-trimester cocaine exposure and thirdtrimester nonexposure, we have several such cases in our program, with a corresponding negative cocaine test of neonatal hair. Cocaine elimination in rodents is much faster than in humans, and this may explain why daily doses lower than 10 mg/kg did not result in measurable concentrations in the pups’ hair. Similarly, it explains the relatively low accumulation in the adult guinea pig hair as compared to humans. While these preliminary animal studies suggest linearity in cocaine accumulation in hair, larger numbers are needed to address the variability of this phenomenon. The excellent dose-response curve between amounts used in humans and hair accumulation may be explained by the selection of individuals who voluntarily reported on their use and by the fact that in Toronto most cocaine is more than 95% pure, thus decreasing the potential effect of adulteration. While larger numbers of cases will have to be analyzed, this pilot project emphasizes the promise of hair analysis as a biological marker for maternal and fetal exposure to cocaine. Being lipid-soluble, nicotine has a large distribution volume (2–3 L/kg), and it readily permeates cell membranes. This xenobiotic is absorbed through the lung, skin, gastrointestinal tract, and nasal mucosa and is actively secreted by the renal tubules. Once absorbed, nicotine rapidly disappears from the blood due to both widespread tissue uptake and metabolism (27,28). The elimination half-life of nicotine in humans ranges between 1 and 3 hours; and therefore monitoring of this chemical in the blood is not likely to reflect the extent of smoking. Citonine, a major metabolite of nicotine, has a much longer elimination half-life (10–14 hours); urinary or salivary measurements of continine have been the most accurate estimate to validate self-reported smoking habits (29). Cigarette smoke enters the body by inhalation; hence estimation of systemic exposure is extremely complicated, as different individuals may have very different modes of smoking in terms of both number and depth of inhalations. Moreover, interindividual variability in distribution and elimination of nicotine and cotinine further makes it difficult to estimate cumulative exposure from single determinations. Our data reveal that the reported number of cigarettes consumed by the pregnant mother does not correlate with hair accumulation of nicotine or cotinine in either mother or fetus. This is not surprising, realizing the large variability in the inhaled dose in addition to the regular sources of pharmacokinetic variability such as distribution and elimination processes. Of importance, there was significant correlation between maternal systemic exposure to nicotine evidenced by hair concentrations of nicotine or cotinine and accumulation of these xenobiotics in fetal hair. This means that like the case of methyl mercury and cocaine, maternal and fetal hair may better estimate long-term systemic exposure to toxic constituents of cigarettes and thereby may yield a better prediction of fetuses at risk. The concentrations of nicotine and cotinine measured by us in the adult hair agree with those measured in the only two other reports located by us (30,31). During the last years there has been increasing awareness of the serious health risks inflicted by passive exposure to cigarette smoke. Our data suggest that, indeed, women and their unborn babies

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are accumulating nicotine and cotinine even when they avoid smoking. Although our sample size is too small to draw definite conclusions, of the four babies of nonsmoking women exposed to ‘‘passive smoking,’’ three had detectable levels of cotinine in their hair. A majority of women abusing cocaine also smoke cigarettes (4). Hence it is probable that there are cumulative adverse effects, each one with its own dose-response characteristics. The use of hair test, therefore, may prove to be crucial in explaining why some fetuses are adversely affected in a major way while others escape with no measurable damage. In summary, we believe that the hair test is likely to develop into a critical tool for assessing the degree and time of fetal exposure to xenobiotics. While our work to date has focused on cocaine and nicotine, other drugs such as opioids, cannabinoids, and amphetamines can already be measured in adult hair, and methodologies for their fetal measurement can be refined. Clinical Case Answer At 4 days of life, meconium testing is not an option. However, if the mother used cocaine regularly during the last 3–4 months of pregnancy, the infant’s hair is likely to be positive for benzoylecgonine. ACKNOWLEDGMENT This work was supported by a grant from the Medical Research Council of Canada. REFERENCES 1. Koren G. Maternal-Fetal Toxicology: A Clinician’s Guide. New York: Marcel Dekker, 1990. 2. Abelson HK, Miller JP. A decade of trends in cocaine use in the household population. Natl Inst Drug Abuse Res Monogr Ser 1985; 61:35–49. 3. Shannon MW, Hite C, Woolf A. Detection of in utero drug exposure among term, apparently healthy newborns. Vet Hum Toxicol 1989; 31:347. 4. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991; 44:405–414. 5. Townsend R, Laing FC, Jeffery RB. Placental abruption associated with cocaine abuse. Am J Radiol 1988; 150:1339–1340. 6. Chasnoff IJ, Bussey ME, Savich R, Stack CM. Perinatal cerebral infarction and maternal cocaine use. J Pediatr 1986; 108:456–459. 7. Chasnoff IJ, Griffith DR, MacGregor S, et al. Temporal patterns of cocaine use in pregnancy: perinatal outcome. JAMA 1989; 261:1741–1744. 8. Oro AS, Dixon SD. Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates. J Pediatr 1987; 111:571–578. 9. Chouteau M, Brickner Namerou P, Leppert P. The effect of cocaine abuse on birth weight and gestational age. Obstet Gynecol 1988; 72:351–354. 10. MacGregor SN, Keith LG, Chasnoff IJ, et al. Cocaine use during pregnancy: adverse perinatal outcome. Am J Obstet Gynecol 1987; 157:686–690. 11. Chasnoff IJ, Burns KA, Burns WJ. Cocaine use in pregnancy: perinatal morbidity and mortality. Neurotoxicol Teratol 1987; 9:291–293. 12. Chasnoff IJ, Chisum GM, Kaplan E. Maternal cocaine use and genitourinary tract malformations. Teratology 1988; 37:201–204.

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13. Little BB, Snell LM, Klein VR, Gilstrap LC. Cocaine abuse during pregnancy: maternal and fetal complications. Obstet Gynecol 1988; 73:157–160. 14. Brody JE. Widespread abuse of drugs by pregnant women is found. New York Times 1989; 137:1–19. 15. Zuckerman B, Frank DA, Hingson R. Effects of maternal marijuana and cocaine use on fetal growth. N Engl J Med 1989; 320:762–768. 16. The health consequences of smoking: The changing cigarette. DHHS publication No (PHS) 81–501. Rockville, MD: US Department of Health and Human Services, Public Health Service. Office on Smoking and Health, 1981, pp 33–61. 17. Triebig G, Zober MA. Indoor air pollution by smoke constituents—a survey. Prev Med 1984; 13:570–581. 18. Martin TR, Bracken ME. Association of low birth-weight with passive smoke exposure in pregnancy. Am J Epidemiol 1986; 124:633–642. 19. Abel EL. Smoking and pregnancy. J Psychoactive Drugs 1984; 16:327–328. 20. Stillman RJ, Rosenberg MJ, Sacks BJ. Smoking and reproduction. Fertil Steril 1986; 46:545– 566. 21. Rush D, Callahan KR. Exposure to passive cigarette smoking and child development. Ann NY Acad Sci 1989; 562:74–100. 22. Longo LD. The biological effects of carbon monoxide on the pregnant woman, fetus and newborn infant. Am J Obstet Gynecol 1111; 129:69–103. 23. Graham K, Koren G, Klein J, et al. Determination of gestational cocaine exposure by hair analysis. JAMA 1989; 262:3328–3330. 24. Ostrea EM Jr, Brady M, Gause S, et al. Drug screening of newborns by meconium analysis: A large-scale, prospective, epidemiologic study. Pediatrics 1992; 89:107–113. 25. Johnston C. Children of cocaine addicts or study of 25 inner city families. Social Worker 1990; 58:53–56. 26. Langone J, Gjiba HB, Van Vunakis H. Nicotine and its metabolites: radio-immunoassay for nicotine and cotinine. Biochemistry 1973; 12:5015–5030. 27. Lenberger L, Rubin A. Physiologic Disposition of Drugs of Abuse. New York: Spectrum, 1978, p 205. 28. Pilotti A. Biosynthesis and mammalian metabolism of nicotine. Acta Physiol Scand 1980; 479:13–17. 29. Haley NJ, Axelrod CM, Tilton KA. Validation of self-reported smoking behavior: biochemical analysis of cotinine and thiocyanate. Am J Public Health 1983; 73:1204–1207. 30. Haley NJ, Hoffmann D. Analysis for nicotine and cotinine in hair to determine cigarette smoker status. Clin Chem 1985; 31(10):1598–1600. 31. Ishiyama J, Nagai T, Toshida S. Detection of basic drugs (metamphetamines, antidepressants and nicotine) from human hair. J Forensic Sci 1983; 28:380–385.

25 Fetal Alcohol Syndrome The Central Nervous System Tragedy Irena Nulman and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Jonathan Gladstone and Bonnie O’Hayon The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION Alcohol is a legal, socially acceptable drug whose use is part of the lives of most American women. In a recent survey, 61.5% of American women reported consuming alcohol in the preceding year. Moreover, its use is highest among women of reproductive age: 75% of women aged 18–34 reported alcohol use in the past year (National Institute on Drug Abuse, 1990), making it by far the most widely used human teratogen, with the number of consumers being several orders of magnitude larger than for any other teratogenic compound (Koren et al., 1994). The spectrum of alcohol’s teratogenic effects spans a wide continuum that includes growth deficiency, central nervous system dysfunction, craniofacial anomalies, and pathological organ and skeletal conditions. Fetal alcohol syndrome (FAS) is the most severe expression of fetal alcohol-related abnormalities (FARA) and may be seen in the offspring of women who drink heavily throughout pregnancy. Presently, alcohol is the most common preventable cause of birth defects and the leading cause of mental retardation, ahead of Down’s syndrome and cerebral palsy. The previous two decades have seen the accumulation of a large body of research into alcohol’s teratogenicity. This chapter provides an overview of FARA, with a focus on the pharmacology of alcohol in both mother and fetus, epidemiology, diagnostic issues, and risk factors.

HISTORICAL PERSPECTIVE While the role of alcohol in causing human teratogenicity was not proven until the seventies, the adverse effects of alcohol consumption during pregnancy have been noted

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throughout history. Several reviews of the history of alcohol and pregnancy are available (Warner et al., 1975; Rossett et al., 1984; Abel, 1990). Judges 13:7 states ‘‘Behold, thou shalt conceive, and bear a son; and now drink no wine or strong drink.’’ Plato is said to have proclaimed that children should not be made in bodies saturated with drunkenness. As well, Aristotle is reported to have stated that ‘‘Foolish, drunken and harebrained women most often bring forth children like unto themselves, morose and languid.’’ During the gin epidemic of 1726, the College of Physicians Report to the British Parliament described parental drinking ‘‘a cause of weak, feeble and distempered children.’’ In 1834, a report on drunkenness to the British House of Commons concluded that infants born to alcoholic mothers sometimes have a ‘‘starved, shriveled and imperfect look.’’ The first scientific study on children of alcoholic mothers was reported in 1899 by Dr. William Sullivan, a Liverpool prison physician. He noted that maternal inebriety was unfavorable to normal development and that jailed and detoxified women had improved birth outcomes. Little attention was paid to the plausibility of alcohol’s teratogenicity until the last few decades. An article by Lemoine et al., published in 1968 in France, provided the first description in the medical literature of the effects of alcohol on the fetus. In was not until 1973, however, with the independent observation of Jones and Smith, that a distinct dysmorphic syndrome associated with gestational alcoholism, the fetal alcohol syndrome (FAS), was described and recognized in the medical literature (Jones and Smith, 1973; Jones et al., 1973). During the last 20 years, thousands of articles have been published in the field of alcohol teratology.

ALCOHOL PHARMACOLOGY Ethanol is a small molecule that is soluble in both water and lipids, enabling it to easily pass through cell membranes. It distributes throughout tissues and cells in proportion to their respective water contents. Therefore, highly vascular organs can equilibrate quickly with arterial blood and have an increased rate of alcohol distribution. During ethanol absorption, the brain, a highly vascular organ, achieves a higher ethanol concentrations more rapidly than most other organs (Goldstein, 1983). The metabolism of alcohol is almost entirely dependent on the liver (Lundsgaard, 1938), the only organ that contains the host of enzymes required to initiate the metabolic pathway. The first step in the metabolism of ethanol is its conversion to acetaldehyde, a process catalyzed by alcohol dehydrogenase (ADH) (Fig. 1).

ADH is a general remover of hydrogen atoms from various compounds and is available in sufficient amounts to deal with ingested alcohol efficiently. ADH catalyzes the transfer of hydrogen atoms from ethanol to nicotinamide adenine dinucleotide (NAD), a cofactor for the reaction. Acetaldehyde is then oxidized to form acetate, which is later converted to carbon dioxide and water. For a given amount of ingested alcohol, women achieve higher blood alcohol levels due to their smaller body sizes and higher fat content, resulting in a smaller volume of distribution for alcohol and less gastric-ADH activity than in men, leading to less first-pass metabolism (Frezza et al., 1990; Seitz et al., 1993).

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Gender differences in ethanol metabolism are also influenced by the sex hormones. Testosterone, for example, depresses the activity of hepatic ADH (Teschke and Wiese, 1982), resulting in a relative increase in ADH activity in the female liver before the age of 50–53 (Maly and Sasse, 1991). There is also a delay in gastric emptying, which occurs during the luteal phase of a women’s menstrual cycle. Among men and women with similar histories of alcohol abuse, more women incur liver injury than men (Morgan and Sherlock, 1977), and such liver damage is typically more rapidly progressive in women than in men (Rankin, 1977). A similar pattern has been described for brain diminution, which occurs in women after significantly shorter ethanol exposure (Mann et al., 1992). The actual blood alcohol concentration is dependent on the amount of ethanol ingested, gastrointestinal motility, vascularity of the mucous membranes, and the concentration and distribution of water in each organ. Since pregnancy may influence these factors, one may expect that the disposition of alcohol in pregnancy will be altered. For obvious ethical reasons, there are no controlled studies on the pharmacokinetics of alcohol in pregnant women. However, one can examine information from observational human and experimental animal studies. There is a delay in the emptying time of a pregnant woman’s stomach, suggesting a lower peak alcohol concentration maintained for a longer duration (Hinckers, 1978). In addition, pregnant women are in a state of water-volume expansion, including water volume from the fetus, placenta, uterus, and amniotic fluid. Since alcohol is distributed according to the water content of body compartments, and the pregnant women has a great volume of distribution of alcohol, this again should contribute to her lower peak blood alcohol concentrations. Pregnancy-induced alteration in volume of distribution may have implications for the fetus because the effect of alcohol on the fetus varies with the change in water concentration throughout pregnancy. In early pregnancy, the fetal water concentration tends to be higher (McCance and Widdowson, 1954), increasing alcohol’s volume of distribution within the fetus. This is meaningful, since ethanol crosses the placenta (Dilts, 1970) and rapidly achieves equilibrium between maternal and fetal fluid (Guerri and Sanchis, 1985). It has been suggested that the altered water content in the mother and fetus may favor the passage of ethanol across the placenta into the fetus. Rat studies reveal an increasing gradient of ethanol concentration in fetal blood, amniotic fluid, and intragastric fetal content when compared to maternal blood (Traves et al., 1995; Lopez-Tejero et al., 1986, 1989a,b). Limited or no ethanol-related ADH activity has been found in the placenta (Pares et al., 1984), and the fetus itself has a low capacity to eliminate alcohol (Guerri and Sanchis, 1985). Ethanol concentration in the amniotic fluid at the end of pregnancy is associated with the contribution of fetal urine to the amniotic fluid (Hayashi et al., 1991). Also, at the end of pregnancy, the fetal sucking reflex develops, which may contribute to the high ethanol concentration found in the fetal intragastric fluid (Traves et al., 1995). Pregnant rats have been found to have significantly lower levels of ADH activity compared to virgin female rats, irrespective of ADH isoenzyme distribution, tolerance, or malnutrition status (Traves et al., 1995). The combination of low ADH activity in the fetal liver (Sanchis and Guerri, 1986b) and marginal ethanol metabolism in the placenta means that maternal metabolism is responsible for the elimination of ethanol from both the mother and the fetus.

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Ethanol freely passes into breast milk and achieves almost the same concentration as in the woman’s blood. Animal studies have shown that chronic ethanol administration results in a loss of mammary cell polarization, reduction in Golgi distyosomal elements, abnormalities in casein maturation and secretion, mammary gland, amino acid uptake, changes in pH and amount of lactose, lipoprotein lipase activity and a decrease in both absolute and relative mammary gland weight and protein content (Sanchis and Guerri 1986a; Vinas et al., 1989). Alcohol interferes with prolactine secretion in lactating and nonlactating women (Volpi et al., 1994). Sabramanian (1996) points out that ethanol has a disruptive effect at the hypothalamic, pituitary, and mammary glands, which modulate mammary gland growth, initiation, and maintenance of lactation.

FETAL ALCOHOL SYNDROME Epidemiology and Economic Burden Many studies have been undertaken to estimate the occurrence of FAS in various North American communities. Results range from a incidence of 0 per 1000 (Abel and Sokol, 1987, 1991) to a prevalence of 120 per 1000 (Robinson et al., 1987). Typically cited is an incidence of FAS of 0.5–3 cases per 1000 births (Abel, 1995). In the United States, with an annual birth rate of 4 million, this figure can be translated into an estimated 2000– 12,000 children with FAS being born per year. Recently Abel reviewed the available epidemiological studies on FAS and presented calculations for the incidence of FAS based on geographical, ethnic, and socioeconomic variables. He concluded that the mean incidence of FAS is estimated to be 0.97 cases per 1000 live births in the general obstetric population. However, the incidence appears to vary both between and within countries. The general incidence of FAS was found to be more than 20 times higher in the United States (1.95 per 1000) than in other countries (0.08 per 1000). Additionally, within the United States, studies conducted at locations characterized by low socioeconomic status (SES) and African-American or Native American populations found incidences of FAS 10 times higher (2.29 cases per 1000) when compared to reports from sites with a predominantly middle–upper SES and Caucasian background (0.26 per 1000). Like other teratogens, the adverse effects of gestational alcohol exposure are not observed in all exposed individuals. FAS is generally seen only among children of women exposed to ‘‘heavy’’ drinking. Heavy drinking is an ambiguous term variably defined by studies as consuming an average of 2 or more drinks per day, or 5 to 6 drinks on some occasions (binge), or a positive Michigan Alcoholism Screening Test score, or a clinical diagnosis of alcohol abuse (Abel and Sokol, 1987). Within this subpopulation of ‘‘heavy’’ drinkers, Abel’s review of the literature (1995) found the incidence of FAS to be 4.3 per 100 live births. In reviewing the epidemiological data, one must keep in perspective that children diagnosed with FAS represent only a small fraction of all the individuals affected with FARA. The combined rate of FAS and alcohol related neurodevelopmental disorders (ARND) was estimated to be 9.1 per 1000 live births, which represents a serious preventable health problem affecting almost 1% of the population (Sampson et al., 1997). Various attempts have been made to assess the economic costs of FAS (Harwood and Napolitano, 1985; Abel and Sokol, 1991; Bloss, 1994). Such estimates are inherently problematic due to uncertainties related to the prevalence of FAS and the extent of lifetime health costs and other problems experienced. This ambiguity is well reflected in American

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cost estimates, which range from $75 million (Abel and Sokol, 1991) to $9.7 billion (Harwood and Napolitano, 1985). Regardless of the discrepancies, the costs of FAS and other FARA are extremely high for the individual, for the family, for the education and health care system, and for society at large. Criteria for Definition and Diagnostic Problems Jones and Smith (1973) coined the term fetal alcohol syndrome (FAS) to describe children they observed born to mothers who were chronic alcoholics throughout gestation. They noted that the affected children had a ‘‘similar pattern of craniofacial, limb and cardiovascular defects associated with prenatal-onset growth and developmental delay.’’ In the two decades since their original definition, the criteria for diagnosis of FAS has been based on the presence of a triad of features: (1) prenatal and/or postnatal growth retardation (weight, length and/or height ⬍ 10th percentile), (2) central nervous system (CNS) damage (signs of neurological abnormality, developmental delay, or intellectual impairment), and (3) characteristic facial dysmorphology (microcephaly, micropthalmia, short palpebral fissures, poorly developed philtrum, thin upper lip, and flattened maxillary area) (Abel, 1990). Numberous problems have come to light that contribute to the difficulty of making the diagnosis of FAS. First, research in the past two decades has demonstrated that in prenatally alcohol-exposed individuals, the presence and/or degree of abnormalities can vary considerably. An affected individual may have an IQ ranging from the normal to the severely mentally retarded range and may have physical features that range from normal to obvious anomalies. Correspondingly, a prenatally alcohol-exposed child may present with normal growth and physical features but with slight or substantial behavioral and cognitive abnormalities. Second, the phenotype of FAS varies with age and may alter or normalize as the child moves through childhood into adolescence and adulthood (Institute of Medicine, 1996a). Third, many of the individual deficits seen in FAS are pathognomonic for fetal alcohol exposure, and similar deficits may be seen in isolation or in combination without any history of prenattal alcohol exposure. Consequently, when the phenotype is ‘‘incomplete’’ or ‘‘atypical’’ or the clinican is inexperienced in this diagnosis, FAS may be misdiagnosed. Syndromes confused with FAS due to similar physical features may include Aarskog syndrome, Williams syndrome, Noonan’s syndrome, Dubowitz syndrome, Bloom syndrome, fetal hydantoin syndrome, maternal phenylketonuria fetal effects, and fetal toluene syndrome. Other syndromes that may be confused with FAS due to similarities in the cognitive and behavioral profiles present include fragile-X syndrome, velocardiofacial syndrome, Turner’s syndrome, Opitz syndrome, and attention-deficit hyperactivity disorder (Institute of Medicine, 1996b). Investigators have recognized that the birth defect known as FAS is only the ‘‘tip of the iceberg’’ of prenatal alcohol-related disabilities (Streissguth, 1996a). This viewpoint considers those with full expression of FAS as only a very small subsection of all the individuals affected physically, developmentally, behaviorally, and/or cognitively by fetal alcohol exposure. Although terminology such as fetal alcohol effect, partial fetal alcohol effect, and alcohol-related birth defect was originally developed to describe abnormalities found in animal studies, usage of those terms has appeared to clinically define those individuals with FARA without full expression of FAS. This has caused considerable confusion and various investigators believe the terms should be used only in research and not clinical, domain (Aase et al., 1995; Sokol and Clarren, 1989). Several attempts have been made to improve and clarify the criteria for diagnosis

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of affected individuals (Clarren and Smith, 1978; Rosett, 1980; Sokol and Clarren, 1989). The most recent and comprehensive advancement was undertaken by the Institute of Medicine (IOM) of the National Academy of Sciences Committee to Study Fetal Alcohol Syndrome (Institute of Medicine, 1996c). The committee attempted to resolve the issues confusing the clinical and research communities by delineating five diagnostic categories for FARA (Table 1). The first category contains those individuals with a diagnosis of FAS (triad of symptoms as above) plus a confirmed history of maternal alcohol exposure (a pattern of excessive intake characterized by substantial, regular intake or heavy episodic drinking). The second group includes individuals with a diagnosis of FAS without a confirmed history of maternal alcohol exposure (accurate history not provided by birth mother, or inaccessible alcohol history for foster/adopted children). The third classification describes individuals as having partial FAS with confirmed maternal alcohol exposure. It includes those with confirmed alcohol exposure during gestation, some of the facial features of FAS, and evidence of growth, neurodevelopmental, behavioral and/or cognitive abnormalities. Two additional categories were devised in which to place individuals with a history of maternal alcohol exposure plus evidence of conditions that have been noted in clinical or animal alcohol teratology research. Category four, alcohol-related birth defects (ARBD), designates those with physical anomalies, while category five, alcohol-related neurodevelopmental disorder (ARND), describes those with neurodevelopmental abnormalities and/or behavioral or cognitive abnormalities. A diagnosis of ARND represents a not less severe spectrum of FARA than a diagnosis of FAS. Dysmorphology As outlined above, FARA is characterized by a triad of features: pre and/or postnatal growth deficiency, visceral defects, specific craniofacial anomalies and CNS dysfunction. While growth deficiency and craniofacial anomalies may be of considerable importance in making the clinical diagnosis of a FARA, it is the structural and functional brain anomalies that ultimately are the most disabling to the individual. Abel (1996) reviewed neuropathological investigations utilizing ultrasound (Ronen, G. M. and Andrews W. L., 1991), computed tomography (CT) (Goldstein G., and Arulanantham K., 1978), magnetic resonance imaging (MRI) (Gabrielly et al., 1990; Schaefer et al., 1991; Robin N. H., and Zacaki E. H., 1994; Mattson et al., 1992; Coulter et al., 1993), positron-emission tomography (PET) (Hannigan et al., 1995), and autopsy (Clarren et al., 1978; Clarren S. K., 1979, 1981; Peiffer et al., 1979; Wisniewski et al., 1983), clearly demonstrating the susceptibility of the brain to the teratogenic insults of alcohol. The affected brain typically is reduced in volume and certain regions (e.g., basal ganglia, corpus callosum, anterior vermis of cerebellum) shows a disproportionately large decrease in size. Other abnormalities seen including cerebral dysgenesis, enlarged ventricles, and abnormal neural/glial migration, indicating that fetal-alcohol-related brain anomalies are structurally and functionally different from those seen in similarly developmentally disabled, functionally impaired microcephalic children (Mattson et al., 1994, 1996; Riley et al., 1996). It is now apparent that a unique pattern of brain anomalies is attributable to prenatal alcohol exposure. While growth deficiencies may normalize and craniofacial abnormalities may become less distinct with age, it is the brain injuries and their corresponding disabilities that are the hallmark of and the most unfortunate aspects of FARA. Normal sensory input is essential for the performance of higher cortical functions. Therefore, early impairment of sensory pathways may contribute to abnormal intellectual

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development. Research into the developing visual system has shown that sensory impairment during critical period of postnatal maturation interferes with normal development of visual perception, neural synapses, myelination, and cell size, number, and organization (Globus and Scheibel, 1967; Wiesel, 1982). A wide range of ophthalmological abnormalities have been found to be associated with FAS, including microphthalmia, strabismus, visual impairment, short horizontal palpebral fissure, blepharoptosis, microcornia, corneal opacity, iris defects, cataracts, glaucoma, persistent hyaloid, and combinations of these abnormalities (Stromland, 1981, 1985; Miller et al., 1984; Chan et al., 1991). Stromland and Hellstrom (1996) have suggested the eye to be a sensitive indicator of adverse effects of prenatal alcohol exposure. Optic nerve hypoplasia (the most common anomaly in their studied cohort) and a large number of other ophthalmological signs were found to be persistent during 11 years of follow-up. Similar observations have been made concerning sensory deprivation in the developing auditory system. FAS children were found to be at high risk for a variety of hearing disorders: delay in the maturation of the auditory system, congenital sensorineural hearing loss, conductive hearing loss secondary to recurrent otitis media, and central hearing disorders (Church and Holloway, 1984). Hearing disorders are strongly associated with craniofacial anomalies, mental impairment, and ocular defects (Northern and Down, 1984). Adequate hearing is necessary for proper speech, language, and intellectual development. A child with hearing loss is more likely to exhibit hyperactivity, distractability, and learning disabilities (Northern and Down, 1984). FAS is one of the most common causes of childhood hearing, speech, and language disorders (Church and Holloway, 1996). But by far, neurobehavioral sequelae of FARA are the most devastating in terms of the affected child’s appropriate integration in society. In a prospective, longitudinal study focusing on the moderate amount of alcohol ingested by ‘‘social drinking,’’ Streissguth et al. (1996b) looked at deficit in growth, morphology, and function-teratogenic outcomes found in children with FAS. The findings of the study were in accordance with the experimental animal literature. At that relatively moderate level of alcohol exposure, it is neurobehavioral function which displays the most reliably enduring adverse effects of prenatal alcohol exposure. These neurobehavioral effects were present from birth through 14 years of age and were dependent on the level of alcohol consumed, generally with no threshold level. During the school-age years, the effects were associated more with binge-type drinking patterns. Drinking before pregnancy recognition was shown to have more adverse outcomes than drinking in midpregnancy, but the two were highly correlated. Slower information processing and attention problems were apparent throughout the school 14 years, while learning difficulties were noted from 7 through 14 years. These effects were observed even in children without physical or facial features associated with FAS. To date, no method exists to quantify the brain damage caused by alcohol and its relation to dysfunctional behavior in an affected child. The behavior of children with FARA varies widely, and many other exposed offspring who do not exhibit full-blown FAS show neurobehavioral deficits as severe as those of FAS. There is no statistical evidence of a ‘‘risk-free’’ drinking level or any threshold level of prenatal alcohol exposure in Streissguth’s (Streissguth et al., 1993) dose-response analysis. Attention, memory, speed and reliability of information processing, arithmetic functioning, and phonological processing were the most affected areas; the neurobehavior abnormalities were not affected by birth weight and were ‘‘highly significant statisti-

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Diagnostic for Fetal Alcohol Syndrome (FAS) and Alcohol-Related Effects (10 M, 1996) Fetal Alcohol Syndrome

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1. FAS with confirmed maternal alcohol exposure A. Confirmed maternal alcohol exposure B. Evidence of a characteristic pattern of facial anomalies that includes features such as short palpebral fissures and abnormalities in the premaxillary zone (e.g., flat upper lip, flattened philtrum, and flat midface). C. Evidence of growth retardation, as in at least one of the following: —low birth weight for gestational age —decelerating weight over time not due to nutrition —disproportional low weight to height D. Evidence of CNS neurodevelopment abnormalities, as in at least one of the following: —decreased cranial size at birth —structural brain abnormalities (e.g., microcephaly, partial or complete agenesis of the corpus callosum, cerebellar hypoplasia) —neurological hard or soft signs (as age appropriate), such as impaired fine motor skills, neurosensory hearing loss, poor tandem gait, poor eyehand coordination 2. FAS without confirmed maternal alcohol exposure B, C, and D as above 3. Partial FAS with confirmed maternal alcohol exposure A. Confirmed maternal alcohol exposure B. Evidence of some components of the pattern of characteristic facial anomalies Either C or D or E E. Evidence of a complex pattern of behavior or cognitive abnormalities that are inconsistent with develpmental level and cannot be explained by familial background or environment alone, such as learning difficulties; deficits in school performance; poor impulse control; problems in social perception; deficits in higher level receptive and expressive language; poor capacity for abstraction or metacognition; specific deficits in mathematical skills; or problems in memory, attention, or judgment.

List of congenital anomalies, including malformation and Cardiac Atrial septal defects Ventricular septal defects Skeletal Hypoplastic nails Shortened fifth digits Radioulnar synostosis Flexion contractures Camptodactyly Renal Aplastic, dysplastic, hypoplastic kidneys Horseshoe kidneys Ocular Strabismus Retinal vascular anomalies Auditory Conductive hearing loss

dysplasias Aberrant great vessels Tetralogy of Fallot Clinodactyly Pectus excavatum and carinatum Klippel-Feil syndrome Hemivertebrae Scoliosis Ureteral duplications Hydronephrosis Refractive problems secondary to small globes

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4. Alcohol-related birth defects (ARBD)

Neurosensory hearing loss

Other

Virtually every malformation has been described in some patients with FAS. The etiologic specificity of most of these anomalies to alcohol teratogenesis remains uncertain. 5. Alcohol-related neurodevelopment disorder (ARND) Presence of: A. Evidence of CNS neurodevelopmental abnormalities, as in any one of the following: —decreased cranial size at birth —structural brain abnormalities (e.g., microcephaly, partial or complete agenesis of the corpus callosum, cerebellar hypoplasia) —neurological hard or soft signs (as age appropriate), such as impaired fine motor skills, neurosensory hearing loss, poor tandem gait, poor eyehand coordination and/or: B. Evidence of a complex pattern of behavior or cognitive abnormalities that are inconsistent with developmental level and cannot be explained by familial background or environment alone, such as learning difficulties; deficits in school performance; poor impulse control; problems in social perception; deficits in higher level receptive and expressive language; poor capacity for abstraction or metacognition; specific deficits in mathematical skills; or problems in memory, attention, or judgment.

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(Reprinted with permission from Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment. Copyright 1996 by the National Academy of Sciences. Courtesy of the National Academy Press, Washington, D.C.)

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cally despite the absence of post-infancy effects of prenatal alcohol on child weight and height.’’

RISK FACTORS IN THE DEVELOPMENT OF FETAL ALCOHOLRELATED ABNORMALITIES The facts that not all children exposed to gestational alcohol consumption develop FARA and the reality that an increased incidence of FAS is associated with low socioeconomic status (SES) and African-American and Native American communities suggest that other risk factors may be interacting with the maternal alcohol exposure, thus further compounding the risk to the fetus. Such risk factors may include poor maternal health, nutrition, and prenatal care; substance abuse; biological susceptibility; and the dose, timing, and pattern of alcohol exposure. To complicate the research into such effects, risk factors tend to cluster in heavily drinking women. We have recently shown that women in Ontario who had engaged in first-trimester binge alcohol consumption were significantly more likely to be single young cigarette smokers and to use cocaine, marijuana, and other illicit drugs (Gladstone et al. 1997). Abel (1995) proposed two categories of maternal risk factors: permissive factors, or predisposing behavioral, social, or environmental (e.g., alcohol consumption pattern, SES) factors, and provocative factors, or the biological condition (e.g., high blood alcohol concentration, decreased antioxidant status) that increase fetal vulnerability to alcohol at the cellular level. Pattern of Drinking and Peak Blood Alcohol Concentration Numerous studies have been undertaken to elucidate the effects of mild, moderate, and heavy maternal alcohol consumption. Definitions of drinking patterns typically represent average daily, weekly, or monthly alcohol intake levels. Unfortunately, the definitions of mild, moderate, and heavy vary considerably among studies, making generalizations and comparisons extremely difficult. It is now evident that the pattern of drinking is a critical factor in predicting future teratogenic effects. Abel and Hannigan (1996) recently summarized this research by claiming that drinking patterns in terms of drinks or amount of absolute alcohol per week during pregnancy is not meaningful given that blood alcohol level is a critical factor. There is a large body of evidence from rodent (Sulik et al., 1981, 1984, 1986; Pierce and West, 1986; West et al., 1990), primate (Clarren and Bowden, 1982; Clarren et al., 1987, 1990, 1992; Carren and Astley, 1992) and human models (Streissguth et al., 1989a, 1989b, 1990, 1993, 1994a,b), indicating that a single binge exposure or period of binge exposures is embryotoxic, fetotoxic, and sufficient to produce a wide spectrum of physical and neurodevelopmental deficits. Consistent findings have demonstrated that alcohol’s teratogenic effects are related to the maternal peak blood alcohol concentration (BAC) obtained and are not simply reflection of the total volume of alcohol consumed. Peak BACs are determined by both the dose and the rate of alcohol consumption. Alcohol consumed in a binge pattern is capable of rapidly producing higher blood alcohol concentrations that require a longer time for the fetus to clear than equal (or even greater) daily amounts that are consumed in a slower or more spread out manner. This observation of a ‘‘peak effect’’ is critical in setting a mechanistic framework for binge drinking, since it suggests that a

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critical threshold of BAC level may be required to induce neurotoxicity. Consequently, this may explain some of the large variability in the prevalence of FAS in the offspring of alcoholics. A very different pattern of BAC would be achieved by two different types of alcoholics: one who spreads 10 drinks throughout the day from morning to evening and one who binges on 10 drinks in the evening (Clarren et al., 1992; Gladstone et al., 1996). From the public health and prevention perspectives, there are several important points to consider regarding the deleterious effects of drinking in a binge pattern during pregnancy. It has been documented that most alcoholic women decrease their consumption of alcohol during pregnancy; nevertheless, when they do drink, they tend to binge (Little and Stressguth, 1978). Another area of concern is the high association between alcohol intoxication and unplanned or unprotected sexual activity (Wechsler and Isaac, 1992; Wechsler et al., 1994; Parker et al., 1994; Meilman, 1993). The fear is that women who engage in a binge style of alcohol consumption may increase their likelihood or unplanned pregnancy and may then, consequently, unknowingly expose the fetus to continued binge until pregnancy is diagnosed. This is particularly alarming in the teenage population, given their high rate of binge drinking (Kusserow, 1991; Johnston et al., 1991), the rising rate of teenage pregnancy (National Center for Health Statistics, 1990), and the tendency of adolescents to recognize their pregnancies later than adults (Cornelius et al., 1994). These factors may combine to make the offspring of teenagers significantly more susceptible to FAS (Gladstone et al., 1996). Effect of Timing on Fetal Central Nervous System Development Another key risk factor that has been shown to hold for both structural alterations and functional impairments is the timing of alcohol exposure. There are particular periods during gestation when the fetus and its central nervous system (CNS) are most susceptible to the harmful effects of alcohol. Although, at present the exact temporal windows of fetal vulnerability are not known, there is some evidence of critical periods for a number of FAS expressions. First-trimester alcohol exposure is critical for organogenesis and for distinctive FAS facial dysmorphology (Sulik et al., 1981, 1986). This is alarming, because 50% of North American pregnancies are unplanned (Skrabanek, 1992), and a majority of women may not be aware of their pregnancies during the first 4–6 weeks of gestation. In light of this information, women who abuse alcohol should be advised of the risk of facial anomalies if alcohol exposure proceeds into the first trimester. Alcohol exposure during gestation is strongly associated with intrauterine growth retardation (IUGR) and somatic growth defects (Ernhart et al., 1985). IUGR is a term describing fetuses or neonates that are small in weight, length and head size for their gestational age. IUGR is not a transitory effect and growth to normal levels (‘‘catch-up’’) is rare (Day et al., 1991a,b). Smith (1986) reported that women who discontinued drinking before the end of the second trimester delivered babies that were not different in weight, length, and head circumference from unexposed infants. Microcephaly is associated with alcohol consumption throughout pregnancy (all three trimesters); this finding being supported by clinical and experimental evidence, and cessation of drinking after the second trimester may lead to improvement in head growth (Smith et al., 1986). Alcohol exposure during the second and third trimesters produces neuronal loss (Miller and Potempa, 1990), altered neuronal circuitry (West and Hamre, 1985), and exten-

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sive gliosis (Goodlett et al., 1993). The third trimester is an especially vulnerable period for the brain in response to alcohol insult (West et al., 1986; Marcussen et al., 1994), and a single exposure to high BACs produced a substantial loss of Purkinje cells (Goodlett et al., 1990). Socioeconomic Status Low SES, a major permissive factor contributing to FAS, is an indicator for poor maternal nutrition, health, decreased access to prenatal care, and increased maternal stress. Each of these may independently and adversely affect pregnancy outcome (Abel and Hannigan, 1996). Although FAS occurs in all races, the population with the largest numbers of FAS is typically poor (Abel, 1995). It is likely that in children affected by FAS born to lowSES families, lack of basic infant care—including nutrition, stimulation, and education— acts in a negative synergistic way to augment the damage caused by neurotoxicity. Genetic Differences Genetic variability in factors such as maternal rate of metabolism of alcohol, the rate of transport of nutrients across the placenta, and uterine blood flow may play a role in influencing the risk and the severity of alcohol-induced fetal damage. Genetic differences were found in neural sensitivity of the developing brain in such basic parameters as brain and cerebellar weight (Goodlett et al., 1989). Genetic factors influencing vulnerability to FAS may include differences in the various isoforms of ADH, although there is no convincing evidence of a racial predisposition to FARA based on enzymatic isoforms (Bosron et al., 1980). Polydrug Use Women who abuse alcohol very commonly abuse other illicit drugs (Coles et al., 1985; Kokotailo et al., 1992; Gladstone et al., 1997). Two examples for such synergistic effects involve cocaine used in combination with alcohol, which produces cocaethylene, an exceptionally active neurotoxic substance (Hearn et al., 1991); and the combination of maternal alcohol consumption and cigarette smoking, which increases the risk for low birth weight, microcephaly, and hearing difficulties (Olsen et al., 1991; 1988; Wright et al., 1983).

POSSIBLE MECHANISMS CONTRIBUTING TO ALCOHOL’S TERTATOGENIC EFFECTS It is presently not possible to fully detail the mechanism with which ethanol exerts its effects during each stage of development. It has been postulated that alcohol-induced fetal CNS abnormalities are mediated through multiple mechanisms (West et al., 1994). Prenatal alcohol exposure leads to disruption of most areas of brain development (West et al., 1994). A number of studies have reported alterations in proliferation, neuronal migration, dendritic growth, conductivity among neurons, and even neuronal death (Miller 1986, 1993; Marcussen et al., 1994).

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Alcohol also has a number of detrimental effects on nonneuronal elements and may affect brain function indirectly by altering the development of the cerebellar and hippocampal microvasculature (Kelly et al., 1990). As ethanol crosses the placenta and the blood-brain barrier, it may affect the fetus directly or indirectly through secondary effects, leading, for example, to constriction of umbilical vessels and resulting in insufficient oxygen supply (Mukherjee and Hodge, 1982). There is still a concern as to whether alcohol per se or acetaldehyde is the teratogen associated with fetal alcohol induced brain damage, since heavy alcohol consumption typically results in high levels of both alcohol and acetaldehyde. Jones et al. (1991) postulated that inhibition of aldehyde dehydrogenase, the enzyme that converts acetaldehyde to acetate, exacerbates the effects of alcohol on the fetus by raising the levels of acetaldehyde. Alcohol interferes with brain cell metabolism by decreasing protein synthesis and DNA methylation, mechanisms most commonly said to explain fetal growth retardation. DNA methylation has been shown to be one of the mechanisms involved in gene activity and function. The embryonic DNA is highly methylated, and alcohol-induced inhibition of fetal DNA methylation may be associated with the teratogenic effects of alcohol described in FAS (Garro et al., 1991). Garro et al., (1991) also demonstrated that acetaldehyde is a 06-methylguanine transferase that has an important role in DNA repair activities. Espina et al. (1988) hypothesized that hypomethylation alters gene expression and may be responsible for the developmental abnormalities observed in FAS. Free-Radical Damage An alternate explanation for alcohol damage has been free radical–induced mitochondrial damage. A study in fetal rat hepatocytes demonstrated that exposure to ethanol inhibits mitochondrial function and thus creates oxidative stress in the hepatocyte and a subsequent drop in ATP levels (Devi et al., 1994). The excess amount of the intermediate of oxygen reduction, O2, and other short-lived reactive oxygenated free radicals was found to be associated with anomalies observed in FAS. Free radicals are molecules with one or more unpaired electrons which are known to be highly unstable, reactive and cytotoxic (De Groot and Littaner, 1989; Nordman et al., 1992). Radicals are normally scavenged by endogenous antioxidative enzymes; alterations of such balance by ethanol may increase oxidative stress (Nordman, 1992), which is highly damaging to cells. These disruptive mechanisms may affect proteins, lipids, chromosomes, and specific receptors. Due to peroxidation, lipids may become free radicals themselves and then may enhance chain reactions and membrane decomposition, manifest by changes in membrane fluidity and ‘‘leaking,’’ levels of phosphoglycolipid composition, and decrease in the activity of calcium ATPase as well as Na⫹- and K⫹-ATPase, all of which have been shown in animal fetuses exposed prenatally to ethanol (Arienti et al., 1993; Burmistrov et al., 1991; Murdoch and Edwards, 1992). Gangliosides—which are actively involved in cellular migration, cell-cell interaction, neurite outgrowth, and other biological processes—were found to be decreased after

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alcohol administration. Alcohol adversely interferes with the interaction of water, membrane proteins, and gangliosides, leading to a new hydrogen bond and membrane fluidization. In animals, prenatal administration of gangliosides was found to antagonize some of the harmful fetal effects of prenatal alcohol (Klemm, 1990; Hungund and Mahadik, 1993). Concentrations of gangliosides and ganglioside-specific enzymes increase dramatically during brain development; therefore it has been suggested that prenatal alcohol exposure may affect the amount of gangliosides and their activity, thus contributing to the formation of FAS. Alcohol-induced cellular damage due to oxygen radicals may also occur independently as ischemia or hypoxia. Neural crest cells, which are devoid of superoxide dismutase, an enzyme that catalyzes the conversion of O2 into H2O2 and O2 and protects tissues against the deleterious effect of O2, are extremely sensitive to alcohol exposure (Davis et al., 1990). This sensitivity may account for facial and visceral malformations, because those structures derive from neural crest cells (Davis et al., 1990). The CNS may be more vulnerable than other organs to alcohol exposure because of its great dependence on uninterrupted blood flow, high content of polyunsaturated fatty acids, and relatively low levels of free radical–scavenging enzymes and antioxidants (Abel, 1995). Micronutrients such as iron, selenium, manganese, riboflavin, niacin, tryptophan, β-carotene, and vitamin E and C are needed for the free radical–scavening enzymatic defense mechanisms. They stabilize free radicals and inhibit their activities. Alcohol abuse is associated with an increase of cellular iron. The involvement of iron in free radical formation increases the potential for cellular damage especially in the brain where lipid peroxidation is very rapid (Nordman et al., 1992). Zinc is known to be essential in the synthesis of protein, DNA, and RNA, critical for cell duplication, and a cofactor in enzymes involved in free-radical defense mechanisms, such as superoxide dismutase. Maternal alcohol intake can reduce fetal zinc levels and reduce the activity of superoxide dismutase. Zinc deficiency during development is teratogenic and, in combination with prenatal exposure, may interact synergistically to reduce fetal body and brain weight (Dreosti, 1993). Acetaldehyde Acetaldehyde production may also cause organic damage, as acetaldehyde is an extremely reactive molecule and affects most body tissues. Although most of it is converted to acetate, some will enter the bloodstream and reach a plateau when both the alcohol dehydrogenase and cytochrome P-450 systems are saturated. Acetaldehyde forms stable adducts with amino acid residues in proteins. These adducts are antigenic, giving rise to antiadduct antibodies that can react with hepatocyte surface antigens, causing the destruction of these liver cells. It is important to note that alcoholics achieve significantly higher acetaldehyde plateaus than nonalcoholics, even when the same blood alcohol level is attained. This is most likely due to the induction of the P-450 system in alcoholics, resulting in a faster conversion of ethanol to acetaldehyde. Prostaglandins Alcohol causes both a direct and indirect increase in prostaglandins in fetal tissues (Collier et al., 1975). Increased prostaglandin levels lead to increased cyclicAMP levels, which,

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in turn, may reduce the rate of cell division (Pastan et al., 1975). In the brain, this process may interfere with stem cell division during neuronal proliferation. Following alcohol exposure in utero, decreased brain weight has been observed in fetuses, with increased prostaglandin E and cAMP levels. The inhibition of prostaglandin production (by injecting acetylsalicylic acid prior to ethanol introduction) halves the number of defective offspring in animal models (Pennington, 1988). Amino Acid Transport An additional proposed mechanism links ethanol-induced growth retardation to fetal malnourishment secondary to ethanol’s interference with placental essential amino acid transport (Lin, 1981). While this could explain the fetal growth retardation commonly seen in FAS, malformation and growth retardation can still be documented when ethanol is directly administered to rat fetuses, thereby circumventing the placenta (Brown et al., 1979). Fetal Hypoxia There is evidence that alcohol-related impairments of essential amino acids (Fisher et al., 1985), glucose (Snyder et al, 1986), or vitamins and minerals (Schenker et al., 1992) may be partly caused by impaired functioning of the oxygen-dependent Na⫹, K⫹-ATPase membrane transport in the presence of hypoxia (Fisher et al., 1986). Ethanol metabolism increases the liver’s demands for oxygen to metabolize alcohol, resulting in oxygen deprivation (Urgarte and Valenzuela, 1971). This relative hypoxia may be further intensified by ethanol-induced contraction of umbilical arteries and veins and impaired oxygen unloading from hemoglobin by acidification of the blood (Yang et al., 1986). It has been suggested that episodes of acidosis and hypoxia are operative in impairing neurological functioning of children with FAS. However, the theory of ethanolinduced hypoxia has recently been challenged, showing, in pregnant ewes, that maternal ethanol infusions actually produced a dose-dependent increase in uterine blood flow and fetal arterial oxygen pressure (Reynolds et al., 1996). Inhibition of Cell-Cell Adhesion Another mechanism proposed for alcohol-induced damage is the sensitivity of L1-mediated neural cell adhesion molecules to ethanol. The L1 gene encodes for an essential cell membrane protein that helps the neuronal membranes stick to each other and to their extracellular matrix. Researchers have recently noted a startlingly similar picture of defects in people with FAS and in those with a rare genetic mutation in the cell adhesion molecule L1; mental retardation, hydrocephalus and agenesis of the corpus callosum have all been observed in children with L1 mutations and with fetal alcohol syndrome (Ramanthan et al., 1996). Subsequent rat studies have demonstrated that ethanol nearly completely inhibited the stickiness of cell adhesion molecules at a blood alcohol level of 0.08%, a level defining legal intoxication in many U.S. states (Ramanthan et al., 1996). The authors of this study concluded that ‘‘because L1 plays a role in both neural development and learning, ethanol inhibition of L1-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders.’’

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Long-Term Potentiation Finally, alcohol has been observed to disrupt long-term potentiation (LTP), a phenomenon that many neuroscientists believe is a prerequisite to memory and learning. LTP refers to long-lasting increases in the strength of synapses between neurons. In a study by Savage and Sutherland (Broun, 1996) pregnant rats were treated with alcohol equivalents of maternal consumption of two to three drinks per day. The adult offspring of the ethanol-treated rats were later subjected to a series of maze tests. Interestingly, they performed as well as controls on standard water-maze learning tests, but they were strikingly worse when presented with a more difficult variation of the test. While controls learned the new maze after just one trial, the offspring of alcohol-ingesting mothers required seven or eight trials to learn the new maze. The brains of the ethanol-exposed offspring were later examined, and it was found that their neurons showed markedly reduced LTP in the hippocampus, an area essential for memory formation. It was also discovered that these neurons, when faced with changing stimuli, failed to release an important neurotransmitter, which is a sign that the neurons had lost the plasticity required for learning. This last theory may prove very important in advancing our knowledge regarding the mechanism of FARA, because to date it proposes to explain how moderate drinking can induce teratogenesis. How much alcohol is considered damaging during pregnancy has never been definitively established because we lack a distinct model of teratogenesis for moderate doses of alcohol.

PRIMARY AND SECONDARY DISABILITIES The majority of scientific assessments have been focused on studying preschool groups of children with gestational alcohol exposure. ‘‘FAS is not just a childhood disorder’’ (Streissguth et al., 1991), and prenatal exposure to alcohol can cause a plethora of abnormalities and disabilities that have lifelong physical, mental, behavioral, and social consequences. To address the long-term outcome of gestational alcohol, Streissguth et al. (1996c) definite as primary disabilities those that reflect the FAS or ARND diagnosis. Secondary disabilities are those that an individual is not born with and that could presumably be prevented through better understanding and appropriate intervention. Primary disabilities associated with FAS or FAE (defined by this research group as some but not all the features of FAS) were examined in 473 individuals aged 3–51 years by presenting a wide spectrum of cognitive, behavioral, and language tests. Patients with FAS (n ⫽ 178) had an average IQ of 79, those with FAE (n ⫽ 295) had an average IQ of 90, but the Adaptive Behavior score was very low in both subgroups (61 and 67, respectively). The FAE individuals were tested with better cognitive abilities compared with those with FAS, but their behavioral functions, especially social adaptability, did not differ. In this study, mental health problems were found in 90% of the sample. Disrupted school experience and trouble with the law were found in 60% of assessed individuals. There was confinement and inappropriate sexual behavior in 50%, alcohol/drug problems were found in 30%, as well as dependent living and problems with employment in 80% of studied population. Rates of secondary disabilities were nearly equal across the sexes. A diagnosis be-

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fore 6 years of age was found to be a strong protective factor for all secondary disabilities (except mental health). Another protective factor was to be diagnosed as FAS rather than FAE. It is the combination of better cognition with poor social adaptability that leads individuals with FAE to disruptive school experience, inappropriate sexual behavior, drug problems, delinquency, dependent living, and unemployment. The determination of protective factors points on the importance of early diagnoses of FAS/FAE and shows that patients with ARND abnormalities have more chances for serious secondary disabilities in their future lives. Early diagnosis with proper intervention may change the appearance and course of the secondary disabilities as opposed to the primary disabilities, which probably are not influenced by intervention.

MENTAL HEALTH PROBLEMS From the beginning of life, many FAS children start to develop medical complications, developmental delays, and psychiatric symptoms. Although hyperactivity and attention deficit are common problems during both preschool and school age (Iosub et al., 1981) psychopathology is not restricted to these core symptoms. In the preschool period, eating disorders, enuresis, speech delay, and stereotypes also occur. Later, during early school age, problems such as speech delay and stereotypes are even more common, and problems such as anxiety or sleep disorders now emerge. Moreover, there is an enormous variety of symptoms and high prevalence for any psychopathology. Steinhausen (1982, 1991a,b, 1996) showed that 63% of FAS children suffered from a single or (more commonly) more than one psychiatric disorder. Mental health problems were found to be the most prevalent secondary disability recorded by Streissguth (1996c). Some 90% of 473 assessed patients presented with one or more psychiatric conditions. The most frequent mental health problem for children and adolescents in this group were attention deficit (61%), depression (50%), suicide threats (43%), and psychotic symptoms (29%). Evidence shows that severity of morphological damage, psychopathology, and mental retardation tends to coincide in a subgroup of severely affected FAS children, who often come from extremely deprived backgrounds that include chronic maternal alcoholism and very often also paternal alcoholism. No study has yet tried to disentangle the effects of the teratogenic and environmental risk factors on the child’s development, although the longitudinal studies have hinted that even a stimulating environment with sensitive parents or a good institution may not sufficiently compensate for prenatal damage due to alcohohl exposure. Although mental retardation and cognitive deficits are overrepresented among FAS children, mental functioning varies widely; many of these children function normally at school. It is interesting that, in contrast to other reports, Steinhausen’s (1993) analyses show no linear relation between degree of morphological damage and intelligence. This relation may level off with increasing age or reflect the fact that dysmorphic features may be a crude measure of morphological damage, especially of the brain. Persisting mental impairment and psychiatric disorders cause serious problems for many FAS adolescents and young adults, and a considerable proportion of these patients remain dependent on support from others.

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PRENATAL ALCOHOL EXPOSURE AND ATTACHMENT At birth, there are signs of CNS dysfunction in infants born to mothers who report drinking large quantities of alcohol during pregnancy. These neonatal effects include irritability, autonomic instability, decreased sucking response, motor immaturity, slow habituation, low levels of arousal, distorted sleep patterns, and withdrawal symptoms (Coles et al., 1984, 1985; Streissguth et al., 1983) High-pitched crying, disturbed sleep, and feeding difficulties often follow withdrawal symptoms and may persist for days and weeks (Coles and Platzman, 1993). Behavioral difficulties may continue into the preschool period, with difficulties in cognitive functioning and sustained attention, emotional instability, increased activity level, rigidity, and irritability (Landesman-Dwyer et al., 1981). These neurobehavioral effects may have a significant impact on the mother-infant interaction and future attachment relationships (Meares et al., 1982). Thus, the effects of alterations in infant behavior on infant attachment may be the most significant result of prenatal exposure to alcohol. O’Connor et al. (1992), using a causal modeling procedure and two alternative models, proposed that alcohol consumption following pregnancy was directly related to the mother’s interaction with her child and resulted in a negative affective response in the child and in insecure attachment. One of the models tested the hypothesis that three independent and direct paths could be drawn between prenatal drinking and infant negative affect, maternal behavior, and attachment behavior, respectively. That model was based on the possibility that alcohol consumption affected mother and infant independently. The results were that this group contained a high number of disorganized infants (32%) and that the mothers of these infants were the heaviest drinkers. Mothers who drank more had infants who displayed more negative affect in interaction and expressed insecure attachment behavior. The mothers of these infants were less stimulating in the interaction process. Black and associates (1986) described children of alcoholics as ignoring, withdrawing, and avoiding conflict. These children were self-reliant and unable to trust other people when they needed help (Cork, 1979); they grew up perceiving adults as uncaring and insensitive. Research suggests a possible link between insecure attachment in infancy and subsequent child behavior problems (Lewis et al., 1984; Erickson et al., 1985; Crowell and Feldman, 1988), thus highlighting the need to examine pathways for later maladaptation. Maternal, emotional, and social aspects associated with the mother’s drinking conspire to weaken the maternal-infant bond. Future research should focus on studying the mechanisms of secure attachment and positive mother-child relationship, because a better understanding of this complex process would lead to early intervention before the primary attachment relationship became disturbed.

PREVENTING ALCOHOL-RELATED FETAL ABNORMALITIES The recognition that prenatal alcohol exposure is associated with long-term physical, cognitive, behavior, and social disabilities calls for cultural, sociological, medical, and public health interventions to prevent FARA. Prevention of fetal alcohol effects, clearly the first line of defense against the effects of prenatal alcohol disorders, should be directed at different levels (Loebstein, 1997; IOM Committee to study FAS, 1996d).

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The primary level of prevention includes universal prevention, which strives to ensure that society as a group is aware of the hazardous consequences of alcohol drinking, particularly during pregnancy, and that abstinence before conception and throughout pregnancy is a prudent choice. Selective prevention intervention targets women who are at greater risk (i.e., women of reproductive age who drink more than occasionally). While prevention and treatment of maternal alcohol abuse are extremely difficult and often unsuccessful, a more tangible measure of primary prevention of fetal alcohol exposure is effective contraception. On the level of secondary prevention, when the diagnosis of heavy drinking in early pregnancy has been made, physicians should discuss the attendant fetal risk with the women and their families in the same way other lifelong risks are communicated. In some cases women may choose to terminate pregnancy, while in other cases they may not. While such decisions remain the responsibility of the woman, the physician has a major obligation to inform her accurately of fetal risk. It is important that everything possible be done to ensure discontinuation of drinking if the women choose to continue with the pregnancy and to ensure successful follow-up after delivery. On the level of tertiary prevention, the medical professionals should intervene as early as possible with FAS and FAND children in an attempt to prevent the development of secondary disabilities. Appropriate screening tools, including biomarkers of alcohol exposure, should be implemented to identify drinking women and affected children. Training programs for physicians in the identification of FARA and development of centers with diagnostic capability including neurodevelopmental testing are essential for early diagnosis and future management of affected children in an attempt to maximize the child’s postnatal development and long-term functioning. Alcohol-related fetal effects are a leading cause of mental delay and other forms of congenital brain injury. They can be prevented completely. Until appropriate policies are developed, there will be no lessening in the number of FARA.

CONCLUSIONS Alcohol is the most widely used human teratogen. Among all current substances of abuse, alcohol consumption during pregnancy poses by far the most serious problem. With alcohol being legally, culturally, and socially accepted, consumption is several orders of magnitude larger than that observed for any other known teratogenic compound. During the last decade a significant body of scientific literature has shown that the most devastating consequences of alcohol exposure are its effects on the CNS, even when it is used in relatively moderate doses. Distinct patterns of brain damage include reduced volume of the diencephalon, vermis, basal ganglia, corpus callosum, and cerebellum with a wide range of impairments at the molecular and biochemical levels, resulting in behavioral effects and mental impairment ranging from minor learning disabilities to mental retardation; hyperactivity; distractibility; reduced visual and auditory memory; poor judgment, adaptability, and social skills; hyperresponsiveness to stress, and somatosensory and auditory problems. FAS and ARND are permanent manifestations of CNS dysfunction, not found to be affected by time or environment. There is also no specific treatment for these disorders. Despite considerable research in the field of alcohol teratology, the timing, specificity, and pathogenesis of alcohol teratogenicity remain uncertain. Similarly, the contribut-

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ing role of risk factors such as socioeconomic variables, prenatal care, maternal health, genetic susceptibility, and concomitant exposures are not yet clear. FAS is not a childhood disorder. There is a preventable long-term progression of the disorder into adulthood, in which the maladaptive behaviors present a risk for a wide range of secondary disabilities. The costs of FARA are tremendously high for the individual, the family, and the education and health care systems as well as society. Primary prevention is the only treatment for the fetal alcohol–induced CNS tragedy.

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26 Moderate Alcohol Consumption During Pregnancy and the Incidence of Fetal Malformations: A Meta-Analysis Dimitris Polygenis and Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

Sean Wharton, Christine Malmberg, Nagwa Sherman, Debbie Kennedy, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Descriptions of deleterious effects of alcohol consumption on the fetus have appeared early in history, although the first scientific study documenting alcohol’s harmful effects was not published until 1968 (70). Fetal alcohol syndrome (FAS), characterized by preand postnatal growth retardation, facial dysmorphology, and central nervous system (CNS) dysfunction, was recognized in 1973 as a consequence of chronic alcohol exposure during pregnancy (31). Since then, major and minor malformations, spontaneous abortion, and decreased birth weight have been among the many reported consequences of heavy alcohol use during pregnancy (1,70). In contradistinction to these reports, the effects of moderate alcohol consumption, defined as less than two drinks per day, on fetal malformations remains unclear. The National Institute of Drug Abuse Survey has recently documented that moderate drinking during pregnancy is common in the Western world (45). An American study (61) found that 25% of pregnant women had drunk an alcoholic beverage in the previous month. Many studies have assessed moderate drinking in pregnancy, reporting conflicting results for the same neonatal outcomes. Our recent meta-analysis has investigated the relationship between moderate alcohol consumption during pregnancy and incidence of spontaneous abortions, stillbirths, and premature birth (14) showing a 35% increase in rates of spontaneous abortion with no effect on incidence of stillbirths and premature births. To date, there has not been a comprehensive analysis addressing the consequences of moderate alcohol consumption on fetal malformations. Consequently, clinicians have difficulty in counseling women on the risk of moderate alcohol consumption in pregnancy.

From Neurotoxicol Teratol 1998; 20(1):61–67. 495

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Because half of the pregnancies in North America are unplanned, many women, often unknowingly, extend drinking into the first trimester of their pregnancy as is reflected by the 10% of daily inquiries to the Motherisk Program concerning alcohol consumption in pregnancy (44). The inconsistency in the medical literature concerning the effect of maternal alcohol exposure on the fetus is partially due to poorly defined study samples and outcome parameters, inadequate research design, difficulty in controlling for confounding factors, and inappropriate statistics (66,70). Specifically, problems arise in quantifying and defining moderate alcohol consumption and in the inaccurate use of terms such as malformation, anomaly, birth defect, dysmorphic, deformation, and dysplasia (74,77). The technique of meta-analysis provides a method to assess and resolve conflict in the literature. This technique utilizes well-defined, objective criteria in selecting and evaluating data from a range of studies to increase statistical power (55). The objective of the present analysis is to determine whether there is an association between moderate alcohol consumption in the first trimester of pregnancy and fetal malformations.

METHOD The relationship between moderate alcohol consumption during pregnancy and occurrence of malformations in the offspring was performed by comparing groups comprised of mothers consuming moderate alcohol amounts, to control groups consisting of abstainers.

Definitions The abstainer group was comprised of subjects who consumed up to, and including two alcoholic drinks per week, whereas the moderate alcohol consumption group incorporated individuals with an alcohol intake of greater than two drinks per week, and up to and including two drinks per day. One alcoholic drink was defined as containing 15 mL, 0.5 oz, or 14 g of absolute alcohol. Offspring were considered to have a malformation if they had any of the conditions or defects as defined by Heinonen et al. (28), exhibiting structural and functional defects at or soon after birth, which have a major impact on the life of the child or those that have to be corrected surgically. An important feature of our analysis was that both study and control groups had to have a similar definition and inclusion of malformations. In some studies the malformations were obtained from the medical records (e.g., Ref. 41), whereas in other cases offspring were independently assessed by study personnel (e.g., Ref. 48). A prerequisite for this analysis was that the exposed and unexposed group had to be analyzed in an identical way.

Search Strategy A computerized literature search was conducted using several data bases including MEDLINE (1966–1995), Embase (1988–1995), PsycLit I (1974–1986), and PsycLit II (1987– mid-1995). Articles examining the relationship between moderate alcohol consumption during pregnancy and the occurrence of malformations were identified using the following keywords: alcohol and pregnancy outcome, alcohol drinking, and the text words alcohol and pregnancy.

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Study Selection The following inclusion criteria were applied to the studies extracted by the literature search: (1) pregnant women; (2) moderate alcohol consumption as defined above; (3) casecontrol or cohort studies; (4) presence of an abstainer group as previously defined; (5) data pertaining to malformations; (6) studies in the English language. The exclusion criteria were: (1) studies in which moderate alcohol consumption, as defined above, could not be separated from other alcohol consumption patterns; and (2) case reports, editorials, and reviews. The ‘‘methods’’ section of each study was examined independently by two investigators to select appropriate studies. The inclusion and exclusion criteria were applied to each article and the results of this assessment recorded on a score sheet (Appendix 1). To limit bias throughout this process, the investigators were blinded to the journal name, authors, and the results by removing all identifying statements and by reviewing only the methods section. In the event that agreement could not be reached between the two investigators, a third investigator was consulted. If the methods section failed to provide sufficient information by which to make a decision, the complete article was reviewed for missing information.

Data Extraction Data extraction was performed on each study by two investigators using a standardized form for dichotomous variables. Each author reviewed all the studies that met the inclusion criteria and a consensus was reached. In the case of disagreement, the study would pass on to a third author for independent assessment; however, this was not necessary because a consensus was reached on all data extracted. All data extracted were entered into standardized 2 ⫻ 2 tables illustrating the number of malformations and nonmalformations in the alcohol- and non-alcohol-consuming groups.

Statistical Methods Odds ratios and 95% confidence intervals for significance were calculated for both case control and cohort studies. An overall Mantel–Haenszel relative risk ratio was calculated with a 95% confidence interval as described by Miettinen (42). A chi-square for heterogeneity of outcome and for homogeneity of samples was also performed. A level of 0.05 ( p) was considered significant. Sensitivity analyses based on differences in study design, results, and sample size were performed to evaluate any possible changes in the risk. As well, a power analysis was performed to identify the validity of the conclusions.

Quality Assessment Quality assessment was performed on all studies accepted for analysis based on criteria adapted from Hartzema (27) (Appendix 2). Two investigators evaluated all the articles for quality and a consensus was reached in all instances.

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RESULTS Over 500 articles were published between 1966 and 1995 on the subject of alcohol and pregnancy outcome. Of these, 61 were identified as relevant for study (2–11,13,15– 26,29,30,32–41,43,46–52,54,56–60,62–65,67–69,71–73,75,76). This initial decision was made by looking at the title of the study and the abstract. Twenty-four studies met our inclusion criteria. Only 7 of the 24 studies were used in the analysis due to problems with data extraction. These problems consisted of inadequate reporting of raw data, inadequate delineation of alcohol consumption, lack of an abstainer group, and failure to define the trimester in which drinking took place. A total of seven studies (8,39,41,43,48,56,63) were combined that examined the relationship between moderate alcohol consumption and fetal malformations (Table 1). Six (8,39,41,43,48,56) of the studies were cohort and one was a case control (63). The odds ratio (OR) for major malformations among the moderate alcohol users was of 1.01 and a 95% confidence interval (CI) of 0.94 to 1.08. The chi-squared (χ 2) for homogeneity yielded a value of 8.26 ( p ⫽ 0.220) confirming that the studies, both case control and cohort, can be combined for analysis. The OR of 1.01 indicates that there is no increased risk of fetal malformations associated with maternal moderate alcohol consumption. Sensitivity Analysis The largest and most recent study (41) represented 66% of the total sample. This study had an OR of 1.05 (95% CI 0.89–1.23). A sensitivity analysis with or without this study was performed to identify the impact of its large sample size on the results. Excluding this study resulted in an OR of 1.00 (95% CI 0.92–1.08) for the remaining six studies. The χ 2 for homogeneity was 7.99 ( p ⫽ 0.157). Removal of this study did not have an effect on the conclusions and the remaining studies were still homogeneous. Three of the seven studies (39,41,43) made up 99% of the total sample. When these studies were removed the resulting OR was 1.20 for the remaining four (95% CI 0.71– 2.02). However, these remaining studies (8,48,56,63) only represented 1% of the total number of pregnancy outcomes. One study (8) in this group had an OR of 9.09 (95% CI 0.49–169.40). This study was further analyzed as the OR differed from all other studies. There were no malformations in the abstainer group or the heavy alcohol consumption group. However, the moderate group had four malformations. Although this study was not significant in terms of risk, further investigation found that birth weight was also included with the group of malformations, possibly skewing the results. Based on these results alone, it would appear that the higher incidence of malformations in this one group may be due to chance or the influence of birth weight. Another study (63) had found a trend toward increased risk of malformations in the alcohol-exposed group (OR 2.30; 95% CI 0.43–12.33). However, it examined women of low socioeconomic class and poor nutritional intake, potentially increasing the risk of malformation. Without this study and the previous one mentioned the overall OR (two studies) becomes 1.00 (95% CI 0.93– 1.08) with a χ 2 of 4.97 ( p ⫽ 0.174). Cornfield’s method for power yielded a Z-score of 26.0 (99.99%). This result ensures that there is no difference between the two study groups. Quality Assessment All of the studies used in the statistical analysis were evaluated in terms of quality to assess whether quality of the study affected its results being positive or negative. This

Results of Studies Comparing Incidence of Fetal Malformations in Mothers with Mode Consumption Congenital defect Type of study

Exposure

Yes

No

Total

OR a

95% CI b

McDonald et al. (41)

Case-control

0.49–1.69

Cohort

2.3

0.43–12.32

Rossett et al. (56)

Cohort

0.37

0.12–1.11

Ouellete et al. (48)

Cohort

1.59

0.76–3.34

Mills et al. (43)

Cohort

0.99

0.91–1.08

Lumley et al. (39)

Cohort

7,357 78,980 86,337 478 479 957 68 60 128 162 264 426 128 150 278 15,295 17,114 32,409 519 9,756 10,275

9.09

Silva et al. (63)

7,191 77,279 84,470 474 479 953 63 58 121 158 247 405 110 136 246 14,108 15,778 29,886 505 9,523 10,028

0.69–1.23

Cohort

166 1,701 1,867 4 0 4 5 2 7 4 17 21 18 14 32 1,187 1,336 2,523 14 233 247

1.05

Davis et al. (8)

Yes No Total Yes No Total Yes No Total Yes No Total Yes No Total Yes No Total Yes No Total

1.13

0.66–1.96

Ref.

a b

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Table 1

OR ⫽ odds ratio. CI ⫽ confidence interval.

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analysis revealed no correlation between quality scores and the negativity (i.e., no association with fetal malformations) or positivity of the results.

DISCUSSION Whereas heavy alcohol consumption by pregnant women has been shown to cause distinct and serious fetal pathology (12,39), the effects of moderate alcohol consumption still remain unclear. This meta-analysis has attempted to assess whether there is a measurable risk of fetal malformations due to moderate alcohol consumption during pregnancy. With more than 20,000 exposed babies we found no increased risk resulting from moderate alcohol consumption defined as less than two drinks per day during the first trimester. These results are not intended to justify drinking during pregnancy. However, because half of the pregnancies in North America are unplanned, millions of women each year consume moderate amounts of alcohol before realizing they have conceived. Our experience in the Motherisk Program indicates that these women experience high levels of anxiety due to misinformation and extrapolation from data on fetal alcohol syndrome in heavy drinkers. A variety of organizations warn women against drinking in pregnancy and stress that any amount can be teratogenic. For example, the Manitoba Medical Association stated in a televised campaign that even one drink can harm the unborn baby. We have recently documented that such campaigns can change women’s perceptions in a misleading way. The present meta-analysis is the first attempt to combine all available fetal safety data following mild to moderate drinking during embryogenesis. This meta-analysis had several limitations, primarily due to the variability in methodology and interpretation of studies on fetal abnormalities and maternal alcohol exposure. Most of these studies are limited by the self-reporting of alcohol use. This method is used to obtain data on alcohol consumption and often underestimates true intake. Problems with self-reporting include underreporting and recall bias (53,66). Underreporting may be a consequence of the stigma associated with drinking during pregnancy. On the other hand, recall bias is the inability to remember accurate time and amount of alcohol, primarily due to the delay between actual consumption and timing of the interview (53). Such difficulties in accurately quantifying alcohol intake is an inherent limitation of most studies. Our study may be limited due to the need to exclude 16 studies due to difficulty in data extraction; this can be explained by the lack of a standardized alcohol consumption scale and the inability to isolate treatment and control groups in accordance with our definition of moderate alcohol consumption. Further difficulties in collecting data from these studies arise as a result of the inconsistency within the medical literature regarding the definition of malformation. Our study used the comprehensive definition delineated by Heinonen et al. in their large collaborative project (44). This strict application of the definition resulted in the exclusion of several studies; however, it increases the validity of the results. Further difficulties inherent in fetal outcome involve the introduction of confounding variables that may concomitantly affect the fetus. Because these studies deal with human subjects, we cannot negate the relative contribution of smoking, other drug use, and socioeconomic status. Because women who drink in pregnancy tend to cluster other reproductive risk factors, our negative association indicates that drinking up to two drinks a day is not associated with major malformations despite potential presence of other risk factors.

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CONCLUSION This meta-analysis suggests that moderate alcohol consumption in the first trimester of pregnancy does not increase the risk of major malformations. Women consuming these amounts before finding out they have conceived should not be misinformed to believe they have a higher than normal teratogenic risk. Such false alarm may lead many of them to consider termination of otherwise wanted pregnancies.

Appendix 1

Criteria for Acceptance of Study into Meta-analysis Article Code Number: Reviewer Number: Selection Criteria Inclusion

Yes

1. Does the study deal with pregnant human females? 2. Was alcohol consumption 0–2 drinks/day (or grams or mL equivalency) 3. Was it a case control or cohort study? 4. Is there a control group that was not exposed to alcohol? 5. Is the measured outcome of fetal malformations as defined in Appendix A?

Exclusion 1. Can you separate the data on 2 drinks alone in a 2 drinks and greater study? 2. Is it a case report, editorial, or review study? 3. Does the study provide sufficient data for analysis? 4. Does the study deal with fetal alcohol syndrome or binge drinking? Comments:

Accept:

No

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Appendix 2A Evaluation Criteria for the Quality of Case-Control Studies Criteria

Score

1 2 3

Was there a defined selection method for cases and controls? Was alcohol exposure ascertained in both groups? Data collection should be structured and the investigator blinded to the outcomes. 4 Time of alcohol exposure should be confirmed. 5 Unbiased exclusion criteria provided for cases and control. 6 Same level of outcome screening for cases and controls. Score 2 if the mother was interviewed and the chart was examined. 7 Are cases and controls homogenous with respect to demographics? 8 Appropriate use of statistics ( p-value and CI) 9 Are objectives and conclusion related to alcohol exposure? Total

Max 1 1 2 1 1 2 1 1 1 11

Appendix 2B Evaluation Criteria for the Quality of Cohort Studies Criteria 1 2 3

Is the sample demographically homogeneous? Was alcohol consumption equally ascertained throughout sample? Was the same screening method used to measure outcome for the entire sample? 4 Were the outcomes uniformly classified throughout sample? 5 Dropout rates and characteristics of dropouts in both groups should be accounted for and comparable. 6 Is the cohort representative of the population using alcohol and is the sample size large? 7 Cohorts should be followed from the beginning of pregnancy. Score 2 if defined as first prenatal visit to physician. 8 Appropriateness of statistics. 9 Are objectives and conclusion related to alcohol exposure? Total

Score

Max 1 1 1 1 1 2 2 1 1 11

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28. Heinonen O, Slone D, Shapiro S. Birth defects and drugs in pregnancy; maternal drug exposure and congenital malformations. Boston, MA: Littleton, 1976. 29. Hollstedt C, Dahlgren L, Rydberg U. Outcome of pregnancy in women treated at an alcohol clinic. Acta Psychiatr Scand 1983; 67:236–248. 30. Jacobson JL, Jacobson SW, Sokol RJ, Martier SS, Ager JW, Kaplan Estrin MG. Teratogenic effects of alcohol on infant development. Alcohol Clin Exp Res 1993; 17:174–183. 31. Jones KL, Smith DW, Ulleland CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1:1267–1271. 32. Kaminski M, Franc M, Lebouvier M, Mazaubrun CD, Rumeau Rouquette C. Moderate alcohol use and pregnancy outcome. Neurobehav Toxicol Teratol 1981; 3:173–181. 33. Kaminski M, Rumeau C, Schwartz D. Alcohol consumption in pregnant women and the outcome of pregnancy. Alcohol Clin Exp Res 1978; 2:155–163. 34. Koide T, Saito Y, Sakamoto T, Murao S. Peripartal cardiomyopathy in Japan. A critical reappraisal of the concept. Jpn Heart J 1972; 13:488–501. 35. Larsson G. Prevention of fetal alcohol effects. Acta Obstet Gynecol Scand 1983; 62:171–178. 36. Lazzaroni F, Bonassi S, Magnani M, Calvi A, Repetto E, Serra G, Podesta F, Pearce N. Moderate maternal drinking and outcome of pregnancy. Eur J Epidemiol 1993; 9:599–606. 37. Little RE, Asker RL, Simon PD, Renwick JH. Fetal growth and moderate drinking in early pregnancy. Am J Epidemiol 1986; 123:270–278. 38. Little RE, Streissguth AP. Drinking during pregnancy in alcoholic women. Alcohol Clin Exp Res 1978; 2:179–183. 39. Lumley J, Correy JF, Newman NM, Curran JT. Cigarette smoking, alcohol consumption and fetal outcome in Tasmania 1981–82. Aust N Z J Obstet Gynaecol 1985; 25:33–40. 40. Mau G. Moderate alcohol consumption during pregnancy and child development. Eur J Pediatr 1980; 133:233–237. 41. McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health 1992; 82:91–93. 42. Miettinen O. Estimability and estimation in case-referrent studies. Am J Epidemiol 1976; 103: 226–235. 43. Mills JL, Graubard BI. Is moderate drinking during pregnancy associated with an increased risk for malformations? Pediatrics 1987; 80:309–314. 44. Motherisk Clinic Statistics: Motherisk Program, The Hospital for Sick Children, Toronto. 45. National Institute on Drug Abuse: National Household Survey on Drug Abuse: 1990 Population Estimates. DHHS Pub. No. (ADM)91-1732. Washington, DC: U.S. Government Printing Office, 1991. 46. O’Connor MJ, Brill NJ, Sigman M. Alcohol use in primiparous women older than 30 years of age: relation to infant development. Pediatrics 1986; 78:444–450. 47. Olsen J. The association between birth weight, placenta weight, pregnancy duration, subfecundity, and child development. Scand J Soc Med 1994; 22:213–218. 48. Ouellette EM, Rosett HL, Rosman P, Weiner L. Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Eng J Med 1977; 297:528–530. 49. Plant ML, Plant MA. Family alcohol problems among pregnant women: links with maternal substance use and birth abnormalities. Dev Med Child Neurol 1986; 28:649–654. 50. Plant ML, Plant MA. Maternal use of alcohol and other drugs during pregnancy and birth abnormalities: Further results from a prospective study. Alcohol Alcohol 1988; 23:229–233. 51. Plant ML. Alcohol consumption during pregnancy: Baseline data from a Scottish prospective study. Br J Addict 1984; 79:207–214. 52. Plant ML. Drinking amongst pregnant women: some initial results from a prospective study. Alcohol Alcohol 1984; 19:153–157. 53. Robles N, Day NL. Recall of alcohol consumption during pregnancy. J Stud Alcohol 1990; 51:403–407.

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54. Roeleveld N, Vingerhoets E, Zielhuis GA, Gabreels F. Mental retardation associated with parental smoking and alcohol consumption before, during, and after pregnancy. Prev. Med. 1992; 21:110–119. 55. Rosenthal R. Meta-analytic procedures for social research. Beverly Hills: Sage, 1984. 56. Rosett HL, Weiner L, Lee A, Zuckerman B, Dooling E, Oppenheimer E. Patterns of alcohol consumption and fetal development. Obstet Gynecol 1983; 61:539–546. 57. Rostand A, Kaminski M, Lelong N, Dehaene P, Delestret I, Klein Bertrand C, Querleu D, Crepin G. Alcohol use in pregnancy, craniofacial features, and fetal growth. J Epidemiol Commun Health 1990; 44:302–306. 58. Rubin D, Krasilnikoff PA, Leventhal JM, Berget A, Weile B. Cigarette smoking and alcohol consumption during pregnancy by Danish women and their spouses a potential source of fetal morbidity. Am J Drug Alcohol Abuse 1988; 14:405–417. 59. Russell M, Skinner JB. Early measures of maternal alcohol misuse as predictors of adverse pregnancy outcomes. Alcohol Clin Exp Res 1988; 12:824–830. 60. Saxen I. Epidemiology of cleft lip and palate. An attempt to rule out chance correlation. Br J Prev Soc Med 1975; 29:103–110. 61. Serdula M, Williamson D, Kendrick J, Anda R, Byers T. Trends in alcohol consumption by pregnant women 1985–1988. JAMA 1991; 265:876–879. 62. Shiono PH, Klebanoff MA, Rhoads GG. Smoking and drinking during pregnancy. JAMA 1986; 255:82–84. 63. Silva AV, Laranjeira RR, Dolnikoff M, Grinfeld H, Masur J. Alcohol consumption during pregnancy and newborn outcome: a study in Brazil. Neurobehav Toxicol Teratol 1981; 3: 169–172. 64. Sokol RJ, Miller SI, Debanne S, Golden N, Collins G, Kaplan J, Martier S. The Cleveland NIAAA prospective alcohol pregnancy study: the first year. Neurobehav Toxicol Teratol 1981; 3:203–209. 65. Staisey NL, Fried PA. Relationships between moderate maternal alcohol consumption during pregnancy and infant neurological development. J Stud Alcohol 1983; 44:262–270. 66. Streissguth P. Summary and recommendations: epidemiologic and human studies on alcohol and pregnancy. Neurobehav Toxicol 1981; 3:241–242. 67. Streissguth AP, Martin DC, Martin JC, Barr HM. The Seattle longitudinal prospective study on alcohol and pregnancy. Neurobehav Toxicol Teratol 1981; 3:223–233. 68. Streissguth AP, Barr HM, Martin DC. Offspring effects and pregnancy complications related to self reported maternal alcohol use. Dev Pharmacol Ther 1982; 5:21–32. 69. Sulaiman ND, du V Florey C, Taylor DJ, Ogston SA. Alcohol consumption in Dundee primigravidas and its effects on outcome of pregnancy. BMJ 1988; 296:1500–1503. 70. Taylor DJ. Pregnancy alcohol consumption. Fetal Maternal Med Rev 1993; 5:121–135. 71. Taylor CL, Jones KL, Jones MC, Kaplan GW. Incidence of renal anomalies in children prenatally exposed to ethanol. Pediatrics 1994; 94:209–212. 72. Tennes K, Blackard C. Maternal alcohol consumption, birth weight, and minor physical anomalies. Am J Obstet Gynecol 1980; 138:774–780. 73. Tikkannen J, Heinonen OP. Risk factors for ventricular septal defect in Finland. Public Health 1991; 105:99–112. 74. Verkerk PH. The impact of alcohol misclassification on the relationship between alcohol and pregnancy outcome. Int J Epidemiol 1992; 21:S33–S37. 75. Walpole I, Zubrick S, Pontre J. Is there a fetal effect with low to moderate alcohol use before or during pregnancy? J Epidemiol Commun Health 1990; 44:297–301. 76. Werler MM, Lammer EJ, Rosenberg L, Mitchell AA. Maternal alcohol use in relation to selected birth defects. Am J Epidemiol 1991; 134:691–698. 77. Wright JT, Barrison I, Toplis PJ, Waterson J. Alcohol and the fetus. Br J Hosp Med 1983; March:260–266.

27 Occupational Exposures Known to Be Human Reproductive Toxins Yedidia Bentur Rambam Medical Center, Technion–Israel Institute of Technology, Haifa, Israel

Eli Zalzstein Soroka Medical Center, Beer-Sheva, Israel

Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A woman working in a battery plant plans pregnancy. Her lead level is 5 µg/dL and she is afraid of adverse effects to her baby.

INTRODUCTION The latter part of the twentieth century has been characterized by a substantial and steady increase in the number of women joining the workforce. Moreover, women are taking jobs that were traditionally held by men only. With increased awareness of reproductive toxicity caused by chemicals, women in the reproductive age range and their families are troubled about potential hazards to unborn babies. Moreover, employers are often concerned about their liability in cases of women working with certain chemicals who experience adverse fetal outcome. Recently, an American battery manufacturer tried to exclude all women of reproductive age from its production line, and a similar thrust has been tried by a Canadian nickel producer. In both cases the workers’ unions rejected the manufacturers’ attempts. In comparison to therapeutic agents, our knowledge of reproductive toxicology of industrial chemicals in humans is in most cases sketchy or missing. Before marketing, the teratogenic potential of drugs must be tested in animals; no such data are required for industrial chemicals. In trying to identify adverse reproductive effects in humans of chemicals that have already been introduced into the workplace, one has to struggle with the plethora of methodological problems covered elsewhere in this book. Moreover, in most cases workers are exposed to more than one chemical, and often it is impossible to identify a chemical culprit causing reproductive toxicity.

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Table 1 A Clinical Approach to Reproductive Hazards of Chemicals 1. 2. 3. 4. 5. 6. 7.

8. 9. a

Identify the chemicals in question by their safety sheets.a Identify symptoms and signs reported to be associated. Rule out underlying conditions that may cause a similar clinical picture (e.g., morning sickness in the first trimester). Obtain a detailed description of the work performed by the woman, length of exposure, and means of protection (ventilation system, respirator, mask, gown, gloves, hood, etc.). Determine whether symptoms and signs are manifest in fellow workers. Obtain the most recent levels of the chemicals in question measured in that particular area. Try to understand the attitude of the woman and her supervisors toward her particular work and toward a possible change of job. Will a change of job affect her income or chances for promotion? Before reporting to the woman on available information, read the data critically and be accurate in your description of what is known. Advise the woman on possible safety measurements to reduce exposure (mask, gloves, ventilation, etc.).

In the United States, a document called a Material Safety Data Sheet is required by law for many chemical agents encountered in the workplace.

Every chemical used in the workplace has safety exposure limits aimed at protecting the workers from toxicity. However, these standards were not meant to protect the fetus, and it is possible that airborne levels (e.g., of metallic mercury) that are safe for the mother may be hazardous for the developing organism. It is beyond the scope of this chapter to discuss the toxic potential of every chemical that may be encountered during pregnancy. Because in the vast majority of cases reproductive toxicology has not been proven in women exposed in the workplace, we prefer to include only cases where such evidence is unequivocal. Every case in which a woman experiences clinical symptoms or signs that may be associated with chemical exposure should be investigated in depth. The nature and conditions of the work should be looked into, including ventilation and means of protection, and it should be determined whether a similar clinical picture exists in fellow workers. If the clinical picture is consistent with the chemical(s) in question, exposure levels must be defined. We often find that women are reluctant to induce such an investigation or even to ask for the installation of recent safety measures because they are afraid of retaliation by the employer. While there is no simple solution for such a situation, the counselor must explain to such women the seriousness of prolonged exposure. Many large plants have hygienists, safety officers, or physicians on the staff, and these health professionals should assist pregnant workers. Table 1 is an algorithm of suggested steps in analyzing the reproductive hazard associated with chemicals to which women receive occupational exposure. DEFINITIONS The following definitions of workplace standards are commonly employed in discussing occupational standards: PEL ⫽ permissible exposure limit set by the U.S. Occupational Safety and Health Administration (OSHA).

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TLV ⫽ threshold limit value set by the American Conference of Governmental Industrial Hygienists (ACGIH). REL ⫽ recommended exposure limit set by the U.S. National Institute for Occupational Safety and Health (NIOSH). (PEL, TLV and REL refer to the airborne concentrations of a substance and represent conditions under which it is believed that nearly all workers may be repeatedly exposed, day after day, without adverse effects.) TWA ⫽ time-weighted average concentration for a normal 8-hour work day and a 40-hour work week to which nearly all workers may be repeatedly exposed, day after day, without adverse effects (NIOSH refers to a 10-hour work day). Usually the values above are expressed as TLV-TWA, PEL-TWA, or REL-TWA. STEL ⫽ short-term exposure limit, set by the ACGIH. It refers to the maximum concentration to which workers can be exposed for up to 15 minutes continuously provided that no more than four excursions per day are permitted, but with at least 60 minutes between exposure periods and provided the daily TLV-TWA is not exceeded. IDLH ⫽ immediately dangerous to life or health, a concentration set by the standards completion program of the (U.S.) National Institute of Occupational Safety and Health (NIOSH), in conjunction with OSHA. Represents the maximum concentration from which (in the event of respirator failure), one could escape within 30 minutes without a respirator and without experiencing any escapeimpairing symptoms or irreversible health effects. Ceiling ⫽ the concentration that should not be exceeded even for an instant. The exposure limits are given in parts per million (ppm) or parts per billion (ppb), or as milligrams per cubic meter (mg/m3). The following formula converts these units: mg/m3 ⫽

ppm ⫻ molecular weight 24.5

It should be noted that all these workplace standards are meant to protect the adult worker; it is unknown whether they also protect the fetus. Therefore, in counseling the occupationally exposed pregnant woman, the availability of airborne concentrations may be useful mainly in two extreme situations: 1. Concentrations close to or below detectable level, in the absence of adverse effects, may suggest low fetal risk. 2. Concentrations higher than TLV(or PEL)-TWA may suggest that the fetus is at risk; the higher the concentration, the larger the possible risk. This approach needs to be validated by controlled studies.

INTERPRETATION OF ANIMAL STUDIES WHEN NO INFORMATION ON PATIENTS EXISTS For most of the chemicals in question, no epidemiological studies exist. In this case animal studies should not be ignored; rather, they should be continuously interpreted. Parameters that may be of help in this process include molecular similarity of the toxin to a known teratogen, dose, relationship between dose and workplace standards and the ‘‘no observ-

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able adverse effect level’’ (NOAEL), route of administration, duration of exposure, gestational age at exposure, species and number of species studied, type of birth defect induced and its incidence, and the greater sensitivity of humans to most developmental toxins.

SUMMARY OF HUMAN DATA The following short statement summarizes published human data on chemicals about which we have been consulted most frequently by pregnant women. Animal studies and chemicals infrequently cited are not included.

Anesthetic Gases There is no evidence to date that a single course of general anesthesia in early pregnancy is capable of inducing teratogenicity. A large prospective study has shown the safety of nitrous oxide (1). Similarly, thiopental, enflurane, and halothane were not shown to cause untoward embryonic or fetal effects (2). Increased rate of miscarriage among operating room personnel was observed in some studies (3–5). However, methodological problems, mainly response bias, preclude any firm conclusions from their results (6). Reduced fertility was found among female dental assistants exposed to high levels of unscavenged nitrous oxide (7). Another study from the same group demonstrated a relative risk of spontaneous abortion of 2.6 (95% CI, 1.3–5.0) associated with exposure of female dental personnel to unscavenged nitrous oxide (8). Most epidemiological studies do not suggest that congenital anomalies occur more often than expected among children of women with occupational exposure to volatile anesthetics during pregnancy. No consistent difference has been observed in the types of patterns of congenital anomalies found in children born to these women when compared with controls (9). Workplace standards (nitrous oxide): TLV-TWA, 50 ppm; REL-TWA, 25 ppm. Every effort should be made to minimize chronic exposure to nitrous oxide. Biomonitoring parameters: complete blood count.

Cadmium There is inconclusive evidence for the adverse effect of cadmium on male fertility (10,11). Cadmium-metallothionein mobilized from the liver has been speculated to be the etiologic agent in pre-eclampsia, as the symptoms of cadmium toxicity resemble those of toxemia of pregnancy (12). In smokers, placental levels were higher (13), and this metal may accumulate in the fetus (14). It may impair placental function by displacing zinc, thereby reducing birth weight (15). However, an association between placental cadmium and birthweight was not found in another study (16). In the presence of placental calcifications, birthweight decreased with increasing cadmium hair levels, especially if it was at least 0.3 ppm (17). Teratogenic effects were not reported in exposed populations (18). Adverse reproductive effects may include low birth weight (19), fewer full-term deliveries, fewer multiple pregnancies, lower birth weight in preterm infants (20), and poorer performance on intellectual and motor skills tests at 6 years of age (21). Cadmium in combination with other heavy metals may have mutagenic effects, but evidence that cadmium alone has

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cytogenetic effects is as yet unconvincing (22–25). Cadmium may be regarded as a potential workplace carcinogen. Workplace standards: TLV-TWA, total dust, as Cd, 0.01 mg/m3; respirable fraction 0.002 mg/m3. Biomonitoring parameters: blood cadmium levels (normal levels differ between smokers and nonsmokers), urinary cadmium-spot or 24-hour collection, urinary metallothionein, and N-acetylglucosaminidase.

Carbon Monoxide (CO), Including Methylene Chloride CO readily crosses the placenta and is eliminated from the fetal circulation more slowly than from the maternal circulation (26). CO poisoning may result in fetal death, stillbirth, or severe neurological deficits (27–29). However, toxicity of this sort has been seen most often in symptomatic maternal poisoning (30). Mild chronic exposure from the second to the seventh month of gestation was associated with multiple fetal anomalies (31). It seems that the fetus is more susceptible than the mother to CO, and some authors believe that there is no margin of safety for CO exposure to the fetus (32). The risk to the fetus from chronic low level exposure is not well documented, and it was suggested that it may pose a risk to the fetus comparable to that from smoking in the mother (33). Methylene chloride is partially metabolized to CO (25–33%) and may induce CO toxicity. A possible increase in risk for spontaneous abortions was suggested but other solvents were also involved (34,35). The U.S. Environmental Protection Agency (EPA) regards this substance as having ‘‘minimal teratogenic potential’’ (36). Concern was raised that occupational exposure to methylene chloride may reduce sperm concentrations (37). For further discussion of methylene chloride, see ‘‘Organic Solvents,’’ below. Methylene chloride is a suspected animal carcinogen. Workplace standards: TLV-TWA, 25 ppm for CO; PEL-TWA for methylene chloride, 25 ppm. Biomonitoring parameters: carboxyhemoglobin (may differ between nonsmokers and smokers). Levels do not necessarily correlate with toxicity.

Cholinesterase Inhibitors Organophosphates and carbamates are irreversible and reversible cholinesterase inhibitors, respectively. The potential of these pesticides to induce human developmental toxicity is unknown. Rodent studies are of concern, but they involve high doses that are unlikely to be encountered by pregnant women. Several case reports and poorly documented studies described malformations after high acute exposures to organophosphate (38–41) but not in others (42–44). In one case report, a suicide attempt with carbofuran (a carbamate insecticide) resulted in fetal death (45). Workplace standards: TLV-TWA, 0.1 mg/m3 for parathion. Biomonitoring parameters: erythrocyte (true) acetylcholinesterase, plasma (pseudo) butirylcholinesterase.

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Dibromochloropropane Occupational exposure to the agricultural nematocide dibromochloropropane has been associated in men with elevated serum gonadotropins, decreased sperm counts, and infertility (46,47). The duration of the exposure may be related to the severity and reversibility of the injury (48–50). A higher percentage of female infants was found after paternal exposure (51,52) but not miscarriages and malformations (53). No chromosomal abnormalities were found in offspring of exposed men (54). Nondisjunction was found in exposed workmen (55). Increased incidence of the frequency of Y chromosomes was not observed in women exposed to dibromochloropropane (46). OSHA determined that this agent may increase the risk of cancer. Workplace standards: TLV, PEL, not listed. Biomonitoring parameters: sperm count, serum testosterone, follicle-stimulating hormone, luteinizing hormone as well as liver and kidney function tests. Epichlorhydrin Several studies showed epichlorhydrin to be mutagenic in workers; the exposure level in one of these studies was 0.13–1.3 ppm (56,57). However, chromosomal aberrations in lymphocytes were not found in another study involving occupational exposure (58). Epichlorhydrin is a testicular toxicant in animals (59) and is a metabolite of dibromochloropropane, which is also a known testicular toxicant in humans and animals (46,47). An unpublished report of the Shell Oil Company claims no decrease in sperm count or hormonal activity among exposed workers, but no details are available (60). Epichlorhydrin is a suspected human carcinogen. Workplace standards: TLV-TWA, 0.5 ppm. Biomonitoring parameters: liver and kidney function tests. Ethylene Dibromide (Dibromomethane) Agricultural workers exposed to ethylene dibromide had reduced sperm concentrations and lower percentage of normal cells (61,62). In one study, mean exposure levels were estimated at 88 ppb with peak levels of 262 ppb (61). In the other study marijuana use was more prevalent in the exposed group (62). There was no effect of ethylene bromide on fertility in wives of exposed workers in three chemical plants in southern United States; however, fertility was significantly reduced at the fourth plant (63). Exposure levels in all plants was ⬍5 ppm. The American Medical Association (AMA) concluded that as of 1980, there was no conclusive human evidence that this agent was a reproductive hazard (64). Ethylene dibromide is a suspected animal carcinogen. Workplace standards: no TLV-TWA; PEL-TWA, 20 ppm. Biomonitoring parameters: blood bromide levels, complete blood count, liver and kidney function tests. Ethylene Oxide Hospital workers exposed to 8-hour weighted mean ethylene oxide concentrations of 0.1– 0.5 ppm had a higher incidence of spontaneous abortions (65). However, the rate of miscar-

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riages among controls was lower than expected and not higher than the expected rate among exposed (7.7 vs. 12.7%, respectively). Similar findings, in addition to increased incidence of gynecological problems, were reported in another study (66). These two studies were criticized for their methodology. A case-control study did not confirm an association with spontaneous abortions and birth defects (67). No increased risk for spontaneous abortions was found with self-reported exposure in female veterinarians (68). Occupational exposure was demonstrated to increase frequency of sister chromatid exchange (69– 73). Ethylene oxide is a suspected human carcinogen. Workplace standards: TLV-TWA, 1 ppm. Biomonitoring parameters: chest x-ray. Formaldehyde No increase in birth defects or spontaneous abortions was observed in women hospital workers occupationally exposed to formaldehyde (65,67). In contrast, an association with miscarriages was suggested in cosmetologists and laboratory workers (74,75). The latter study did not show an increase in birth defects. A Soviet study reported excess menstrual disorders and low-birth-weight infants, but the women involved had done heavy lifting and the study had methodological problems (76). Formaldehyde is a suspected human carcinogen. Workplace standards: TLV-TWA, not found; TLV-ceiling, 0.3 ppm; PEL-TWA, 1 ppm; REL-TWA, 0.016 ppm. Biomonitoring parameters: urine formate; but the use of this agent for biological monitoring is questionable because of large normal variation. Glutaraldehyde Miscarriage rate adjusted for possible risk factors was not found to be increased in a questionnaire study of women undergoing surgical sterilization in hospitals (65). Workplace standards: TLV-ceiling, 0.2 ppm; intended change 0.05 ppm; PELTWA, not listed. Biomonitoring parameters: liver and kidney function tests, chest x-ray, and pulmonary function tests, especially when respiratory tract irritation presents. Halogenated Hydrocarbon Solvents The reader is also referred to the discussion of organic solvents, below (see also Chapter 28). Chloroprene Soviet studies have suggested that chloroprene may induce menstrual disorders, decreased sperm motility, and changes in sperm morphology. It seems that high doses are more toxic to the testes, but the effect of near-TLV concentrations is unclear. A threefold increase in abortion rate was reported in wives of workers exposed to 0.3–1.9 ppm, but the significance of this finding is unclear (77). A French study quoted in a NIOSH document observed impotence and reduced libido during overexposure to chloroprene which disap-

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peared after removal from exposure (78). There is limited evidence that this agent may be mutagenic in humans (77). Workplace standards: TLV-TWA, 10 ppm. Biomonitoring parameters: liver function tests; chest x-ray in overexposure. Chloroform (see also Organic Solvents, Chapter 29) Chloroform crosses the human placenta (79). In 492 laboratory workers with first-trimester exposure to organic solvents, including chloroform, there was no increased frequency of congenital anomalies (80). A more recent study supports this finding (75). Higher frequencies of acquired chromosomal aberrations were observed in women occupationally exposed to organic solvents, including chloroform, and in the children of these exposed women (81). Chloroform is a potential human carcinogen. Workplace standards: TLV-TWA, 10 ppm. Biomonitoring parameters: liver and kidney function tests. Hexachlorophene Hexachlorophene was detectable in maternal and cord blood of this bactericidal agent after vaginal use during labor (82). Occupational exposure of women medical personnel during hand washing was suggested to increase the frequency of a heterogeneous group of congenital malformations (83). However, this study was criticized for its methodology, and a more comprehensive and careful epidemiological study could not confirm this association (84). A similar conclusion was achieved in a case control study of children with various anomalies (85). Maternal occupational exposure to hexachlorophene or phenylphenol during the sixth to ninth months of pregnancy was possibly associated with mental retardation, odds ratio 3.1, 90% CI 1.0–9.7 (86). The AMA Council on Scientific Affairs concluded that pregnant women should not use hexachlorophene-containing products (87). Workplace standards: TLV-, PEL-, or REL-TWA, not listed. Biomonitoring parameters: blood hexachlorophene levels; but correlation with clinical effects is not good. Tetrachloroethylene (see also Organic Solvents, Chapter 29) Women of reproductive age who work in dry-cleaning facilities may receive substantial exposure to tetrachloroethylene, since environmental air levels may range between 200 and 4000 mg/mL (30–540 ppm). Sperm from exposed dry-cleaning workers were found to be round, which is believed to be a mark of infertility (88). Wives of dry-cleaning workers required longer periods of time to become pregnant, but they did not have fewer pregnancies or increased spontaneous abortions (89). A case-control study of laundry and dry cleaner workers suggested high exposure to tetrachloroethylene be associated with increased risk of spontaneous abortions, odds ratio 3.4, 95% CI 1.0–11.2 (90). Other epidemiological studies could not find such an association (91,92). The frequency of malformations was no greater than expected (90,93). Although limited epidemiological studies suggest that tetrachloroethylene may induce liver cancer, the data are not satisfactory to reach a definite conclusion on its carcinogenicity in humans (94). Workplace standards: TLV-TWA, 25 ppm. Biomonitoring parameters: blood and expired air levels, liver and kidney function tests, urinalysis, urinary trichloroacetic acid and thioether. Trichloroethylene (see also Organic Solvents, Chapter 29) Trichloroethylene has been reported to cross the placenta (95). Controversy exists whether

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trichloroethylene can cause spontaneous abortions (96,97). Methodological problems limit interpretation of the results. An increased incidence of congenital heart disease among offspring of mothers with first-trimester exposure to contaminated groundwater was reported, but a direct cause-and-effect relationship has not been established (98). Another study did not find such an association (99). Although trichloroethylene may be carcinogenic in animals, this effect has not been clearly found in humans (100). Workplace standards: TLV-TWA, 50 ppm. Biomonitoring parameters: blood and breath levels, renal and liver function tests. Lead For a detailed discussion the reader is referred to Chapter 29. Lead crosses the placenta (101) and accumulates in the fetus (102). It may induce abortions and prematurity (103,104). A dose-related association with minor malformations has been suggested (105). Children with cord blood lead levels exceeding 10 µg/dL scored lower on developmental tests (106). Lead was shown to cause infertility in exposed men (107) and possibly chromosomal aberrations (108). The latter association is still unclear. Workplace standards: TLV-TWA, 0.05 mg/m3; REL-TWA, 0.1 mg/m3; action level, 0.03 mg/m3. Biomonitoring parameters: blood lead levels (if employee’s level ⱖ40 µg/dL or ⱖ30 µg/dL if he or she intends to have children, removal from exposure should be considered), erythrocyte protoporphyrin, and the lead mobilization test may be used to assess total body burden, especially if blood levels are borderline. Mercury Elemental (Metallic) Mercury Occupational male exposure was reported to induce impotence and decreased libido (109) but not infertility (110). Paternal exposure to mercury, confirmed by urinary levels, was suggested to be associated with spontaneous abortions (111). Menstrual disorders were reported in several studies (112,113), as well as infertility (114). Mercury crosses the placenta, and fetal blood levels may be comparable or even higher than maternal level (115–118). No increase in spontaneous abortions was found in female dental assistants exposed to mercury (119,120). Although other authors report more spontaneous abortions (average exposure level 0.08 mg/m3), it is difficult to separate the effects of other occupational exposures from those of mercury (121,122). There are positive (123) and negative (120,124,125) reports on the ability of metallic mercury to induce birth defects, especially neurological. Higher cord blood mercury concentrations were associated with slightly decreased performance on neurobehavioral tests in a study of 917 7-year-old children (126). Fetal and newborn toxic mercury level was estimated to be 3 µg/g (127). Since daily uptake of mercury from dental amalgam is low (2–5 µg), it was suggested that restriction of amalgam therapy in pregnant women is unwarranted (128). In a study of sheep, mercury was shown to be released from maternal dental amalgam fillings and to be transferred to the fetus. Although no toxic effects were found, these authors recommended avoidance of the use of dental amalgams containing mercury (129).

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Workplace standards: TLV-TWA, 0.025 mg/m3; REL-TWA, 0.05 mg/m3; suggested guideline in pregnancy, 0.01 mg/m3. Biomonitoring parameters: blood levels, preshift urine collection, kidney function tests, nerve conduction velocities. Inorganic Mercury This metal may cross the placenta (130) and affect central nervous system (CNS) development (131). However, a specific embryopathy has not been reported. Indoor exposure to mercury-containing latex paint was shown to result in an increased urine mercury level (132). Workplace standards: TLV-TWA, 0.025 mg/m3; REL-TWA, 0.05 mg/m3. Biomonitoring parameters: as for elemental mercury. Organic Mercury Pregnant women treated with mercurials had a higher incidence of spontaneous abortions (133). Methyl mercury may accumulate in the fetus. This is suggested by higher blood mercury level found in infants born to mothers exposed to methyl mercury in contaminated bread (134). Two epidemics of cerebral palsy, microcephaly, and psychomotor retardation were reported after in utero exposure to methyl mercury in Japan (contaminated fish) and Iraq (bread made of contaminated grain) (135–138). Workplace standards: TLV-TWA, alkyl compounds, 0.01 mg/m3. Biomonitoring parameters: as for elemental mercury, hair analysis. Organic Solvents For more detailed discussion, the reader is referred to Chapter 28. Because of the complexity and diversity of exposure to organic solvents, adequate epidemiological studies are difficult to conduct and interpret. Several studies suggest these agents to be associated with spontaneous abortions (139–143), especially the aliphatic hydrocarbons (144). Other studies could not confirm this association (145,146). The uncertainty is even larger when congenital malformations are considered (147–150). Workplace standards: TWA, according to the agents involved. Biomonitoring parameters: according to the agents involved. Organochlorine Insecticides Endosulfan, Dieldrin, Chlordane No occupational reproductive information is available. Lindane At least 10% can be absorbed through human skin (151). Lindane crosses the human placenta (152), and fetal levels are comparable to maternal level (153,154). This insecticide may induce menstrual disorders, infertility (155), excess blood loss after delivery, and lower birth weights (156). Although anecdotal reports found higher placenta, fetal, and maternal blood lindane levels in cases of spontaneous abortions and premature deliveries (156,157), other studies could not find a relationship between lindane levels and stillbirth (158) or other pathological conditions of pregnancy (159). Lower levels of testosterone

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and other sex hormones (160) and reversible oligospermia and high ratio of dead sperm (161) were reported in males occupationally exposed to lindane. Workplace standards: TLV-TWA, 0.5 mg/m3. Biomonitoring parameters: serum levels may be useful in documenting acute toxicity. DDT DDT can cross the human placenta at term (162,163). It is unclear whether the insecticide can induce pregnancy complications in humans (152,164–167). Although chlorinated hydrocarbons were found in seminal fluid and cervical mucus of infertility patients (167), their role in reproductive problems is uncertain. The EPA banned the use of DDT because it is stored indefinitely in human tissue. Workplace standards: TLV-TWA, 1 mg/m3. Biomonitoring parameters: serum levels may reflect cumulative exposure. Heptachlor No increase in the incidence of birth defects was observed in Hawaii in infants exposed in utero to milk contaminated with heptachlor (168). The exposure could not be quantitated in either the study or the control group. After similar incidents in Arkansas, Missouri, and Oklahoma, one report on a neonate who developed gliosarcoma was noted, but heptachlor could not be established as the primary oncogen (169). This agent may be mutagenic in human fibroblasts (170). Workplace standards: TLV-TWA, 0.05 mg/m3. Phenol No clear association with birth defects was found in women occupationally exposed to phenol among other disinfectants (85). Phenol may induce methemoglobinemia, especially in infants. Based on this possibility, it was suggested in one review that phenol may affect the human fetus (171). Workplace standards: TLV-TWA, 5 ppm. Biomonitoring parameters: blood and urine free phenol or conjugated phenol, methemoglobin determination during or at end of shift, nonspecific. Polychlorinated Biphenyls (PCBs) and Polybrominated Biphenyls (PBBs) In the Yusho epidemic in Japan (1968), pregnant women were exposed to rice oil contaminated with PCBs. The following adverse pregnancy outcomes were reported: stillbirth; gray-brown discoloration of skin, gingiva, and nails (cola-colored babies); parchment-like skin with desquamation; exophthalmos; teeth present at birth; conjunctivitis; and low birth weight (172–177). Skin discoloration slowly disappeared after birth, and normal weight was gained afterward (174–177). Persistent signs included recurrent acne and nail pigmentation (178). In a similar epidemic in Taiwan (1979), children exposed in utero had developmental delay in addition to the foregoing abnormalities (179). No association could be demonstrated between cord blood, placenta, and milk PCB levels and birth weight or head

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circumference (180). Children exposed in these epidemics also scored lower than controls on developmental tests, especially those who had low birth weight and were more severely affected (181). It seems that males were more susceptible to the teratogenic effects of PCBs (172). Small head circumference and low birth weight were found in offspring of women exposed to PCB-contaminated fish in the Great Lakes (182). The children exposed in the Great Lakes region of the United States also had small but significant impairment in short-term memory (183). Workplace exposure was also associated with low birth weight as well as shorter gestation (184). PCBs are considered to be potential human carcinogens (185). Thirty-three farm children exposed in utero or in early pregnancy to PBBs were normal in growth and in results of physical examination and neurological assessment at the age of 37 months (186). Workplace standards: TLV-TWA: 42% chlorine, 1 mg/m3 (skin notation); 54% chlorine, 0.5 mg/m3 (skin notation). Biomonitoring parameters: PCBs can be measured in blood, urine, milk, and adipose tissues. One should consider background levels. Styrene The reader is also referred to the discussion of organic solvents in Chapter 29. Two studies from the former Soviet Union showed low concentrations of styrene to be associated with menstrual disorders (187,188). However, a large American study on women exposed to styrene in reinforced plastics companies failed to show this association (189). Styrene has been shown to cross the human placenta (79). In a study on 2209 workers (511 females), again in the reinforced plastics industry, no increase in birth defects was found (190). Chronic occupational exposures to styrene have sometimes been associated with chromosomal damage in germ cells and lymphocytes (191–193). Workplace standards: TLV-TWA, 50 ppm. Biomonitoring parameters: urinary mandelic acid; other possible tests include phenylglyoxylic acid in urine and blood styrene level. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, Dioxins) There was no increase in malformations following the Seveso dioxin accident (194). Another study suggesting that TCDD may have induced malformations and embryopathy in this accident (195) was shown to have methodological problems that invalidated its finding (196). Offspring of Vietnam veterans exposed to Agent Orange (about 50% 2,4,5-trichlorophenoxyacetic acid contaminated by TCDD) were not found to have increased incidence of malformations (197,198). The data of these studies could not address questions regarding association with defects of rare types or defects in offspring of selected groups of veterans. A study involving 370 men occupationally exposed to TCDD and other dioxins in a Michigan plant did not reveal adverse reproductive outcome (199). TCDD is a potential human carcinogen. Workplace standards: TLV-TWA, not listed. Biomonitoring parameters: liver and kidney function tests, complete blood count, serum lipids, prothrombin time, uroporphyrins, fat biopsies.

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Vinyl Chloride (Chloroethylene) Impotence and loss of libido were reported by men occupationally exposed to high levels of vinyl chloride monomer (200,201). Increased rate of miscarriages was found in wives of male vinyl chloride workers (202). This study was criticized for its methodology of data collection and response bias (203,204). Later studies could not demonstrate such an association (205–207). Although several studies suggested an association between congenital anomalies (especially CNS) and the presence in the community of vinyl chloride industries (208–210), these reports should be considered to be inconclusive. The presence of other pollutants and personal factors were not controlled (211), and there was no relation between parental occupation in a vinyl chloride plant and congenital anomalies in the offspring (210,212). Mutagenicity studies on exposed workers are controversial, but it seems that chromosomal aberrations may be related to duration and extent of exposure, especially if greater than 20 ppm (213). Vinyl chloride is a human carcinogen. Workplace standards: TLV-TWA, 5 ppm; PEL-TWA, not listed. Biomonitoring parameters: liver and kidney function tests; complete blood count; other tests may include urinary thiodiglycolic acid and uroporphyrins, as well as pulmonary function tests after exposure to dust.

Radiation For a detailed discussion on the effects of ionizing and nonionizing radiation and video display terminals on pregnancy, the reader is referred to Chapter 32. Clinical Case Answer Her lead level (5 µg/dL) is below any known teratogenic concentration. REFERENCES 1. Crawford JS, Lewis M. Nitrous oxide in early human pregnancy. Anaesthesia 1986; 41:900– 905. 2. Heinonen OP, Slone D, Shapiro S. Birth Defect and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977. 3. Ferstanding LL. Trace concentration of anesthetic gases. Acta Anesth Scand 1982; 75(suppl): 38–43. 4. Tannenbaum TN, Goldberg RJ. Exposure to anesthetic gases and reproductive outcome: a review of the epidemiologic literature. J Occup Med 1985; 27:659–668. 5. Spence AA. Chronic exposure to trace concentration of anaesthetics. In: Gray TC, Nunn JS, Utting JE, eds. General Anaesthesia, 4th ed. London: Butterworth, 1980, pp 189–201. 6. Axelsson G, Rylander R. Exposure to anaesthetic gases and spontaneous abortion: response bias in a postal questionnaire study. Int J Epidemiol 1982; 11:250–256. 7. Rowland AS, Baird DD, Weinberg CR, et al. Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med 1992; 327:993–997. 8. Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol 1995; 141:531–538. 9. Friedman JM. Teratogen update: anesthetic agents. Teratology 1988; 37:69–77. 10. Schray SD, Dixon RL. Occupational exposures associated with male reproductive dysfunction. Annu Rev Pharmacol Toxicol 1985; 25:567–592.

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171. Kuntz WD. The pregnant woman in industry. Am J Ind Hyg Assoc 1976; 37:423–426. 172. Kuratsure M, Yoshimura Y, Matsuzaka J, Yamagushi A. Epidemiologic study on Yusho, a poisoning caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyls. Environ Health Perspect 1972; 1:119–128. 173. Miller RW. Congenital PCB poisoning: a reevaluation. Environ Health Perspect 1985; 60: 211–214. 174. Kodama H, Ota H. Studies on the transfer of PCB to infants from their mothers. Jpn J Hyg 1977; 32:567–573. 175. Funatsu I, Yamashita F, Ito Y, et al. Polychlorobiphenyls (PCB) induced fetopathy: 1. Clinical observation. Kurume Med J 1972; 19:43–51. 176. Taki I, Hisanaga S, Amagase Y. Report on Yusho (chlorobiphenyls poisoning) in pregnant women and their fetuses. Fukuoko Acta Med 1969; 60:471–474. 177. Yamashita F. Clinical features of polychlorobiphenyls (PCB)-induced fetopathy. Paediatrician 1977; 6:20–27. 178. Gladen BC, Taylor JS, Wu YC, Ragan NB, Rogan WJ, Hsu CC. Dermatological findings in children exposed transplacentally to heat-degraded polychlorinated biphenyls in Taiwan. Br J Dermatol 1990; 122:799–808. 179. Rogan WJ, Gladen BC, Hung KL, et al. Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 1988; 241:334–336. 180. Rogan WJ, Gladen BC, McKinaly JD, et al. Neonatal effects of transplacental exposure to PCBs and DDE. J Pediatr 1986; 109:335–341. 181. Yu M, Hsu C, Gladen BC, Rogan WJ. In utero PCB/PCDF exposure: relation of developmental delay to dysmorphology and dose. Neurotoxicol Teratol 1991; 13:195–202. 182. Fein GG, Jacobson JL, Jacobson SW, Schwartz PM, Dowler JK. Prenatal exposure to polychlorinated biphenyls effects on birth size and gestational age. J Pediatr 1984; 105:315– 320. 183. Jacobson JL, Jacobson SW, Humphrey HEB. Effects of in utero exposure to polychlorinated biphenyls and related contaminants and cognitive functioning in young children. J Pediatr 1990; 116:38–45. 184. Taylor PR, Lawrence CE, Hwang HL, Paulson AS. Polychlorobiphenyls’ influence on birthweight and gestation. Am J Public Health 1984; 74:1153–1154. 185. Letz G. The toxicology of PCBs—an overview for clinicians. West J Med 1983; 138:534– 540. 186. Weil WB, Spencer M, Benjamin D, Seagull E. The effect of polybrominated biphenyl on infants and young children. J Pediatr 1981; 98:47–51. 187. Pokrovskii VA. Gig Prof Zabol 1967; 11:17–20. Quoted in Styrene Monograph, Reprotext Information System. Denver: Micromedex, 1992. 188. Zlobina NS, Izyumora AS, Ragule NY. The effect of low styrene concentrations on the specific functions of the female organism. Gig Tr Prof Zabol 1975; 12:21–25. 189. Lemasters GK, Hagen A, Samuels SJ. Reproductive outcomes in women exposed to solvents in 36 reinforced plastics companies: I. Menstrual dysfunction. J Occup Med 1985; 27:490– 494. 190. Harkonen H, Tola S, Korkala ML, Hernberg S. Congenital malformations, mortality and styrene exposure. Ann Acad Med Singaport 1984; 13(suppl 2):404–407. 191. Meretoja T, Vainio H, Sorsa M, Harkonen H. Occupational styrene exposure and chromosomal aberrations. Mutat Res 1977; 56:193–197. 192. Meretoja T, Jarventaus H, Sorsa M, Vainio H. Chromosome aberrations in lymphocytes of workers exposed to styrene. Scand J Work Environ Health 1978; 4(suppl 2):259–264. 193. Nordenson I, Beckmann L. Chromosomal aberrations in lymphocytes of workers exposed to low levels of styrene. Hum Hered 1984; 34:178–182. 194. Mastroiacovo P, Spagrolo A, Marni E, Meazza L, Bertollini R, Segni G. Birth defects in the Seveso area after TCDD contamination. JAMA 1988; 259:1668–1672.

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195. Tognoi G, Bonaccarsi A. Epidemiological problems with TCDD (a critical review). Drug Metab Rev 1982; 13:447-M9. 196. Friedman JM. Does agent orange cause birth defects? Teratology 1984; 29:193–221. 197. Donovan JW, MacLennan R, Adena M. Vietnam service and the risk of congenital anomalies: a case-control study. Med J Aust 1984; 140:394–397. 198. Erickson JD, Mulinare J, McClaim PW, et al. Vietnam veterans’ risk for fathering babies with birth defects. JAMA 1984; 252:903–912. 199. Townsend JD, Bodner KM, Van Peenen PFD, Olson RD, Cook RR. Survey of reproductive events of wives of employees exposed to chlorinated dioxins. Am J Epidemiol 1982; 115: 695–713. 200. Walker AE. A preliminary report of a vascular abnormality occurring in men engaged in the manufacture of polyvinyl chloride. Br J Dermatol 1975; 93:22–23. 201. Walker AE. Clinical aspects of vinyl chloride disease: skin. Proc R Soc Med 1976; 69:286– 289. 202. Infante PF, McNhchael AJ, Wagoner JK, Waxweiler RJ, Falk H. Genetic risks of vinyl chloride. Lancet 1976; 1:734–735. 203. Buffer PA. Some problems involved in recognizing teratogens used in industry. Contrib Epidemiol Biostat 1979; 1:118–137. 204. Paddle GM. Genetic risks of vinyl chloride. Lancet 1976; 1:1079. 205. Sanotsky IV, Davtian RM, Glushchenko VI. Study of the reproductive function in men exposed to chemicals. Gig Tr Prof Zabol 1980; 5:28–32. 206. Lindbohm M, Hemminki K, Kyyronen P. Spontaneous abortions among women employed in the plastics industry. Am J Ind Med 1985; 8:579–586. 207. Mur JM, Manderean L, Deplan F, Paris A, Richard A, Hemon D. Spontaneous abortion and exposure to vinyl chloride. Lancet 1992; 339:127–128. 208. Infante PF. Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann NY Acad Sci 1976; 271:49–57. 209. Edmonds LD, Falk H, Nissim JE. Congenital malformations and vinyl chloride. Lancet 1975; 2:1098. 210. Edmonds LD, Anderson CE, Flynt JW, James LM. Congenital central nervous system malformations and vinyl chloride monomer exposure: a community study. Teratology 1978; 17: 137–142. 211. Hemminki K, Vineis P. Extrapolation of the evidence on teratogenicity of chemicals between humans and experimental animals: chemicals other than drugs. Teratogen Carcinog Mutagen 1985; 5:251–318. 212. Theriault G, Iturra H, Gingras S. Evaluation of the association between birth defects and exposure to ambient vinyl chloride. Teratology 1983; 27:359–370. 213. Vinyl chloride. In: Barlow SM, Sullivan FM, eds. Reproductive Hazards of Industrial Chemicals. London: Academic Press, 1982, pp 566–582.

28 The Common Occupational Exposures Encountered by Pregnant Women Yedidia Bentur Rambam Medical Center, Technion–Israel Institute of Technology, Haifa, Israel

Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A woman working in a word processing center was told by her girlfriend that exposure to video terminals may have adverse effects on fetal life. Your patient, who has just learned that she is pregnant, depends very much on this job, as her husband is unemployed.

INTRODUCTION It is clear from animal experiments and human epidemiological studies that industrial chemicals have the potential of being reproductive toxins. However, our knowledge of the reproductive toxicology of industrial chemicals in humans is sparse or absent. Before therapeutic agents are marketed, their teratogenic potential must be tested in animals; these data are not always required for chemicals. Other factors also may differ between medical and occupational exposures. In the workplace the exposure is usually to several chemicals, which may change between working days or even within a single day. In some cases one has to deal with possible unknown by-products. The amounts of the chemicals absorbed are often unclear, and the circumstances of exposure may vary from plant to plant or even within the same operation. Every chemical in the workplace has safety exposure limits aiming at protecting the worker. However, these standards were not designed to protect the fetus. Hence, even if one can obtain exposure levels, one is never sure whether safe levels to the mother are also safe for her unborn baby; lead is a good example of such a discrepancy (1,2). An interesting attempt to approach this problem is illustrated by a recent study that suggested 20 ppm as a pregnancy guidance value for occupational exposure to toluene (3). This choice was based on ‘‘no observable adverse effect level’’ (NOAEL)

Modified from the authors’ article in the American Journal of Obstetrics and Gynecology 1991; 165(2):429–437, with permission. 529

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of 500, 400, and 200 ppm in pregnant rabbits, rats, and mice and their offspring, respectively, and applying safety factors for interspecies and intraspecies variation. In approaching the occupationally exposed woman, the following steps are suggested: 1. Obtain medical, obstetric, and genetic history from the patient and her spouse, including the use of cigarettes, alcohol, and drugs. 2. Identify the chemicals in question, if possible, by their material safety data sheets (MSDS). 3. Obtain a detailed description of the process the patient is operating, the work she performs, the length of exposure, and the means of protection used (ventilation system, hood, respirator, mask, gown, gloves, etc.). 4. Obtain information on possible exposure from nearby work stations. 5. Identify symptoms and signs reported to be associated with the chemicals and temporal relationship to the exposure. 6. Rule out underlying conditions that may cause a similar clinical picture (e.g., morning sickness). 7. Determine whether there are symptoms and signs manifest in fellow workers. 8. Ascertain the pregnancy outcome in other workers. 9. Obtain occupational history of the spouse. 10. Obtain the most recent levels of the chemicals in question or radiation measured in that particular area and their relation to the recommended threshold limit value–time-weighted average (TLV-TWA). 11. Find out whether employees are being regularly examined by an occupational physician and whether biological monitoring is done (e.g., blood lead levels, urinary phenol excretion, blood count for benzene, hepatic aminotransferase for carbon tetrachloride). 12. Try to understand the attitude of the woman and her supervisors toward her particular work and toward a possible change of job. Will a change of job affect her income or chances for promotion? 13. Search as many data sources as possible and evaluate the data critically to allow the patient to receive the most accurate information. 14. Convey the information to the patient, estimate the risk (if possible), and advise about ways to assess severity of exposure (environmental and biological measurements) and on possible safety means to reduce exposure (ventilation, mask, gloves, etc.). The Motherisk Program in Toronto is an antenatal counseling service for health professionals, women, and their families dealing with exposures to drugs, chemicals, radiation, and infections in pregnancy and lactation. In 1990 between 40 and 50 telephone calls were processed daily. Women are referred to a clinic if they have been exposed to known or suspected teratogens, long-term drug therapy, new drugs on which there is sparse or no information, and drugs of abuse, or if they have experienced occupational exposure. After the expected day of confinement, follow-up of pregnancy outcome is performed, and all data are computerized for clinical and research use. In 1988, a total of 5040 telephone calls were received; 167 (3.3%) of them were due to occupational exposures to video display terminals (Table 1). This exposure is the one most frequently encountered in the workplace. Organic solvents were the concern of up to 150 of the callers, most of

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Table 1 Distribution of Telephone Consultations for Occupational Exposures in 1988 Exposure Number of consultations

Video display terminal

Organic solvents

Lead

Miscellaneous

167

56

6

13

5040

them entailing the use of oil-based paints, some of them at home. In 56 the exposure to organic solvents occurred in the workplace, and 24 of them were followed in the clinic (Table 2). In all, 29 patients were advised for exposure to lead (mostly in the form of paints); 6 were occupationally exposed, and 3 were seen in the clinic. The Drugs and Chemicals in Pregnancy Program in Haifa, Israel, was established in 1991 and is affiliated with the Israel Poison Information Center. Its objectives are similar to those of the Motherisk Program in Toronto; however, it is mainly oriented to poisoning, radiation, chemical, and occupational exposures in pregnancy. An important referring center is the Israel Teratological Counselling Service in Jerusalem. In addition to textbooks, the Drugs and Chemicals in Pregnancy Program uses several computerized databases including Drugdex, Poisindex, Hazardous Substances Data Bank, Registry of Toxic Effects of Chemical Substances, Reprotext, Reprotox, TERIS, Shepard’s Catalog of Teratogenic Agents—online, Canadian Centre for Occupational Health and Safety—CCINFO, Toxline, and Medline. The most common exposures in 1996 were organic solvents (25%), metals (17%), pesticides (7.5%), and ionizing radiation (7.5%). Most of the women occupationally exposed to organic solvents and all those exposed to ionizing radiation were laboratory technicians (academic or industrial). Those exposed to pesticides were involved in various agricultural tasks. Different distribution of occupations among women and lack of awareness to reports on the use of video display terminals in pregnancy may explain the different pattern of calls between the programs in the two countries. Table 2 Distribution of Occupational Exposures with Clinic Follow-Up in 1988

Organic solventsc Video display terminalsd Lead e Polychlorinated biphenyls Miscellaneousf a

Number of cases

Total clinic visits (%) a

Occupational exposures seen in clinic (%) b

24 5 3 2 5

6.3 1.3 0.8 0.5 1.3

66.6 13.8 8.3 5.5 13.8

A total of 380 patients were seen in the clinic. Thirty-six patients with occupational exposures were monitored in the clinic. c Two patients were exposed to organic solvents and lead. d Four patients came to the clinic because of drug exposure. e Two patients were exposed to lead and organic solvents. f Each patient was exposed to multiple chemicals; no organic solvents. b

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This chapter reviews the state of our knowledge on the reproductive hazards of these exposures and gives the clinician updated information with which to advise women.

EXPOSURES Video Display Terminals For discussion of this subject, the reader is referred to Chapter 32: ‘‘Ionizing and Nonionizing Radiation in Pregnancy.’’ Organic Solvents In our clinics, we often counsel women who are occupationally exposed to numerous chemicals, most of which are organic solvents. A proper consultation in such cases is extremely difficult, because it is hard to estimate the predominant chemicals and their byproducts. Even if one identifies the more toxic agents, it is still hard to assess the circumstances of exposure. For many chemicals one can measure neither airborne nor blood levels. Smelling the odor of organic solvents is not indicative of a significant exposure, because the olfactory nerve can detect levels as low as several parts per million, which are not necessarily associated with toxicity. For example, the odor threshold of toluene is 0.8 ppm, whereas TLV-TWA is 100 ppm. Finally, reproductive information on many solvents is at best sparse, either limited to animal studies or nonexistent. Organic solvents are a structurally diverse group of low-molecular-weight chemicals that are liquids and are able to dissolve other organic substances (4). They are ubiquitous in our industrialized society, both at work and at home, and they may be encountered as individual agents or in complex mixtures such as gasoline. Chemicals in the solvent class include aliphatic hydrocarbons (such as mineral spirits, varnish, and kerosene), aromatic hydrocarbons (benzene, toluene, xylene), halogenated hydrocarbons (carbon tetrachloride, trichloroethylene, methylcellosolve), aliphatic alcohols (acetone), glycols (ethylene glycol), and glycol ethers (methoxyethanol) (5,6). Fuels are mixtures of various hydrocarbons. The mechanisms by which many solvents exert their toxicity are unclear and may vary from one solvent to another. Halogenated hydrocarbons such as carbon tetrachloride may generate free radicals (4). Simple aromatic compounds such as benzene may disrupt polyribosomes (7), whereas some solvents are thought to affect lipid membranes and to penetrate tissues such as the brain. Incidental exposures may include vapors from gasoline, lighter fluid, spot removers, aerosol sprays, and paints (8). The short-duration, low-level exposures may go undetected. More serious exposures occur mainly in industrial or laboratory settings during such manufacturing and processing operations as dry cleaning, working with paint removers, thinners, floor and tile cleaners, and glues, and using laboratory reagents. Gasoline or glue sniffing, although not occurring in the occupational setting, is another source of exposure to organic solvents during pregnancy. Workers with short-term exposure to organic solvents experience fatigue, concentration disorder, feelings of drunkenness, dizziness, pneumonitis, and vomiting (5). Longterm exposure (e.g., to benzene) may irreversibly affect the central nervous system and liver and may cause blood disorders. Although the toxic effects of organic solvents are relatively well known in the adult, there is a paucity of information on the impact of in utero exposure.

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In 1988 the Motherisk patient population included 150 (2.9%) cases of telephone counseling and 24 clinical consultations dealing with organic solvents (Tables 1 and 2). Most of the occupationally exposed women were seen in the clinic, and most of them were involved in manufacturing, processing, and application of paints and glues. Others were machinists, laboratory technicians, and dry cleaners. It is beyond the scope of this chapter to review all the organic solvents, so we chose toluene as an illustrative example of exposure. This agent is used in a variety of mixtures and products. Also important, it is a common substance of abuse. Toluene is an aromatic hydrocarbon used as a solvent for paints, thinners, coatings, and glues (5). It is a popular replacement for the more chronically toxic benzene solvents. Most exposures involve inhalation; however, absorption is almost complete after oral administration (5). Toluene inhalation by pregnant rats induced decreased fetal weight and retardation of skeletal growth (9,10). No malformations were demonstrated in rats or mice after inhalation (10,11), but oral administration to mice induced cleft palate (12). Two other studies in rats showed exposure to 2000 ppm, but not to 600 ppm, to cause body weight suppression of dams and offspring, high fetal mortality, and embryonic growth retardation. No anomalies were observed. In one of these studies, exposure took place from 14 days before mating until day 7 of gestation (13,14). The male reproductive system was also affected when inhalation of 2000 ppm began 60 days before pairing (14). Fetal neuromotor abnormalities may be induced by inhalation of 800 mg/mL of toluene (more than twice the TLV-TWA) by pregnant rats (15). However, subcutaneous injection of toluene (1.2 g/kg) to rats did not result in behavioral changes (10). A study from 1977 compared pregnancy outcomes among 168 women occupationally exposed to varnishes containing toluene (55 ppm) with those of 201 control women (16). While there were twice as many low-birth-weight infants in the toluene-exposed group, the two groups did not differ with regard to fertility, course of pregnancy, perinatal mortality, or adverse effects in the newborn. Unfortunately, congenital defects were not evaluated. It was suggested that occupational exposure to aromatic solvents, mainly to toluene, may be associated with various birth defects, predominantly renal-urinary or gastrointestinal (17). Toluene-exposed shoe workers had a higher rate of spontaneous abortions: odds ratio 9.3, 95% confidence interval (CI) 1.0–84.7 (18). Chinese shoe workers exposed to toluene and benzene had a significantly higher rate of menstrual disorders and spontaneous abortions (19). Significant association with spontaneous abortions was found among women laboratory workers (odds ratio 4.7, 95% CI 1.4–15.9). No association was found with congenital anomalies (20). Abuse of large quantities of pure toluene by inhalation throughout pregnancy was reported to result in microcephaly, central nervous system (CNS) dysfunction, minor craniofacial anomalies, and variable growth deficiencies in three patients (21). These features resembled the pattern of malformations described in connection with exposure to alcohol or certain anticonvulsant medications and were named ‘‘fetal solvent syndrome.’’ Pearson et al. proposed a common mechanism of craniofacial teratogenesis for toluene and alcohol—namely, a deficiency of craniofacial neuroepithelium and mesodermal component due to embryonic cell death (22). More features of toluene embryopathy are discussed at the end of this section. Many organic solvents are teratogenic and embryotoxic in laboratory animals, depending on specific solvent, dose, route of administration, and animal species (4,7). Malformations described include hydrocephaly, exencephaly, skeletal defects, cardiovascular abnormalities, and blood changes. Other abnormalities include poor fetal development and neurodevelopmental deficits. In some of the studies exposure levels were high enough to induce maternal toxicity.

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Because of the complexity and diversity of organic solvents and because exposure usually involves more than one agent and different circumstances, adequate human epidemiological studies are difficult to conduct and interpret. In addition, studies are subjected to selection, recall and response bias and are not always controlled for other risk factors (age, smoking, etc.). Other confounders include small sample size, definition of exposure, insensitive measures of effect, and inability to analyze dose-response relationship. Isolated case reports suggesting that solvent-related embryopathy may occur in humans have appeared for many years. In one report, five of nine women who gave birth to infants with caudal regression syndrome had been exposed to solvents, including xylene, trichloroethylene, methylchloride, acetone, and gasoline (23). These agents do not belong to the same subgroup of organic solvents, and it is impossible to identify the potential culprit. Several epidemiological studies suggested association between adverse pregnancy outcome and exposure to organic solvents. Although these solvents may have common chemical features, there is no indication that they were teratogenic as a group or individually. These studies reported esophageal stenosis or atresia in babies of female laboratory workers (24), omphalocele or gastroschisis in offspring of mothers in the printing industry (25), and an association between increased risk of malformations and laboratory work in the pharmaceutical and paper industries (26,27). A Mexican study suggested that children of ex-workers of the same factory who were in direct contact with methyl cellosolve and ethylene glycol without protection had peculiar facies, mental retardation, and musculoskeletal and sensorial abnormalities (28). An experimental study supported this finding (28). Case control studies of central nervous system defects in Finland showed an association with organic solvents (29,30). However, when the study was extended for 3 more years, the authors could not prove this association (31). A study based on occupational titles in Denmark suggested that malformations of the CNS were related to fathers exposed to solvents and employed as painters (odds ratio 2.8 and 4.9, respectively) (32). A cumulative case referent study covering 3.5 years suggested an association of organic solvents with cleft palate (33). A case-control study comparing maternal exposure to any organic solvent between 200 infants with oral clefts and 400 controls estimated the odds ratio to be 1.62 (95% CI 1.04–2.52). Comparison of nine subgroups of solvents showed only the odds ratio associated with halogenated aliphatic solvents to be significant (4.40, 95% CI 1.41–16.15) (34). The prevalence of exposure to organic solvents at work during the first trimester was 10.4% among 569 mothers of children with cardiovascular malformation, compared with 7.8% in the control group (35). This retrospective study found an adjusted relative odds ratio of 1.3 for cardiovascular malformations and 1.5 for ventricular septal defects, both probably insignificant. In 1991 this group published assessments of risk factors for cardiovascular defects in general and ventricular septal defect (VSD) specifically in Finland and again found no significant association with exposure at work to organic solvents (36,37). Maternal alcohol consumption during the first trimester was more common among mothers of VSD infants than among controls (47 vs. 38%, respectively, p ⬍ 0.05) (37). A study from California could not demonstrate any difference in neurobehavioral development and growth between children exposed in utero to organic solvents and a group of matched, unexposed children (38). Another study published by the same group suggested an association between exposure to organic solvents and preeclampsia (39). No correlation was found between laboratory work and sister chromatid exchanges and micronuclei in 59 Canadian laboratory workers (40). There was, however, an association between such exchange and recent or past smoking.

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Spontaneous abortions were reported in 262 factory workers in Denmark; when this study was controlled for gravidity, however, there was no longer a statistically significant increased risk (41). No increased risk for miscarriage was found in university laboratory workers exposed to organic solvents (42). Conversely, shift work in these workers was related to a higher miscarriage rate (relative risk 3.2). This study did not demonstrate any differences in perinatal death rates or in the prevalence of malformations among women working with organic solvents when compared with controls. Spontaneous abortions were found among women exposed to organic solvents during their work in a hospital laboratory (43), in electronic plants (44,45), in photolithography areas in the semiconductor industry (46), and in microelectronic equipment assembly plants (47). In the latter study, the odds ratio of spontaneous abortions, which was 0.9 before the women began to assemble microelectronic components, increased to 5.6 after the commencement of this employment. However, many of these studies are limited by recall bias, small sample size, wide confidence intervals, and variable exposures, which in many cases are not quantitated. In this respect, it is interesting to mention Lindbohm’s study, which examined the rate of medically diagnosed spontaneous abortions among women occupationally exposed to at least one of six organic solvents (styrene, trichloroethylene, xylene, tetrachloroethylene, toluene and 1,1,1-trichloroethane) who were also biologically monitored (48). Reference values of hygiene standards were exceeded in 38% of styrene exposures and were reached in 15% of tetrachloroethylene exposures. The adjusted odds ratio of spontaneous abortions for solvent exposure was significantly increased (2.2, 95% CI 1.2–4.1), especially for exposure to aliphatic hydrocarbons (3.9, 95% CI 1.1–14.2), for graphics workers (5.5, 95% CI 1.3–20.8), and for toluene-exposed shoe workers (9.3, 95% CI 1.0–84.7). Confounding factors, again, are small sample size and multiple exposures in some cases. Association of spontaneous abortions with exposure to aliphatic hydrocarbons, but not with the use of solvents as a group, was also suggested in a large case-control study (49). Among 561 pregnancies in female workers at two semiconductor plants in the eastern United States, potential exposure to mixtures containing ethylene glycol ethers was associated with increased risks of spontaneous abortion (RR in the high exposure group 2.8, 95% CI 1.4–5.6). This risk exhibited a dose-response trend (50). In a case-referent study, the odds ratio of spontaneous abortions was increased by paternal exposure to several organic solvents, maternal exposure to organic solvents, and maternal heavy lifting (51). The cohort was too small to permit the evaluation of the effect of these parameters on congenital malformations. No effect of paternal exposure to ethylene glycol ethers on spontaneous abortions was found in another study (50). Reduced fertility was found among female workers in the semiconductor industry exposed to ethylene glycol ethers (odds ratio 4.6 in the high exposure group, 95% CI 1.6–13.3) and in various other industries (50,52). A discussion of organic solvents would be incomplete without mentioning the fetal solvent (or gasoline) syndrome. In 1979 a syndrome of anomalies (hypertonia, scaphocephaly, mental retardation, and other CNS effects) was suggested in two children in a small American Indian community where gasoline sniffing and alcohol abuse are common (53). Four other children had similar abnormalities, but in their cases it was impossible to verify gasoline sniffing. The contribution of the lead in the gasoline or the alcohol abuse in producing these abnormalities is unclear. In another case, a child with nearly classic fetal alcohol syndrome was born to a mother with major addiction to solvents, mainly toluene (54). Heavy alcohol consumption was also reported in that woman, and

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the authors questioned a possible interaction between solvents and alcohol. Toluene embryopathy was described in two additional children whose mothers probably did not abuse alcohol (55). Paint sniffing, namely toluene, resulted in severe renal tubular acidosis in five pregnant women (56). Fetal heart rate tracing and dynamic ultrasonographic examinations were normal in four of five. Three neonates exhibited growth retardation, and two had anomalies and hyperchloremic acidosis. Renal tubular acidosis was observed in more than half the women who abused toluene, especially in the long-duration abusers (57). This study showed that among 21 newborns exposed to toluene in utero, preterm delivery, perinatal death, and growth retardation were significantly increased. Developmental delay was a common finding in these children. Another study reported on two neonates with transient renal tubular dysfunction due to maternal toluene sniffing throughout the pregnancies. These infants were dysmature and had some dysmorphic features (58). A more recent publication described a premature newborn with renal tubular acidosis probably due to maternal sniffing of paint containing toluene (59). It is important to remember that the mothers in many of these cases showed signs of solvent toxicity, indicating heavy exposure. In our experience this is not the case in most occupational exposures during pregnancy. In summary, there is a relatively large number of studies suggesting that organic solvents may have the potential to induce spontaneous abortions (60,61). It appears also that congenital malformations cannot be excluded as a reproductive hazard. However, it is hard to prove or quantitate this suspicion, certainly not for solvents as a group. One may even expect that a ubiquitous exposure to solvents would by chance alone be associated with an increase in birth defects, which may differ from one study to another. While fetal toxicity is biologically sensible in cases of intoxicated mothers, the evidence of fetal damage from levels that are not toxic to the mother is scanty, inconsistent, or missing. Lead The third most common occupational exposure in pregnancy encountered by the Canadian investigators was lead. It accounted for 29 (0.6%) of the telephone consultations provided by the Motherisk Program during 1988. Three of them were followed up in the Motherisk Clinic (Tables 1 and 2). The vast majority of lead exposures involved artists using glass staining techniques or workers in the paint manufacturing sector of the automotive and aircraft industries. Other occupational sources of lead exposure during pregnancy reported in the literature include the printing, smeltering, and battery industries (62). Not only is lead an occupational hazard, it also can enter the body from contaminated soil and drinking water (63), by residence close to industrial areas or from a lead-exposed spouse (64,65), and by consumption of moonshine whisky (66). Other nonoccupational factors which were shown to be associated with increased maternal or cord blood levels include the use of lead-glazed pottery and canned food, low socioeconomic status and fall and winter (67,68). High milk intake and diets rich in calcium are associated with lower lead levels (67,68). Although it seems that blood lead levels in the United States are declining (69), including in cord blood (70), much lower levels are now being considered toxic than in the past [⬍10 µg/dL in children (71) and ⬍40 µg/dL in adults (72)]. Lead intoxication is still a hazard in the industrialized countries, and pregnant women are at risk. Lead crosses the placenta (73,74), possibly by both passive diffusion and active transport (74), and it is unclear whether placental permeability to lead is constant throughout gestation (73,75–77). Transplacental transfer of lead has been shown in the human

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fetus as early as 12–14 weeks of gestation, along with increasing amounts of lead in fetal tissues with advancing gestational age (78). Fetal bone and liver may have higher lead concentrations than maternal tissues (79). Calciotropic factors determine the uptake and storage of lead in the bone compartment. Thus, pregnancy-induced changes in calciumrelated regulatory factors may result in mobilization of lead from the bone to more bioavailable compartments in the mother and fetus (62,80). Iron deficiency may further increase the susceptibility to lead toxicity. During the late nineteenth and early twentieth centuries, women in the pottery and white lead industries used lead as an abortifacient (62). European studies from that time found infertility, abortion, stillbirth, fetal death, and microcephaly to be associated with industrial lead exposure (64,81–84). Even paternal lead exposure was found as early as 1860 to affect fertility and viability of the offspring (85). Wives of lead workers were reported to have more abortions, stillbirths, and premature births than women in the general population (64,86). Consequently, the employment of women in plants involving a lead hazard was forbidden (87). Although these studies should be evaluated with consideration of the high fetal and neonatal loss for other working women at that time (88), most of the studies from the nineteenth century and later, confirmed the early observations. For example, a study comparing the course and lead values in 249 pregnancies in Columbia, Missouri, with 253 occurring at the center of America’s lead belt at Rolla, Missouri, showed that 96% versus only 70% were delivered at term (89). In addition, 17% of the lead-exposed pregnancies had premature rupture of membranes, as compared with only 1% in the nonexposed group. Maternal and fetal blood lead levels in the cases of premature membrane rupture and preterm delivery were higher than in controls. Significantly higher lead concentrations were found in membranes of patients with stillbirths and preterm births, but there was a low correlation between membrane and antenatal blood lead concentrations (90). A detailed Japanese study showed an increase in spontaneous abortions among female lead workers from a prelead rate of 45.6 per 1000 to 84.2 per 1000 (the rate in nonexposed employees was 59.1 per 1000) (91). A Danish study showed that when lead was used as an abortifacient, 60% of the pregnancies in the first trimester ended in abortion (92). Moreover, women with a history of childhood lead poisoning were suggested to be at higher relative risk (RR) for having spontaneous abortions or stillbirths (RR 1.6, 95% CI, 0.6–4.0) and having children with learning disabilities (RR 3.0, 95% CI 0.9–10.2) (93). A dose-dependent decrease in hypothalamic gonadotropin-releasing hormone and somatostatin was found in lead-treated guinea pigs and their fetuses (94). Although the relevance of these changes is unclear, they may partially explain decreased reproductive capacity. A study from Boston (4354 cases) suggested that lead may be associated, in a doserelated fashion, with an increased risk for minor anomalies (95). The relative risk increased from 1.0 at 0.7 µg/dL to 2.73 at the level of 24 µg/dL. The anomalies discovered did not have a specific pattern and were of little health consequence. They included hemangiomas (14 of 1000 births), hydrocele (27.6 of 1000 male infants), minor skin anomalies (12.2 of 1000 births), and undescended testicles (11 of 1000 male infants). Lead also affects the male gonads; chromosomal alterations, as well as abnormalities in sperm count, vigor, and morphological features were demonstrated in workers and experimental animals (96–98). Marital life records of lead-exposed men showed 24.7% of the marriages to be infertile compared with 14.8% in the nonlead control group. The rate of prematurity or stillbirth was 8.2%, whereas in the control group it was 0.2% (98). In a case referent study, a significant increase in spontaneous abortions was found in the

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wives of workers occupationally exposed to lead whose blood level was greater than 1.5 µmol/L (31 µg/dL) during or close to the time of spermatogenesis (99). The adjusted odds ratio for low birth weight among infants whose fathers were potentially exposed to high levels of lead from 6 months before pregnancy to the end of it was 4.7, 95% CI 1.1– 2.0. This effect was most prominent for low-birth-weight infants who were both preterm and small for gestational (100). Although increased numbers of chromosomal aberrations (gaps, breaks, fragments, chromatid aberrations) have been reported in lead workers, the contribution of lead itself is still unclear (62). Lead also seemed to have a small but demonstrable association with pregnancyinduced hypertension and elevated blood pressure at the time of delivery, but not with preeclampsia (101,102). One of the main concerns regarding lead is its ability to cause neuropsychological impairment in children. In the late 1970s half the children in the United States under 5 years of age had blood lead levels exceeding 20 µg/dL, and among urban black children the figure approached 60% (103). At this level a variety of enzymatic and neurophysiological processes are impaired. Until recently, it was unclear at what level deficits in children’s learning and behavior become apparent, nor was the contribution of in utero exposure clearly identified. In a series of studies from Boston (1,2), blood lead levels and development were monitored in a group of urban children from birth to the age of 2 years. No infant had a cord blood lead level exceeding 25 µg/dL, the level regarded at that time by the Centers for Disease Control as the upper normal limit for children. At all ages children whose cord level was greater than 10 µg/dL scored lower in the Mental Development Index of the Bayley Scales [4.8-point difference between the low (⬍3 µg/dL) and high (⬎10 µg/dL) groups]. At the age of 6 months, scores on the Psychomotor Development Index were not significantly related to cord blood lead level. Scores were not related to infants’ postnatal blood lead levels. At the age of 57 months the performance of these children was tested on the McCarthy Scale of Children’s Ability (104). Surprisingly, at this age there was no association between prenatal lead exposure and children’s cognitive function, except for children with high postnatal exposure (⬎10 µg/dL), particularly at 24 months of age. A study from Cincinnati obtained similar initial results (105). Comparable to the Boston study, neuropsychological follow-up of the Cincinnati cohort, as assessed by the Kaufman Assessment Battery for Children at the age of 4 years, was inversely associated with higher neonatal blood lead level only in children from the poorest families (106). The relationship between prenatal low level lead exposure and neurobehavioral development was not confirmed in another study (107). However, the mean cord lead level was 8.1 µg/dL, which is lower than the cutoff point of 10 µg/dL suggested by the Boston study. A Mexican study suggested high maternal lead levels in the last two trimesters to be associated with altered baby cry and auditory function. The authors suggest this to contribute to developmental delays by affecting early communication between caretaker and baby (108). It is still unclear at what gestational age the fetus is most sensitive. Since the fetal brain develops throughout gestation, it is conceivable that lead deposition at any stage may be harmful. However, it seems that low-level prenatal lead-induced neurodevelopmental impairment may be reversible, provided the exposure is discontinued. It has been suggested that cord blood levels above 15 µg/dL induce a modest decrease in fetal growth (109). The on stature effect of lead exposure (in utero as well as during the first year of life) was transient 33 months of age, if subsequent exposure to

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lead was not excessive (110). Another study could not confirm an association between prenatal lead exposure and neonatal size (111). These data suggest that low levels of lead delivered to the fetus may be toxic and may cause behavioral and developmental impairment. It led the Centers for Disease Control to reduce the acceptable level for young children from 25 to 10 µg/dL (71). Animal studies are consistent with these findings (112–116), and it is possible that brain lead levels remain elevated longer than blood levels after short-term exposure (117,118). It is also possible that the fetus is more sensitive to lead than the young child. Possible mechanisms for the brain damage include interference with embryonic nutrition and energy supply, competition with cations such as zinc, iron, or calcium (119), interference with mitochondrial function (120) and synthesis of cytochromes, and effect on deoxyribonucleic acid synthesis (121). A study in Toronto found that about 90% of newborns had cord blood levels below 3 µg/dL and none above 10 µg/dL (122), whereas in Boston, about one-third had such levels and one-third had levels exceeding 10 µg/dL. In Braunschweig, Germany, only 4.7% of the neonates had cord blood lead level above 10 µg/dL (123). This range of results illustrates the difference between different urban environments. The data above imply that it is important to detect, as early as possible, babies potentially exposed in utero to excess lead. Several studies documented a high correlation between maternal and cord blood lead levels, usually being 80–98% of the maternal level (65,73,76,124–127). In one of them, mean cord levels were 10.1 µg/dL, compared with 10.3 µg/dL in the mother (r ⫽ 0.6377) (76). However, it is not advisable to assume lead exposure throughout pregnancy from a single blood measurement, because of the changes in maternal blood levels and placental permeability to lead (2). An alternative method of assessing long-term lead exposure and estimating in utero exposure is head hair analysis, which reflects cumulative values (128,129). A questionnaire was developed by the Centers for Disease Control that combined housing conditions, smoking status and high consumption of canned foods. This questionnaire is given to pregnant women for identification of children at risk for lead poisoning and has a sensitivity of 89.2% and a negative predictive value of 96.4% (130). It cannot substitute biomonitoring of the pregnant woman in the workplace. On the basis of the higher susceptibility of the fetal brain to lead, it may be argued that treatment should be instituted even when levels are low; however, the effectiveness of this approach has not been studied. More realistically, removal of the woman from the source of exposure is the first step. From the chelating agents available, BAL (dimercaprol) is a very toxic compound that has been shown to induce skeletal abnormalities in fetal mice (131). One woman who was treated for arsenic intoxication, in the sixth month of pregnancy, gave birth to a normal child (132). Ethylenediaminetetraacetate (EDTA) is less toxic, but it can chelate calcium, zinc, and other trace elements and may adversely affect the fetus. In one case it was given at the eighth month of gestation (at maternal level of 240 µg/dL) without complication (88). The infant was normal with an undetected cord lead level. However, the sensitivity of the assay was very low (⬍60 µg/dL was undetectable). This infant had normal mental and developmental assessments at age 4. In another patient treated with calcium EDTA at the same gestational age, it appeared that the treatment did not adequately reduce the infant’s lead burden (133); this child had a blood lead level of 60 µg/dL at the time of delivery and radiological evidence of bony changes suggestive of prolonged exposure. A 17-year-old female in her 39th week of

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pregnancy who had a blood lead level of 79 µg/dL with a corresponding amniotic fluid lead level of 90 µg/dL was treated with 2 g/day Ca-EDTA for 3 days. Eight days later her blood lead level was 26 µg/dL. She delivered a normal-appearing girl, and the cord blood lead concentration was 79 µg/dL. Based on this result, the authors suggested a delay in the crossing of the placental barrier by Ca-EDTA (134). d-penicillamine is less effective than dimercaprol and Ca-EDTA, and in the doses used in lead poisoning it may cause connective tissue abnormalities (mainly cutis laxa) in human fetuses (135). There is no experience with the use of the new oral chelators 2,3-dimercaptosuccinic acid (DMSA) and dimercaptopropane-1-sulfonate (DMPS) in human pregnancy. At doses between 100 and 1000 mg/kg/day, DMSA induced increases in resorptions and in postimplantation loss, as well as reduced fetal weight, but there was no teratogenicity in rats (136). Changes in mineral metabolism were suggested as one possible mechanism (137). The therapeutic dose in adults is 30 mg/kg/day. Similar effects were observed with DMPS in mice (138). Both chelators prevented arsenic teratogenicity and embryotoxicity in mice (139,140). Since these chelators are less toxic, it is hoped that they will indicate the appropriate chelators for use in pregnancy. More critical research is needed to assess the need for treatment of low-level exposures, to establish the criteria for instituting therapy, to evaluate the response, and to identify the chelator of choice. In the case of a woman occupationally exposed to lead, it is important to measure her blood lead concentrations and compare them with the mean levels measured in the same city. Several women employed in stained glass workshops had lead levels well below or near the mean recently determined for women in Toronto (122), indicating that their lead load was within the expected range. Should there be a substantially higher lead level in such patients, they would be advised to discontinue their occupational exposure.

SUMMARY Of the three most common occupational exposures in pregnancy, video display terminals do not represent a reproductive risk. Organic solvents may damage the fetal brain at high exposure levels, such as those encountered in substance abuse. There is no clear evidence to suggest that maternal exposure to allowable levels causes fetal damage. There seems to be an increased risk of spontaneous abortion for certain organic solvents. In the case of lead, a dose-response fetal risk appears to have been established, and lead levels should be monitored to avoid fetal risk. Clinical Case Answer Video terminals do not emit radiation that can affect the fetus. This has been proved by direct measurements as well as by epidemiological studies in pregnant women. REFERENCES 1. Bellinger DC, Needelman HL, Leviton A, Waternaux C, Rabinowitz MB, Nichols ML. Early sensory-motor development and prenatal exposure to lead. Neurobehav Toxicol 1984; 6: 387–402. 2. Bellinger DC, Leviton A, Waternaux C, Needelman HL, Rabinowitz MB. Longitudinal anal-

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4. 5. 6.

7. 8. 9.

10. 11. 12. 13.

14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

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74. Kostial K, Momcilovic B. Transport of lead-203 and calcium-47 from mother to offspring. Arch Environ Health 1974; 29:28. 75. Alexander F, Delves H. Blood lead levels during pregnancy. Arch Environ Health 1981; 48: 35–39. 76. Gershanick J, Brooks G, Little J. Blood lead values in pregnant women and their offspring. Am J Obstet Gynecol 1974; 119:508–511. 77. Lubin H, Caffo A, Reece R. A longitudinal study of interaction between environmental lead and blood lead concentrations during pregnancy, at delivery and in the first 6 months of life. Pediatr Res 1978; 12:425. 78. Rajegowda BK, Glass L, Evans HE. Lead concentration in newborn infants. J Pediatr 1972; 80:116. 79. Karlog O, Moller KO. Three cases of acute lead poisoning: analysis of organs for lead and observations on polarographic lead determinations. Acta Pharm 1958; 15:8–16. 80. Silbergeld EK. Lead in bone: implication for toxicology during pregnancy and lactation. Environ Health Perspect 1991; 91:63–77. 81. Oliver T. A lecture on lead poisoning and the race. Br Med J 1911; 1:1096–1098. ¨ ber eine hereditare Folge der chronischen Blievergiftung. Arch Gynaecol 1881; 82. Rennert O. U 16:109. 83. Chyzzer A. Des intoxications par le plomb se pre`sentant dans le ce´ramique en Hongrie. Natl Acad Sci (Budapest) 1908; 44:906–911. 84. Legge TM. Industrial lead poisoning. J Hyg 1901; 1:96. 85. Paul C. E´tude sur l’intoxication lente par les preparations de plomb; de son influence par le produit de la conception. Arch Gen Med 1869; 5:513–533. 86. Deneufbourg H. L’intoxication saturnine dans ses rapports avec la grossesse. Thesis, Universite´ de Paris, 1905. 87. Hamilton A. Industrial Poisons in United States. New York: Macmillan, 1929, pp 8–17, 110–115. 88. Angle CR, McIntire MS. Lead poisoning during pregnancy. Am J Dis Child 1964; 108:436– 439. 89. Fahim MS, Fahim Z, Hall DG. Effects of subtoxic lead levels on pregnant women in the state of Missouri. In: Proceedings of the International Conference on Heavy Metals in the Environment, Toronto, Oct. 27–31, 1975. 90. Baghurst PA, Robertson EF, Oldfield RK, et al. Lead in the placenta, membranes, and umbilical cord in relation to pregnancy outcome in a lead-smelter community. Environ Health Perspect 1991; 90:315–320. 91. Nogaki K. On action of lead on body of lead refinery workers: particularly conception, pregnancy and parturition in case of females and on vitality of their newborn. Excerpta Med 1958; 4:2176. 92. Pindborg S. On solverglodforgifting i Denmark. Ugeskr Lacg 1945; 107:1–6. 93. Hu H. Knowledge of diagnosis and reproductive history among survivors of childhood plumbism. Am J Public Health 1991; 81:1070–1072. 94. Sierra EM, Tiffany-Castiglioni E. Effects of low-level lead exposure on hypothalamic hormones and serum progesterone levels in pregnant guinea pigs. Toxicology 1992; 72:89– 97. 95. Needelman HL, Rabinowitz M, Leviton A, Linn S, Schoenbaum S. The relationship between prenatal exposure to lead and congenital anomalies. JAMA 1984; 251:2956–2959. 96. Deknudt GH, Leonard A, Ivanov B. Chromosome aberrations observed in male workers occupationally exposed to lead. Environ Physiol Biochem 1973; 3:132–138. 97. Lancranjan I, Popsecu H, Gavanescu O, Klepsch I, Serbanescu M. Reproductive ability of workmen occupationally exposed to lead. Arch Environ Health 1975; 30:396-MI. 98. Stofen D. Less noted European papers on lead. In: Proceedings of the International Symposium on Environmental Health Aspects of Lead, Amsterdam, Oct. 2–6, 1972, pp 473–485.

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120. Holzman J, Hsu JS. Early effects of lead on immature rat brain mitochondrial respiration. Pediatr Res 1976; 10:70–75. 121. Choi DD, Richter G. Stimulation of DNA synthesis in rat kidney by repeated administration of lead. Proc Soc Exp Biol Med 1973; 142:446-M9. 122. Koren G, Cheng M, Klein J, et al. Lead exposure in mothers and infants in Toronto, 1989. Can Med Assoc J 1990; 142:1241–1244. 123. Meyer J, Genenich HH, Robra BP, Windorfer A. Determinants of lead concentration in the umbilical cord blood of 9189 newborns of a birth cohort in the government district of Braunschweig. Zentralb Hugg Umweltmed 1992; 192:522–533. 124. Angell NF, Lavery JP. The relationship of blood lead levels to obstetric outcome. Am J Obstet Gynecol 1982; 142:40–46. 125. Zetterlund B, Winberg J, Lundgren G, Johansson G. Lead in umbilical cord blood correlated with the blood lead of the mother in areas with low, medium or high atmospheric pollution. Acta Paediatr Scand 1977; 66:169–175. 126. Milman N, Christensen JM, Ibsen KK. Blood lead and erythrocyte zinc protoporphyrin in mothers and newborn infants. Eur J Pediatr 1988; 147:71–73. 127. Wan BJ, Zhang Y, Tian CY, Cai Y, Jiang HB. Blood lead dynamics of lead-exposed pregnant women and its effects on fetus development. Biomed Environ Sci 1996; 9:41–45. 128. Laker M. On determining trace element levels in man: the uses of blood and hair. Lancet 1982; 2:260–262. 129. Huel G, Everson RB, Manger I. Increased hair cadmium in newborns of women occupationally exposed to heavy metals. Environ Res 1984; 1:115–121. 130. Stefanak MA, Bourguet CC, Benzies-Styku T. Use of the Centers for Disease Control and Prevention childhood lead poisoning risk questionnaire to predict blood level elevations in pregnant women. Obstet Gynecol 1996; 87:209–212. 131. Schardein JL. Chemical antagonists. In: Schardein JL, ed. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985, pp 534–545. 132. Kantor MI, Levin PM. Arsenical encephalopathy in pregnancy with recovery. Am J Obstet Gynecol 1948; 56:370–374. 133. Timpo AE, Amin JS, Casalino MB, Yuceoylu AM. Congenital lead intoxication. J Pediatr 1979; 94:765–767. 134. Peral M, Boxt M. Radiographic findings in congenital lead poisoning. Radiology 1980; 136: 83–84. 135. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation, 2nd ed. Baltimore: Williams & Wilkins, 1986, p 331. 136. Domingo JL, Ortega A, Paternain JL, Llobelt JM, Corbella J. Oral meso-2,3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats—teratogenicity and alterations in mineral metabolism: 1. Teratological evaluation. J Toxicol Environ Health 1990; 30:181–190. 137. Paternain JL, Ortega A, Domingo JL, Llobelt JM, Corbella J. Oral meso-2,3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats—Teratogenicity and alterations in mineral metabolism: II. Effect on mineral metabolism. J Toxicol Environ Health 1990; 30:191–197. 138. Bosque MA, Domingo JL, Pater JL, Llobelt JM, Crobelia J. Evaluation of the developmental toxicity of 2,3-dimercapto-1-propanesulfonate (DMPS) in mice: effect on mineral metabolism. Toxicology 1990; 62:311–320. 139. Domingo JL, Bosque MA, Piera V. Meso-2,3-dimercaptosuccinic acid and prevention of arsenite embryotoxicity and teratogenicity in the mouse. Fundam Appl Toxicol 1993; 17: 314–320. 140. Domingo JL, Bosque NM, Llobelt JM, Corbella J. Amelioration by BAL (2,3-dimercapto1-propanol) and DMPS (sodium 2,3-dimercapto-1-propanesulfonic acid) of arsenite developmental toxicity in mice. Ecotoxicol Environ Safety 1992; 23:274–281.

29 Pregnancy Outcome Following Maternal Organic Solvent Exposure: A MetaAnalysis of Epidemiological Studies Kristen I. McMartin, Merry Chu, Ernest Kopecky, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION Organic solvents are a structurally diverse group of low-molecular-weight liquids that are able to dissolve other organic substances. Chemicals in the solvent class include aliphatic hydrocarbons (mineral spirits, varnish, kerosene), aromatic hydrocarbons (benzene, toluene, xylene), halogenated hydrocarbons (carbon tetrachloride, trichloroethylene), aliphatic alcohols (methanol), glycols (ethylene glycol), and glycol ethers (methoxyethanol) (1). Fuels are a mixture of various hydrocarbons. They are generally ubiquitous in industrialized society, both at work and in the home. They may be encountered as individual agents or in complex mixtures such as gasoline. Incidental exposures may include vapors from gasoline, lighter fluid, spot removers, aerosol sprays, and/or paints. These short duration and low level exposures may often go undetected. More serious exposures occur mainly in industrial or laboratory settings during manufacturing and processing operations such as dry cleaning, regularly working with paint removers, thinners, floor and tile cleaners, glue, and as laboratory reagents. Gasoline or glue sniffing, albeit not occurring in the occupational setting, is another source of exposure to organic solvents during pregnancy. Counseling pregnant women who are occupationally exposed to numerous chemicals (mostly organic solvents) is problematic because it is difficult to estimate the predominant chemicals and their by-products. Even after identifying the more toxic agents, it is still difficult to asses the circumstances of exposure; for many chemicals, one can measure neither airborne nor blood levels. Smelling organic solvents is not indicative of a significant exposure, as the olfactory nerve can detect levels as low as several parts per million, which is not necessarily associated with toxicity. As an example, the odor threshold of toluene is 0.8 parts per million, whereas the TLV-TWA (threshold limit value—time

From Am J Ind Med 1998; 34:288–292. 547

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weighted average) is 100 parts per million. In addition, reproductive information on many individual solvents is at best sparse, either limited to animal studies or nonexistent. Many organic solvents are teratogenic and embryotoxic in laboratory animals, depending on the specific solvent, dose, route of administration, and particular animal species (1). The various malformations described include hydrocephaly, exencephaly, skeletal defects, cardiovascular abnormalities, and blood changes. Also, some studies suggest poor fetal development and neurodevelopmental deficits. In a portion of these studies, exposure levels were high enough to induce maternal toxicity. Organic solvents are a diverse, complex group and because exposure usually involves more than one agent and different circumstances, adequate human epidemiological studies are difficult to interpret. Many studies are subject to recall and response bias and are not always controlled for other risk factors such as age, smoking, ethanol, and concurrent drug ingestion. It is difficult to prove or quantify the suspicion that organic solvents are a reproductive hazard. One may even expect that a ubiquitous exposure to solvents would by chance alone be associated with an increase in birth defects or spontaneous abortions, which may differ from one study to another. While fetal toxicity is biologically sensible in cases of intoxicated mothers, evidence of fetal damage from levels that are not toxic to the mother is scanty, inconsistent, or missing. The tool used to analyze the literature for an overall summary of risk between in utero inhalation exposure to organic solvents and adverse pregnancy outcome is metaanalysis. Our meta-analysis aimed at two outcomes of interest—major malformations and spontaneous abortion.

METHODS A literature search was conducted to collect studies for the meta-analysis. Using Medline, Toxline, and Dissertation Abstracts databases spanning 1966–1994, literature was identified concerning the problem. In addition, colleagues were consulted (regarding unpublished studies) whose area of interest is in occupational exposure and reproductive toxicology. All references from the extracted papers and case reports were investigated. Standard textbooks containing summaries of teratogenicity data were consulted for further undetected references. Key words employed for database searching included pregnancy, organic solvent, chemical, occupational exposure, adverse fetal outcome, malformation, congenital abnormalities, birth defect, teratogen, abortion, and spontaneous abortion. The ‘‘methods’’ section from each article was selected out and identifying markers of the study, such as author name, institution, journal title, and year, were removed to minimize bias in selecting articles for analysis. The nonidentifiable articles were stapled to a data collection sheet and presented to two reviewers for selection into analysis according to preestablished inclusion criteria. Inclusion criteria consisted of human studies of any language: 1. 2. 3. 4.

case-control or cohort-study in design maternal inhalation occupational organic solvent exposure outcome was a major malformation as defined by Heinonen (2) and/or spontaneous abortion (ⱕ20 weeks) as defined by Cunningham et al. (3) first trimester pregnancy exposure

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Exclusion criteria consisted of animal studies, noninhalation exposure, case reports, letters, editorials, review articles, and studies that did not permit extraction of data from 2 ⫻ 2 tables. The inclusion of the articles was agreed upon by consensus by independent reviewers and reasons for exclusion were identified. Data from each study were also extracted independently by reviewers. Data were entered into 2 ⫻ 2 tables. For subgroup analysis, we also identified and analyzed cohort and case-control studies specifically involving solvent exposure. Major malformations were defined as malformations which were either potentially life threatening or a major cosmetic defect (2). Spontaneous abortion was defined as the spontaneous termination of pregnancy before 20 weeks gestation based on the date of the first day of the last normal menses (3). After the data were entered in 2 ⫻ 2 tables, risk ratios (RR) for cohort studies and odds ratios (OR) for case-control studies were calculated. To determine the significance of individual studies, χ 2 and 95% confidence intervals (CI) were calculated. To obtain an estimate of the risk ratio for major malformations in exposed vs. unexposed infants, an overall summary OR was calculated by the method of Mantel-Haenszel. A 95% CI was calculated using the method described by Miettinen. The equations and methods of these analyses have been described by Einarson et al.(4). Homogeneity was calculated using chi-square. Power analysis and the extent of publication bias were estimated using Orwin’s formula (4).

RESULTS The literature search yielded 559 articles. Of these, 549 were rejected for various reasons, including: animal studies (298), case reports/series (28), review articles (58), editorials (13), duplicate articles (10), not relevant (62), malformation not specified (29), spontaneous abortion not defined (31), unable to extract data (4), no indication of timing of exposure (16). Five papers were included in the major malformation analysis (Table 1) and five papers were included in the spontaneous abortion analysis (Table 2). Malformations Five studies describing results from organic solvent exposure were identified (Table 3). The summary OR obtained was 1.64 (95% CI: 1.16–2.30). The test for homogeneity yielded a chi-square of 2.98 (df ⫽ 4, p ⫽ 0.56). When studies were analyzed separately according to study type, the chi-square value from Breslow and Day’s test for homogeneity

Table 1

Studies of Teratogenicity of Organic Solvents Meeting Criteria for Meta-Analysis

Authors Axelsson et al. (5) Tikkanen et al. (6) Holmberg et al. (7) Cordier et al. (8) Lemasters (9)

Study type

Data collection

C CC CC CC C

R R R R R

Malformation described ‘‘serious malformations’’ cardiac malformations CNS, oral clefts, musculoskeletal, cardiac defects ‘‘major malformations’’ ‘‘major malformations’’

Abbreviations: CC ⫽ case control; C ⫽ cohort; R ⫽ retrospective.

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Table 2 Studies of Spontaneous Abortion of Organic Solvents Meeting Criteria for Meta-Analysis Authors

Study type

Data collection

CC C C C C

R R P R P

Windham et al. (10) Lipscomb et al. (11) Shenker et al. (12) Pinney (13) Eskenazi et al. (14)

Abbreviations: CC ⫽ case control; C ⫽ cohort; R ⫽ retrospective; P ⫽ prospective.

of effect for cohort studies was 0.52 (df ⫽ 1, p ⫽ 0.47) and for case control studies it was 0.01 (df ⫽ 2, p ⫽ 0.99). Meta-analysis of both the cohort studies and case-control studies produced similar results, i.e., they demonstrate a statistically significant relationship between organic solvent exposure in the first trimester of pregnancy and fetal malformation. The summary OR for cohort studies was 1.73 (95% CI: 0.74–4.08) and 1.62 (95% CI:1.12–2.35) for case-control studies. A subanalysis was performed that excluded unpublished studies from the summary OR. After removing Lemasters (9), the summary statistic was 1.54 (1.07–2.21). The file drawer issue can be examined using Orwin’s formula (similar to power analysis). The power analysis as suggested by Orwin yielded an average effect size for five studies: Cohen’s d ⫽ 0.071, the value of d for cohort studies was 0.064 and for case Table 3 Results of Studies Comparing Outcomes of Fetuses Exposed or Not Exposed to Organic Solvents Congenital defect Reference

Exposure

Axelsson et al. (5)

Organic solvents

Tikkanen et al. (6)

Organic solvents

Holmberg et al. (7)

Organic solvent

Cordier et al. (8)

Organic solvents

Lemasters (9)

Styrene

Total

yes no total yes no total yes no total yes no total yes no total yes no total

Yes

No

Total

3 4 7 23 546 569 11 1,464 1,475 29 234 263 4 13 17 70 2,261 2,331

489 492 981 26 1,026 1,052 7 1,438 1,475 22 285 307 68 822 890 612 4,100 4,712

492 496 988 49 1,572 1,621 18 2,902 2,950 51 519 570 72 835 907 682 6,354 7,036

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control studies it was 0.076. All three are low in absolute value and are considered small according to Cohen’s criterion. According to Orwin’s formula, decreasing the overall effect size to 0.05 (small effect) would require the addition of two studies with an effect size d ⫽ 0.001 (small effect size).

Spontaneous Abortion Five papers describing results from organic solvent exposure were identified (Table 4). The summary OR obtained was 1.25 (95% CI: 0.99–1.58). The test for homogeneity yielded a chi-square ⫽ 4.88 (df ⫽ 4, p ⫽ 0.300). When studies were analyzed separately according to study type, the chi-square value from Breslow and Day’s test for homogeneity of effect for cohort studies was 4.20 (df ⫽ 3, p ⫽ 0.241). Meta-analysis of both cohort and case-control studies produced similar results, i.e., they do not demonstrate a statistically significant relationship between organic solvent exposure in pregnancy and spontaneous abortion. The summary OR for cohort studies was 1.39 (95% CI: 0.95–2.04) and 1.17 (95% CI: 0.87–1.58) for case control studies. A subanalysis was performed that excluded unpublished studies from the summary OR. By removing Pinney (13), the summary statistic was 1.31 (1.01–1.69) and by excluding Schenker et al. (12) from the analysis, the summary statistic was 1.22 (0.96–1.55). Removing both unpublished studies yielded an OR of 1.27 (0.97–1.66). Power analysis suggests that an additional one study with a similar effect size would make the summary OR of 1.25 significant.

Table 4 Results of Studies Comparing Outcomes of Fetuses Exposed or Not Exposed to Organic Solvents Spontaneous abortion Reference

Exposure

Windham et al. (10)

Any solvent product

Lipscomb et al. (11)

Organic solvent

Schenker et al. (12)

Organic solvents

Pinney (13)

Organic solvents

Eskenzi et al. (14)

Organic solvents

Total

yes no total yes no total yes no total yes no total yes no total yes no total

Yes

No

Total

89 272 361 10 87 97 12 16 28 35 25 60 4 7 11 150 407 557

160 575 735 39 854 893 8 21 29 228 166 394 97 194 291 532 1,810 2,342

249 847 1,096 49 941 990 20 37 57 263 191 454 101 201 302 682 2,217 2,899

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DISCUSSION While estimates for clinically recognized spontaneous abortions as a proportion of all pregnancies vary, the proportion of spontaneous abortions narrowly range from 9–15% in different populations (15). The variation depends not only on the characteristics of the population but also on the methodology used in studies, for example, the selection of the study population, the source of pregnancy data, and the definition of spontaneous abortion (15). Evidence of fetal damage or demise from organic solvent levels that are not toxic to the pregnant women is inconsistent in the medical literature. The risk for major malformations and spontaneous abortion from maternal inhalation organic solvent exposure during pregnancy was summarized using meta-analysis. Besides being more objective than the traditional methods of literature review, it has the ability to pool research results from various studies, thereby increasing the statistical strength/power of the analysis. This is especially useful in epidemiologic studies such as cohort studies or case control studies, since very often large numbers of subjects are required in order for any problem to be significantly addressed. This is particularly true for teratogenic studies, where the frequencies of malformation are often very low. Five studies were included in the spontaneous abortion analysis. The overall ORs of 1.25 indicates that maternal inhalation occupational exposure to organic solvents is associated with a tendency toward a small increased risk for spontaneous abortion. The addition of one study of similar effect size would have rendered this trend statistically significant. Removing the two unpublished studies from the analysis further demonstrates a tendency toward a small increased risk for spontaneous abortion (1.27 (0.97–1.66)). When studies were analyzed according to study type the summary OR for cohort studies was 1.39 (95% CI: 0.95–2.04). For the case control study the summary OR was 1.18 (95% CI: 0.87–1.58). Their combinability seems justified on the basis of the lack of finding heterogeneity among the results. This article addresses the use of organic solvents in pregnancy. Organic solvent is a very broad term that includes many classes of chemicals. There may still exist rates of abortion higher than the value reported with certain groups of solvents. However, a detailed analysis of classes of solvents is in order to incriminate a particular solvent. Not all of the studies have examined the same groups of solvents in terms of both extent and range of solvents as well as frequency and duration of exposure. Hence it would be very difficult to obtain any clear estimate of risk for a given solvent, given the limited number of studies available. To improve further studies of this type, a call for better reporting (in particular, to industrial hygiene assessment) in articles is in order, as it is difficult to judge the ‘‘representativeness’’ of a summary effect if the populations being pooled seem to be heterogeneous. In this meta-analysis, major malformations were defined by Heinonen (2) as ‘‘potentially life threatening or a major cosmetic defect.’’ In the general population there is a 1–3% baseline risk for major malformations. Estimate incidence via cohort studies indicated two studies with a total of seven malformations in 564 exposures, or 1.2% rate of malformations, which falls within the baseline risk for major malformations. Five studies were included in the malformation analysis. Study size ranged from 570 to 2,950. The overall summary OR was 1.64 (95% CI: 1.16–2.30), which indicates that maternal inhalation occupational exposure to organic solvents is associated with an increased risk for major malformations. Tests for homogeneity showed a relatively homo-

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553

geneous group of studies. When studies were analyzed according to study type, the summary OR for cohort studies was 1.73 (95% CI: 0.74–4.08). The summary OR for case control studies was 1.62 (95% CI: 1.12–2.35). Their combinability remains justified on the basis of the lack of finding heterogeneity among the results. Removing the unpublished study from the analysis again demonstrated a statistically significant result [1.54 (1.07– 2.21)]. Publication bias is the tendency for statistically significant studies to be submitted and accepted for publication in preference to studies that do not produce statistical significance. This may be the case for solvent exposure and major malformations. Determining the extent of possible publication bias is not unlike power analysis for nonsignificant results. Each provides some quantitative measure of the magnitude of the findings with respect to disproving them and requires judgment for interpretation. A formula for estimating the significance of the file drawer problem when a meta-analysis produces significant results would be Orwin’s formula, as discussed for the previous power analysis. There are some considerations to bear in mind when interpreting results of the malformation and spontaneous abortion meta-analysis: 1. Environmental exposure in pregnancy is seldom an isolated phenomenon; therefore, analysis of human teratogenicity data may require stratification for a number of factors, depending on the intended focus of the analysis. 2. Organic solvents belong to many classes of chemicals. Not all of the studies have examined the exact same groups of solvents in terms of both extent and range of solvents as well as frequency and duration of exposure. 3. The malformations listed in each of the papers seems to reflect a diverse range of anomalies. One might expect to notice a particular trend in malformations between studies; however, this does not appear to be the case. Our review of the literature reveals that to the best of our knowledge there are no studies that prospectively examine occupational exposure to organic solvents during pregnancy and pregnancy outcome with regard to malformations as the primary objective. Because of the potential implications of this review to a large number of women of reproductive age occupationally exposed to organic solvents, it will be important to verify this cumulative risk estimate by a prospective study. Similarly, it is prudent to minimize women’s exposure to organic solvents by ensuring appropriate ventilation systems and protective equipment.

REFERENCES 1. Schardein J. Industrial solvents. In Schardein J, ed. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985, pp 645–658. 2. Heinonen O. Major malformations. In Heinonen O: Birth Defects and Drugs in Pregnancy. Littleton, MA: PSG Publishing, 1977, pp 65–81. 3. Cunningham FG, McDonald PC, Gant N. Abortion. In Cunningham FG, McDonald PC, Gant N, eds. Williams Obstetrics, 18th ed. Norwalk, CT: Appleton & Lange, 1989; pp 489–509. 4. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiologic studies. Drug Intell Clin Pharm, 1988; 22:813–824. 5. Axelsson G, Liutz C, Rylander R. Exposure to solvents and outcome of pregnancy in university laboratory employees. Br J Ind Med 1884; 41:305–312.

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6. Tikkanen J, Heinonen O. Cardiovascular malformations and organic solvent exposure during pregnancy in Finland. Am J Ind Med 1988; 14:1–8. 7. Holmberg PC, Kurpa K, Riala R, Rantala K, Kuosma E. Solvent exposure and birth defects: an epidemiologic survey. Prog Clin Biol Res 220:179–185. 8. Cordier S, Ha MC, Ayme S, Goujard J. Maternal occupational exposure and congenital malformations. Scand J Work Environ Health 1992; 18:11–17. 9. Lemasters GK. An Epidemiological Study of Pregnant Workers in the Reinforced Plastics Industry Assessing Outcomes Associated with Live Births. Cincinnati, OH: University of Cincinnati Press, 1983. 10. Windham GC, Shusterman D, Swan SH, Fenster L, Eskenazi B. Exposure to organic solvents and adverse pregnancy outcome. Am J Ind Med 1991; 20:241–259. 11. Lipscomb JA, Fenster L, Wrensch M, Shusterman D, Swan S. Pregnancy outcomes in women potentially exposed to occupational solvents and women working in the electronics industry. J Occup Med 1991; 33:597–604. 12. Schenker MB, Gold EB, Beaumont JJ, Eskenazi B, Hammond SK, Lasley BL, McCurdy SA, Samuels SJ, Saiki CL, Swan SH. Final Report to the Semiconductor Industry Association. Epidemiologic Study of Reproductive and Other Health Effects Among Workers Employed in the Manufacture of Semiconductors. University of California at Davis, 1992. 13. Pinney SM. An Epidemiological Study of Spontaneous Abortions and Stillbirths on Semiconductor Employees. Cincinnati, OH: University of Cincinnati Press, 1990. 14. Eskenazi B, Bracken MB, Holford TR, Crady J. Exposure to organic solvents and hypertensive disorders of pregnancy. Am J Ind Med 1988; 14:177–188. 15. Lindbohm ML. Parental Occupational Exposure and Spontaneous Abortion. Tampere, Finland: University of Tampere, 1991.

30 A Proactive Approach for the Evaluation of Fetal Safety in Chemical Industries Kristen I. McMartin and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Women, their families, and employers are concerned about potential fetal risks that may be associated with occupational exposure to chemicals. To be able to assess such risks in a particular plant, one has to quantify local exposure and contrast it with evidence-based literature data. There are, however, numerous obstacles that prevent such risk assessment from being routinely performed. In the reproductive literature, there are few studies that actually quantify exposure levels. In the instance where authors attempt to quantify or stratify exposure, the exposure frequencies and the exposure doses are inconsistent between studies. For many chemicals one can measure neither airborne nor blood levels. Smelling the odor of organic solvents is not indicative of a significant exposure, as the olfactory nerve can detect levels lower than several parts per billion, which are not necessarily associated with toxicity. Odor thresholds for some solvents are far below several parts per million (ppm). Examples of some odor thresholds (1) include carbon disulfide [0.001 ppm vs. TLV-TWA (skin) 10 ppm], acetaldehyde (0.03 ppm vs. TLV-TWA 25 ppm), and ethyl mercaptan (2 ⫻ 10⫺5 ppm vs. TLV-TWA 0.5 ppm) (2). In the workplace, exposure is usually to several chemicals, which may change between working days or even within a single day. In some instances one has to deal with possible unknown by-products. The amounts of chemicals absorbed are often unclear and the circumstances of exposure may vary from workplace to workplace or even within the same operation. In addition, reproductive information on many solvents is sparse, in general being either limited to animal studies or nonexistent. Typically, investigations into fetal safety are induced by single deformities or clusters of specific malformations or by symptomatology in exposed women. We present a proactive consultation process where, for a selected chemical compound to which women working in a particular petroleum production plant may be exposed, actual exposure data are contrasted with literature values and a risk assessment was constructed.

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METHODOLOGY An agent inventory list was used to analyze the component (the name of material or agent), exposure group, number of employees within an exposure group, and routine rating factor for routine work. Exposure group is defined as a group of employees who have similar exposures to chemical, physical, and/or biological agents when (1) holding different jobs but working continuously in the same area (e.g., process workers) or (2) holding unique jobs in an area or moving frequently between areas (e.g., maintenance workers). The routine rating factor for routine work (work which is part of the normal repetitive duty for an exposure group) is defined as follows:

Rating Factor (RF) 0 1–5

Definition No reasonable chance for exposure Minimal, exposure not expected to exceed 10% of the occupational exposure limit (OEL) Some daily routine exposures may be expected between 10% and 50% of the OEL Some daily routine exposures may exceed 50% of the OEL

6–9 10–15

The rating factor (RF) can be assessed using industrial hygiene professional judgment or monitored data. The RF is the product of exposure assessment (EA) and frequency factor rating score (FFRS). Exposure assessment is rated as follows: 0: 1: 2: 3:

no exposure actual exposure is ⬍ 10% of OEL actual exposure is ⱕ 10% and 50% of the OEL actual exposure is ⱖ 50%.

FFRS range is a dimensionless unit ranging from 0 to 5. Frequency of contact with the agent in time units (e.g., 2 h/week) is categorized in FFRS where: 0: no contact 5: continuous exposure NRRF is the nonroutine rating factor for nonroutine work defined as job task or activities done seasonally, occasionally, or cyclical. The definitions listed for RRF apply. An exposed/biomonitoring impact report was utilized in order to separate and determine the number of male and female employees out of the total number of employees for each exposure group. A summary of the number of female and male employees in various exposure groups was calculated for this specific site. For each component in the document entitled ‘‘Agent Distribution by Exposure Group,’’ the total number of exposed female employees was calculated by adding the number of female employees in each exposure group for that component. Subsequently, a listing was created with respect to individual chemicals, including rating factors, for female exposure in the products and chemicals divisions. In addition, a literature search was performed for each chemical that incorporated female occupational exposure during

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pregnancy with human teratogenicity and spontaneous abortion as the pregnancy outcomes. Most of the selected female reproductive toxicology studies examined in this document explicitly state chemical exposure levels: either as parts per million, stratifying as to number of days of exposure or as estimates of the percentage of the threshold limit values. Medline, Toxline, and Dissertation Abstracts databases were utilized to search for all research papers published in any language from 1966 to 1996 using the key words birth defects, fetal abnormality, teratogenicity, malformation, organic solvent, occupational exposure, spontaneous abortion, and abortion. All references from extracted papers, standard textbooks, and case reports were investigated, in addition to personal contact with external colleagues, to obtain unpublished literature. In total, 559 studies were obtained from the literature search. Of these, only 21 studies explicitly stated some sort of exposure level for the various chemicals. These literature chemical exposure levels and subsequent pregnancy outcomes were compared to IOL chemical exposure indices. The following is a condensed review of three of the many chemical exposures encountered, namely benzene, tetrachloroethylene, and toluene. For other compounds, Table 1 contrasts literature values with IOL chemical exposure indices.

RESULTS Benzene Mukhametova and Vozovaya (3) analyzed the records of 510 pregnant women and their previous pregnancy history. The women were gluing operatives in a mechanical–rubber product factory. Of these, 250 women were gluers exposed to petroleum and chlorinated hydrocarbons, particularly dichloroethane and methylene chloride; 260 women constituted the control group. Exposure levels in the air were not given but were stated to be for petroleum ‘‘as a rule within or lower than the maximum permissible levels’’ and for chlorinated hydrocarbons, ‘‘in 58.8% of the tests did not exceed the maximum permissible level, but in 41.5% they were 1.2–2.4 times higher.’’ Apart from exposure by inhalation there was additional exposure through skin contact with these substances. The women were studied by ‘‘detailed interrogation’’ using a team including an obstetrician, gynecologist, therapist, and hemopathologist. Abortion (mostly induced) was the outcome of the majority of pregnancies in both groups; only 25.8% of pregnancies in the gluing operatives and 30.3% in controls resulted in normal childbirth. However, there was a significant difference in the incidence of spontaneous abortions and premature births (figures for these two were not given separately); in the gluing operatives, 17.2% of pregnancies ended in this manner, compared with 4.9% in controls. The reproductive histories of gluing operatives before and after they started work at the factory showed a 3.4-fold increase in spontaneous abortions and a 3.7-fold increase in premature births. The frequency of premature births increased with duration of employment in the factory; in the control group of workers, there was a marked reduction (figures not given) in those two types of events after starting work in the factory. In the gluers, pregnancy and birth complications were recorded in 35.6% of all pregnancies compared with 15.5% in controls; these comprised mainly ‘‘late toxicoses’’ (toxemia?) in 16.8% of gluers compared with 8.4% of controls, premature births in 11.2% of gluers compared with 4.2% of controls, and threatened abortion in 4.0% of gluers compared with 1.5% of controls. It should be noted that these latter figures for premature births, when taken into

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Table 1 Examples of IOL Compound Exposure Indices vs. Literature Values Chemical

Reference

Literature exposure levels

Aniline

Posluzhnyi, 1979 (24)

‘‘Low exposure area’’

Benzene

Mukhametova and Vozovaya, 1972 (3)

‘‘Within or lower than the maximum permissible levels’’

Cadmium

Tsvetkova, 1970 (25)

Cadmium oxide 0.1–25 mg/m3 Cadmium salts 0.16–35 mg/m3 Metallic cadmium 0.02– 25 mg/m3

Dichloromethane

Taskinen et al., 1986 (26) Windham et al., 1991 (27)

⬎Once a week ⬍Once a week ⬎10 h/week ⬍10 h/week

Chloroform

Taskinen et al., 1986 (26)

⬎Once a week ⬍Once a week

Mercury

Gondharuk, 1977 (28)

‘‘Trace amounts to 0.08 mg/m3 ’’

IOL exposure levels No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: 2 ppm No reasonable chance for exposure to some daily exposures may be expected between 10–50% OEL TLV-TWA: 10 ppm No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: Total dust/particulate: 0.01 mg/m3 Respirable fraction: 0.002 mg/m3 No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: 50 ppm No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: 10 ppm No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: Alkyl compounds 0.01 mg/m3 All forms except alkyl (vapour) 0.05 mg/m3 Aryl/inorganic compound 0.1 mg/m3

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Continued

Chemical Styrene

Tetrachloroethylene

Toluene

559

Reference Saamanen, 1991 (29) Harkonen, 1984 (30)

Lauwreys et al., 1983 (15) Ludwig et al., 1983 (16)

Euler, 1967 (17) Syrovadko, 1977 (19) Ng et al., 1992 (21)

Literature exposure levels 70–100 ppm 20–300 ppm

21 ppm 4.0–149.0 ppm

298 ppm 13–120 ppm 50–150 ppm

IOL exposure levels No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: 50 ppm TLV-STEL: 100 ppm No reasonable chance for exposure to minimal exposure not expected to exceed 10% OEL TLV-TWA: 25 ppm TLV-STEL: 100 ppm No chance for exposure to some daily exposure exceeding 50% of the OEL TLV-TWA: 50 ppm

conjunction with the earlier combined figures for spontaneous abortion and premature births, imply very low spontaneous abortion rates of 5.0% for gluers and 0.7% for controls. The accuracy of the above data may therefore be in some doubt, thought the figures may be low because some of the induced abortions might otherwise have occurred spontaneously. It is not known how closely the two groups were matched for factors other than age and being in work. There may have been nutritional and socioeconomic differences between the two groups that could contribute to the pregnancy problems. Thus it is not known what relative contribution, if any, exposure to benzene and chlorinated hydrocarbons may have had to the outcomes observed. Holmberg (4) published a study of 14 mothers of children with congenital central nervous system (CNS) defects with their matched pair controls. Case mothers had been exposed to organic solvents during the first trimester of pregnancy significantly more often than controls ( p ⬍ 0.01). Of the 120 cases of CNS defects collected from the Finnish Register of Congenital Malformations in 1976–1978, 16 had been exposed to organic solvents, compared with 3 controls. Two of the 16 cases were excluded (one because of rubella infection, the other with diagnosis of Beckwith-Wiedemann syndrome). Of the remaining 14 cases, one had been exposed to benzene, dichloromethane, methanol, and ether in a laboratory, and her child was a stillborn anencephalic. The mother was aged 32 and had no previous abortions or malformed children; she was not given any drugs during pregnancy. However, no conclusions can be drawn on the basis of this one case. When the study was extended for 3 more years, the authors could not prove this association (5).

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Comparison with IOL Levels Routine rating factors and nonroutine rating factors in the Products and Chemicals Division vary from 00 to 06, indicating no reasonable chance for exposure to minimal exposure (⬍10% OEL) and that some daily exposures may be expected between 10 and 50% of the OEL. Benzene has a TLV-TWA of 10 ppm (2). In Mukhametova and Vozovaya’s study (3), exposure levels in the air were not given but were stated to be for petroleum products ‘‘as a rule within or lower than the maximum permissible levels’’ and for chlorinated hydrocarbons, which, ‘‘in 58.8% of the tests did not exceed the maximum permissible level, but in 41.5% they were 1.2–2.4 times higher.’’ The ‘‘maximum permissible level’’ at the time of the study was neither stated nor referenced. Based on the estimated benzene exposure levels in Mukhametova and Vozovaya (3), keeping in mind both the year the study was performed and the corresponding occupational hygiene standards at that time, IOL benzene levels are expected to be lower than the Mukhametova and Vozovaya study (3).

Tetrachloroethylene/Perchloroethylene In four Finnish studies the occurrence of spontaneous abortion was analyzed from records of the hospital discharge registry of the National Board of Health (6–9). This registry contains information on all women who had been hospitalized with spontaneous abortion, amounting to about 90% of all spontaneous abortions in Finland. These data were analyzed according to occupations. For women in the dry cleaning business who may have been exposed to perchloroethylene, the risk of spontaneous abortion was higher than for all women. In the study by Lindbohm (9) an adjusted relative risk of 1.48 (95% CI 1.09–2.02) was found for laundry workers. It is not clear, however, whether occupational exposure to perchloroethylene or some other factors related to laundry work explain this observed risk. An important point of these studies is the lack of data about the intensity of exposure to perchloroethylene or other chemicals and about confounding factors such as smoking, alcohol, medication and previous abortions. McDonald et al. (10,11) did not find an excess of spontaneous abortion in more than 200 current and previous pregnancies of women working in laundry dry cleaning shops. They interviewed the women in a large survey in 11 Montreal maternity departments as soon as possible after delivery or treatment for miscarriage. However, 25% of the women admitted for spontaneous abortion were not reached for an interview during their brief stay in the hospital. A high proportion of early and complete abortions were not recorded because not all women who spontaneously abort go to the hospital. Another limitation is that no exposure data were presented. In a retrospective study among 67 women working in dry cleaning shops in Rome, 102 reported pregnancies were compared: 56 occurred to these women when they were employed in dry cleaning shops and 46 while they did not work outside their homes (12). No indication of an increased risk of spontaneous abortion was found. Hemminki et al. (8), McDonald et al. (11) and Bosco et al. (12) did not observe any higher prevalence of malformations in the children of women who were working as dry cleaners. No chemical exposure levels were specified. Ahlborg (13) performed a case-referent study of women engaged in laundry or dry cleaning work. The aim was to examine if tetrachloroethylene exposure increased the risk of ‘‘adverse pregnancy outcome’’ (spontaneous abortion, perinatal death, congenital malformations, or birth weight ⬍1500 g). Pregnancies and outcomes were identified in

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national registers and exposure data were obtained from the women by postal questionnaires. Tetrachloroethylene exposure during the first trimester of pregnancy was classified into the following three categories based on information given by the women in the questionnaires: ‘‘High’’—operating dry cleaning machines or spot removing with tetrachloroethylene at least 2 hours per week, ironing/pressing dry cleaned cloth more than 20 hours per week, or cleaning and filling the machines at least three times. ‘‘Low’’—other work at workplaces where dry cleaning with tetrachloroethylene was performed. ‘‘Unexposed’’— worked at workplaces where no dry cleaning with tetrachloroethylene was performed. Conditional logistic regression analysis yielded an adjusted odds ratio for any level of tetrachloroethylene exposure during the first trimester of 1.1 (95% CI: 0.6–2.0) after accounting for several potential confounding factors. Low tetrachloroethylene exposure yielded an odds ratio of 1.1 (0.6–2.2) and high tetrachloroethylene exposure yielded an odds ratio of 1.1 (0.5–2.2). Kyyronen et al. (14) performed a case-control study to determine whether exposure to tetrachloroethylene during the first trimester of pregnancy has harmful effects on pregnancy outcome. The study involved dry cleaner and laundry workers throughout Finland who had become pregnant during the study period. Controls were age-matched but otherwise unselected women giving birth to normal babies in the study period. Cases were defined as women who had been treated for spontaneous abortion or had delivered a malformed child. One pregnancy only was randomly selected per worker and the final study population was 130 women with spontaneous abortions and 24 with malformed infants. Three age-matched controls were selected for each abortion case and five for each malformation case. The reported exposure to tetrachloroethylene was assessed as ‘‘high’’ when (1) the work tasks included dry cleaning for at least 1 hour daily on average or (2) the women reported handling tetrachloroethylene at least once a week. The criteria for ‘‘low’’ exposure were (1) work tasks including pressing at a dry cleaners’ or spot removing or (2) the handling of tetrachloroethylene less than once a week. High exposure to tetrachloroethylene was found to be significantly associated with spontaneous abortions [OR ⫽ 3.4 (1.0–11.2)]; however, frequent use of solvents other than tetrachloroethylene [OR ⫽ 1.5 (0.4–5.4)] was not associated with spontaneous abortion. With regard to congenital malformations, any level of tetrachloroethylene was not significantly associated with malformations [OR ⫽ 0.8 (0.2–3.5)]; however, handling of other solvents (solvents not specified) at any level was statistically significant [OR ⫽ 5.9 (1.0–35.7)]. The Institute of Occupational Health in Finland conducted measurements of tetrachloroethylene in air in some of the largest dry cleaners during 1973–83 (14). The concentrations in the workers’ breathing zone varied from 3–29 cm3 /m3 in dry cleaning machine operating tasks and from 3–19 cm3 /m3 in the general air of the workroom. During the cleaning of the button strainer the transient tetrachloroethylene concentration was as high as 100 cm3 /m3. This procedure was done every other day and lasted only for a few minutes. During other short procedures such as emptying or filling the dry cleaning machine, 4– 34 cm3 /m3 concentrations of tetrachloroethylene were measured. Results suggest moderate and occasionally high exposure to tetrachloroethylene and are comparable with reports from other countries where concentrations of around 20 cm3 /m3 have been measured (15,16). Lauwerys (15) examined tetrachloroethylene concentrations of six dry cleaning shops in Belgium. The time-weighted average exposure of workers to tetrachloroethylene amounted to 21 ppm (range 9–38 ppm).

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The National Institute for Occupational Safety and Health (NIOSH) conducted industrial hygiene surveys at 44 commercial dry cleaning facilities in five states as part of an industry-wide study to assess the health effects of long-term, low level exposures to tetrachloroethylene (16). The time-weighted average (TWA) and peak exposures were determined by collecting personal air samples, using activated charcoal tubes and batteryoperated pumps. TWA exposures of the machine operators ranged from 4.0 to 149.0 ppm. The geometric mean tetrachloroethylene exposure of the machine operators (22 ppm) differed significantly from the mean exposures of the pressers (3.3 ppm) and seamstresses (3.0 ppm) and the concentrations in the front counter areas of the facilities (3.1 ppm). The geometric mean 5-minute peak tetrachloroethylene exposure during textile transfer was 44 ppm while the mean 15-minute exposure was 33 ppm. No significant differences were found between exposures when either the TWA of the peak data were grouped by geographic location (i.e., state) or by the type of processing equipment used (i.e., ‘‘combination’’ units vs. separate washing and drying units). Comparison with IOL Levels The routine rating factors and nonroutine rating factors for tetrachloroethylene from the Products and Chemicals Division ranged from 00 to 01, indicating no reasonable chance for exposure to minimal exposure not expected to exceed 10% of the OEL. The TLVTWA is 170 mg/m3 (25 ppm) and TLV-STEL is 685 mg/m3 (101 ppm) (2). In comparison to Lauwreys et al. (15), who reported tetrachloroethylene exposure levels that averaged 21 ppm, and Ludwig et al. (16), who reported TWA exposures of dry cleaning machine operators ranging from 4.0 to 149.0 ppm, IOL tetrachloroethylene exposure levels are considerably lower than those reported in the literature. Toluene A few case reports of malformations in association with toluene exposure have appeared. Euler (17) reported two cases of multiple malformations where the anomalies were similar in children born to women who worked in shoemaking and were exposed to a soling solution containing toluene and trichloroethylene. The average concentration of toluene in the air was 298 ppm (1.12 mg/L) and of trichloroethylene 230 ppm (1.22 mg/L). No further details of these cases were given. Toutant and Lippmann (18) reported a single case of adverse pregnancy outcome in a woman addicted to solvents ( primarily toluene). The woman, aged 20 years, had a 14-year history of daily heavy solvent abuse and a 3-year history of alcohol intake of about a six-pack of beer weekly. On admission to the hospital, she had ataxia, tremors, mild diffuse sensory deficits, short-term memory loss, blunted affect, and poor intellectual functioning compatible with severe solvent and/or alcohol abuse. The male child born at term was microcephalic with a flat nasal bridge, hypoplastic mandible, short palpebral fissures, mildly low-set ears, pronounced sacral dimple, sloping forehead, and incoordination of arm movements, with unusual angulation of the left shoulder and elbow. There was a poor sucking reflex and movements were jerky at 2–4 days of age, though this improved spontaneously. No joint or muscular abnormalities were found at physical examination or x-ray. The authors of this report point out the similarities between this case and fetal alcohol syndrome and suggest that there may be an analogous ‘‘fetal solvent syndrome’’ or that excessive solvent intake may enhance the toxicity of alcohol. Syrovadko (19) studied the outcome of pregnancy in a substantial number of women exposed to toluene. Toluene exposure averaged 55 ppm (range 13–120 ppm). The factory

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had its own maternity section, where the women had their deliveries. Records of labor and newborns were examined for 133 women in contact with toluene and for 201 controls from the factory offices. There was no detectable effect on fertility. In the exposed group, records showed a mean pregnancy rate of 3.2 per worker compared with 2.6 per worker in the control group. There were no significant differences between exposed and control groups in the mortality or adverse effects on the newborn. Average birth weights did not differ significantly (exposed group 3432 ⫹/⫺34 g, control group 3518⫹/⫺28 g), but there were twice as many babies of low birth weight (2500–3000 g) in the exposed group as in the controls (20% compared with 9%, p ⬍ 0.05). In the study of Holmberg et al. (4) on CNS defects in children born to mothers exposed to organic solvents during pregnancy, 3 of the cases were exposed to toluene or toluene in combination with other solvents. In the first case, a child with hydranencephaly died 24 days after birth. There was exposure to toluene, xylene, white spirit, and methyl ethyl ketone from rubber-products manufacture. A previous child had also died from brain injury. The second case involved an infant who had multiple abnormalities of hydrocephalus, agenesis of the corpus callosum, pulmonary hypoplasia, and diaphragmatic hernia, and died 2 hours after birth. There was exposure to toluene through metal products manufacture. In the third case an infant with lumbar meningomyelocele survived. There was exposure to toluene and white spirit. A case-referent study (20) of selected exposures during pregnancy among mothers of children born with oral clefts was done in Finland. The study covered the initial 3.5 years’ material and was a more detailed extension of earlier retrospective studies of environmental factors in the causation of oral clefts using material accumulated from the Finnish Register of Congenital Malformations. Significantly more case mothers (fourteen) than referent mothers (three) had been exposed to organic solvents during the first trimester of pregnancy. The mothers were considered ‘‘substantially’’ exposed if their estimated continuous exposure had been at least one-third of the current TLV concentration or if the estimated peak exposure had reached the TLV concentration, e.g., during home painting in confined spaces. Various solvents included lacquer petrol, xylene, toluene, acetates, alcohols, denatured alcohol, methyl ethyl ketone, methylene chloride, turpentine, styrene, and aromatic solvent naphtha (C4–C14 aromates). Ng et al. (21) examined the risk of spontaneous abortion in workers exposed to toluene. Rates of spontaneous abortions were determined using a reproductive questionnaire administered by personal interview to 55 married women with 105 pregnancies. They were employed in an audio speaker factory and were exposed to high concentrations of toluene (mean 88 ppm, range 50–150 ppm). These rates of spontaneous abortion were compared with those among 31 women (68 pregnancies) who worked in other departments in the same factory and had little or no exposure to toluene (0–25 ppm) as well as with a community control group of women who underwent routine antenatal and postnatal care at public maternal health clinics. Significantly higher rates of spontaneous abortion were noted in the group with higher exposure to toluene (12.4 per 100 pregnancies) compared with those in the internal control group (2.9 per 100 pregnancies) and in the external control group (4.5 per 100 pregnancies). Among the exposed women, significant differences were also noted in the rates of spontaneous abortion before employment (2.9 per 100 pregnancies) and after employment in the factory (12.6 per 100 pregnancies). Tikkanen et al. (22) performed a study to explore for possible associations between occupational factors and cardiovascular malformations. Information on the parents of 160 infants with cardiovascular malformations and 160 control parents were studied. Two trained interviewers from the Institute of Occupational Health in Helsinki collected de-

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tailed data on occupational and leisure time exposures using a specially designed questionnaire. They interviewed all case and control mothers. Most mothers were interviewed at their Maternity Care Centers during the first postnatal visit at 3 months after delivery. Mother’s work attendance during pregnancy was recorded. An open question asked the mother to describe her ordinary workday and all different work phases in detail. An industrial hygienist blindly grouped the exposure information into qualitative and quantitative categories. In many instances the hygienist received further information on exposure through personal contacts with the employers by visiting the places of work where the exposure occurred or by asking the mothers for details of domestic exposures. The mother was considered ‘‘substantially’’ exposed to organic solvents if the estimated continuous exposure was at least one third of the ACGIH threshold limit value concentration or the estimated short-term exposure reached the TLV concentration (while painting kitchen walls). Organic solvents were categorized as ‘‘hydrocarbons,’’ ‘‘alcohols,’’ and ‘‘miscellaneous.’’ Hygiene assessments of exposures were classified as ‘‘any exposure intensity’’ (at any period in pregnancy and in the first trimester only) and ‘‘substantial exposure intensity’’ (at any period in pregnancy and in the first trimester only). Of the 320 mothers, 41 case and 40 control mothers reported an exposure to organic solvents. The hygiene assessment indicated some solvent exposure in 27 case and 25 control mothers. A total of 21 case and 16 control mothers had been exposed in the first trimester. Of these, 6 case and 2 control mothers had been exposed substantially to hydrocarbons [unadjusted OR 3.0, CI (0.7–13.8)]: one case and one control mother to toluene at work, five cases and one control mother to lacquer petrol while painting indoors at home for 1 to 2 days. Lindbohm et al. (23) investigated the association between medically diagnosed spontaneous abortions and occupational exposure to organic solvents (case-control design). The study population was composed of women biologically monitored for solvents. The workers were classified into exposure categories on the basis of work description and the use of solvents as reported in the questionnaires and on biological exposure measurements. Three exposure levels were distinguished: high, low, and none. The level of exposure was assessed on the basis of the reported frequency of solvent use and the available information on typical levels of exposure in that particular job as based on industrial hygiene knowledge. The feasibility of biological monitoring data for classification of exposure was limited because the solvent measurements describe only short-term exposure (from 2 hours to a few days) and only 5% of the workers had been measured during the first trimester of pregnancy. Therefore, exposure classification was based mainly on the work task description and reported solvent usage and in the end, the limited monitoring results supported the conclusion. Exposure was defined as ‘‘high’’ if the worker handled the solvents daily or 1–4 days a week and the level of exposure according to biological exposure measurements or industrial hygiene measurements available at the Institute of Occupational Health was high. Exposure was defined as ‘‘low’’ if the worker handled solvents 1–4 days a week and the level of exposure according to the measurements of the Institute was low or if the worker handled solvents less than once a week. Otherwise, the level of exposure was defined as ‘‘none.’’ After classification, the work tasks and the related exposures were listed by the level of exposure, which was checked by an independent, experienced industrial hygienist. The final population for the analysis was restricted to the matched case-control sets who confirmed their pregnancy and reported in detail their occupational exposures during early pregnancy (73 cases and 167 controls). The odds ratios for tetrachloroethylene and aliphatic hydrocarbons, adjusted for potentially confounding factors, increased with the level of exposure. For toluene the reverse

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was the case. Tetrachloroethylene low exposure had an odds ratio of 0.5 and 95% confidence interval (0.1–2.9) and high exposure had an odds ratio of 2.5 (0.6–10.5). Aliphatic hydrocarbon low exposure had an odds ratio of 1.1 (0.3–3.9) and high exposure had an odds ratio of 3.9 (1.1–14.2). Toluene low exposure had an odds ratio 1.8 (0.7–4.7) and high exposure odds ratio was 1.4 (0.4–4.9). Aliphatic hydrocarbons were not biologically monitored, but industrial hygiene measurements had been performed by the Institute of Occupational Health in two printing houses that contributed subjects to this study. In two of four measurements, the concentrations of white spirit in air exceeded, during the cleaning of the printing machine, the Finnish threshold limit value (150 ppm). All the printers included in this study reported that their work included cleaning of the machine. The association of tetrachloroethylene, toluene, and aliphatic hydrocarbons with spontaneous abortions was also examined by detailed occupational task. The odds ratio of spontaneous abortion for aliphatic hydrocarbons was increased among graphic workers [5.2 (1.3–20.8)] and painters [2.4 (0.5–13.0)] but not among other workers. However, in the latter group the proportion of highly exposed was only 30%, whereas in the two former groups it was 69%. The odds ratio was increased also among toluene-exposed shoe workers [odds ratio 9.3 (1.0–84.7)] and dry cleaners exposed to tetrachloroethylene [odds ratio 2.7 (0.7–11.2)]. The mean level of blood tetrachloroethylene measurements, taken nearest to the pregnancy, was higher among dry-cleaning workers than among other workers monitored for tetrachloroethylene exposure (2.11 µmol/L, 6 samples, vs. 0.43 µmol/L, 7 samples). The results of the study support the hypothesis of a positive association between spontaneous abortion and exposure to organic solvents during pregnancy and suggest that exposure, especially to aliphatic hydrocarbons, increases the risk of abortion. The highest risk for aliphatic hydrocarbons was found among graphic workers who were employed as offset-printing workers or printing-trade workers. They used the solvents for cleaning the printing machines and as diluent for printing ink. In cleaning the machines, exposure to mixtures of nonaromatic mineral oil distillates with 0–15% aromatic compounds may reach a high level for a short period. Usually they were not used alone. The workers were also exposed, among other things, to toluene, 1,1,1-trichloroethane, thinner, and xylene. Although the data suggest that the findings are due to aliphatic hydrocarbons, combined solvent effects cannot be excluded because of the multiple exposures to different solvents. The mean level of blood toluene measurements among the shoe workers was slightly higher (0.51 µmol/L, 13 morning samples) than the mean among the other tolueneexposed workers (0.38 µmol/L, 10 morning samples). The shoe workers also reported use of toluene more frequently than the other toluene-exposed workers. Industrial hygiene measurements had been performed in three of the five workplaces of the shoe workers. The concentration of toluene in air varied from 1 to 33 ppm. Other solvents detected were acetone and hexane. In two of the three shoe factories from which industrial hygiene measurements were available, relatively high levels of hexane (33–56 ppm) were measured. Hexane, being an aliphatic compound, may have contributed to the excess of spontaneous abortions. Comparison with IOL Levels The routine rating factor and nonroutine rating factor from the Products and Chemical Divisions range from 00 to 11, indicating no reasonable chance for exposure to some daily exposures exceeding 50% of the OEL. The TLV-TWA for toluene is 50 ppm (2). The Euler (17) case reports reported air concentrations of 298 ppm for toluene and 230 ppm for trichloroethylene. Both of these air concentrations exceed current standards, and

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no further details of these cases were given. Syrovadko (19) reported a toluene exposure of 55 ppm (range 13–120 ppm), again exceeding current standards. Holmberg (4) and Tikkanen (22) reported workers ‘‘substantially’’ exposed if their estimated continuous exposure had been at least one-third of the current TLV concentration or if the estimated peak exposure had reached the TLV concentration. Similarly, Ng (21) described high concentrations of toluene (mean 88, range 50–150 ppm), exceeding current standards. All these exposure levels for toluene exceed the current threshold limit value. IOL toluene exposure levels are considerably lower than any value reported in the literature. In Lindbohm et al. (9), for two of four air measurements, the concentrations of white spirit exceeded the Finnish Threshold Limit Value (150 ppm) during the cleaning of the printing machine. Industrial hygiene measurements were performed in three of the five workplaces of the shoe workers. The concentration of toluene in air varied from 1 ppm to 33 ppm. Other solvents detected were acetone and hexane. In two of the three shoe factories from which industrial hygiene measurements were available, relatively high levels of hexane (33–56 ppm) were noted. The routine rating factor and nonroutine rating factor from the Products and Chemicals Divisions for hexane isomers range from 00 to 05, indicating no reasonable chance for exposure or minimal exposure not expected to exceed 10% of the occupational exposure limit (OEL). The routine rating factor and nonroutine rating factor from the Products and Chemicals Divisions for N-hexane ranges from 00 to 07, indicating no reasonable chance for exposure or some daily exposures between 10 and 50% of the OEL. The TLVTWA of N-hexane is 50 ppm or 176 mg/m3 (2). The TLV-TWA of other hexane isomers is 500 ppm or 1760 mg/m3, and the TLV-STEL is 1000 ppm or 3500 mg/m3 (2). In comparison with the previous hexane levels reported in the literature, IOL hexane exposure levels are substantially lower.

DISCUSSION The Motherisk program is an information and consultation service for women, their families, and health professionals on the safety/risk of exposure to drugs, chemicals, radiation, and infection during pregnancy and lactation. Chemical exposure in the workplace is a common source of concern among our patients and health professionals. In 1991 we were approached by the medical department of Imperial Oil Limited to develop a proactive approach of risk evaluation of their female workers. The paradigm developed and used by us could be extrapolated to any other chemical operation. Its advantage is in its proactive nature, which aims at informing workers and preventing potential fetal risks while also preventing unjustified fears which may lead women to quit their jobs or, in extreme cases, even consider termination of otherwise wanted pregnancies. Upon comparing the occupational literature that presented any quantifiable chemical exposure dose or estimate of dose for any chemical with the IOL routine rating factors in the Products and Chemicals Divisions, we could conclude that IOL chemical exposure levels overall were lower than those reported in the literature. Of utmost importance is the need in published occupational reports for at least some industrial hygiene documentation—namely, improved reporting of a quantifiable chemical exposure dose (for example, as implemented and currently utilized by IOL) and, ideally, a standard and consistent way of reporting this in the occupational literature.

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ACKNOWLEDGMENT Supported in part by a studentship from Imperial Oil Limited, Toronto and by the Motherisk Research Fund. REFERENCES 1. Ellenhorn MJ, Barceloux DG. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. New York: Elsevier, 1988. 2. Anonymous. Threshold limit values for chemical substances and physical agents and biological exposure indices. ACGIH 1993–1994. 3. Mukhametova GM, Vozovaya MA. Reproductive power and the incidence of gynecological affections in female workers exposed to the combined effect of benzine and chlorinated hydrocarbons. Gig Tr Prof Zabol 1972; 16:6–9. 4. Holmberg PC. Central nervous system defects in children born to mothers exposed to organic solvents during pregnancy. Lancet 1979; 2:177–179. 5. Kurppa K, Holmberg PC, Hernberg S, et al. Screening for occupational exposures and congenital malformations. Scand J Work Environ Health 1983; 9:89–93. 6. Hemminki K, Saloniemi I, Luoma K, et al. Transplacental carcinogens and mutagens: childhood cancer, malformations and abortions as risk indicators. J Toxicol Environ Health 1980; 6:1115–1126. 7. Hemminki K, Niemi ML, Koskinen K, et al. Spontaneous abortions among female chemical workers in Finland. Int Arch Occup Environ Health 1980; 45:123–126. 8. Hemminki K, Lindbohm ML, Hemminki T, et al. Reproductive hazards and plastics industry. Prog Clin Biol Res 1984; 141:79–87. 9. Lindbohm ML, Hemminki K, Kyyronen P, et al. Parental occupational exposure and spontaneous abortion in Finland. Am J Epidemiol 1984; 120:370–378. 10. McDonald AD, Armstrong B, Cherry NM, et al. Spontaneous abortion and occupation. J Occup Med 1986; 28:1232–1238. 11. McDonald AD, Armstrong B, Cherry NM, et al. Occupation and pregnancy outcome. Br J Indus Med 1987; 44:521–526. 12. Bosco MG, Figa-Talamanca I, Salerno S, et al. Health and reproductive status of female workers in dry cleaning shops. Int Arch Occup Environ Health 1987; 59:295–301. 13. Ahlborg G. Pregnancy outcome among women working in laundries and dry cleaning shops using tetrachloroethylene. Am J Ind Med 1990; 17:567–575. 14. Kyyronen P, Taskinen H, Lindbohm ML, et al. Spontaneous abortion and congenital malformations among women exposed to tetrachloroethylene in dry cleaning. J Epidemiol Commun Health 1989; 43:346–351. 15. Lauwerys R, Herbrand J, Buchet JP, et al. Health surveillance of workers exposed to tetrachloroethylene in dry cleaning shops. Int Arch Occup Environ Health 1983; 52:69–77. 16. Ludwig HR, Meister MV, Roberts DR, et al. Worker exposure to perchloroethylene in the commercial dry cleaning industry. Am Ind Hyg Assoc J 1983; 44:600–605. 17. Euler HH. Animal experimental studies of an industrial noxa. Arch Gynakol 1967; 204:258– 259. 18. Toutant C, Lippmann S, et al. Fetal solvent syndrome. Lancet 1979; 8130:1356–1357. 19. Syrovadko ON. Working conditions and health status of women handling organosilicon varnishes containing toluene. Gig Tr Prof Zabol 1977; 21:15–19. 20. Holmberg PC, Hernberg S, Kurppa K, et al. Oral clefts and organic solvent exposure during pregnancy. Int Arch Occup Environ Health 1982; 50:371–376. 21. Ng TP, Foo SC, Yoong T, et al. Risk of spontaneous abortion in workers exposed to toluene. Br J Ind Med 1992; 49:804–808.

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22. Tikkanen J, Heinonen OP, et al. Cardiovascular malformations and organic solvent exposure during pregnancy in Finland. Am J Ind Med 1988; 14:1–8. 23. Lindbohm ML, Taskinen H, Sallman M, et al. Spontaneous abortion among females exposed to organic solvents. Am J Ind Med 1990; 17:447–463. 24. Podluzhnyi PA. Importance of the nutrition factor in the comprehensive social hygiene study of the health of female workers in the chemical industry. Gig Sanit 1979; 1:44–47. 25. Tsvetkova RP. Materials on the study of the influence of cadmium compounds on the generative function. Gig Tr Prof Zabol 1970; 14:31–33. 26. Taskinen H, Lindbohm ML, Hemminki K, et al. Spontaneous abortion among women working in the pharmaceutical industry. Br J Ind Med 1986; 43:199–205. 27. Windham GC, Shusterman D, Swan SH, et al. Exposure to organic solvents and adverse pregnancy outcome. Am J Ind Med 1991; 20:241–259. 28. Gondharuk GA. Problems relating to occupational hygiene of women in production of mercury. Gig Tr Prof Zabol 1977; 5:17–20. 29. Saamanen A. Altisteet tyossa 9. Styreeni, Helsinki, Institute of Occupational Health, 1991. 30. Harkonen H, Tola S, Korkala ML, et al. Congenital malformation, mortality and styrene exposure. Ann Acad Med Singapore 1984; 13:404–407.

31 The Use of Herbal Medicine in Pregnancy and Lactation A Clinician’s Guide Michael Gallo and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Michael J. Smith The Canadian College of Naturopathic Medicine, Toronto, Ontario, Canada

Heather Boon The University of Toronto, Toronto, Ontario, Canada

Clinical Case A 25-year-old Caucasian woman was advised by a naturopath and a friend to take echinacea for a cold. However, both her pharmacist and physician advised against its use, since she is 16 weeks pregnant. Can she take echinacea safely during pregnancy? INTRODUCTION Complementary and alternative medicine (CAM) is an umbrella term used to describe a number of health care therapies that are generally considered to fall outside the conventional medical model (383). The use of CAM has increased dramatically, with the market in the United States estimated to be worth $27 billion (384). In Canada a similar trend exists, with the market estimated to be $2.3 billion and almost three quarters of the population stating that they have used a form of CAM in their lifetime (385). Herbal medicine (also known as botanical medicine, phytotherapy, phytomedicine, herbalism, and herbology) is considered to be one of the primary complementary and alternative therapies (383). Between 1990 and 1997, it has been estimated that the use of herbal medicines increased by 380% in the United States (384), with the market sales estimated at $3.24 billion (386). In its most basic sense, herbal medicine can be simply defined as the use of plants and plant remedies in the treatment and prevention of disease (387). Unfortunately the situation is more complex than this, with a number of different paradigms and philosophies present in clinical practice. This heterogeneous practice has led to a number of incongruities, most notably the wide variance in dosage that exists in erroneously referring to a homeopathic or nutritional supplement as a herbal medicine. Consequently it is often necessary for the clinician to confirm that the patient is actually taking a herbal medicine (383). 569

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A common misconception that exists, among patients and practitioners alike is that the term safe and natural are interchangeable (388,389). While this is not the case, it has led to added difficulties in assessing risk posed by herbal medicine. It is known that consumption of herbal medicine can result in direct adverse effects, such as allergic reactions, nausea, vomiting, and sedation (388,390). In addition, the potential exists for herbal remedies to interact with conventional pharmacotherapy (391). It is estimated that 15 million people annually (almost 20% of all prescription users) take either herbal or nutritional supplements concurrently with prescription drugs (384). There seems to be reluctance on the part of consumers to report adverse drug reactions (ADR) resulting from herbal products when compared with conventional drugs (392). When an ADR does occur there is a lack of systematic universal reporting. In addition, poor quality controls in manufacturing procedures have led to the erroneous reporting of serious adverse effects by herbal agents where adulterants are actually responsible (63,390,393). Therefore, even when adverse effects and/or interactions with conventional drugs are reported in the literature, it is important to note whether the herbal product was authenticated. To complicate matters further, there is often a lack of disclosure on the part of the consumer to the health care provider when herbal remedies lead to ADR. It has been estimated that over 60% of users do not inform their primary physician that they are using CAM (384). The use of herbal medicine in pregnancy and lactation poses a number of concerns. While these agents have a long history of use in pregnancy, during delivery, and for lactation, clinically relevant sources of information on the safety/risk of such products is lacking (186). There is also a lack of consistency between reference sources. The popularity of herbal products has resulted in an increasing number of women and their health care providers contacting the Motherisk Program regarding the safety/ risk of such remedies in pregnancy and lactation. The following chapter includes 30 of the most common herbal medicines discussed over the counseling line. They are listed by species and family names. Each is identified by its primary constituents and pharmacological actions as reported in the literature. Many herbs exhibit lesser therapeutic actions that may not be covered in this chapter. Common uses are the main indications for each herb. Although variation in dose is possible for each herb, only standardized doses are listed. Adverse effects, cautions, contraindications, and drug interactions are based on reported clinical cases or possible theoretical concerns. This chapter is not intended to be an authorative text on herbal medicine. A number of excellent texts already exist, and readers are referred to them for more complete information (1,2,53,288,394). Although the question of efficacy poses particular challenges for herbal medical practice, it is not addressed. This chapter concentrates primarily on information relating to the use of these herbs in pregnancy and lactation and the safety/ risk of such use. A review of the literature quickly shows that studies in this area are lacking. Often clinical or evidence-based information does not exist. This chapter is intended to provide the clinician with a review of the available information on each herb and to list possible implications for pregnancy and lactation.

Clinical Case Answer Although the safety of echinacea use in pregnancy has not been established, there are no reported contraindications. A prospective controlled study is being completed at the Motherisk Program and analysis of the data at this time suggests that the rate of major

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malformations between the echinacea group (n ⫽ 206) and a control group (n ⫽ 206), matched for material illness is not statistically significant.

Alfalfa (Medicago sativa L., Fabaceae) Primary Constituents: saponins, isoflavone flavonoids (genistein, daidzein, formononetin), amino acids (canavanine), alkaloids, coumarins, carbohydrates, vitamins (A, B1, B6, B12, C, E, K) (1–6) Primary Pharmacological Actions: nutritive (1,7); hypercholesterolemic (2,8,9); phytoestrogenic (10,11); anticoagulant (10) Common Uses: hypercholesterolemia; management of menopause and menstrual discomfort (2) Dose (1): dried herb: 5–10 g three times per day liquid extract: 5–10 mL three times per day Adverse Effects/Toxicology: gastrointestinal upset and diarrhea (10); photosensitivity (12) and reactivation of systemic lupus erythematosus (SLE) have been reported (13–15) Cautions/Contraindications: discontinue use if allergic skin reaction occurs; patients with a history of SLE should avoid use (13) Drug Interactions: high vitamin K content may lead to interactions with anticoagulants (1,2); phytoestrogenic properties of isoflavones suggests a possible interaction with hormone replacement therapy and oral contraceptives (1) Implications for Pregnancy/Lactation: dietary use should not pose a risk; phytoestrogenic nature of herb would suggest caution in pregnancy and lactation (1,2)

Aloe Vera [A. vera (L.) Burm.f., Aloeaceae] Primary Constituents: Aloe vera gel: polysaccharides (acemannan), enzymes, vitamins, minerals (1,17– 23) Aloes: anthraquinone glycosides (24) Primary Pharmacological Actions: Aloe vera gel: immunostimulant (25–32); antibacterial (33,34); antimicrobial (35); anti-inflammatory (36–39); antiviral (40–42) Aloes: laxative (2,18) Common Uses: Aloe vera gel: wound healing (1,43), treatment of skin irritations (eczema, psoriasis) (2) Aloes: constipation (18) Dose (2): Aloe vera gel: strength varies between brands Aloes: 50–200 mg three times per day when used as a laxative Adverse Effects/Toxicology: Aloe vera gel: rare contact dermatitis (44–47) Aloes: anthraquinone glycosides are colonic irritants (7); chronic use may lead to severe cramping (1) and bloody diarrhea; kidney irritation and possible

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nephritis; electrolyte imbalances possible due to acute and chronic toxicity (18,24) Cautions/Contraindications: Aloe vera gel: discontinue use if skin reaction occurs Aloes: chronic use for relief of constipation not recommended; not advised in patients with appendicitis, abdominal pain, or renal disease (1,2) Drug Interactions: none reported Implications for Pregnancy/Lactation: conflicting reports of anti-implantation, abortifacient, and estrogenic effects in animal studies (48); anthraquinone glycosides may lead to electrolyte imbalances and interfere with absorption of nutrients when used chronically; aloes should be considered contraindicated in pregnancy and lactation (2); topical use of aloe vera gels not expected to pose a risk in pregnancy (1)

Black Cohosh [Cimicifuga racemosa (L.) Nutt., Ranunculaceae] Primary Constituents: alkaloids, tannins, terpenoids, flavonoids (formononetin) (1,49,50) Primary Pharmacological Actions: number of ‘‘endocrine active agents’’ have been identified with various pharmalogical properties including decreasing luteinizing hormone secretion and binding to estrogen receptors with no effect on follicle-stimulating levels (2,49,50); hypotensive (51) and antibacterial actions (52) have been documented in vitro and in vivo for related species Common Uses: management of premenstrual syndrome, dysmenorrhea, and menopause (53) Dose (1): dried herb: 0.3–2.0 g three times per day liquid extract: 0.3–2.0 mL daily Adverse Effects/Toxicology: at higher doses headaches, nausea, vomiting, dizziness, nervous and cardiovascular depression may occur (1,2), stomach/gastric pain (53) Caution/Contraindications: limited toxicity at standard doses Drug Interactions: none reported Implications for Pregnancy/Lactation: contraindicated in pregnancy and lactation since estrogen receptor binding has been noted in vitro (1,54); unconventional health care practitioners have been known to use this herb to aid delivery

Burdock (Arctium lappa L., Asteraceae) Primary Constituents: aldehydes, carbohydrates (inulin), polyacetylenes, volatile oils, sesquiterpene lactones(arctiopicrin) (1,55) Primary Pharmacological Actions: folkloric evidence suggests diaphoretic (55,56); diuretic (55–58); laxative (58); antipyretic properties (55); hypoglycemic (59); antibacterial (52); antimicrobial (1,59,60); antimutagenic (1,55,61); fiber extracted from burdock root has been shown to protect against the potentially harmful effects of a number of artificial food additives in rats (2,62)

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Common Uses: oral and topical use for skin conditions such as eczema and psoriasis (1,55); orally also used for rheumatic conditions and infection (2,55) Dose (1): dried herb: 2–6 g three times per day liquid extract: 2–8 mL three times per day tincture: 8–12 mL three times per day decoction: 500 mL per day Adverse Effects/Toxicology: temporary worsening of presenting symptoms is noted (2) Caution/Contraindications: based on hypoglycemic action of root caution advised for diabetic patients (1); potential for allergic reaction in individuals with a known allergy to the sunflower (Asteraceae) family Drug Interactions: no reported cases; however, potential for interaction with oral hypoglycemic agents (1) Implications for Pregnancy/Lactation: uterostimulant action has been noted in vivo suggesting caution in pregnancy (1,55,63); use during lactation is not advised since sesquiterpene lactones are reported to be excreted in breast milk (64) Calendula (Calendula officinalis L., Asteraceae) Primary Constituents: flavonoids, volatile oils, terpenoids, polysaccharides (1,65,66) Primary Pharmacological Actions: anti-inflammatory action noted in vivo due possibly to inhibition of lipoxygenase activity (7–69); immunostimulant (70); antiviral (71); antibacterial (71,72); antineoplastic (71,73) Common Uses: orally has been used for gastritis, ulcers, and minor digestive irritation (1,2); applied topically for skin abrasions and minor burns (2,74) Dose (1): dried herb: 1–4 g three times per day liquid extract: 0.5–1.0 mL three times per day tincture: 0.3–1.2 mL three times per day Adverse Effects/Toxicology: no reported toxicity Cautions/Contraindications: potential exists for an allergic reaction to occur in individuals sensitive to members of the sunflower (Asteraceae) family (2) Drug Interactions: no reported interactions in humans Implications for Pregnancy/Lactation: oral use not recommended in pregnancy since traditionally an emmenagogue (7); estrogenic activity would suggest avoidance in pregnancy and lactation (75); extracts of this herb have been used externally to aid in postpartum wound healing (2) Capsicum (Capsicum annum L., Solanaceae) Primary Constituents: capsaicinoids (capsaicin), volatile oils, carotenoids, vitamins A and C (1) Primary Pharmacological Actions: capsaicin selectively inhibits the release of substance P, resulting in a number of clinical actions, most notably analgesia (76); folkloric evidence suggests use as a digestive and cardiovascular stimulant (2) Common Uses: topical use has been used for pain management (77–81), such as in diabetic neuropathy (82–86), and neuralgia (87–90)

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Dose (1): herb/fruit: 30–120 mg three times per day tincture: 0.3–1 mL daily (strength varies among topical products) Adverse Effects/Toxicology: internally can irritate mucosal membranes (1), causing lacrimation and nasal secretions (76) Cautions/Contraindications: should be avoided by patients with a known skin allergy, gastric irritation, or hypertension (2) Drug Interactions: caution advised for patients on antihypertensive agents and monoamine oxidase inhibitors (MAOIs) (1); hepatic metabolism of drugs may be increased (1,2,91) Implications for Pregnancy/Lactation: dietary levels of capsicum should be considered safe in pregnancy and lactation, although safety of medicinal use is less clear; extracts of leaves and stems are not used therapeutically, but in animal studies they have been shown to be uterine stimulants (2,63); capsicum should be used with caution during lactation due to the herb’s pungent nature (1) Chamomile, German (Matricaria recutita L., Asteraceae) Primary Constituents: coumarins, flavonoids (apigenin), volatile oils (chamazulene, (⫺)alpha-bisabolol, spiroethers) (1,92) Primary Pharmacological Actions: anti-inflammatory (92–94); spasmolytic (92,93,95); antiulcerogenic (92,93,96); hypnotic and anxyioltic actions (97,98); anti-inflammatory properties (could be a result of the inhibition of leukotriene synthesis as well potential antioxidant properties) (99,100) Common Uses: digestive aid and gastrointestinal discomfort (peptic ulcers, gastritis, colic, diarrhea) (2); insomnia, tension and anxiety (1,92,93); applied topically for skin irritations (93,101,102) Dose (2,92): dried herb: 1–4 g three times per day liquid extract: 1–4 mL three times per day tincture: 3–10 mL three times per day Adverse Effects/Toxicology: allergic reactions following both oral and topical use have been reported (92,103) (including two cases of anaphylactic reactions) (104,105); vomiting may occur following excessive doses (1,92) Cautions/Contraindications: potential exists for cross-sensitivity in individuals known to be allergic to members of the sunflower (Asteraceae) family (2,106) Drug Interactions: the apigenin constituent is a central benzodiazepine receptorligand; therefore interaction with agents such as anxiolytics and hypnotics is possible (98) Implications for Pregnancy/Lactation: traditional emmenagogue and abortifacient (7); no teratogenicity reported, however, resorption of fetuses and reduction in birth weight has been observed in animal studies following administration of high doses (2,107); caution advised with high dose, although no contraindications exist in pregnancy or lactation at this time Chaste Tree (Vitex agnus-castus L., Verbenaceae) Primary Constituents: iridoids (agnuside), alkaloids, flavonoids, volatile oils (1) Primary Pharmacological Actions: reported to increase the release of luteinizing

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hormone and prolactin by inhibiting the release of follicle-stimulating hormone from the anterior pituitary (108) Common Uses: premenstrual syndrome, menstrual cycle irregularities, menopause (108,109); mastodynia; acne resulting from a hormonal imbalance (1,110); insufficient lactation; situations associated with hyperprolactinemia (111,112) Dose: fruit: 0.5–1.0 g three times per day (1) extract: 40 drops standardized to fruit content (9 g/100 mL) daily (2) Adverse Effects/Toxicology: nausea, headache, diarrhea, dyspepsia, acne, pruritus, and menstrual irregularities have been reported to a limited degree (2,108) Cautions/Contraindications: patients on hormone therapy should avoid use (1) Drug Interactions: patients on hormone therapy or oral contraceptives should avoid use (1); possible interaction with dopamine antagonists such as haloperidol and metoclopramide (2) Implications for Pregnancy/Lactation: a case of multiple follicular development has been noted in patients undergoing unstimulated in vitro fertilization treatment with the use of herbal medicine containing chaste tree (113); given the pharmacology of this herb and emmenagogue properties, use not recommended during pregnancy; although information is limited, stimulation of lactation has been noted without altering the composition of the breast milk (1,2) Cranberry (Vaccinium macrocarpon Ait., Ericaceae) Primary Constituents: proanthocyanides, fructose, terpenoids, unidentified large molecular weight compound (2) Primary Pharmacological Actions: have not been well established, however, cranberry is purported to inhibit bacterial adherence to the urinary tract (2,114– 117) Common Uses: prophylaxis use against urinary tract infections (18–120) Dose (2,118): capsules: 300–400 mg twice daily juice: 150–600 mL daily Adverse Effects/Toxicology: no evidence of toxicity Cautions/Contraindications: none reported Drug Interactions: none reported Implications for Pregnancy/Lactation: based on available information unlikely to be a concern in pregnancy and lactation Dandelion (Taraxacum officinale G.H. Weber ex Wiggers, Asteraceae) Primary Constituents: terpenoids (triterpenoids), phytosterols, inulin, minerals (potassium), vitamin A (1,121) Primary Pharmacological Actions: dandelion root used principally as a digestive aid and choleretic agent (122), while the leaf exerts a diuretic action (123); hepatoprotective (124); antimicrobial (125); hypoglycemic (126); antiinflammatory (127) Common Uses: root suggested for hepatobiliary disorders, dyspepsia, and loss of appetite (2); leaves used mainly for water retention (1)

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Dose (1): dried herb: 2–8 g of root or 4–10 g of leaves three times per day liquid extract (leaves): 4–10 mL three times per day tincture (root): 5–10 mL three times per day Adverse Effects/Toxicology: allergic reaction to herb can occur (1,128) Cautions/Contraindications: allergic response possible in individuals with a known allergy to the sunflower (Asteraceae) family; caution suggested in cases of occlusion of the bile ducts, empyema, and paralytic ileus (2); source of dandelion should be observed since reports of heavy metal contamination (129) Drug Interactions: possible interaction with dandelion leaves and diuretics (1) Implications for Pregnancy/Lactation: folkloric evidence would suggest avoidance during pregnancy; however, generally not expected to be a concern (1); prudent to avoid high dose during pregnancy and lactation

Devil’s Claw (Harpagophytum procumbens DC., Pedaliaceae) Primary Constituents: carbohydrates, iridoids (harpaside, harpagoside), phenols (1,130–132) Primary Pharmacological Actions: anti-inflammatory (133,134), antirheumatic (74,135,136); analgesic (1); cardiovascular activity (137,138) Common Uses: joint inflammation due to rheumatoid arthritis and gout (1); indigesion and dyspepsia (2,56,139,140) Dose (1,2): dried herb: 400–500 mg three times per day dried tuber: 0.1–0.25 g three times per day liquid extract: 0.1–0.25 mL three times per day tincture: 0.5–1.0 mL three times per day Adverse Effects/Toxicology: adverse effects appear to be rare being limited to mild digestive upset (2) Cautions/Contraindications: digestive bitter, therefore can theoretically increase stomach acid secretions, caution advised in patients with active peptic ulcer and gall bladder disease (1,2) Drug Interactions: none reported, however, cardiovascular activity suggests a possible interaction with treatments for cardiac problems (1) Implications for Pregnancy/Lactation: safety in pregnancy and lactation has not been established; some doubt that devil’s claw is a traditional abortifacient (141)

Dong Quai [Angelica sinensis (Oliv.) Diels, Apiaceae] Primary Constituents: furanocoumarins (bergapten), volatile oils (1,142,143) Primary Pharmacological Actions: traditional use in gynecological disorders and obstetrics (see common uses); hypotensive (144,145); antiarrhythmic (144, 145); antilipidemic (1); analgesic (146) Common Uses: menopause (147); dysmenorrhoea (144,146); amenorrhea (2,143, 144)

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Dose (1): dried herb: 1–2 g of root/rhizome or 2–5 g of leaves three times per day liquid extract: 0.5–2.0 mL of root/rhizome or 2–5 mL of leaves three times per day tincture: 0.5–2 mL of root/rhizome or 2–5 mL of leaves three times per day Adverse Effects/Toxicology: although not seen in angelica root specifically, concerns exist regarding the presence of furanocoumarins, which may result in possible photosensitization, resulting in a dermatitis-like skin reaction (2, 139,148); diarrhea possible since herb may exert a relaxant action on smooth muscle of digestive tract (139) Cautions/Contraindications: folkloric evidence cautions against use in acute illnesses such as hypermenorrhea and hemorrhagic disease (144) Drug Interactions: caution is recommended in patients receiving oral anticoagulants (1) Implications for Pregnancy/Lactation: although widely used for gynecological disorders and obstetrics (including as a tonic aiding recovery postpartum and treatment of gestational hypertension) (2,149), considered a traditional emmenagogue and abortifacient (7); first trimester use and patients with a history of spontaneous abortions cautioned since dong quai known to influence uterine muscle in vitro (2,144); caution is prudent in pregnancy and lactation

Echinacea [E. angustifolia DC., E. purpurea (L.) Moench, E. pallida (Nutt.) Nutt., Asteraceae] Primary Constituents: carbohydrates (polysaccharides) (150,151), glycoproteins (2); amides (alkamides) (152–154), caffeic acid derivatives (echinacoside, cichoric, cynarin) (155–158)* Primary Pharmacological Actions: immunostimulatory action (159–162); antiinflammatory (163,164); antibacterial (2); antiviral (165); antineoplastic (166) Common Uses: upper respiratory tract (common cold and flu) and lower urinary tract infections (2,167) Dose (1): dried herb: 1 g three times per day liquid extract: 0.25–1.0 mL three times per day tincture: 1–2 mL three times per day Adverse Effects/Toxicology: no reported toxicity Cautions/Contraindications: should be avoided by individuals with a known allergy to the sunflower (Asteraceae) family (53); caution in patients with progressive systemic diseases (tuberculosis, multiple sclerosis) and autoimmune conditions (diabetes mellitus, lupus, rheumatoid arthritis) (2,7) Drug Interactions: immunostimulatory action suggests caution with immunosuppressant agents (2)

* Although the three species are often considered interchangeable, their chemical constituents do differ (2).

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Implications for Pregnancy/Lactation: prospective controlled study being completed at the Motherisk Program and analysis of data at this time suggests the rate of major malformations in the study group (n ⫽ 196) versus the disease-matched control group (n ⫽ 195) is not statistically significant; safety during lactation has not been established Evening Primrose (Oenothera biennis L., Onagraceae) Primary Constituents: fixed oils (linoleic acid and gamma linolenic acid) (1,168) Primary Pharmacological Actions: essential fatty acid involved in prostaglandin biosynthetic pathways (1,169) Common Uses: management of dermatological conditions (atopic eczema) (170– 174); gynecological disorders and obstetrics [premenstrual syndrome (175, 176); menopause (177); mastalgia (178,179) and endometriosis (180)]; psychiatric conditions (1,181); diabetic neuropathy (182); rheumatoid arthritis (183); multiple sclerosis (184); Sjo¨gren’s syndrome (180,185) Dose: dose varies depending on the indication (standard adult dose is 2–8 g daily) (2) Adverse Effects/Toxicology: gastrointestinal discomfort (indigestion, diarrhea, nausea) and headache have been reported to a limited degree (1) Cautions/Contraindications: caution advised for patients with a history of mania or epilepsy (1,2) Drug Interactions: possible concerns with phenothiazines, nonsteroidal antiinflammatory drugs, corticosteroids, anticoagulants, and beta-adrenergic antagonists (2) Implications for Pregnancy/Lactation: although no teratogenicity has been seen in animal studies, safety information is limited; less than 4 g daily suggested to be safe (186); caution advised during lactation since milk composition may be affected (187) Feverfew [Tanacetum parthenium (L.) Schultz-Bip., Asteraceae] Primary Constituents: sesquiterpene lactones (parthenolide), volatile oils, pyrethrins, flavonoids (1,188–190) Primary Pharmacological Actions: analgesic (189); anti-inflammatory (191); antipsoriatic (189,190) Common Uses: migraine prevention (192–194); arthritis (195) Dose (1): dried herb: 50–200 mg daily Adverse Effects/Toxicology: trials have reported mouth ulcers and gastrointestinal discomfort (abdominal pain, indigestion, diarrhea, flatulence) (139,193); ‘‘post-feverfew syndrome’’ has been described in the literature (1,2,193) Caution/Contraindications: individuals with known allergies to the sunflower (Asteraceae) family should avoid use (196,197) Drug Interactions: no reported cases; one review suggests possible interaction with anticoagulant therapy (2) Implications for Pregnancy/Lactation: traditional emmenagogue and abortifacient (7); not recommended for use in pregnancy and lactation

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Ginger (Zingiber officinale Roscoe, Zingiberaceae) Primary Constituents: oleo-resin (gingerols, shogaols), carbohydrates, volatile oils (1,198) Primary Pharmacological Actions: antiemetic/antinauseant (2,199); antiulcerogenic (200–203); anti-inflammatory (204,205); hypoglycemic (206); cardiotonic (207); analgesic (208) Common Uses: antinauseant [motion sickness (209,210), pregnancy (211), druginduced (212,213)]; digestive aid (dyspepsia, gastrointestinal upset) (214); management of inflammatory conditions (osteoarthritis, rheumatoid arthritis, myalgias) (2,215–217) Dose (1): dried herb (rhizome): 0.25–1.0 g three times per day Adverse Effects/Toxicology: low toxicity rating; heartburn and dyspepsia have been reported (2) Cautions/Contraindications: none reported Drug Interactions: none reported, however, based on pharmacological actions caution advised when patients using cardiac, diabetic, and anticoagulant therapy (1,2) Implications for Pregnancy/Lactation: no teratogenicity was seen in a study group taking 250 mg of powdered ginger four times daily for the treatment of hyperemesis gravidarum (211); although a traditional abortifacient at standard therapeutic dose, it can be taken during pregnancy (2,218) Ginkgo (Ginkgo biloba L., Ginkgoaceae) Primary Constituents: terpenoids (ginkolides), flavonoids (bilobides, flavone glycosides) (1,219,220) Primary Pharmacological Actions: vasodilator (219,221); spasmolytic (222,223); antithrombotic (224,225); antioxidant (226–230); neuroprotective effect (231, 232) Common Uses: dementia (233–235)/memory impairment (236–239); cerebral insufficiency (219,240,241); intermittent claudication (242); Raynaud’s syndrome (2); tinnitus (243,244); vertigo (245–247) Dose (2): dried herb (leaves): 300 mg daily standardized extract: 40 mg three times per day Adverse Effects/Toxicology: mild adverse reactions include gastrointestinal discomfort and headache (1); spontaneous bleeding has also been reported (2,249) Cautions/Contraindications: none reported Drug Interactions: none reported; may theoretically potentiate the effect of anticoagulants (2) Implications for Pregnancy/Lactation: safety in pregnancy and lactation has not been established Goldenseal (Hydrastis canadensis L., Ranunculaceae) Primary Constituents: isoquinoline alkaloids (hydrastine, berberine, canadine) (1,250)

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Primary Pharmacological Actions: antimicrobial (58,251,252); astringent (74,253); antipyretic (253); antineoplastic (254,255) Common Uses: infections of the upper respiratory (1) and genitourinary tract (256– 258) Dose (1): dried herb: 0.5–1.0 g three times per day liquid extract: 0.3–1.0 mL three times per day tincture: 2–4 mL three times per day Adverse Effects/Toxicology: toxicity at high dose can cause nausea, vomiting, diarrhea, hypotension, myocardiac depression, dyspnea, hyperreflexia, parasthesia, convulsions, and death through respiratory failure (1,2,7); contact ulceration of mucosal membranes reported (1) Cautions/Contraindications: contraindicated in hypertensive patients (1,58) Drug Interactions: none reported Implications for Pregnancy/Lactation: contraindicated in pregnancy based on uterine stimulant actions of hydrastine, berberine, and canadine (1,2,7,63); safety during lactation has not been established

Hops (Humulus lupulus L., Cannabaceae) Primary Constituents: volatile oils, oleoresins, flavonoid glycosides, tannins (1,259) Primary Pharmacological Actions: sedative (74,253,259,260); spasmolytic (7,253); antimicrobial (1,261,262); anti-inflammatory (263) Common Uses: insomnia, agitation, digestive aid, irritable bowel syndrome (57,253) Dose: dried herb: 0.5–1.0 g three times per day (57) liquid extract: 0.3–1 mL three times per day (2) tincture: 2–4 mL three times per day (2) Adverse Effects/Toxicology: allergic response including anaphylactic reaction most frequently reported (1,7,264,265); animal studies have shown hops can be fatal when administered parenterally (1) Cautions/Contraindications: patients with a history of depression should avoid use (1,2,253) Drug Interactions: sedative action may potentiate the effects of hypnotics and alcohol (1,2) Implications for Pregnancy/Lactation: contains hormone substances and possible estrogenic activity (7,58,266); antispasmodic activity in the uterus reported in vitro (1); should be avoided in pregnancy and lactation

Juniper (Juniperus communis L., Cupressaceae) Primary Constituents: flavonoids, tannins, volatile oils (monoterpenes, sesquiterpenes) (1,267) Primary Pharmacological Actions: diuretic (139); antiviral (139,268); hypoglycemic (269,270); anti-inflammatory (271); astringent (1) Common Uses: genitourinary tract infections (74,272); rheumatic conditions (arthritis) (56); cystitis (2,272); digestive aid (56)

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Dose (1): dried herb(fruit): 1–2 g three times per day liquid extract: 2–4 mL three times per day tincture: 1–2 mL three times per day Adverse Effects/Toxicology: topical use documented to cause burning, erythema, inflammation, blistering, and possible contact dermatitis (2); high oral dose associated with kidney and gastrointestinal irritation, nephrotoxicity, diuresis, albuminuria, hematuria, discolored urine, tachycardia, and hypertension (1,7) Cautions/Contraindications: although refuted by a recent report (273), herb generally considered contraindicated in kidney disease (2) Drug Interactions: not advised in patients receiving hypoglycemic and diuretic agents (1) Implications for Pregnancy/Lactation: traditional emmenagogue and abortifacient (7,274–276); proposed uterostimulant, anti-implantation, and antifertility properties would suggest avoidance in pregnancy (1,2,63,277); safety during lactation has not been established

Kava (Piper methysticum G. Forst, Piperaceae) Primary Constituents: kavalactones (pyrones), alkaloids, flavonoids (278,279) Primary Pharmacological Actions: anxiolytic (280–282); spasmolytic (279); analgesic (283); neuroprotective (284); anticonvulsant (285) Common Uses: anxiety (283,286,287); tension and restlessness (2); headaches (74,283) Dose (2): dried herb: 1.5–3.0 g daily liquid extract: 3–6 mL daily (100 mg standardized kava extract two or three times daily) Adverse Effects/Toxicology: allergic skin reactions resulting in a pruritic skin condition (278,288); high dose associated with disturbances of vision (photophobia, diplopia, and oculomotor paralysis) (2); gastrointestinal discomfort (2); equilibrium disturbances (283) Cautions/Contraindications: dopamine antagonism by kava suggests caution in Parkinson’s disease (289); contraindicated in depression (2) Drug Interactions: no reported interaction with centrally acting drugs, however, potential exists (2,290) Implications for Pregnancy/Lactation: safety has not been established in pregnancy and lactation

Licorice (Glycyrrhiza glabra L., Fabaceae) Primary Constituents: coumarins, terpenoids (glycyrrhizin, glycyrrhetinic acid), flavonoids (isoflavones), volatile oils (1,291,292) Primary Pharmacological Actions: gastroprotective and antiulcerogenic (293,294); anti-inflammatory (295,296); spasmolytic agent (291); antibacterial (297); antiviral (298–300); antiparasitic (301,302); hepatoprotective (303)

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Common Uses: ulcers (gastric, duodenal, peptic) (291,304,305); canker sores and orofacial herpes (306); coughs and bronchitis (307,308); management of stress and fatigue (2); premenstrual syndrome (2) Dose: powdered root: 1–4 g daily (1) solid extract: 250–500 mg daily (2) Adverse Effects/Toxicology: common adverse effects include headache, lethargy, and edema (2); high dose is documented to cause pseudohyperaldosteronism with hypertension and hypokalemia (1,7,309); overconsumption has resulted in death (308,310–312) Cautions/Contraindications: not recommended in patients with cardiovascular, kidney, and liver disease (1,2) Drug Interactions: possible interaction with hypoglycemic drugs (loop and potassium-sparing diuretics), cardiac glycosides, and hormonal therapy (1,2); increases the half-life of hydrocortisone and prednisolone (2) Implications for Pregnancy/Lactation: traditional emmenagogue and abortifacient (7); although no clinical cases documented, one authoritative text suggests the action of licorice on estrogen may exacerbate gestational hypertension (1); medicinal use during pregnancy and lactation would not be advised Ma Huang (Ephedra sinica Stapf., Ephedraceae) Primary Constituents: alkaloids (ephedrine, pseudoephedrine), tannins, volatile oils, flavonoid glycosides (2,313) Primary Pharmacological Actions: cardiostimulant (7,314); hypotensive/hypertensive (7,313); bronchodilator (314); decongestant (315) Common Uses: weight loss (316–320); bronchial asthma (58) and bronchitis (11,58) Dose: Food and Drug Administration (FDA) suggests a maximum dose of 8 mg of ephedrine every 6 hours up to 24 mg daily for no more than 7 days (2,321) Adverse Effects/Toxicology: reactions to ma huang or ephedrine include headache, restlessness, dizziness, insomnia, gastrointestinal discomfort, hypertension, palpitations, tachycardia, nausea, and vomiting (7); high dose has been associated with hallucinations, paranoia, mania, and psychosis (2,322,323); deaths have resulted from excessive use (324,325) Cautions/Contraindications: due to the reported pharmacological actions, ma huang and ephedrine are not recommended in heart disease, hypertension, thyroid disease, diabetes, anxiety, glaucoma, impaired cerebral circulation, pheochromocytoma, and thyrotoxicosis (2) Drug Interactions: actions may be potentiated by aspirin and stimulants such as caffeine (321,326–328); avoid use with antidepressants and antihypertensives (2) Implications for Pregnancy/Lactation: no reported teratogenicity; ma huang not recommended in pregnancy and lactation due to uterostimulant properties of ephedrine (2) Passionflower (Passiflora incarnata L., Passifloraceae) Primary Constituents: alkaloids, flavonoids (1,329,330) Primary Pharmacological Actions: sedative/hypnotic (56,331–334); anxiolytic (335); spasmolytic (253,331); analgesic (253,331)

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Common Uses: indicated for symptoms of insomnia, tension, and restlessness (2,336) Dose (1): dried herb: 0.25–1.0 g three times per day liquid extract: 0.5–1.0 mL three times per day tincture: 0.5–2.0 mL three times per day Adverse Effects/Toxicology: a case of vasculitis has been reported with a herbal preparation containing passionflower (337) Cautions/Contraindications: excessive use may cause oversedation (1) Drug Interactions: no reported drug interactions in clinical practice; however, caution advised if patient is receiving centrally acting medications (2) Implications for Pregnancy/Lactation: constituents have shown uterine stimulant activity in animal studies (1), caution advised in pregnancy and lactation Peppermint (Mentha x piperita L., Laminaceae) Primary Constituents: volatile oils (menthol), flavonoids, tannins (139,338) Primary Pharmacological Actions: carminative (139,253,339); spasmolytic (53, 340,341); antimicrobial (342) Common Uses: gastrointestinal discomfort (nausea, vomiting, diarrhea, indigestion) (253,343); irritable bowel disease (344,345); spastic colon (346–348); colds and flu (253,343) Dose: peppermint oil capsules used three times daily (2) Adverse Effects/Toxicology: the use of peppermint oil for irritable bowel disease has been reported to cause heartburn and esophageal reflux (345); buccal products have been associated with contact irritation (2); high dose can cause gastrointestinal upset and atrial fibrillation (7,349); hemolysis and jaundice possible in cases of glucose-6-phosphate dehydrogenase deficiency (7) Cautions/Contraindications: contraindicated in patients with achlorhydria and glucose-6-phosphate dehydrogenase deficiency (2,345,350) Drug Interactions: none reported Implications for Pregnancy/Lactation: traditional emmenagogue and abortifacient (2,7); however, no reported contraindications in pregnancy and lactation Slippery Elm (Ulmus rubra Muhl., Ulmaceae) Primary Constituents: carbohydrates (mucilage), tannins (1) Primary Pharmacological Actions: demulcent/emollient (7,57,139,253); antitussive (57,139,253); astringent (253) Common Uses: orally used for gastrointestinal complaints (ulcers, gastritis, diarrhea) (1), and coughs (139); traditionally has been used topically for wounds, sores, boils, and abscesses (2,253) Dose (1): powdered bark: 4–16 mL three times per day liquid extract: 5 mL three times per day Adverse Effects/Toxicology: no reported toxicity Cautions/Contraindications: no reported contraindications Drug Interactions: none reported Implications for Pregnancy/Lactation: traditional abortifacient actions reported with

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whole bark, however, powdered slippery elm unlikely to be a concern (1); safety during lactation has not been established St. John’s Wort (Hypericum perforatum L., Clusiaceae) Primary Constituents: anthraquinone (hypericin, isohypericin, protohypericin), flavonoids, phenols, tannins, volatile oils (1,351) Primary Pharmacological Actions: antidepressant (352–354); antiretroviral (2,355– 357) Common Uses: depression (358–362) Dose (1): dried herb: 2–4 g three times per day liquid extract: 2–4 mL three times per day tincture: 2–4 mL three times per day Adverse Effects/Toxicology: delayed hypersensitivity and photodermatitis have been reported in the literature (1,363–365); other possible adverse effects include gastrointestinal discomfort, constipation, dizziness, dry mouth, sedation, and restlessness (2,364) Cautions/Contraindications: in cases of hypersensitivity or photodermatitis use should be discontinued; not recommended in patients with cardiovascular disease or pheochromocytoma (2) Drug Interactions: based on antidepressant action of herb, should not be used in patients already receiving a conventional antidepressant agent (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) (1,2) Implications for Pregnancy/Lactation: slight in vitro uterotonic activity has been suggested, therefore caution advised with use during pregnancy and lactation (366) Tea Tree Oil (Melaleuca alternifolia Cheel, Myrtaceae) Primary Constituents: volatile oils (terpinen-4-ol and cineole) (367) Primary Pharmacological Actions: antimicrobial and antiseptic (139) Common Uses: fungal infections (including vaginal yeast infections) (368–370,371) Dose: standard therapeutic levels do not exist; one report suggests oil should contain 30% or more of terpinen-4-ol and less than 15% of cineole (2,367) Adverse Effects/Toxicology: topical use may result in skin irritation (372) Cautions/Contraindications: oral use of tea tree oil would not be advised (2) Drug Interactions: none reported Implications for Pregnancy/Lactation: safety in pregnancy and lactation has not been established Uva-ursi [Arctostaphylos uva-ursi (L.) Spreng., Ericaceae] Primary Constituents: flavonoids, iridoids, phenolic glycosides (arbutin, methylarbutin), tannins, terpenoids (2,373–376) Primary Pharmacological Actions: antiseptic (2); antimicrobial (139,377); astringent (1,253)

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Common Uses: urinary tract infections (139) Dose (1): dried herb (leaves): 1.5–4.0 g three times per day liquid extract: 1.5–4.0 g three times per day Adverse Effects/Toxicology: high levels of hydroquinone were reported to cause tinnitus, nausea, vomiting, cyanosis, convulsions, collapse, and death (7) Cautions/Contraindications: caution advised with chronic use and large doses; high tannin content suggests long-term use has the potential to lead to chronic liver impairment (1); patients with a kidney disorder should avoid use (2) Drug Interactions: none reported Implications for Pregnancy/Lactation: although no evidence of teratogenicity or harm, generally not recommended for use in pregnancy and lactation (378)

Wild Yam [Dioscorea villosa L., Dioscoreaceae] Primary Constituents: steroidal saponins (dioscin, dioscorin) based on diosgenin (2) Primary Pharmacological Actions: anti-inflammatory; antirheumatic; antispasmodic (7,253,379) Common Uses: gastrointestinal discomfort (including irritable bowel disease) (2); rheumatism and arthritis (7,253); gynecological conditions (dysmenorrhea and ovarian pains) (2) Dose (2): dried herb: 5–10 g three times per day liquid extract: 1–2 mL three times per day tincture: 2–4 mL three times per day Adverse Effects/Toxicology: none reported, although literature on this herb is limited Cautions/Contraindications: none reported Drug Interactions: none reported Implications for Pregnancy/Lactation: traditional contraceptive based on diosgenin content (7,74); suggestions that diosgenin would be a substrate for steroidal substances such as progesterone and dehydroepiandrosterone (DHEA) have been refuted (2,380–382); due to possible emmenagogue effect, use in pregnancy and lactation would not be advised (7) REFERENCES 1. Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health Care Professionals. London: The Pharmaceutical Press, 1996. 2. Boon H, Smith M. The Botanical Pharmacy. Toronto: Quarry Press, 1999. 3. Natelson S. Canavanine to arginine ratio in alfalfa (Medicago sativa), clover (Trifolium), and the jack bean (Canavalia ensiformis). J Agric Food Chem 1985; 33:413–419. 4. Natelson S. Canavanine in alfalfa (Medicago sativa). Experentia 1985; 41:257–259. 5. Polachek I, Zehavi V, Naim M, et al. Activity of compound G2 isolated from alfalfa roots against medically important yeasts. Antimicrob Agents Chemother 1986; 30:290–294. 6. Berrang B, Davis KHJ, Wall ME, Hanson CH, Pedersen ME. Saponins of two alfalfa cultivars. Phytochemistry 1974; 13:2253–2260.

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7. Koren G. Maternal-Fetal Toxicology: A Clinician’s Guide, 2nd ed. New York: Marcel Dekker Inc., 1994. 8. Malinow MR, McLaughlin P, Stafford C. Alfalfa seeds: effects on cholesterol metabolism. Experimentia 1980; 36:562–563. 9. Molgaard J, Von Schenck H, Olsson AG. Alfalfa seeds lower low density lipoprotein cholesterol and apolipoprotein B concentrations in patients with type II hyperlipoproteinemia. Atherosclerosis 1987; 65:173–179. 10. Briggs C. Alfalfa. Can Pharm J 1994; March: 84–86. 11. Leung AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics, 2nd ed. Toronto/New York: John Wiley & Sons, 1996. 12. De Smet PA, et al. Adverse Effects of Herbal Drugs, 2nd ed. New York: Springer-Verlag, 1992. 13. Roberts JL, Hayashi JA. Exacerbation of SLE associated with alfalfa ingestion (letter). N Engl J Med 1983; 308(22):1361. 14. Malinow MR, Bardana EJ, Pirofsky B, Craig S, McLaughlin P. Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: role of a non-protein amino acid. Science 1982; 216:415–417. 15. Rosenthal GA. The biological effects and mode of action of L-canavanine, a structural analogue of L-arginine. Q Rev of Biol 1977; 52:155–178. 16. Alcocer-Varela J, Iglesias A, Iorente L, Alarcon-Segovia D. Effects of L-canavanine on T cells may explain the induction of systemic lupus erythematosus by alfalfa. Arthritis Rheum. 1985; 28(1):52–57. 17. Shelton RW. Aloe vera, its chemical and therapeutic properties. Int J Dermatol 1991; 30(10): 679–683. 18. Canigueral S, Vila R. Aloe. Br J Phytother 1994; 3(2):67–75. 19. Bruce WGG. Medicinal properties in the aloe. Excelsa 1975; 5:57–68. 20. Reynolds T. The compounds in aloe leaf exudates: a review. Bot J Linnean Soc 1985; 90: 157–177. 21. Sabeh F, Wright T, Norton SJ. Purification and characterization of a glutathione peroxidase from the aloe vera plant. Enzyme Protein 1993; 47:92–98. 22. Yamaguchi I, Mega N, Sanada H. Components of the gel of Aloe vera (L.) Burm. f. Biosci Biotechnol Biochem 1993; 57(8):1350–1352. 23. Afzal M, Ali M, Hassan RAH, Sweedan N, et al. Identification of some prostanoids in aloe vera extracts. Planta Med 1991; 57:38–40. 24. The Lawrence Review of Natural Products. Aloe. Monograph. Levittown, PA: Pharmaceutical Information Associates, 1988. 25. Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (Carrisyn). Int J Immunopharmacol 1988; 10(8):967–974. 26. Shida T, Yogi A, Nishimura H, Nishioka I. Effects of aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med 1985; 51:273–275. 27. McDaniel HR, et al. An increase in circulating monocyte/macrophages is induced by oral acemannan in HIV-1 patients. Am J Clin Pathol 1990; 94:516–517. 28. Egger SF, Brown GS, Kelsey LS, et al. Studies on optimal dose and administration schedule of a hematopoietic stimulatory b-(1,4)-linked mannan. Int J Immunopharmacol 1996; 18(2): 113–126. 29. Marshall GD, Gibbons AS, Parnell LS. Human cytokines induces by acemannan. J Allergy Clin Immunol 1991; 91:295. 30. Ramamoorthy L, Kemp MC, Tizard IR. Effects of acemnannan on the production of cytokine in a macrophage cell line RAW264.7. Joint Meeting of the European Tissue Repair Society and Wound Healing Society. Amsterdam: The Netherlands; 1993. 31. Zhang L, Tizard IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel. Immunopharmacology 1996; 35:119–128.

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32. Karaca K, Sharma JM, Nordgren R. Nitric oxide production by chicken macrophages activated by acemannan, a complex carbohydrate extracted from Aloe vera. Int J Immunopharmacol 1995; 17(3):183–188. 33. Bruce WG. Investigations of antibacterial activity in the aloe. S Afr Med J 1967; 51: 984. 34. Lorenzetti LJ, Salisbury R, Beal JL, et al. Bacteriostatic property of Aloe vera. J Pharm Sci 1964; 53:1287. 35. Heggers JP, Pineless GR, Robson MC. Dermaide/Aloe vera gel comparison of the antimicrobial effects. J Am Med Technol 1979; 41:293–294. 36. Hanley DC, Solomon WAB, Saffran B, et al. The evaluation of natural substances in the treatment of adjuvant arthritis. J Am Podiatr Med Assoc 1982; 72:275–284. 37. Davis RH, Leitner MG, Russo JM, et al. Anti-inflammatory activity of Aloe vera against a spectrum of irritants. J Am Podiatr Med Assoc 1989; 79:263–276. 38. Parish LC, Witkoski JA, Millikan LE. Aloe vera: its chemical and therapeutic properties. Int J Dermatol 1991; 30:679. 39. Davis RH, DiDonato JJ, Johnson RWS, et al. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr Med Assoc 1994; 84(12): 614–621. 40. Kahlon JB, Kemp MC, Yawei N, et al. In vitro evaluation of the synergistic anti-viral effects of acemannan in combination with azidothymidine and acyclovir. Mol Biother 1991; 3:214– 223. 41. McDaniel HR, et al. Extended survival and prognostic criteria for acemannan treated HIV1 patients. Antiviral Res 1990; 13(1):117. 42. Kahlon JB, Kemp MC, Carpenter RH, et al. Inhibition of AIDS virus replication by acemannnan in vitro. Mol Biother 1991; 13:127–135. 43. Davis RH, DiDonato JJ, Hartman GM, et al. Anti-inflammatory and wound healing activity of growth substance in aloe vera. J Am Podiatr Med Assoc 1994; 84(2):77–81. 44. Dominguez-Soto L. Photodermatitis to aloe vera. Int J Dermatol 1992; 31:372. 45. Hogan DJ. Widespread dermatitis after topical treatment of chronic leg ulcers and stasis dermatitis. Can Med Assoc J 1988; 138:336–338. 46. Nakamura T, Kotajima S. Contact dermatitis from aloe arborescens. Contact Dermatitis 1984; 11:51. 47. Shoji A. Contact dermatitis to Aloe arborescens. Contact Dermatitis 1982; 8:164–167. 48. Tewari PV, Mapa HC, Chaturvedi RR. Experimental study on estrogenic activity of certain indigenous plants. J Res Indian Med Yoga Homeopathy 1976; 11:7–12. 49. Jarry H, Harnischfeger G. Untersuchugen zur endokrinen Wirksamkeit von Inhaltsstoffen aus Cimicifuga racemosa: Einfluss auf die Serumspiegel von Hypophysenhormonen ovariektomieter Ratten. Planta Medica. 1985; 51:46–49. 50. Jarry H, Harnischfeger G, Duker E. Untersuchugen zur endokrinen Wirksamkeit von Inhaltsstoffen aus Cimicifuga racemosa: in vitro Bindung von Inhaltsstoffen an ostrogenrezeptoren Ratten. Planta Med 1985; 51:316–319. 51. Genazzani E, Sorrentino L. Vascular action of acteina: active constituents of Actea racemosa L. Nature 1962; 194:544–545. 52. Moskalenko S. Preliminary screening of Far-Eastern ethnomedicinal plants for antibacterial activity. J Ethnopharmacol 1986; 15:231–259. 53. Blumenthal M, Brusse WR, Goldberg A, et al. The Complete Commission E Monographs. Austin, TX: American Botanical Council, 1998. 54. Bradley P. British Herbal Compendium. Bournemouth, England. BHMA, 1992, p 239. 55. Chandler F, Osborne F. Burdock. Can Pharm J. 1997; 130(5):46–49. 56. Weiss R. Herbal Medicine. Beaconsfield, Quebec: Beaconsfield Publishers, 1988. 57. Wren R. Potter’s New Encyclopedia of Botanical Drugs and Preparations. Saffron Walden: C.W. Daniel Company, 1988, p 362.

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32 Ionizing and Nonionizing Radiation in Pregnancy Yedidia Bentur Rambam Medical Center, Technion–Israel Institute of Technology, Haifa, Israel

Clinical Case You sent a female patient for thyroid scan, suspecting hyperthyroidism. She returns to your office a few days later in panic because she had not known she was pregnant when the scan was performed. She has been told by several people, including one physician, that the radioactive iodine will cause thyroid damage to her 6-week fetus. What would be your advice?

INTRODUCTION Radiation is an anxiety-provoking term. In the minds of many, it is impossible to separate the psychological and physical effects of the atomic bomb from the effects of low-dose ionizing radiation. This anxiety is only aggravated by our knowledge of the carcinogenic effects on people (e.g., radium-dial workers, uranium miners, patients who receive radiotherapy or isotope therapy, and the victims of high exposures following the bombings of Hiroshima and Nagasaki and the accident at Chernobyl) of high exposures to radiation. Such discomfort may explain in part the ignorance of the public and many scientists and physicians regarding the qualitative and quantitative effects of ionizing radiation in spite of the extensive studies that have been carried out. Another source of confusion is the fact that the term radiation is applied to x-ray, ultrasound, microwave, and other forms. Therefore, it has even been suggested that radiation should be applied to high-energy ionizing radiation (x-rays, gamma rays and radionuclides); whereas radar, broadcast-range FM radio waves, diathermy, and microwaves should be termed long-wavelength electromagnetic waves or, in the case of ultrasound, sound waves (1). Despite the increase in concern regarding the effects of ionizing radiation on health and reproduction, the medical use of x-rays has continued to grow. In 1980 the number of x-ray procedures in the United States was 225 million (roughly equal to the total population) (2). Approximately 80 million fertile men and women were exposed to x-ray procedures in that year. About 30,000 fertile women may have been exposed to abdominal x-rays in early pregnancy (3). In the United Kingdom, approximately 12% of the total radiation dose to the population is due to man-made irradiation; from that, about 94% is 603

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due to medical procedures (4). About 21 million radiodiagnostic studies were carried out annually in 1977 in the United Kingdom, of which about 6% were fluoroscopic investigations (5). Although fluoroscopies involve mainly the abdominal region and are associated with high-dose exposure, the use of gonadal shields is still low (6). It is in this context of anxiety, ignorance, and confusion and, on the other hand, increasing medical use of ionizing radiation that the reproductive effects of diagnostic and therapeutic uses of ionizing radiation are reviewed here.

HISTORY Until 1895, when Wilhelm Roentgen devised a method to generate x-rays, human beings were exposed only to natural sources of ionizing radiation. Background radiation, as this form of energy is also called, consists of electromagnetic and particulate forms of ionizing radiation coming from the sun and the stars; radionuclides in the soil; and gamma rays, x-rays, and alpha and beta particles from rocks and air. Roentgen’s invention introduced to science and medicine an enormous new source of ionizing radiation. The diagnostic uses of x-rays were developed rapidly following this discovery. In addition, this radiation was used for cancer therapy and also for tinea capitis (7), enlarged tonsils and adenoids (8), thymic enlargement (9), and infertility (10). In 1896 Antoine Becquerel discovered that certain elements emit radiation. It was not until 1906, after the French physicist accidentally burned himself while carrying a radioactive compound in his pocket, that the possible therapeutic uses of radioisotopes were conceived. Only after the bombings of Hiroshima and Nagasaki in World War II had provided live evidence of the hazards posed by radiation were serious studies conducted regarding its delayed genetic effects and somatic damage. The medical uses of x-rays were intensely scrutinized, with a particular focus on what harm might be done to developing humans, including the mutagenic and carcinogenic effects of ionizing radiation.

DEFINITIONS Ionizing radiation can be expressed in units of exposure (roentgen), its absorbency into human tissue (rad, gray), and as the biological effectiveness of absorbed radiation (rem) (11). The roentgen (R) is the international unit of x- or gamma radiation equal to the amount of radiation that produces, in 1 cm3 of dry air at 0°C and standard atmospheric pressure, ionization of either sign equal to one electrostatic unit (esu) of charge. The rad is a unit of absorbed dose of ionizing radiation equal to an energy of 100 ergs/s of irradiated material: 100 rad ⫽ 1 Gy (gray) ⫽ 1 J/kg. The rem (roentgen-equivalent man) is the dosage of an ionizing radiation that will cause the same biological effect as 1 R of x-ray or gamma ray dosage; 100 rem ⫽ 1 Sv (sievert). The relationship between the absorbed energy (in rad or Gy) and the effectiveness of that energy in causing damage incorporates a factor called the relative biological effectiveness (RBE): 1 rem ⫽ 1 rad/RBE or 1 Sv ⫽ 1 Gy/RBE. Thus, RBE is a correction factor for predicting the biological effect of absorbed radiation. For radiation in soft tissue, RBE is about 1; hence rad and rem (or Gy and Sv) are often used interchangeably.

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The density of the radiation-induced ionizations in any tissue is directly related to the energy transferred to the irradiated substance, which is expressed as the linear energy transfer (LET).

MECHANISM OF ACTION X-rays and gamma rays are short-wavelength electromagnetic rays. Ionizing radiation in the form of high-energy photons in gamma rays and lower-energy x-ray photons can alter the normal structure of the biochemical components of a living cell through direct and indirect mechanisms. The direct mechanism involves disrupting the atom’s structure of biological molecules by adding sufficient energy to incite electron shells to free an electron from its atomic orbit and produce a charged or ionized compound and a free electron. The indirect mechanism involves the radiolysis of water (which makes up more than 60% of the content of living cells) to form radicals like OH, H⫹, H2, and H2O2. These reactive compounds can attack and disrupt neighboring molecules. Particulate radiation is generated from the spontaneous disintegration of radioactive compounds, which results in the emission of alpha particles (helium nuclei), beta particles (electrons), and other forms of energy. Nuclear fission generates a variety of heavy charged particles, fission fragments, and unchanged neurons. These subatomic particles can also disrupt the atomic structure of biological molecules by inducing ionizations. Particulate radiation does not penetrate tissues deeply, but it does generate ions densely along a short path (high LET). X-rays and gamma rays penetrate tissues deeply but generate ions sparsely along their path (low LET). The harm that follows from a single, random modification in a cell component (such as the genetic structure of stem cells) as a result of ionizing radiation (or any other toxin), termed a stochastic effect, may still allow the cells to proliferate. A nonstochastic effect is produced by numerous and/or repeated instances of damage. Stochastic effects can theoretically originate in a single deleterious effect, which can be associated with extremely low levels of radiation. Thus, an experimentally derived dose-response curve for effects such as carcinogenesis, mutagenesis, and maybe even abortions may not include a threshold dose below which no adverse effects occur. On the other hand, the doseresponse curve for nonstochastic effects (e.g., cataract formation) would be expected to show a threshold dose, which defines the smallest dose of radiation that induces detectable harm. Similarly, Smith (12) separares the harmful effects of ionizing radiation into two classes: 1. Deterministic effects, which result in loss of tissue function, usually at doses in excess of a few hundred millisieverts (tens of rems). Its dose-frequency relationship is sigmoid, and a tissue-specific dose threshold exists. This type of injury may also involve various compensatory and repair mechanisms. When the radiation dose is fractionated, there is greater repair and proliferation, hence increasing the tolerance of the tissue. This radiobiological observation of tolerance dose for most tissues guides the radiotherapist in judging the regimen to avoid unwanted side effects.

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2.

Stochastic effects, as discussed earlier. Since no dose threshold is assumed for these effects, there is great uncertainty as to how best to predict unavoidable injurious effects that may result, for instance, from exposure to an ionizing radiation dose equivalent to the natural background levels.

BIOLOGICAL EFFECT Before discussing the biological effect of ionizing radiation, it is important to refer to some of the findings of the review of the 30-year study of the survivors of the Hiroshima and Nagasaki bombings (13). It was clearly shown in this study that radiation effects are dose-dependent. More than 90% of survivors received much less than 10 rad from the atomic bombs. The possibility that such survivors will develop any disease from atomic bomb exposure is no greater than those of nonexposed individuals. Those who received higher doses have greater risks.

Testes In various animal experimental studies, it was shown that prenatal doses of ionizing radiation between 50 and 500 rad can induce testicular hypoplasia and sterility (11). This radiosensitivity differed among different animal species (14) and according to the gestational state (15). Fertility data from radiotherapy patients (16) is often of limited value, because illness and simultaneous administration of cytotoxic agents can also alter sperm production. In a study sponsored by the U.S. Atomic Energy Commission (AEC), normal men received large, defined doses of x-irradiation to the testes and were monitored for alterations in testicular cell populations, spermatogenesis, and fertility (17,18). Testicular radiation doses of 15–100 rad caused a decline in the sperm count about 50 days after irradiation, probably through an effect on the spermatogonia. A 15-rad dose caused only oligospermia. Doses of 50–80 rad and higher produced aspermia within 2–6 months. A decline in the sperm count was produced in less than 50 days after a single dose of 400 rad. It seems that this higher dose affected the spermatids, which are produced in the later stages of spermatogenesis. This finding in humans of increased radiosensitivity at earlier stages of cell division is consistent with findings in experimental models (19,20). The findings of the recovery phase in the AJEC study suggested that repopulation of germinal cells becomes less and less efficient as radiation exposures increase (18). Histological recovery (increasing number of spermatogonia) was observed about 7 months postirradiation doses of 100–600 rad. After 100 rad, the appearance of sperm in seminal fluid coincided with the earliest sign of histological recovery (7 months). But sperm production was not detectable until 11 and 24 months after doses of 200 and 600 rad, respectively. Similar findings were observed in the mouse (21), but its testicular tissue is significantly less radiosensitive than that of the human (22). It was also suggested in the human study (18) that radiation interfered with normal gonadotropin production by Leydig cells, thereby causing an increase in their number as a compensatory mechanism. The complete recovery of normal sperm concentrations after doses of between 100 and 600 rad took between 9 months and 5 years (18). Some men who had been accidentally exposed to large doses of radiation fathered children after even longer periods of time (23). Mouse experiments

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suggest that fertility can return when the sperm count is only 10% of its normal density (24). Ovaries In the prenatal period, radiation sensitivity is high in oogonia that are undergoing mitosis (11). The mammalian primary oocyte arrested in meiosis has been found to have varying radiosensitivity, depending on the subject’s age and the species studied (25,26). In vitro studies indicate that the human oocyte may be among the most radioresistant (27), whereas other studies show the mouse’s oocyte to be among the most radiosensitive (28,29). Irradiation was shown in animals to cause rapid changes in germ-cell structure characterized by a condensation of the chromosomes and damage to the nuclear envelope (28,30). Damaged oocytes either undergo repair (31) or are eliminated from the ovary within days or weeks (28,29). Doses of radiation sufficient to destroy most of the small primordial follicles have little effect on oocytes in Graafian follicles (27). The radiation dose administered influences mainly the proportion of oocytes affected but not the time course of degenerative changes (32). It seems that exposure in utero to low-dose radiation has little effect on human fertility, although the data are very limited. A fertility study on 180 women showed that 1–5 rad of gonadal radiation during infancy did not significantly affect the number of children born or the age distribution of births when compared with control data (33). Brent has estimated that acute doses below 25 rad absorbed by the fetus during gestation are unlikely to result in sterility in the human female or male (14). The observation in animals that moderate doses of radiation (50 rad) increased litter size, probably owing to superovulation (28,34,35), may have provided the empirical basis for the treatment of infertile women with x-rays in the past (10). Other human data showed that radiotherapy involving 6W rad in women over 40 years of age induced permanent menopause (16). Younger women exposed to this dose of radiation are likely to recover normal menstrual function and fertility. A fractionated dose of 2000 rad over 5–6 weeks is considered likely to produce complete sterility in 95% of girls and young women (16). An extended period of amenorrhea is expected after radiation doses that are inadequate to cause complete sterility (11). Young women with postirradiation amenorrhea were reported to resume their menstrual cycle only after a successful pregnancy (27,36,37). Gestation In a study looking at the outcome of pregnancy in survivors of Wilms’ tumor, it was suggested that radiation induces somatic damage to abdominopelvic structures (38). This type of radiotherapy involves gonadal exposure of about 900 rad (one exposure) or 1100– 1600 rad in fractionated doses (11). Among 114 pregnancies in women who had received abdominal radiotherapy for Wilms’ tumor, an adverse outcome occurred in 34 (30%) in the form of perinatal deaths (17 pregnancies) and low-birth-weight infants (18 pregnancies). In comparison, only in 2 (30%) out of 77 pregnancies in nonirradiated females with Wilms’ tumor and in the wives of male patients with Wilms’ tumor was there an adverse outcome. The absence of adverse outcomes in the pregnancies fathered by irradiated males suggests that radiation-induced germinal mutation is an unlikely explanation. This is supported by similar findings in other studies (39,40). In addition, shortened trunk, scoliosis,

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fibrosis of the abdominal musculature, and functional impairment of visceral organs have been reported in women who received curative radiation for Wilms’ tumor in childhood (41–43). Possible mechanisms for this impaired gestation are reduced distensibility of the irradiated uterine musculature and the abdominal cavity as well as uterine vascular insufficiency (11). This high risk of adverse pregnancy outcome should be considered in the counseling and prenatal care of women who have received abdominal radiotherapy for Wilms’ tumor. A British study showed that female survivors of childhood cancer who had been given abdominal or gonadal irradiation had excessive miscarriages (19%) compared with a control group of females with similar neoplasms who were not irradiated (9%) (44). Leukemic children who received prophylactic irradiation of the central nervous system had, in adulthood, lower fertility expressed as a lower first-birth rate (rate ratio 0.39) than those without radiation, indicating that doses of 18–24 Gy to the brain may possibly be a risk factor (45). Hypothalamic or pituitary injury is a suggested mechanism. In both these studies (44,45), there was no increased risk for congenital anomalies. Genetic Disorders Demonstrating the genetic effects of ionizing radiation in humans is limited by the difficulty in establishing a causal link between chromosomal damage and radiation exposure in the presence of other environmental mutagens. Chromosomal abnormalities are believed to be associated with 50% of spontaneous abortions and 8–10% of stillbirths (46). Radiation genetic damage cannot be distinguished from this high natural occurrence of human genetic disorders. Animal studies have shown that radiation can induce subtle genetic abnormalities in small, short-lived organisms (47) and that repeated small doses of radiation caused fewer mutations than the equivalent amount of radiation administered as a single dose (20,48). Animal data also suggest that radiation-induced point mutations could not account for even a small proportion of radiation-induced teratogenicity unless it simply involves cell death (1). An increase in chromosomal breakage was observed in lymphocytes from pregnant women exposed in vitro to ionizing radiation. This increase in radiosensitivity was in strong correlation with the amount of pregnancy hormones, especially progesterone (49). Upon looking at children born to radiation-exposed and unexposed survivors of the bombings of Hiroshima and Nagasaki, no significant difference was found regarding the incidence of stillbirths, congenital abnormalities, and neonatal fatalities (50). An apparent increase in abnormal pregnancies that correlated with increasing radiation dose was not found to be statistically significant. The data also suggested an increase in congenital problems when either mother or father had been exposed to ionizing radiation, but no cumulative effect was present in the data collected for births in which both parents had been exposed to radiation. A case-control study of 67 infants with trisomy 21 and their matched controls showed no association with medical radiography. The relative risk of trisomy for a radiographic examination involving direct irradiation of the ovaries prior to conception (mean ovarian dose 2.19 and 2.41 mGy for case and controls, respectively) was 0.8; the 95% confidence interval (CI) was 0.34–1.83 (51). There are no reports of excessive genetic disorders in geographical areas where the annual background radiation is known to be as high as 1.3 rem (10 times the average background exposure in the United States) (52,53). The Committee on the Biological Effects of Ionizing Radiation of the U.S. National Acad-

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emy of Sciences has estimated that 50–250 rem would be the dose of radiation sufficient to double the natural human mutation rate (47). Table 1 shows the known spontaneous incidence of genetic disorders causing serious handicaps per million live-born, together with estimates of additional radiation-induced defects. It seems that no correlation has been demonstrated between exposure to ionizing radiation and the incidence of genetic disorders in any human population at any dose level (47,54). If medical and occupational exposures are kept within recommended limits, radiation is responsible for few if any of the genetic disorders occurring spontaneously (55). Teratogenesis During the preimplantation period of gestation (0–2 weeks), the embryo is most sensitive to the lethal effect of radiation (56,57), probably owing to genetic damage (11,56), and is insensitive to its growth-retarding and teratogenic effects (1). During early organogenesis, the embryo is very sensitive to the growth-retarding, teratogenic, and lethal effects of irradiation but can recover somewhat from the growth-retarding effects in the postpartum period (1). It seems that the time period for radiation-induced multiple malformations other than of the central nervous system is the second to fourth week of gestation, representing 5% of the length of pregnancy, versus, for instance, 14% of the pregnancy in rat (11). During the early fetal period the fetus exhibits central nervous system sensitivity to radiation, and it can be growth retarded at term, from which it recovers poorly in the postpartum period; at the same period, however, the fetus has diminished sensitivity to multiple-organ teratogenesis (58,59). During the later fetal stages, the fetus will not be grossly deformed by radiation. If the radiation exposure is high enough, it will sustain permanent cell depletion of various organs and tissues (14,60). Cell death, mitotic delay, and disturbances of cell migration are among the mechanisms postulated for the irradiation effects, but it is difficult to determine which of them are most important in radiationinduced embryopathology. In addition, the same mechanism may not have the same importance in different stages of the pregnancy. For instance, cell death may be of minimal importance in the preimplantation period because of the embryo’s capacity for repair and the pluripotent nature of each remaining viable cell at this early stage (1,61,62). In later

Table 1

Estimated Genetic Effects of Radiation per Million Live-Born Offspring Additional effects of exposure of 1 rem/30-year generation

Genetic disorders Recessive Autosomal dominant and X-linked Irregularly inherited Chromosomal aberrations a

Incidence

First generation

At equilibrium a

1,000 10,000

Very few 5–65

Very slow increase 40–200

90,000 6,000

Very few 10

20–900 Slight increase

Refers to later generations when the rate of elimination of defective genes is balanced by the rate of additional mutations. Source: Modified from Ref. 47.

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stages of the pregnancy, the fetus loses this ability and cell death then becomes a primary factor. Tables 2 and 3 summarize the effects of different radiation doses at various stages of the pregnancy. The classic effects of radiation on the developing mammal are gross congenital malformations, intrauterine growth retardation, and embryonic death. Central nervous system effects and growth retardation are the cardinal effects. Each of these effects has a dose-response relationship and a threshold exposure below which there is no difference between the irradiated population and the control population (1). Microcephaly and Mental Retardation Many studies indicate that microcephaly is the most common malformation observed in human beings randomly exposed to high doses of radiation during pregnancy (63–70). In Goldstein and Murphy’s studies, where the radiation dose was greater than 100 rad, out of 75 pregnancies, there were 16 microcephalic children, and almost all were developmentally delayed (64,65). A total of 28 children had severe disturbances of the central nervous system. In another study, Dekaban reported that 22 of 26 infants exposed to hundreds of rad between the third and twentieth week of human gestation were microcephalic, developmentally delayed, or both (63). Severe mental retardation following in utero exposure to the atomic bombs was not observed in any patient receiving in utero less than 50 rad (71). It has also been documented that 10–20 rad of low-LET radiation will not increase the incidence of microcephaly in experimental animals (14). A retrospective study showed that medical ionizing radiation of more than 300 mrad in the second and third trimesters is related to a significant yet minimal decreasing head circumference at birth (72). Analysis of the data on survivors of atomic bombings in Japan using refined estimates of the absorbed dose in fetal tissues demonstrated that the highest risk for forebrain damage occurred at 8–15 weeks’ gestational age (73). These data were consistent with a linear doseresponse model, which did not indicate the existence of a threshold dose. The authors estimated the probability of increasing the incidence of mental retardation was 0.4% rad of radiation (i.e., four additional cases of mental retardation for each 1000 births). In contrast, the data collected for in utero exposures after the 15th week of gestation were not linearly related to dose, suggesting that a nonlinear model with a threshold dose for radiation effects best fits the data for this period of gestation. During 8–15 weeks of gestation, the risk of impaired central nervous system development was five times greater than that estimated for 16–25 weeks. Radiation exposure before the eighth week of gestation and after the 25th week was not associated with an increased risk of mental retardation. In a recent study, Yoshimaru et al. assessed school performance of prenatally exposed survivors of the atomic bombings using the DS86 dosimetry system instituted in 1986. They found that damage to the fetus exposed at 16–25 weeks after fertilization appeared similar to that seen in the 8- to 15-week group (74). Otake et al. reviewed 45 years’ study on brain damage among prenatally exposed survivors of Hiroshima and Nagasaki (75). Again, they noted an increased frequency of severe mental retardation, a diminution in IQ score and school performance, and increased occurrence of seizures among individuals exposed in the 8th through 25th week postconception, especially in the 8- to 15-week period. Sixty percent of those with severe mental retardation had small head size, and 10% of survivors with small head size were mentally retarded. A linear dose-response model fitted the data. There was strong evidence of threshold at 0.12–0.23 Gy (12–

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Table 2 A Compilation of the Effects of 10 Rad or Less Acute Radiation at Various Stages of Gestation in Rat and Mouse a Stage of gestation (days) Feature Mouse Rat Corresponding human gestation period Lethality Growth retardation at term Growth retardation as adult Gross malformations (aplasia, hyperplasia, absence or overgrowth of organs or tissues) Cell depletions, minimal but measurable tissue hypoplasia Sterility Significant increase in germ-cell mutations Cytogenic abnormalities Neuropathology Tumor induction e,f Behavior disordersg Reduction of life spane a

Preimplantation

Implantation

Early organogenesis

Late organogenesis

Fetal stages

0–4.5 0–5.5 0–9

4.5–6.5 5.5–8.0 9–14

6.5–8.5 8–10 15–28

8.5–12.0 10–13 28–50

12–18 13–22 50–280

⫹b ⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫾c

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫺ ⫾

⫺ ⫾

⫺ ⫾

⫺ ⫾

⫺ ⫾

⫺

⫺

⫺

⫺

⫺

⫺c ⫺ ⫺ ⫺

⫺ ⫺ ⫺ ⫺

⫺ ⫾ ⫺ ⫺

⫺ ⫾ ⫺ ⫺

⫺ ⫾ ⫺ ⫺

Dose fractionation or protraction effectively reduces the biological results of all the pathological effects reported to this table. (⫺) indicates no observed effect; (⫾) questionable but reported or suggested effect; (⫹) demonstrated effect. b At this stage the murine embryo is most sensitive to the lethal effects of irradiation. With 10 rad in the mouse, Rugh reports a slight decrease in litter size in the mouse (58). c Rugh reports exencephalia with 1 and 25 rad in a strain of mice with a 1% incidence of exencephalia. Others have not been able to repeat these results (56). d Recent reevaluation of the atomic bomb victims data suggests the possibility that mental retardation is a risk in the 10- to 20-rad range. This is not supported by most other data. e The potential for mutation induction exists in the embryonic term cells or their precursors. Several long-term studies indicate that considerably greater dose in mice and rats do not affect longevity, tumor incidence, incidence of congenital malformations, litter size, growth rate, or fertility. f Stewart and others have reported that 2-rad increases the incidence of malignancy by 50% in the offspring. See text for discussion. g Piontkovskii (1) reports behavioral changes in the rat after 1 rad daily irradiation. This work has not been reproduced. Source: From Ref. 1.

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Table 3

A Compilation of the Effects of 100-Rad Acute Radiation on Embryonic Development at Various Stages of Gestation in Rat and Mouse a Stage of gestation (days)

Feature

0–4.5 0–5.5 0–9 ⫹⫹⫹b,c ⫺ ⫺ ⫺ ⫺ ⫺ ⫾ ⫾ ⫺ ⫺ ⫺ ⫺ ⫺

Implantation

Early organogenesis

Late organogenesis

Fetal stages

4.5–6.5 5.5–8.0 9–14 ⫹ ⫹ ⫹ ⫺

6.5–8.5 8–10 18–36 ⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹

8.5–12.0 10–13 36–50 ⫾ ⫹⫹ ⫹⫹⫹ ⫾d

12–18 13–22 50–280 ⫺ ⫹ ⫹⫹ ⫺d

⫺ ⫺ ⫾

⫾ ⫾ ⫾

⫺ ⫺ ⫾ ⫺ ⫺

⫹ ⫹⫹⫹ ⫾ ⫾ ⫺

⫹⫹ ⫺ ⫾ ⫹a ⫹ ⫹⫹⫹ ⫾ ⫾ ⫺

⫹k ⫹⫹e ⫾ ⫹a ⫹ ⫹⫹ ⫾ ⫾ ⫺

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Mouse Rat Corresponding human gestation period Lethality Growth retardation at term Growth retardation as adult Gross malformations (aplasia, hyperplasia, absence or overgrowth of organs of tissues) Cell depletions, minimal but measurable tissue hypoplasia Sterility Significant increase in germ-cell mutations f Cytogenic abnormalities c,g Cataracts Neuropathology Tumor induction h Behavior disorders i Reduction in life span j (in nonmalformed embryos)

Preimplantation

Dose fractionation or protraction effectively reduced the biological result of all the pathological effects reported in this table. (⫺) no observed effect; (⫾) questionable but reported or suggested effect; (⫹) demonstrated effect; (⫹⫹) readily apparent effect; (⫹⫹⫹) occurs in high incidence. c Russell (cited in Ref. 1) reported that 200 rad increased the incidence of XO aneuploidy in 2–5% of offspring in mice with a spontaneous incidence of 1%. A dose of 100 rad kills substantial numbers of mouse and rat embryos at this stage, but the survivors appear and develop normally. d One hundred rad produces changes in the irradiated fetus that are subtle and necessitate detailed examination and comparison with comparable controls. e The male gonad in the rat can be made extremely hypoplastic by irradiation in the fetal stages with 15 rad. In the mouse the newborn female is most sensitive to the sterilized effects of radiation. Much of this research on other animals cannot be applied to the human. f The potential for mutation induction exists in embryonic germ cells or their precursors. The relative sensitivity of the embryonic germ cells when compared to adult germ cells is not known. Several long-term studies in animals do not indicate any exceptional differences. g Footnote refers to the aneuploidy produced in a strain of mice with a 1% incidence of spontaneous XO aneuploidy. Bloom (cited in Ref. 1) has reported a much higher percentage of chromosome breaks in human embryos receiving 100–200 rad in utero than in adults receiving the same dose of irradiation. As yet there have been no diseases associated with this increase in frequency of chromosome breaks. h Animal experiments and the data from Hiroshima and Nagasaki do not support the concept that in utero irradiation is much more tumorigenic than extrauterine irradiation, on the other hand, Stewart and colleagues (96,97,99) and many others report that irradiation from pelvimetry (2 rad) increases the incidence of leukemia and other tumors. i A statistically significant increase in percentage of mental retardation occurs with this dose of radiation. On the other hand, normal intelligence has been found in children receiving much higher doses in utero. j Animal experiments indicate that survivors of in utero irradiation have a life span that is longer than that of groups of animals given the same dose of radiation during their extrauterine life and the same life expectancy as nonirradiated controls. k There is a consensus that the brain maintains a marked sensitivity to radiation throughout all of gestation. Mental retardation is a serious risk at this dose. Source: From Ref. 1. b

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613

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23 rad) at 8–15 weeks’ exposure (when two probably non-radiation-related cases of Down’s syndrome were excluded) and a 0.21-Gy (21-rad) threshold at 16–25 weeks’ exposure. Regression analysis of IQ scores and school performance showed greater linearity with the new dosimetry system (DS86) than with the old (T65DR). These two parameters were similar to those in a control group for those exposed in utero to doses under 0.1 Gy (10 rad). Reanalysis of these data using an exponential-linear model suggested the 95% lower bound of the threshold for severe mental retardation to be 0.06–0.31 Gy (6– 31 rad) and 0.25–0.28 Gy (25–28 rad) for exposures 8–15 weeks and 16–25 weeks postovulation, respectively (76). Other studies of this population also suggest that in utero radiation may affect intelligence test scores, with the greatest sensitivity during the 8th–15th weeks of gestation (2,77). One estimate of the dose-response relationship was a 20-point loss on IQ tests for each additional Gy (100 rad) of exposure. The relationship between dose and intelligence test scores is not yet well established, and the findings have to be refined to a demonstrable level of statistical significance or clinical relevance (2,77). Smith quotes two studies that demonstrated a downward shift in the Gaussian distribution of IQ with an estimated probability coefficient indicating a loss of 30 IQ points per sievert (100 rem) fetal dose at 8– 15 weeks after conception (12). A similar but smaller shift to lower intelligence was detectable following exposure through the period from 16–25 weeks but not at other periods of pregnancy. The estimates above are associated with numerous uncertainties (11): the number of subjects in each age-defined exposure group was small and estimates of fetal absorbed dose and prenatal age at exposure cannot be confirmed. During the 8th–15th weeks of human fetal development, there is a well-characterized period of neuronal proliferation and migration in which cells that begin in the ventricular regions of the growing brain migrate into the various layers of the emerging cerebral cortex (78). The apparent absence of an effect prior to the eighth week suggests that neuronal proliferation is capable of adequately replacing lost cells, or the effects on cell migration during weeks 8–15 postconception may be the crucial component of cerebral damage caused by radiation (11). In utero radiation doses as low as 15 cGy (15 rad) affected cell migration in developing rat cerebral cortex possibly through effect on the neural cell adhesion molecule N-CAM (79). The finding of a small head size in the populations of affected neonates (80) is related to a reduction in cell number, which in turn could be due to impairment of neuronal proliferation and/or massive cell killing (73). The finding of mental retardation in infants with normal head size (64,65,77) could be explained by glial cell proliferation after irradiation, as shown in animal studies (81). Other Malformations In two studies from 1929 on 75 pregnancies, quoted above, besides microcephaly and mental retardation (16 infants), two children were born with hypoplastic genitalia, one with cleft palate, and one with hypospadias, abnormality of the large toe, and abnormality of the ear (64,65). There were various abnormalities of the eyes, including microphthalmia, cataracts, strabismus, retinal degeneration and optic atrophy. In a study of 26 infants exposed to radiation between the 3rd and 20th weeks of gestation; 22 were seriously affected. The most frequent abnormalities reported were small size at birth and stunted growth, microcephaly, mental retardation, microphthalmia, pigmentary changes of the retina, genital and skeletal malformations, and cataracts (63). All the malformed children exhibited

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growth retardation. The estimated protracted exposure was 250 rad. The patients were irradiated for dysmenorrhea, menorrhagia, myomata, arthritis or tuberculosis of the sacroiliac joint, and malignant tumors of the uterus or cervix. In 1930 a typical camptomelic dwarf was born to a woman who had received high-dose radiation from the second to the fifth months of gestation (82). This rare syndrome had not been described prior to 1930, and the authors were not in a position to recognize its possible genetic cause. Growth Retardation Growth retardation, microcephaly, and mental retardation are predominant observable effects following acute exposures exceeding 50 rad (low-LET radiation) (1). Radiationinduced morphological malformations have never been reported in humans without the coexistence of growth retardation or a central nervous system abnormality (mainly microcephaly, mental retardation, and readily apparent eye malformations) (1). In a study mentioned above, growth retardation was reported in all children malformed in utero following large doses of maternal pelvic x-irradiation (63). Impairment of growth was also detected among adolescents who had been exposed in utero to gamma and neutron radiation in Hiroshima and Nagasaki (83). The abnormal findings in this population included reduced height and weight (68,84) and reduced head and chest circumference (80,85). Diagnostic irradiation involving less than 5 rad to the human fetus has not been observed to cause congenital malformations or growth retardation (86–92), but not all such studies are negative (93). Animal studies support the contention that gross congenital malformations will not be increased in a human pregnant population exposed to 5 rad or less (1,94). In addition, most human exposures to extensive diagnostic radiation studies are fractionated and/ or protracted. The likelihood of producing malformations with this type of radiation is lower than with an acute exposure to low-LET radiation (95,96). One might suggest that functional or biochemical changes may be produced at low levels and with low incidence; so far this has not been proven, at least not regarding thyroid function, liver function, and fertility (1). Oncogenesis Epidemiological studies involving adults and children have established the potential of ionizing radiation to induce leukemia and solid tumors (47,97). It has also been shown that carcinoma of the thyroid was more prevalent in infants irradiated for thymic hyperplasia (98). Einhorn has suggested that the period of organogenesis may be highly resistant to carcinogenesis, possibly because of the existence of highly active regulators influencing development that may control cancer (99). However, a few studies have suggested that in utero radiation may be leukemogenic and may even induce other cancers (100–103). The present estimate is that a 1- to 2-rad in utero radiation exposure increases the chance of leukemia developing in the offspring by a factor of 1.5–2.0 over the natural incidence (1). In comparison, a 2-rad dose delivered to an adult population would not make a perceptible change in the incidence of leukemia even for very large population groups (104,105). An investigation utilizing data on the incidence of neoplastic disease in twins exposed in utero to diagnostic obstetrical x-ray examinations suggested a 2.4-fold risk of childhood cancer (106). Based on this finding and earlier estimates, the increase in neoplastic diseases associated with low-dose ionizing radiation is believed to range between 100 and 2 cases per million persons exposed per rad (102,107,108). The British Oxford Survey of Childhood Cancer estimates the risk following human in utero irradiation for cancer induction,

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including leukemia, to be 0.022/Gy (0.00022/rad) (109). This risk, based on a survey of the doses (mean fetal dose 6 mGy or 0.6 rad) associated with United Kingdom routine obstetric radiology in late pregnancy in the period 1958–1961, was estimated to be 0.04– 0.05/Gy or 0.004–0.005/rad (95% Cl, 0.008–0.095/Gy) (110). Among the survivors of the atomic bombings exposed in utero, there were only 18 incident cases of cancer in the years 1950–1984, 5 of them in the zero-dose group (111). Two of these patients had childhood cancer during the first 14 years of life; both were exposed to 0.30 Gy (30 rad) or more. All the others developed cancer in adulthood. The estimated relative risk for cancer at 1 Gy (100 rad) uterine dose was 3.77. The Life Span Study from Japan, based on the new DS86 dosimetry system, indicates an upper-bound of risk on 95% Cl of 0.028/Gy (0.00028/rad) (112). In a review of several studies dealing with this issue, it has been noted that when one considers the variety of control groups and the sampling variability, the results are remarkably consistent in showing an excessive frequency of leukemia among children whose mothers were exposed to radiation during pregnancy (113). A major criticism of these studies has focused on the possible confounding effects of selection factors leading to prenatal x-ray and the possibility that these selection factors may be independently related to increased risk of malignancy (47). In some studies, the number of patients was small, whereas other studies could not demonstrate any increase in leukemia following higher in utero diagnostic radiological procedures (89,114) or exposure to doses, including the atomic bomb (115,116). An identical increased risk of leukemia was reported whether the mother had received radiation from diagnostic procedures shortly before or after conception (117), but this was not proven in another study (118). It should be pointed out that siblings of leukemic children have an incidence of leukemia of 1:720 per 10 years, which is greater than the 1: 2000 risk of leukemia following pelvimetric exposure and the 1: 3000 probability of leukemia in the general population of children followed for 10 years (Table 4) (1). In addition, several animal studies could not demonstrate a significant increase in the incidence of cancer after in utero irradiation (119– Table 4 Risk of Leukemia in Various Groups with Specific Epidemiological and Pathological Characteristics in Populations Followed Up for 10–30 Years

Group Identical twin of leukemic twin Irradiation-treated polycythernia vera Bloom’s syndrome Hiroshima survivors who were within 1000 m of the hypocenter Down’s syndrome Irradiation-treated patients with ankylosing spondylitis Siblings of leukemic children Children exposed to pelvimetry in utero (gestational exposure) U.S. white children ⬍15 years old Source: From Refs. 1 and 119.

Approximate risk 1/3 1/6 1/8 1/60 1/95 1/270

Increased risk over control population 1000 500 375 50 30 10

Occurrence Weeks to months 10–15 years ⬍30 years old Average, 12 years ⬍10 years old 15 years

1/720 1/2000

4 1.5

To 10 years ⬍10 years

1/2800

1

To 10 years

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121). A recent study suggested that diagnostic radiography involving low-dose ionizing radiation of the order of 10 mGy (1 rad) received by the fetus may increase the risk of childhood cancer. The excess absolute risk coefficient at this level of exposure is approximately 6%/Gy (122). At present, it is not clear whether radiation exposure during either preconception or postconception is a causative or associative factor in the increased incidence of leukemia (1,123). Genetic or other environmental factors may be more important than prenatal diagnostic radiation in the production of leukemia. That Japanese bomb survivors exposed in utero to up to 500 rad apparently did not experience a significant increase in carcinogenesis proves the complexity of this tissue. Smith, from the International Commission on Radiological Protection, concludes that in utero irradiation is not considered likely to significantly influence the lifetime risk of a person living to old age who is irradiated throughout life (12). Although it seems that a dose of less than 10 rad to the implanted embryo does not result in a significant increase in the incidence of congenital malformations, growth retardation, or fetal death, low-risk tumorigenic or genetic hazards cannot be ruled out (1). It is one thing to avoid radiation because of a potential hazard, but it is another matter to recommend therapeutic abortion on this basis.

RADIODIAGNOSIS IN PREGNANCY Diagnostic radiology usually involves a radiation dose of 0.02–5.0 rad. Thus, from a clinical standpoint, estimating the risk of gestational effects from a dose of x-ray radiation smaller than 5 rad is of primary importance. The radiation risk, especially in diagnostic radiation, should always be evaluated with consideration of the significant normal risks of the pregnancy. Spontaneous risks of pregnancy are two orders of magnitude greater than the theoretical risks of diagnostic radiation. Table 5 lists an estimation of the risks of radiation in the human embryo based on human epidemiological studies and mouse and rat radiation embryological studies. As can be seen from Tables 6 and 7, the maximum theoretical risk to the human embryos exposed to doses of 5 rad or less is extremely small. Extrapolation of risk estimates after intrauterine exposures to the atomic bomb may not be applicable to low-level radiodiagnostic exposures. For instance, an analysis of data from Hiroshima and Nagasaki suggested that any dose of radiation between the 8th and 15th weeks of gestation could increase the risk of microcephaly and mental retardation by 0.4%/rad and possibly decrease intellectual development (73). Not only was the cohort small, but also the doses of radiation at Hiroshima and Nagasaki that produced these effects came from uncontrolled radiation sources that differed significantly in the two cities (124). Consequently, it cannot be considered readily comparable to the low-LET, filtered radiation used in diagnostic radiology (2). For example, in Hiroshima, severe mental retardation was not found in individuals exposed in utero to less than 50 rad, whereas in Nagasaki the risk for central nervous system damage was not increased even at levels of 50–150 rad (125). It is estimated that the overall risk of malformations and cancer for fetuses exposed in utero during the first 4 months of the pregnancy ranges between 0 and 1 case per 1000 radiated by 1 rad (126). This estimate is reinforced by the U.S. National Council on Radiation Protection, which stated that the risk of malformations at 5 rad or less was negligible when compared to the other risks of pregnancy (127). For stochastic phenomena such as

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Table 5 Estimation of the Risks of Radiation in the Human Embryo Based on Human Epidemiological Studies and Mouse and Rat Radiation Embryologic Studies

Embryonic age (days) 11–5 18–28 36–50 50–100 To term

Minimal lethal dose (rad) 10 25–50 50 ⬎50 ⬎100

Approximate LD50 (rad) ⬍100 140 200 ⬎100 Same as mother

Minimum dose (rad) for permanent growth retardation in the adult No effect in survivors 20–50 25–50 25–50 ⬎50

Increased incidence of mental retardation

Minimum dose for recognized gross anatomic malformation (rad)

Minimum dose for induction of genetic carcinogenetic and minimal cell depletion phenomena Unknown

20–50 c 50a 50a 100

20 50 —b

Unknown Unknown Unknown Unknown

a

Information published by Otake and Shull (73) suggests an increased risk at lower exposures. Anatomical malformations of a severe type cannot be produced this late in gestation except in the genitourinary system and tissue hypoplasia in specific organ systems, such as the brain and testes. c Severe CNS anatomic malformations more likely than mental retardation. Source: From Ref. 1. b

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Estimate of Risks of 1-Rad Exposure (Low LET) to the Developing Human Embryo

Age (days) 1 18–28 50 Late fetus to term

Mutagenic effect a–c No data 10⫺7 per locus

Childhood carcinogenic effect (Stewart) d

Maximum childhood carcinogenic effect (ABCC) b,e

Gross congenital malformation, death, growth retardation

Permanent cell depletion

No data 3.2 ⫻ 10⫺4 3.2 ⫻ 10⫺4 3.2 ⫻ 10⫺4

No data 5 ⫻ 10⫺6 5 ⫻ 10⫺6 5 ⫻ 10⫺6

?f Same as controls

No effect b ?

Radiation in Pregnancy

Table 6

a

Based on an estimated doubling dose for mutagenesis of 100 rad, assuming a linear dose-response curve and no threshold for mutagenic effects. The mutagenic effects have not been studied in the preimplantation period, or during the perimplantation period, the surviving embryos are not reduced in size even when the dose is very high, although at this stage the embryo is very sensitive to the lethal effects of radiation. c The estimate is assumed to be adult risk because there was no increased carcinogenic effect in the population of exposed fetuses in Hiroshima and Nagasaki. d Stewart’s (cited in Ref. 1) data would indicate that the embryo is more sensitive to the carcinogenic effect of radiation than the adult. This is a controversial matter, and others (59,116) feel that this association may be other than a radiation effect. e Atomic Bomb Casualty Commission data on carcinogenesis do not indicate that the embryo and fetus are at increased risk. The risk presented is the same carcinogenic risk attributed to adults, assuming maximal effect at low doses—namely, a linear dose-response curve- and no threshold for carcinogenic effects. f Radiation-induced embryonic death might possibly be a stochastic effect in the first few days of gestation, although the present data involving hundreds of embryos indicate no effect at 5–10 rad. Source: From Ref. 1. b

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Table 7 Risk of 0.5 Rem (Maximum Permissible Exposure for Women Radiation Workers with Reproductive Potential) Risk

0 rem

Spontaneous abortion Major congenital malformations Severe mental retardation Childhood malignancy/10year period Early to late onset genetic disease Total risk (using Stewart, cited in Ref. 1) Ratio of total risk to additional risk of radiation Total risk (using ABCC data) a Ratio of total additional risk of radiation

Additional risk of 0.5 rem

6

150,000/10 30,000/106

0 0

5000/106 7000/106 /10 years

0 166/106 /10 years or 2.5/106 / 10 years (ABCC data) a Risk is in next generation

100,000/106

166/106 1721 : 1 285,700/106

2.5/106 (ABCC data) a 114,280 : 1

a Data from Atomic Bomb Casualty Commission. Source: From Ref. 1.

cancer and genetic anomalies, it is estimated that the current practice of radiology in the United States increases spontaneous frequency by less than 1% (128). Performing several radiodiagnostic procedures in a pregnant woman should be avoided, since the radiation dose may accumulate to a hazardous level, especially in the sensitive period of 8–15 weeks postconception. There is general agreement that no woman should be denied a medically justified radiodiagnostic procedure because she is pregnant (77,127). On the other hand, unnecessary use of x-ray procedures is not good medical practice either. The immediate medical care of the mother should take priority over the risks of diagnostic radiation exposure to the embryo. Elective procedures such as employment examinations or follow-up examinations once a diagnosis has been made need not be performed on a pregnant woman even though the risk to the embryo is very small (1). If other procedures can provide adequate information without exposing the embryo to ionizing radiation, they should be used. Examples of such alternative procedures are ultrasound and using a computed tomography (CT) scout view for pelvimetry and excretory urography; with these techniques, radiation doses are significantly lower than with conventional x-ray techniques (129). The International Commission on Radiological Protection recommended the 10-day rule with regard to the question of when during the menstrual cycle elective x-ray studies should be scheduled (77). They pointed out that it is most improbable that a woman will be pregnant in the 10-day interval following onset of menstruation. This should be regarded as the choice time to perform radiological examinations of the abdomen and pelvis in women of childbearing age (77,127). The pregnancy status of the patient can be determined in several ways: 1.

Asking for the date of the last menstrual period and the previous menstrual period, and asking whether the patient possibly could be pregnant.

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2. Performing a pregnancy test in cases of uncertainty regarding the pregnancy status. 3. Performing pregnancy tests on all women of reproductive age admitted to the hospital. Using cost/benefit analysis and simple probability calculations, it was shown that as general public policy, pregnancy tests and elective scheduling procedures are of little value, especially when looking at the current estimates of the morbidity that is associated with low-dose radiodiagnostic procedures (3). It is important to discuss with the patient why the diagnostic study is indicated even though she may be pregnant, as well as the possible risks to her offspring. Some authors recommend acquiring written consent before the procedure is initiated (2). When it has been decided to perform the radiodiagnostic examination, every effort should be made to minimize the expected fetal dose. This can be accomplished by modifying the examination by using only selected views (anteroposterior vs. posteroanterior), by using efficient collimators, by the deliberate adjustment of maternal bladder volume, and by using lead apron protectors of the pelvic and abdominal areas (3,15,130).

ESTIMATION OF RADIATION DOSE Before reviewing the embryonic exposures from various radiodiagnostic procedures, it is important to review the unavoidable radiation the embryo receives (i.e., the background radiation), which includes cosmic rays from outer space, terrestrial radiation from ground and building materials, plus naturally occurring radioisotopes ingested or inhaled (55,131) (Table 8). The total dose to the embryo is less than 100 mrad during the 9 months of pregnancy. This dose will vary in different parts of the world and at different elevations, owing to variation in the terrestrial and cosmic ray radiation. Actually, the embryonic/ fetal dose during the pregnancy is less than the maternal because of the higher water content of the embryo (131).

Table 8 Exposures of a Pregnant Woman to Naturally Occurring Background Radiation During 9 Months of Pregnancy a Exposure (mrad/9 months) Type of radiation Potassium 40 ( 40 K) Daughters of radium-226 Carbon 14 ( 14 C) External terrestrial Cosmic rays Total exposure a

Mother soft tissue

Embryo soft tissue

14–18 — 0.5–1.3 36 37 90

10–14a — 0.5–1.3 36 37 ⬍86

The dosage to the embryo is less because the embryo has a higher water content and a higher extracellular volume than the adult. Ossification does not occur in the early stages of pregnancy; therefore, radium and strontium localization would occur only in the latter portion of gestation. Source: From Ref. 131.

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In evaluating the need for a radiodiagnostic procedure during pregnancy or in counseling a pregnant woman who has been inadvertently exposed to such a procedure, it is important to estimate the embryonic/fetal exposure. Whenever one is dealing with radiodiagnosis or radiotherapy, it is always wise to obtain the estimated embryonic/fetal exposure dose from the radiologist involved in the procedure. This is essential because of the differences in radiation dose delivered by using different equipment and techniques, as discussed further on. A few methods are available for estimating organ exposure dose in radiodiagnostic examinations: 1. 2.

3.

4.

Thermoluminescent dosimeters (TLD) enable direct measurement of entrance skin doses and doses to superficial organs of interest (132). The Monte Carlo technique is a mathematical method whereby entrance doses are converted to organ doses (133). For some organs (thyroid, breast, testes, and lungs) the dose measured with TLD is often higher, probably as a result of the limitations of the Monte Carlo method in simulating actual irradiation (132). A computerized program is available to enable estimation of output parameters of an x-ray machine from a single test exposure and using the data for organ dose estimates (134). Experimentally determined normalized depth-dose curves can be used in conjunction with monographic localization of the embryo/fetus (130).

Methods 1 and 2 are the most frequently used. Table 9 summarizes the estimated fetal exposure for various radiodiagnostic procedures as found in several studies (132–136). Fetal exposure is usually regarded as equivalent to uterine or ovarian exposure. The highest dose to the fetus is delivered by barium enema and urethrocystography, whereas the lowest doses are delivered by examinations of remote areas (e.g., skull, thorax). Table 10 shows the estimated fetal dose during CT (137). In another reference, a typical scan study of the abdominal area (several slices) was estimated to give an ovarian dose of 0.5–1.1 rad (138). Scattered radiation to the ovaries during CT scanning of the head measures less than 1 mrad per single scan (139). Fetal dose estimates vary among different studies, as can be readily seen in Table 9. A few factors influence the fluoroscopic and radiographic radiation exposure (4): 1. 2.

3. 4. 5.

Type of x-ray equipment. Exposure may vary by a factor of 2 or more with the use of different intensifiers and cameras. Differences in technique used by the radiologist may contribute to the variation of exposure by a factor of 1.7 for fluoroscopy and 25 for radiography. Differences in technique may involve variations in fluoroscopic exposure time, number of films taken, beam size, maintenance of image quality, and imaging area. Automatic versus manual control of fluoroscopy. Obesity index, which depends on height and weight of the patient. Cooperation of the patient.

MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) (interchangeably called nuclear magnetic resonance, NMR) may replace the CT scanner for some diagnostic imaging. With MRI, patients are

Radiation in Pregnancy Table 9

623

Average Fetal Exposure Dose in Various Radiodiagnostic Procedures (mrad) a

Examination

Sweden, 1977 (135) ⬍1

Head, sinus Full spine Cervical spine Dorsal spine Lumbar spine Lumbosacral region Shoulder, clavicle, sternum Arm Pelvis Hip and femur Femur (lower two thirds) Lower leg, knee Lungs, ribs Lung (photofluorography) Lungs and heart Abdomen Upper GI tract Small intestine Barium enema Cholecystography, cholangiography Urography (IVP) Retrograde pyelography Urethrocystography Pelvimetry Obstetrical abdomen Hysterosalpingography Cerebral angiography Mammography Dental (single exposure) a b

⬍1 ⬍100 620 180 ⬍1 ⬍1 190 370 50 ⬍1 ⬍3 ⬍10 ⬍5 200 56 180 700 24 880 800 1500 460 150 590 ⬍10

⬍0.01 128 ⬍0.01 0.6 408 639 ⬍0.01 194 128

0.5

UK, 1986 (133) ⬍1 ⬍1 346

Italy, 1987 (132) ⬍1 227 ⬍1 ⬍1 385 ⬍1

165

⬍1

238 51

⬍1 ⬍1 233 151

0.06 263 48

⬍1 289 360

822 5

1600 60

1534

814

358

505

b

0.01

Fetal dose is considered as equivalent to uterine or ovarian dose. Not computed, but treated as negligible relative to absorbed dose to the female breasts (212–766 mrad).

Table 10 Fetal Exposure During Computed Tomography Examination Chest Chest/abdomen Abdomen Abdomen/pelvis Pelvis a

USA, 1980 (136)

Fetal dose (mrad) a 30 450 240 640 730

Fetal dose is considered equivalent to ovary dose. Source: Modified from Ref. 137.

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subjected to very high magnetic fields (static, rapidly varying, and radiofrequency), but studies thus far have not indicated any potential hazard to the unborn child (140,141). MRI is considered by some clinicians to be the method of choice for antenatal pelvimetry (142,143). It was also suggested for evaluation of lumbar herniated disk in pregnancy (144). Mice exposed to MRI at the magnetic isocenter or at the entrance to the magnetic lumen had a significantly higher rate of eye malformations than controls (145). However, the mouse strain used in this study was genetically prone to these malformations. Cultured lymphocytes exposed to MRI during growth and division do not exhibit an increase in chromatid or chromosome lesions (146). The National Radiological Protection Board has indicated that although there is evidence to suggest that the developing embryo is not sensitive to the magnetic field encountered in NMR clinical imaging, more studies are needed to rule out adverse developmental effects. Until more conclusive evidence is available, therefore, it is considered prudent to exclude pregnant women from this procedure during the first trimester, when organ development is taking place (147).

RADIOTHERAPY Radiotherapy involves large doses of radiation that are likely to affect the fetus deleteriously, especially if given to the abdominal region. If the dose delivered to the embryo during the early organogenetic period is hundreds of rad, the embryo will probably be aborted. During the second and third trimesters there is high chance of irreversible damage to the central nervous system. If the fetus absorbs 50 rad or more at any time during gestation, there is a significant possibility that the fetus may be damaged (1). As mentioned earlier, the fetal exposure dose should be estimated by the radiologist, and the parents should be informed about the real probability of malformations and damage to the central nervous system. In some instances the human fetus has survived and has even appeared normal after exposure to doses exceeding 50 rad (63,148), but this of course should not be regarded as the rule.

OCCUPATIONAL EXPOSURE Women of childbearing age working regularly with radiation must be monitored (by film or TLD badge) if there is a reasonable possibility of receiving more than a quarter of their maximum quarterly recommended limit of 1.25 rem (149). Few workers, male and female, actually receive an annual dose approaching 5 rem (55). The National Council on Radiation Protection and Measurements recommends a maximum permissible dose equivalent to the embryo and fetus from occupational exposures of the expectant mother of 0.5 rem during the entire pregnancy (150), or 0.05 rem per month (151). If average annual exposure exceeds 3 rem or if there are peak periods of higher exposure, the worker of childbearing age may receive more than 0.5 rem in the first 2 months of the pregnancy (55). Women radiologists can work without interruption during pregnancy if proper precautions are taken, even with a heavy daily workload (152). The U.S. Nuclear Regulatory Commission suggests that women who are or expect to become pregnant and whose fetuses could receive 0.5 rem or more before birth seek ways to reduce their exposure within their present job or delay having children until they change job locations (153).

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PATERNAL IRRADIATION The effects of radiation on the testes were discussed earlier in this chapter. The Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) showed a downward but insignificant trend in birth weight and fetal growth in infants to fathers who received diagnostic x-ray examinations likely to deliver significant gonadal doses within 1 year prior to conception (154). A study looking at the proportion of malformations in children fathered by testicular cancer patients treated with radiotherapy did not reveal any difference compared to a control group or to the incidence of malformations in the general population (155). The effects of paternal irradiation have been studied in Hiroshima and Nagasaki survivors. No increase in malformations, fetal death rate, or birth weight were found (156,157). Another study showed an association between childhood leukemia and paternal preconception occupational exposure involving radiation (odds ratio, 3.23; 95% CI, 1.36–7.22) as well as with other factors such as wood dust and benzene (158). Ionizing radiation alone gave an odds ratio of 2.35 (95% CI, 0.95–6.22). Preliminary results of the Oxford Survey of Childhood Cancers suggest preconception paternal exposure to radionuclides was associated with relative risk of 2.87 (95% CI, 1.15–7.13) for childhood cancer (159). The association between paternal preconceptional radiation dose and childhood leukemia has not been confirmed by studies using objectively determined doses (160). The results of many of these studies are confounded by small numbers and multiple exposures of some parents.

COSMIC RAYS (AIR TRAVEL) Exposure to cosmic rays varies with the change in altitude, latitude, and solar activity. The flux of cosmic rays increases by approximately 100% for every 1.5–2.0 km above sea level (2). Assuming that a jet aircraft flies at an average altitude of 8 km, the mean dose rate is 0.84 µGy/h (84 µrad/h) compared to 0.04 µGy/h (3 µrad/h) at sea level. For example, the cosmic ray dose to a person flying from New York to Paris round trip is 31 µGy (3.1 mrem) for subsonic flight and 24 µGy (2.4 mrem) for supersonic flight (subsonic flight is usually at an altitude of approximately 11 km; supersonic flight is at about 19 km) (2). Although supersonic flights take place at higher altitudes, the overall absorbed dose is less, since the flight is faster by a factor of two to three. The average annual effective dose equivalent from cosmic rays for airline crew members is 0.8 mSv (80 mrem). Astronauts on Apollo space missions and lunar landings have been in the range of 2 mrem/h (2).

COUNSELING THE PREGNANT WOMAN In all instances of counseling parents concerning the hazards to the embryo/fetus exposed to radiation, biological knowledge is only one facet to be considered. As mentioned earlier, the hazards of exposure to diagnostic radiation (0.02–5.0 rad) present an extremely low risk to the embryo when compared with the ‘‘spontaneous’’ risks. More than 15% of human embryos abort spontaneously. About 3% may have major malformations, 4% have intrauterine growth retardation, and 8–10% have early- or late-onset genetic disease (1).

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A systematic approach of patient evaluation should be used to obtain the following information: Stage of pregnancy at time of exposure Menstrual history Previous pregnancy history History of congenital malformations and genetic diseases Other potentially harmful exposures and environmental factors during the pregnancy Maternal and paternal age Type of radiation study, dates, and numbers of studies performed Estimate of the fetal exposure by a radiologist or medical physicist Status of the pregnancy—wanted or unwanted Emotional maturity of the family Religion and ethical values of the family The applicable abortion laws should also be taken into consideration. This information should be evaluated with both patient and counselor to arrive at a decision. The information delivered to the patient should be clearly documented in the medical record, including the idea that every pregnancy has a risk of problems. It also should be conveyed that the notion of no increased risk does not mean that the counselor is guaranteeing the outcome of the pregnancy. The physician may consider performing an ultrasound examination to rule out radiation-induced microcephaly or growth retardation. The maximal theoretical risk attributed to a 1-rad exposure, approximately 0.003%, is thousands of times smaller than the spontaneous risks of malformations, abortions, or genetic diseases (1). Thus, the present maximal permissible occupational exposures of 0.5 rem for pregnant women and 5 rem for medical exposure are extremely conservative. There is no medical justification for terminating pregnancy because of radiation exposure in women exposed to 5 rad or less (1). The specter of radiation hazards should not be invoked to circumvent a social or legal problem. Although radiodiagnosis involves fetal doses of less than 5 rad, which are not considered to be teratogenic, many pregnant women exposed to it perceive their teratogenic risk as unrealistically high (161). This may be due to the anxiety provoked by the term radiation and by misinformation. An effective counseling process in these cases was shown to reduce the perception of teratogenic risk from 25.5 ⫾ 4.3% to 15.7 ⫾ 3.0% ( p ⬍ 0.05), thus preventing unnecessary termination of otherwise wanted pregnancies (161).

RADIONUCLIDES Physics and Biology An element has a fixed number of protons, which determines its atomic number, but it may have a variable number of neutrons. For instance, ″C, ″C, and 14C, which have six, seven, and eight neutrons, respectively, are referred to as isotopes of carbon, and each of them is a nuclide. Many nuclides have an unstable nucleus, owing to too many or too few neutrons; they are called radionuclides (radioisotopes). They disintegrate spontaneously and emit various forms of energy, collectively called radiation. The rate of disintegration is measured in units such as the becquerel (Bq) and the curie (Ci); 1 Bq is 1 disintegration per second and 1 Ci is the rate of disintegration of 1 g of pure 226Ra (1 Ci ⫽

Radiation in Pregnancy

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3.7 ⫻ 1010 Bq). The half-life is the time required for half of a sample of radionuclide to decay. Table 11 shows the half-life and type of radiation of various radionuclides (162). The heavy alpha particle (positively charged particles; helium nuclei) has a very high LET but penetrates tissue poorly (in contrast to x-rays and gamma rays). Therefore, radionuclides are relatively nonhazardous when used externally, but they can be toxic if

Table 11 Physical a and Effective b Half-Life and Type of Radiation of Various Radioisotopes Radionuclide

Physical t 1/2

137

30.1 years 4.54 days 5730 years 27.7 days 270 days 71 days 5.27 years 78.26 h 65 h 67 h 99.5 min 13.2 h 60 days 8.06 days 74 days 44.6 days 64.4 h 46.6 days 14.3 days 1.28 ⫻ 10 9 years 12.36 h 120 days 2.6 years 15.02 h 64.8 days 28.5 years 87.4 days 6.02 h 73.5 h 3.8 years 3.6 days 160 years 12.35 years 36.4 days 5.25 days 64.1 days

Cs Ca 14 C 51 Cr 57 Co 58 Co 60 Co 67 Ga 198 Au 111 In 113m In 123 I 125 I 131 I 192 I 59 Fe 197 Hg 203 Hg 32 P 40 K 42 K 75 Se 22 Na 24 Na 85 Sr 90 Sr 35 S 99m Tc 201 Tl 204 Tl 224 Ra 226 Ra 3 H 127 Xe 133 Xe 90 Y 47

a

Effective t 1/2 70 days 4.5 days 12 days 27 days 9 days 8 days 10 days 62 h

42 days 8 days 42 days 55.2 h 11 days 14 days 12 h 11 14 64 15 44

days h days years days

3.6 days 44 years 12 days

64 h

Radiation β ⫺, e ⫺, γ β ⫺, γ β⫺ e ⫺, γ e ⫺, γ β ⫹, γ β ⫺, γ γ β ⫺, e ⫺, γ γ e ⫺, γ γ e ⫺, γ β ⫺, e ⫺, γ β ⫺, e ⫺, γ β ⫺, γ e ⫺, γ β ⫺, e ⫺, γ β⫺ e ⫺, β ⫺, γ β ⫺, γ e ⫺, γ β ⫹, γ β ⫺, γ e ⫺, γ β ⫺ (DR) c β⫺ e ⫺, γ γ (DR) β ⫺, γ β, α (DR) α, e ⫺, γ (DR) β⫺ e ⫺, γ β ⫺, e ⫺, γ β⫺

The time required for the activity to decrease by 50%. The time required for the amount of a particular specimen of a radionuclide in a system to be reduced to half its initial value as a consequence of both radioactive decay and other processes, such as biological elimination. c Daughter radiation (daughter radionuclide is the decay product of a radionuclide). Source: Modified from Refs. 2 and 162. b

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ingested. The distribution of absorbed energy is rather uniform in embryos exposed to xrays and gamma rays. Conversely, radionuclides have a predictable but variable energy distribution in the embryo, depending on placental permeability, fetal distribution or tissue affinity, and the nature of radiation emitted (alpha particle, beta particle—identical with electrons or positrons, but arising from the nucleus; gamma ray electromagnetic radiation with wavelength much shorter than that of light or any combination). For example, 131 I will be absorbed and incorporated readily into the fetus with the development of the thyroid, as will plutonium and strontium with the development of the skeletal system. Thus, estimating the absorbed dose and hazards of a radionuclide is more complex than estimating externally administered radiation. The mechanism of action of this form of ionizing radiation as well as its potential to cause congenital malformations, central nervous system damage, growth retardation, or embryonic death was discussed earlier in this chapter. Types of Radionuclide The number of agents available in nuclear medicine has expanded rapidly, and 150 substances containing 74 different radionuclides from 36 elements have been in use (163). Over the years, the use of particular radionuclides has changed, the frequency of various procedures in nuclear medicine has increased, several procedures have been introduced, and others have been eliminated (131). For example, placental localization with isotopes (even with 99m Tc, which delivers a very low dose to the fetus) has been completely replaced by ultrasound. Radioactive Iodine The usual forms of iodine are 123I, 125 I, and 131 I. Isotope 125 I is used to label minute doses of hormones for in vivo and in vitro assays; 123I is used for uptake studies; 131 I can be given bound to protein or as the inorganic ion. It is used for thyroid uptake scanning and treatment of thyrotoxicosis and thyroid carcinoma as well as for other medical purposes not related to the thyroid. Inorganic iodides readily cross the placenta, in contrast to protein-bound iodides. Over time, substantial amounts of iodide are released from the protein and then cross the placenta. The fetal thyroid has more affinity to iodides than does the maternal (Table 12), and it begins to absorb and incorporate the iodide by the tenth week of gestation (126). Ablative doses of 131 I given to the mother may result in fetal thyroid destruction. So far, the lowest dose reported to destroy the fetal thyroid was 12.2 mCi in a fractionated manner; 9.2 mCi of 131 I was given after the 74th day of gestation Table 12 Thyroidal Radioiodine Dose of the Fetus Gestation period

Fetal/maternal ratio (thyroid gland)

Dose to thyroid (fetus) (rad/µCi) a

10–12 weeks 12–13 weeks 2nd trimester 3rd trimester Birth imminent

— 1.2 1.8 7.5 —

0.001 (precursors) 0.7 6.0 — 8.0

a Rad/µCi of 131 I ingested by mother. Source: From Ref. 131, derived from data in Ref. 163.

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(165). There are no reports of immediate deleterious fetal effects from tracer doses of radioactive iodine (131), but there is a theoretical possibility of induction of thyroid carcinoma. The fetal whole-body dose consists mainly of gamma rays, whereas the fetal thyroid dose is a combination of gamma rays and beta particles. This makes the fetal whole-body dose significant compared with the thyroid dose. Other Radionuclides Many radionuclides are bound to macroaggregates and macromolecules; they cross the placenta in small amounts, and the radiation dose delivered to the fetus is very small. For example, 99m Tc is used in many diagnostic procedures. Sodium 99m Tc pertechnetate is used for thyroid imaging. The radiation dose delivered with this radionuclide is lower than that of iodide because of its short physical half-life and short duration in the thyroid (since little of it is organically bound). Radioactive phosphorus or gold is used in the treatment of polycythemia or peritoneal malignancies. High dose radioactive phosphorus may result in embryonic abnormality and death in animals; this is also the case for radioactive strontium (166). Inorganic radioactive potassium, sodium, phosphorus, cesium, thallium, selenium, chromium, iron, and strontium cross the placenta readily, but their use is very limited. Dose Estimation The dose to the embryo is dependent on the form of the radionuclide, the site of administration, and the nature of the disease. In any case of exposure to radionuclides during pregnancy, the embryonic dose should be calculated. Often this dose will be less than the maternal dose because the nature of the radionuclide limits its ability to cross the placenta. Methods to estimate the dose to the embryo from radionuclides have been devised (164,167). Adult administered activity in various clinical radiopharmaceutical procedures is presented in Table 13 (131,168–170). The estimated embryonic/fetal doses from several radionuclides and nuclear medicine procedures are shown in Tables 14 and 15 (171). Risk Estimation Although it has been suggested that background and fallout radiation contribute to spontaneous mutation rate and congenital malformations, most studies have not found a correlation between levels of background radiation and any health hazard, including adverse pregnancy outcome (163,172–174). It is important to remember these data when considering that many of the exposures from nuclear medicine procedures are within the order of magnitude of background radiation. The reproductive effects of radionuclides have been less studied and less generalized than those of external radiation. This may be attributed to differences in placental permeability, nonrandom distribution of the radiation, existence of specific target organs, biological differences, or disease states that may affect the metabolism, and the exponential decrease in radiation dose rate over time. In addition, because the amount of energy absorbed over a given length of time (LET) is different for various radiations, 1-Gy aliquots from different radionuclides are not necessarily equally toxic (163). Teratogenic, embryonic/fetal, and growth-retarding effects in laboratory animals have been demonstrated for 137 Cs, 32 P, 89 Sr, 90 Sr, and [3 H]thymidine (175). It is likely that

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Table 13 Clinical Radiopharmaceutical Procedures Radiopharmaceutical 32

Study

Adult administered activity

P-sodium phosphate Cr-albumin 51 Cr-chromate 51 Cr-chromate 51 Cr-chromate 51 Cr-chromate red blood cells 57 Covitamin B12 60 Covitamin B12 59 Fe-citrate

Therapy, polycythemia vera GI protein loss Red cell survival Red cell mass Red cell in vivo Spleen imaging

2.3 mCi/m 2 50 µCi IV 160 µCi IV 25 µCi IV 160 µCi IV 200 µCi IV

Vitamin B12 absorption Vitamin B12 absorption Iron absorption

59

In vivo counting for effective hematopoiesis Iron plasma clearance and turnover Iron red blood cell uptake Tumor imaging Abscess imaging Pancreas imaging

0.5 µCi PO 0.5 µCi PO 5 µCi PO (700 µg ferrous ammonium sulfate, 300 mg ascorbic acid) 20 µCi IV

51

Fe-citrate

59

Fe-citrate Fe-citrate 67 Ga-citrate 67 Ga-citrate 75 Se-selenomethionine 59

99m

20 µCi IV 20 µCi IV 3–4 mCi IV 3–4 mCi IV 250 µCi IV or 4 µCi/kg, whichever is less 15 mCi IV 15 mCi IV

Tc-diphosphonate Tc-diphosphonate or pyrophosphate 99m Tc-DTPA

Myocardial imaging Bone imaging

99m

Kidney imaging Kidney imaging

15–20 mCi IV (no perchlorate) 15 mCi IV 15 mCi IV

Pericardial imaging

10 mCi IV

Lung perfusion study

3 mCi IV

Placenta imaging

1–2 mCi IV

Lung perfusion study

3 mCi IV

Venous imaging for thrombosis Vascular flow Thyroid uptake when uptake is low, organification blocked Ectopic gastric tissue (e.g., Meckel’s diverticulum) Brain imaging

6 mCi IV 20 mCi IV 1–3 mCi IV

99m

Tc-DTPA Tc-DTPA iron ascorbate 99m Tc-human serum albumin 99m Tc-human albumin microspheres 99m Tc-human serum albumin 99m Tcmacroaggregated albumin 99m Tc-macroaggregates 99m Tc-pertechnetate 99m Tc-pertechnetate 99m

99m

Tc-pertechnetate

99m

Tc-pertechnetate

Brain imaging

100 µCi/kg 15–20 mCi IV (200 mg potassium perchlorate orally prior to exam)

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Continued

Radiopharmaceutical 99m

Tc-pertechnetate

99m

Tc-sulfur colloid Tc-sulfur colloid 99m Tc-sulfur colloid 111 In-DTPA 123 I-iodide 123 I-iodide 99m

123

I-iodide

123

Study Carotid or cerebral hemisphere studies Bone marrow imaging Spleen imaging Liver imaging Cerebrospinal fluid rhinorrhea Thyroid uptake TSH thyroid uptake study

T3 suppression thyroid uptake

I-iodide I-iodohippurate 123 I-iodohippurate 125 I-human serum albumin 131 I-fibrinogen 131 I-iodide 131 I-iodide

Thyroid imaging Kidney function Kidney imaging Plasma volume

131

I-iodide

T3 suppression

131

I-iodide I-iodide

Thyroid imaging Thyroid therapy

I-iodohippurate

Kidney function

123

131

131

131

I-iodohippurate I-oleic acid 131 I-rose bengal 131 I-triolein 127 Xe gas 133 Xe gas 129 Cs-chloride 169 Yb-DTPA 169 Yb-DTPA 201 Tl-chloride 131

Venous imaging for thrombosis Thyroid uptake TSH uptake study

Kidney imaging Intestinal fat absorption studies Liver imaging Intestinal fat absorption studies Lung ventilation study Lung ventilation study Myocardial imaging Cerebrospinal fluid rhinorrhea Normal pressure hydrocephalus Myocardial imaging

Source: From Ref. 131, derived from data in Refs. 168–170.

Adult administered activity 20 mCi IV 10 mCi IV 3 mCi IV 3 mCi IV 0.5 mCi IT 100 µCi PO 100 µCi PO (10 U Thytropar im ⫻ 3 days prior to test) 100 µCi PO (25 µg cytomel t.i.d. ⫻ 7 days prior to test) 100 µCi PO 1–2 mCi IV 1–2 mCi IV 4 µCi IV 100 mCi 10 µCi PO 10 µCi PO (10 U Thytropar IM ⫻ 3 days prior to test) 10 µCi PO (25 µg cytomel t.i.d. ⫻ 7 days prior to test) 100 µCi PO 5–20 mCi PO for thyrotoxicosis; 75–100 mCi PO for thyroid cancer 3.5 µCi/kg body weight IV not to exceed 300 µCi 200 µCi IV 50 µCi PO 3 mCi IV 50 µCi PO 15 mCi by inhalation 15 mCi by inhalation 5–6 mCi IV 0.5 mCi IT 1 mCi IT 3 mCi IV

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Table 14 Dose Estimated to Embryo from Radiopharmaceuticals (136) Radiopharmaceutical

Embryo dose (rad/mCi administered)

99m

Tc-human serum albumin Tc-lung aggregate 99m Tc-polyphosphate 99m Tc-sodium pertechnetate 99m Tc-stannous glucoheptonate 99m Tc-sulfur colloid 123 I-sodium iodide (15% uptake) 131 I-sodium iodide (15% uptake) 123 I-rose bengal 131 I-rose bengal

0.018 0.035 0.036 0.037 0.040 0.032 0.032 0.100 0.130 0.680

99m

Source: From Ref. 171, derived from data in Ref. 167.

similar effects could be demonstrated for any radionuclide if the exposure could be adjusted to deliver a cytotoxic dose of radiation to the embryo. Doses to the embryo from standard nuclear medicine procedures are low. This may not be the case for radioactive iodine used for the treatment of thyrotoxicosis and thyroid carcinoma. It is extremely important that a competent expert calculate the fetal dose in any case of fetal or embryonic exposure. If the calculated dose to the embryo is 10 rad or more (about 100 mSv), the offspring should be considered to have a significant risk of a radiation-induced abnormality (163). The Collaborative Perinatal Project monitored 21 exposures to diagnostic radionuclides (131 I, mainly unbound) in the first trimester and found one malformation with standardized relative risk (SRR) of 0.72 (176). For exposures during the whole pregnancy, 3 out of 50 had malformations with SRR of 1.99. It is not mentioned what radionuclides were used in this group, and in addition the numbers were small. However, apart from the well-documented thyroid damage from radioactive iodine, there have been no controlled studies demonstrating an association between nuclear medi-

Table 15 Fetal Radiation Dose from Various Nuclear Medicine Procedures Study Pericardial imaging Placenta imaging Lung perfusion study Brain imaging Bone marrow imaging Spleen imaging Liver imaging Thyroid uptake (15% uptake) Thyroid imaging (15% uptake) Thyroid therapy

Radioisotope

Fetal dose (rad)

Tc-human serum albumin Tc-human serum albumin 99m Tc-lung aggregate 99m Tc-pertechnetate 99m Tc-sulfur colloid 99m Tc-sulfur colloid 99m Tc-sulfur colloid 131 I-rose bengal 123 I-iodide 131 I-iodide 131 I-iodide 131 I-iodide

0.18 0.018–0.036 0.105 0.555–0.74 0.32 0.096 0.096 2.04 0.0032 0.001 0.01 0.05–2.0 (thyrotoxicosis) 7.5–15.0 (thyroid cancer)

99m 99m

Source: Data derived from Refs. 131 and 171.

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cine procedures and adverse pregnancy outcome. Nevertheless, it is recommended that pregnant women not undergo nuclear medicine procedures. The use of radioactive iodine should be avoided during pregnancy unless essential for the medical care of the mother and there is no substitute. Even if administered during the first 5–6 weeks of human gestation, when the fetal thyroid has not yet developed, the total fetal dose should be estimated. In any case of exposure to radionuclides when it is known that the patient is pregnant or in any case of inadvertent exposure, the guidelines outlined in the section on counseling the pregnant woman should be followed.

The Chernobyl Accident Accidents in nuclear plants, such as that at Chernobyl in the former Soviet Union, may pose a threat to human reproduction. It seems obvious that lethal radiation levels were reached, and such an exposure can cause fetal damage. Air contamination and radionuclides deposited on the skin or the ground serve as an external source of irradiation, and the inhalation or ingestion of radionuclides in food (especially milk) is considered to be internal exposure. European cities reported doses of radiation of 0.1–1.0 mSv (177), which is equivalent to an extra year of background radiation. Exposure to such levels is unlikely to increase the incidence of gross congenital malformations. An increase in adverse phenomena related to stochastic effects might be expected; for example, increased risk of thyroid carcinoma induced in young children by 131 I-contaminated milk (178) and a dramatic increase (over 100-fold in some areas) in childhood thyroid cancer in Belarus, Ukraine, and Bryansk (179). In Greece, infants exposed in utero to ionizing radiation from the Chernobyl accident had two to six times (95% Cl, 1.4–5.1) the incidence of leukemia compared to unexposed children. No significant difference in leukemia incidence was found among children aged 12–47 months and after preconception exposure (180). In the heavily contaminated southern part of Germany, there was a higher rate of trisomy-21 among fetuses conceived during the period of greatest radioactive exposure (181). In Finland there were no differences in the expected/observed rates of congenital malformations, preterm births, and stillbirths (182). In Hungary no measurable germinal mutagenic effect was revealed (183), and in Norway no dose-response associations were observed with perinatal health problems (184). In both countries the rate of live births (183) and the total number of pregnancies (184) somewhat decreased, although there was no increase in the rate of induced or legal abortions. Interestingly, on the other hand, there was an increased rate of termination of pregnancies in Greece and Denmark in the months after the Chernobyl accident, even though the radiation doses measured in these countries were not large enough to induce birth defects (185,186). Thus we see that high levels of anxiety can be invoked even by low amounts of radiation; in these two countries this anxiety caused more fetal deaths than the radiation itself. The importance of good and reliable counseling in such cases cannot be overemphasized.

RADON Radon is an odorless, colorless, tasteless, and inert gas. It has several isotopes and radon daughters, all emitting mainly alpha radiation.

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Radon in houses comes from building materials, the soil under the house, the water, and the domestic gas. Some building materials such as aerated concrete with alum shale and phosphogypsum from sedimentary ores have higher radium concentrations and cause enhanced radon concentrations indoors. Radon exhalation from walls, floors, and ceilings is dependent on radium concentration, emanation power, diffusion coefficient in the material, and quality and thickness of the applied sealant. Ventilation rate, as determined by meteorological conditions and human activities, has a strong influence on radon levels. Radon and its daughters, after being attached to environmental airborne dust, stick to bronchial epithelial lining, releasing ionizing radiation (alpha particles) which may induce cancerous transformation. Increased risk of lung cancer has been clearly documented in uranium miners and certain other miners exposed to radon and its daughters. The level of risk has not been so well quantitated in environmental exposure. There is an additive relationship between radon exposure and cigarette smoking for lung cancer risk. No teratogenic effect was observed among the offspring of pregnant rats exposed to about 10,000 times the typical radon levels in houses (187). There are no human data on the effect of maternal exposure to radon during pregnancy. Since radon’s main hazard is the ionizing radiation, a small risk cannot be excluded. The main emission consists of alpha particles, which do not penetrate tissues deeply but have high linear energy transfer. A study of 491 males employed at uranium mines revealed in their offspring low birth weight and a decreased male/female ratio (188). Indoor air concentration of radon should equal outdoor air concentration (0.2–0.7 pCi/L, or 7.4–26 Bq/m3). Environmental standards for indoor residential air radon are 4– 8 pCi/L (148–296 Bq/m3), as guided by the Environmental Protection Agency and the National Council on Radiation Protection, respectively. These levels may be lowered in the future.

VIDEO DISPLAY TERMINALS Over the last years, the microprocessor has brought video display terminals (VDTS) into offices and homes, and a massive increase in their use has been observed. It was estimated that in the United States 7 million people were occupationally exposed to VDTs in 1980 (189). The earliest complaints by operators of VDTs were concerned with visual problems and musculoskeletal discomfort (147). Migraine, epilepsy (one case), and facial dermatitis were also reported (147). The scale of expansion in the use of VDTs has prompted interest in the reproductive effects of radiation from these devices. Physics The VDT is a cathode ray tube that directs electrons at a screen coated with a fluorescent target, generally phosphor. The bombardment of the target with electrons causes the fluorescent material to emit light. Television sets operate in the same manner. The energy emitted by VDTs is in the form of electromagnetic radiation. It consists of ionizing radiation (x-ray), the biological effects of which have been discussed earlier in this chapter, and nonionizing radiation (ultraviolet, visible light, infrared, microwave, and electromagnetic fields), some of which can transmit energy to tissues as heat. It is important to remember that electromagnetic radiation decreases in proportion to the square of the distance between

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a point source and the observer. Therefore, one might expect a rapid decrease in radiation with increasing distance from the screen. X-rays emitted by the cathode ray tube are entirely absorbed by the glass screen (189). Several studies could not detect measurable ionizing radiation from VDTs (e.g., 0.01–0.05 mrad/h) (190–195). Ultraviolet and visible light are emitted by the phosphor target of the VDT screen. The amount of ultraviolet radiation measured from VDTs is two to five orders of magnitude less than that of the environment (191,193). The amount of heat produced from this type of radiation is estimated to be 1.75 ⫻ 10–6 cal (196). In addition, the wavelength of ultraviolet radiation emitted from VDTs is not less than 336 nm (193); the harmful range is considered to be higher than 300 nm. No infrared radiation has been detected from VDTs tested (191,193). Nonionizing radiation in the form of microwave and extremely low frequency (ELF: 45–60 Hz) and very low frequency (VLF: 15 kHz) electromagnetic fields emitted from VDTs is in the same frequency range given off by most electrical appliances at home (191,197). This amount of radiation is two orders of magnitude less than background (193). Some VDTs are equipped with a flyback transformer, responsible for moving the arm of the cathode ray tube back and forth. People coming near the back casing of such a unit may be exposed to lower-frequency electromagnetic radiation, with powers measured up to 800 mW/cml (196). The casing can be modified to solve this problem. Risk Estimation Over the last years, a few clusters of adverse pregnancy outcomes among women VDT operators were reported (55,147,196). These clusters included spontaneous abortions, prematurity, neonatal respiratory disease, Down’s syndrome, and birth defects. The malformations reported, which were different in each affected child, included clubfoot, underdeveloped eye, cleft palate, congenital heart defect, and neural tube defect. None of the reports of abnormal pregnancy presented a distinct or reproducible syndrome. Current regulations require that x-ray emissions from any cathode ray tube be less than 0.5 mR/h at 5 cm (55). Even at this maximum level, radiation exposure to the uterus (50 cm from the screen) would be minimal. A woman sitting at a VDT console for 30 hours a week would accumulate a maximum uterine dose of 0.006 rem during the first trimester, about one-quarter of the natural background radiation dose she would be receiving at the same time (198). As the fetus grows, it may be physically closer to the terminal, but it would be shielded increasingly by the amniotic fluid. The amount of nonionizing radiation emitted is very small and consists of frequencies that have not been shown to be harmful. Exposure to an improperly shielded flyback transformer would be associated with absorbing significant low frequency radio waves. Animal studies investigating magnetic field-induced abnormalities in chick embryos are inconclusive (199–201). Epidemiological studies dealing with these issues are fraught with pitfalls. A study reviewing occupations that might entail work with VDTs showed that in pregnancies in which a VDT had not been used, the rate of spontaneous abortions was 5.7%. The rate was 8.2 and 9.3% for women working with VDTs less and more than 15 hours weekly, respectively. In contrast, the rate of spontaneous abortions among women from groups not using VDTs was 7.8% (202). These results were found later on by the authors themselves to be subject to selection bias and recall bias (203). In another study, response bias

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seemed to be a possible explanation for a suggested association with adverse reproductive effects (204). Comparison of mothers of malformed children and their paired referents found no evidence that exposure to VDTs caused birth defects (205). No mention was made in that report of miscarriages. Schnorr et al. compared a cohort of female telephone operators who used VDTs at work with a cohort of operators who did not use VDTs (197). Operators who used VDTs had higher abdominal exposure to VLF electromagnetic fields (15 kHz), but not to ELF fields (45–60 Hz). VDT operators had no excess risk of spontaneous abortions, and there was no dose-response relation when the women’s hours of VDT use per week were examined. In a case control study in Finland, no association was found between cardiovascular malformations and the use of VDTs at work or home among other parameters studied (206). In another case control study the risk of congenital urinary tract anomalies was found not to be materially associated with VDTs (207). Based on the current data and the fact that a very large number of women are exposed occupationally to VDTs, it seems likely that the clusters reported were encountered by chance (196). It appears that VDTs offer no known radiation hazard (55). In some countries, pregnant women may request a leave from working with VDTs, and they may be allowed to do so on the grounds of reducing worry (208,209).

MICROWAVES, RADAR, RADIO WAVES, FM, AND DIATHERMY Physics Microwave, radar, radio wave, FM, and diathermy radiation sources all involve electromagnetic waves ranging in frequency from 27.5 MHz (diathermy) to 104 –105 MHz (microwave communications) (1). The electromagnetic waves generated by diathermy are highly penetrating and can easily heat the human body. Microwaves of 2450 or 915 MHz produce hyperthermia but are less penetrating. Microwaves exceeding 10,000 MHz produce significant hyperthermia at skin level but are minimally penetrating (1). This type of radiation is incapable of producing ionizations within tissues (14,210). Biological Studies Mice exposed during gestation days 0–19 to a 20-kHz magnetic field had a significant decrease in weight of whole brain, detectable on postnatal day 308. There was a decrease in DNA level and an increase in the activities of 2,3-cyclic nucleotide 3-phospodiesterase (marker for oligodendrocytes), nerve growth factor and acetylcholinesterase in the cortex (211). Chick embryos exposed to 428-MHz radiofrequency radiation at a power density of 5.5 mW/cm2 for more than 20 days had higher rates of embryo lethality and teratogenicity (212). A few animal studies using a 27.12-MHz radiofrequency field showed an increased rate of resorption, incomplete cranial ossification, birth defects, reduced fetal weight, prenatal death, and reduced body weight in the exposed dams (213–215). Those effects were related to increased maternal body temperature. In one study, 41.5°C was estimated to be a threshold temperature over which there is an increased incidence of adverse reproductive effects (214). In another study, it appeared possible to ascribe some of the effects to a specific action of the radiofrequency radiation occurring independently of the rise in the temperature (213). When 100-MHz radiofrequency was studied in rats, no increase in maternal colonic temperature or adverse pregnancy outcome was observed (216). This exposure resulted in a specific absorption rate (SAR) of 0.4 W/kg, which

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corresponds to the maximum permissible level defined in 1982 by the American National Standards Institute. Since the unknowns and uncertainties are potentially significant, it was considered to apply a safety factor of 10, with a resultant SAR limit of 0.04 W/kg (217). Individuals working near FM radio stations, radar, and microwave ovens are not exposed to the maximum permissible levels suggested for occupational and medical exposures (1). Human studies looking at adverse reproductive effects of radiofrequency radiation are controversial (218). Investigations of human exposures to radiofrequency radiation are confounded by difficulties in determining the type and true extent of exposures, in selecting an appropriate control group for comparisons, in determining the existence and influence many concomitant environmental factors, and in establishing the presence or measuring the frequency or severity of subjective complaints as well as objective findings in the studied populations (218). In Danish physiotherapists exposed to high frequency electromagnetic radiation, there was a lower rate of male children (23.5%), and these infants also had low birth weight (219) but no increase in congenital malformations (220). In a case-control study, maternal exposure to microwave ovens was not found to be associated with cardiovascular malformations (206). Risk Estimation There is no way to receive exposure from a microwave oven without bypassing several safety interlocks. In addition, it is easy to shield microwaves with a proper screen or metal foil (1). If there were a door leak, it could theoretically result in a measurable exposure. But it should be remembered that electromagnetic radiation decreases in proportion to the square of the distance, so there should be no consequences several meters away from the microwave oven. The eye and the embryo are the most vulnerable to the thermal effects of microwave radiation because they cannot dissipate heat efficiently (1). The nonthermal effects have not been clearly demonstrated, but they are still being investigated. There is no indication that this type of electromagnetic radiation can produce malignancy or mutations (1). Microwave ovens properly handled should be regarded as safe. Prenatal use of electric blankets and electrically heated water beds was not found to be associated with urinary tract anomalies unless subfertility existed (207).

ULTRASOUND Ultrasound is a widely used diagnostic modality in obstetrics and other fields. Its use in fetal monitoring and fetal diagnosis is rapidly expanding, and it has replaced obstetrical x-ray examinations. Deep tissue heating with ultrasound is a standard technique in physical therapy. Physics Sound is a mechanical energy form in which small particles in a medium are made to oscillate. The oscillation of air molecules at frequencies of 20–20,000 Hz produces sound. Sound waves with a frequency above this range are called ultrasound. Medical ultrasound involves frequencies of 1–20 MHz, and the medium is water and tissues instead of air.

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The intensity of the sound energy, its alteration, and the exposure time determine the amount of energy reaching a given tissue. In a diagnostic ultrasound examination, a significant proportion of the energy is absorbed and the rest is reflected. The reflection of the sound energy provides the basis for the imaging technique. The fraction of the energy absorbed reduces heat within tissues. It is estimated that ultrasound intensities of 1 W/cm2 will result in tissue temperature elevation of 0.8°C/min (221). In Doppler fetal heart detectors, intensities are 0.75–75.0 mW/cm2 (222). Intensities for diagnostic sector scanners may reach peak values of 2– 200 mW/cm2 (223). The theoretical temperature rise 2 cm from an external fetal monitor remains less than 1°C even after prolonged use (221). In addition, further temperature loss occurs owing to removal of heat by circulating blood and by conduction of heat to other tissues. The nonthermal effects include tissue disruption by the production of cavitation and streaming owing to the movement of particles in the sound field (1). None of these effects occur with the energies utilized in diagnostic ultrasonography (1). Risk Estimation In vitro studies have raised the possibility that commonly used ultrasound irradiation causes significant cellular damage (224–228). Detectable biological effects from diagnostic ultrasound were not demonstrated in mammalian studies (223,229,230). The American Institute of Ultrasound in Medicine concluded, in 1982, that there are no independently confirmed significant biological effects of ultrasound in mammals in the low megahertz frequency range and when intensities are below 100 mW/cm2. Higher intensities with exposure time less than 500 seconds are not associated with biological effects as long as the product of intensity and exposure time is less than 50 J/cm2 (223). Epidemiological studies did not demonstrate that diagnostic ultrasound has any measurable or significant effects. The fetal anomaly rate was found to be 2.7%, which is comparable to the anomaly rate in the general population (231). No difference was demonstrated in several measurements at birth, in neurological examination, or in developmental testing at 11–15 months of babies exposed antenatally to ultrasound done for amniocentesis (232). Another study also did not find any difference in several birth parameters as well as neurological and cognitive testing at 7–12 years of age (233). In addition, it was concluded that diagnostic ultrasound is safe with regard to the risk of childhood malignancy between birth and the sixth year (234). After this period there appears to be a doubt, but the numbers are very small. Therapeutic ultrasound involves higher intensity and may produce deep tissue heating in a study where pregnant rats were exposed to shock-wave lithotriptor, fetuses located nearest the focal area of maximum shock-wave energy showed lower mean weight than controls but no recognizable gross or microscopic fetal damage (235). Because of the potential of hyperthermia to induce birth defects, it is advisable to avoid this form of treatment during pregnancy (223). Another issue which drew attention is medical workers exposed to contact ultrasound waves, i.e., no airspace between the energy source and the biological tissues. This is more hazardous than exposure to airborne ultrasound because air transmits less than 1% of this kind of energy. Although no definite conclusions could be drawn on its potential to cause adverse pregnancy outcome, avoiding unnecessary exposure of medical workers was suggested (236).

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Industrial ultrasound also involves very high intensities, and it is unlikely that there will be energy transfer to tissues (223). The only exception is in the case of existence of a satisfactory coupling medium. In addition, standard safety precautions should provide adequate shielding of the ultrasound source.

LASER Physics The atomic nucleus is surrounded by electrons in orbits. When an electron is jumped, or excited, from an allowed orbit to a higher level, energy in the form of a photon is absorbed. When the electron returns to a lower energy state, a photon is omitted. This spontaneous emission can be accelerated if the excited state atom is struck by a photon of exactly the same energy as the spontaneously emitted photon. This accelerated process is called stimulated emission, and it yields two photons of the same energy level, which leaves the atom in exactly the same direction and phase. Laser (light amplification by stimulated emission of radiation) is an active electron device that uses this process and converts input power into coherent electromagnetic radiation in the range of optic frequencies (ultraviolet, visible, or infrared). Unlike radiation emitted from the usual light sources, the laser produces a very narrow and intense beam of coherent light. The typical laser instrument consists of an energy input source, an active medium (atoms capable of undergoing stimulated emission), feedback mechanisms (totally and partially reflecting mirrors), and standard optical devices to focus the electromagnetic energy. The active medium may be solid (e.g., ruby crystal), liquid (e.g., tunable dyes), gas (e.g., helium-neon, carbon dioxide, argon ion), or a semiconductor. The choice of an active medium depends on the output power and wavelength required for a given application. Output may be delivered in a continuous wave, in a single pulse, or as a series of pulses. Carbon dioxide and excimer lasers produce extremely high output power, up to 109 W. Lasers have various applications in the areas of materials processing, information handling, communication, research, arts and entertainment, and more. Examples of medical applications of lasers include surgery (carbon dioxide laser), various ophthalmological procedures (argon and excimer lasers), vaporization of lung tumors during bronchoscopy (neodymium:yttrium-aluminum-garnet laser), and coronary angioplasties (excimer laser). The American National Standards Institute classified lasers into four classes (I–IV) in order of increasing risk of hazard (237).

Biological Studies The effects of laser in biological tissues can be divided into thermal and nonthermal; the latter may include driving chemical reactions, breaking atomic bonds, and creation of shock waves. Skin and eye damage is due mainly to denaturation of proteins resulting from hypothermia. Other hazards may include electrical shock, metal fumes released from processed material, and collateral radiation (e.g., intense light, arc lamps, ultraviolet radiation), which may induce delayed painful photokeratitis (237). The magnitude of damage depends not only on the type of laser involved and its output power, but also on the duration of exposure.

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Carbon dioxide laser surgery is used in obstetrics and gynecology via laparoscope for treatment of ectopic pregnancy (238) and intra-abdominally for reproductive pelvic surgical procedures (tubal anastomosis, adhesiolysis, etc.) (239). Endoscopic fetal surgery by excimer laser (40 and 10 Hz) was studied in premature lambs (240). Laser incisions were associated with smaller zones of devitalization compared to conventional cutting techniques using a scalpel. Albino rat embryos exposed to infrared laser beams (0.89 µm, 300 Hz for 256 and 128 s) had more preimplantation deaths and some disturbances in formation of the osseous skeleton (241). Helium-neon lasers induced an increase in neuritic outgrowths of olfactory bipolar receptor cells in rat fetuses (242). More studies are needed to evaluate the teratogenic potential of laser and its role in fetal therapy of malformations.

SUMMARY It is well established that ionizing radiation may have adverse reproductive effects. At present, there is no indication that radiodiagnostic doses of ionizing radiation (⬍5 rad) during pregnancy increase the incidence of gross congenital malformations, intrauterine growth retardation, or abortion. The risks of acute exposures involving doses exceeding 5 rad are far below the spontaneous risks of the developing embryo. On the other hand, this does not mean that there are definitely no risks to the embryo exposed to low doses of ionizing radiation. It has not been determined whether there is a linear or exponential dose-response relationship or a threshold exposure for genetic, carcinogenic, celldepleting, and life-shortening effects. Unnecessary x-ray or nuclear medicine procedures during pregnancy are not good medical practice, whereas medically indicated diagnostic roentgenograms are appropriate for pregnant women. A systematic approach of patient evaluation should be followed in any case of exposure during pregnancy and not only to consider the biological effects of ionizing radiation. So far, it has not been proven that exposure to nonionizing radiation (VDT, microwave, ultrasound, etc.) below the maximal permissible level is associated with measurable adverse reproductive outcome. At present, ultrasound not only improves obstetrical care but also reduces the necessity of diagnostic x-ray examinations. Nevertheless, continued surveillance and more studies of potential risks are necessary. Clinical Case Answer At 6 weeks of gestation, fetal thyroid is not capable of concentrating iodine. Therefore, before 8–10 weeks such risk does not exist. Calculation of fetal dose should be performed as described in this chapter. REFERENCES 1. Brent RL. The effects of embryonic and fetal exposure to X-ray, microwaves and ultrasound. In: Brent RL, Beckman DA, eds. Clinics in Perinatology, Teratology, Vol 13. Philadelphia: Saunders, 1986, pp 615–648. 2. Mettler FA, Moseley RD. Medical Effects of Ionizing Radiation. New York: Grune & Stratton, 1985, pp 206–209.

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172. Brent RL. The prediction of human disease from laboratory and animal tests for teratology, carcinogenicity and mutagenicity. In: Lasagna L, ed. Controversies in Therapeutics. Philadelphia: Saunders, 1980, pp 134–150. 173. Brent RL. Cancer risks following diagnostic radiation exposure. Pediatrics 1983; 71:288– 289. 174. Brent RL. The Effects of Ionizing Radiation, Microwaves and Ultrasound in the Developing Embryo: Clinical Interpretations and Applications of the Data, vol 14. Chicago: Year Book, 1984, pp 1–87. 175. Schardein JL, ed. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985, pp 659–668. 176. Heinonen OP, Sione D, Shapiro S. Diagnostic aids, technical aids and rare drugs. In: Birth Defects and Drugs in Pregnancy. Littleton, MA: PSG Publishing, 1977, pp 409–415, 444. 177. Webb GAM, Simmonds JR, Wilkins BT. Radiation levels in Eastern Europe. Nature 1986; 321:821–822. 178. Baverstock KF. A preliminary assessment of the consequences for inhabitants of the UK of the Chernobyl accident. Int J Radiat Biol 1986; 50:III–XIII. 179. Rytomaa T. Ten years after Chernobyl. Ann Med 1996; 28:83–87. 180. Petridou E, Trichopoulos D, Dessypris N, Flytzani V, Haidas S, Kalmanti M, Koliouskas D, Kosmidis H, Piperopoulou F, Tzortzatou F. Infant leukaemia after in utero exposure to radiation from Chernobyl. Nature 1996; 382:352–353. 181. Sperling K, Pelz J, Wegner RD, Schulzke I, Struck E. Frequency of trisomy 21 in Germany before and after the Chernobyl accident. Biomed Pharmacother 1991; 45:255–262. 182. Harjulehto T, Rahola T, Suomola M, Arvela H, Saxen L. Pregnancy outcome in Finland after the Chernobyl accident. Biomed Pharmacother 1991; 45:263–266. 183. Czeizel AE. Incidence of legal abortions and congenital abnormalities in Hungary. Biomed Pharmacother 1991; 45:249–254. 184. Irgens LM, Lie RT, Ulstein M, et al. Pregnancy outcome in Norway after Chernobyl. Biomed Pharmacother 1991; 45:233–241. 185. Trichopoulos D, Zavitsanos X, Koutis C, Drogari P. The victims of Chernobyl in Greece: Induced abortions after the accident. BMJ 1987; 295:1100. 186. Knudsen LB. Legally induced abortions in Denmark after Chernobyl. Biomed Pharmacother 1991; 45:229–231. 187. Cross FT. A review of experimental animal radon health effects data. NTIS (National Technical Information Service) Report/DE91-016710, 1991. Quoted in TERIS, Micromedex, Inc., Vol. 95, 1998. 188. Wiese WH, Skipper BJ. Survey of reproductive outcomes in uranium and potash mine workers: Results of first analysis. Ann Am Conf Govern Ind Hyg 1986; 14:187–192. 189. Bergman T. Eye care health effects of video display terminals. Occup Health Saf 1980; 49: 24, 26–28, 53–55. 190. Lazarus MG, Bourke JA. Problems associated with use of video display units by bank clerical staff. Med J Aust 1982; 2:186. 191. Letourneau EG. Are video display terminals safe? Can Med Assoc J 1981; 125:533. 192. Weiss MM, Peterson RC. Electromagnetic radiation emitted from video computer terminals. Am Ind Hyg Assoc J 1979; 40:300–309. 193. Weiss MM. The video display terminals is there a radiation hazard? J Occup Med 1983; 25: 98–100. 194. US Radiological Health Bureau. An Evaluation of Radiation Emission from Video Display Terminals, US Department of Health and Human Services (Food and Drug Administration) Publication No 81-8153. Washington, DC: Government Printing Office, 1981. 195. Hubar JS, Draus P. Determining the radiation exposure from visual display terminals used in dentistry. J Can Dent Assoc 1991; 57:131–132.

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196. Fabro S, Brown NA, Scialli AR. Video display terminals and human reproduction. Reprod Toxicol (Med Lett) 1984; 3:1–4. 197. Schnorr TM, Grajewski BA, Hornung RW, et al. Video display terminals and the risk of spontaneous abortions. N Engl J Med 1991; 324:727–733. 198. Hirning CR, Aitken JH. Cathode-ray tube x-ray emission standard for video display terminals. Health Phys 1982; 43:727–731. 199. Delgado JMR, Leal J, Monteagudo JL, Gracia MG. Embryological changes induced by weak, extremely low frequency electromagnetic fields. J Anat 1981; 134:533–551. 200. Ubeda A, Leal J, Trillo MA, Jimenez MA, Delgado JMR. Pulse shape of magnetic fields influences chick embryogenesis. J Anat 1983; 137:513–536. 201. Maffeo S, Miller MW, Carstensen EL. Lack of effect of weak low frequency electromagnetic fields on check embryogenesis. J Anat 1984; 139:613–618. 202. McDonald AD, Cherry NM, Delorme C, McDonald JC. Work and pregnancy in MontrealPreliminary findings on work with visual display terminals. In: Pearce BG, ed. Allegations of Reproductive Hazards from VDUs. Loughborough: Humane Technology, 1984, pp 161– 175. 203. McDonald AD, Chesy NM, Delrome C, McDonald JC. Visual display units and pregnancy: Evidence from the Montreal survey. J Occup Med 1986; 28:1226–1231. 204. Goldhaber MK, Polen MR, Hiat RA. The risk of miscarriage and birth defects among women who use visual display terminals during pregnancy. Am J Ind Med 1988; 13:695–706. 205. Kurppa K, Holmberg PC, Rantala K, Nurminen T. Birth defects and video display terminals. Lancet 1984; 2:1339. 206. Tikkanen J, Heinonen OP. Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology 1991; 43:591– 600. 207. Li DK, Checkoway H, Mueller BA. Electric blanket use during pregnancy in relation to the risk of congenital urinary tract anomalies among women with a history of subfertility. Epidemiology 1995; 6:485–489. 208. Bergqvist U, Knave B. Video display work and pregnancy-Research in the Nordic countries. In: Pearce BG, ed. Allegations of Reproductive Hazards from VDUs. Loughborough: Humane Technology, 1984, pp 49–53. 209. Bayne VJ. Paper outlining a trade union response to the allegations of reproductive hazards from VDUS. In: Pearce BG, ed. Allegations of Reproductive Hazards from VDUs. Loughborough: Human Technology, 1984, pp 111–126. 210. Brent RL. X-ray microwave and ultrasound: The real and unreal hazards. Pediatr Ann 1980; 9:469–473. 211. Dimberg Y. Neurochemical effects of a 20 kHz magnetic field on the central nervous system in prenatally exposed mice. Bioelectromagnetics 1995; 16:263–267. 212. Saito K, Suzuki K, Motoyoshi S. Lethal and teratogenic effects of long-term low-intensity radio frequency radiation at 428 MHz on developing chick embryo. Teratology 1991; 43: 609–614. 213. Tofani S, Agnesod G, Ossola P, Ferrini S, Bussi R. Effects of continuous low level exposure to radiofrequency radiation on intrauterine development in rats. Health Phys 1986; 51:489– 499. 214. Lary JM, Conover DL, Johnson PH, Hornung RW. Dose-response relationship between body temperature and birth defects in radiofrequency-irradiated rats. Bioelectromagnetics 1986; 7:141–149. 215. Lary JM, Conover DL, Foley ED, Hanser PL. Teratogenic effects of 27.12 MHz radiofrequency radiation in rats. Teratology 1982; 26:299–309. 216. Lary JM, Conover DL, Johnson PH. Absence of embryotoxic effect from low-level (nonthermal) exposure of rats to 100 MHz radiofrequency radiation. Scand J Work Environ Health 1983; 9:120–127.

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217. Cahill DF. A suggested limit for population exposure to radiofrequency radiation. Health Phys 1983; 45:109–126. 218. Roberts NJ Jr, Michaelson SM. Epidemiological studies of human exposure to radiofrequency radiation: a critical review. Int Arch Occup Environ Health 1985; 56:169–178. 219. Larsen AI, Olsen J, Svane O. Gender-specific reproductive outcome and exposure to highfrequency electromagnetic radiation among physiotherapists. Scand J Work Environ Health 1991; 17:324–329. 220. Larsen AI. Congenital malformations and exposure to high-frequency electromagnetic radiation among Danish physiotherapists. Scand J Work Environ Health 1991; 17:318–323. 221. National Council on Radiation Protection Measurements. NCRP Report No 74, Bethesda, MD: NCRP, 1983, p 72. 222. World Health Organization, Environmental Health Criteria 22. WHO, Geneva, 1982. 223. Fabro S, Brown NA, Scialli AR. Ultrasound in industry and medicine. Reprod Toxicol (Med Lett) 1984; 3:17–20. 224. Liebeskind D, Bases R, Mendez F, Elequin F, Koenigsberg M. Sister chromatid exchanges in human lymphocytes after exposure to diagnostic ultrasound. Science 1975; 205:1273– 1275. 225. Haupt M, Martin AO, Simpson JL, et al. Ultrasonic induction of sister chromatid exchanges in human lymphocytes. Hum Genet 1981; 59:221–226. 226. Siegel E, Goddard J, James AE Jr, Siegel EP. Cellular attachment as a sensitive indicator of the effects of diagnostic ultrasound exposure on cultured human cells. Radiology 1979; 133:175–179. 227. Liebeskind D, Bases R, Elequin F, et al. Diagnostic ultrasound: Effects on DNA and growth patterns of animal cells. Radiology 1979; 131:177–184. 228. Liebeskind D, Bases R, Koenigsberg M, Koss L, Raventos C. Morphological changes in the surface characteristics of cultured cells after exposure to diagnostic ultrasound. Radiology 1981; 138:419–423. 229. Au WW, Obergoenner N, Goldenthal KL, Corry PM, Willingham V. Sister chromatid exchanges in mouse embryos after exposure to ultrasound in utero. Mutat Res 1982; 103:315– 320. 230. Wegner RD, Obe G, Meyenburg M. Has diagnostic ultrasound mutagenic effects? Hum Genet 1980; 56:95–98. 231. Hellman LM, Duffus GM, Donald I, Sunden B. Safety of diagnostic ultrasound in obstetrics. Lancet 1970; 11:1133–1135. 232. Scheidt PC, Stantey F, Bryla DA. One year follow-up of infants exposed to ultrasound in utero. Am J Obstet Gynecol 1978; 131:743–748. 233. Stark CR, Orleans M, Haverkamp AD, Murphy J. Short- and long-term risks after exposure to diagnostic ultrasound in utero. Obstet Gynecol 1984; 63:194–200. 234. Wilson MK. Obstetric ultrasound and childhood malignancies. Radiography 1985; 51:319– 320. 235. Smith DP, Graham JB, Prystowsky JB, Dalkin BL, Nemcok AA Jr. The effects of ultrasoundguided shock waves during early pregnancy in Sprague Dawley rats. J Urol 1992; 147:231– 234. 236. Magnavita N, Fileni A. Occupational risk caused by ultrasound in medicine. Radiol Med (Torino) 1994; 88:107–111. 237. Krieger GR, Larson J. Lasers. In: Sullivan JB Jr, Krieger GR, eds. Hazardous Materials Toxicology: Clinical Principles of Environmental Health. Baltimore: Williams & Wilkins, 1992, pp 1165–1174. 238. Koninckx PR, Witters K, Brosens J, Stemers N, Oosterlynck D, Meuleman C. Conservative laparoscopic treatment of ectopic pregnancies using the CO2 laser. Br J Obstet Gynaecol 1991; 98:1254–1259.

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239. Kelly RW, Diamond MP. Intra-abdominal use of the carbon dioxide laser for microsurgery. Obstet Gynecol Clin North Am 1991; 18:537–544. 240. Schmidt S, Decleer W, Gorissen-Bosselmann S, et al. Endoscopic fetal surgery by excimer laser: An experimental study in premature lambs. J Perinat Med 1991; 19:231–235. 241. Bandazhevskii IuI, Emel’ianchik IuM. Effect of infrared impulse laser irradiation on the development of albino rat embryos. Arkh Anat Gistol Embriol 1991; 100:15–18. 242. Mester AF, Snow JB Jr, Shaman P. Photochemical effects of laser irradiation on neuritic outgrowth of olfactory neuroepithelial explants. Otolaryngol Head Neck Surg 1991; 105: 449–456.

33 Prenatal Diagnosis in Clinical Practice David Chitayat The Toronto Hospital and the Hospital for Sick Children, Toronto, Ontario, Canada

Kathy Hodgkinson The Newfoundland and Labrador Genetics Program, St. John’s, Newfoundland, Canada

INTRODUCTION The prenatal diagnosis and treatment of both inherited and noninherited disorders have undergone significant changes over the last decade. The ability to detect developmental defects before birth allows informed choices prior to and during a pregnancy, the luxury of qualified reassurance with negative results (especially for those at high genetic risk), and the possibility of early treatment, either prenatally or at birth. The delivery of these services is multidisciplinary, including many clinical and laboratory services. Every pregnancy has a 2–3% risk of producing a child with a major congenital abnormality. Of this group, 20% have multiple abnormalities, of which only 40% have a known cause. Chromosome abnormalities account for 6%, single-gene disorders for 7.5%, and teratogenic exposure during pregnancy or maternal diseases for 6.5%; the remainder are considered to be multifactorial—that is, due to an interaction between genetic and environmental factors (1). The overall risk for any form of congenital disorder in any pregnancy, however, is low. To detect the majority of these disorders, invasive and noninvasive diagnostic methods have been developed. The latter include a detailed assessment of family, medical, and obstetric history and fetal imaging techniques including ultrasound and magnetic resonance imaging (MRI). More recently, first- and second-trimester biochemical screening of maternal serum has become available. Invasive techniques involve direct fetal/placental sampling and include midtrimester amniocentesis, transcervical and transabdominal chorionic villus sampling (CVS), percutaneous umbilical blood sampling (PUBS), embryoscopy, and other fetal biopsy methods. The cells obtained are used for cytogenetic, molecular genetic, and biochemical investigations. Further avenues include preimplantation diagnosis for both chromosome abnormalities and single-gene disorders and analysis of nucleated fetal cells in maternal blood. This chapter offers an overview of the subject and briefly describes the methods used in prenatal diagnosis, the indications for each procedure, and the associated risks.

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INVASIVE PRENATAL DIAGNOSTIC PROCEDURES The invasive diagnostic procedures are associated with fetal morbidity and mortality thus are not clinically applicable for most pregnant women. The indications for their use are outlined in Table 1. Increased Risk for Fetal Chromosome Abnormality This is the most common indication for prenatal testing. The procedures used to obtain fetal cells are amniocentesis, CVS, PUBS, and preimplantation blastomere biopsy. Amniocentesis and CVS utilize cell culture techniques, where cells are cultured in flasks or on cover slips in appropriate growth medium until a sufficient number of cells are available to harvest. Routine cytogenetic techniques are then applied and a fetal karyotye is obtained (2). More recently the detection of chromosomal aneuploidy in interphase cells with fluorescent in situ hybridization techniques (FISH) using a denatured, single-stranded DNA probe to a single-stranded target DNA that has been denatured in place on a microscope slide has become routine for specific indications (3). In PUBS, the fetal blood lymphocytes are stimulated by phytohemagglutinin and cultured for 48–72 hours prior to chromosome analysis. In preimplantation blastomere biposy, one or two blastomeres are biopsied from the cleaved embryo by making a hole in the zona pellucida and aspirating the blastomeres.

Table 1 Indications for Invasive Prenatal Diagnosis 1. Cytogenetic analysis Techniques: CVS, amniocentesis, PUBS, preimplantation diagnosis, rarely direct biposy Considerations Maternal age Abnormal maternal serum markers (AFP, hCG, uE3, inhibin) Previous child with a chromosome abnormality Parental chromosome rearrangement Ultrasound abnormality Parent contiguous gene disorders Sex determination in X-linked disorders Parental exposure to therapeutic irradiation 2. DNA analysis (mutation or linkage analysis) Techniques: CVS, amniocentesis, preimplantation blastomere biopsy, rarely PUBS Autosomal recessive conditions Autosomal dominant conditions Sex-linked conditions 3. Biochemical/histopathological analysis Techniques: CVS, amniocentesis, direct fetal biopsy Single-gene disorders 4. As a result of biochemical screening Techniques: amniocentesis, transabdominal CVS, PUBS Considerations Raised MSAFP Increased risk for trisomy 18 and/or 21 on MSS Abbreviations: AFP, α-fetoprotein; CVS, chorionic villus sampling; MSAFP, maternal serum α-fetoprotein; MSS, maternal serum screening; PUBS, percutaneous umbilical cord sampling.

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Comparison of CVS and Amniocentesis

Total risk of miscarriage Risk of miscarriage due to procedure Chance of obtaining result Time for chromosome result Accuracy of chromosome diagnosis Detection of spina bifida

CVS

Amniocentesis

Approx. 5% Approx. 1% 96% 3–4 weeks Highly accurate No

Approx. 3% Approx. 0.5% 99% 3–4 weeks Highly accurate Yes

The biopsied blastomeres are used for mutation analysis using the polymerase chain reaction (PCR) technique and chromosome analysis using the FISH technique. The association of fetal chromosome aneuploidy, specifically Down syndrome, and advanced maternal age is well established (4) (Tables 2 and 3). Since most pregnancies, however, occur in younger women (in their second and third decades), only 30% of all chromosomally abnormal babies are born to women above the age of 35. To detect all cases, invasive procedures would have to be offered to all pregnant women. As they are expensive and carry a risk for miscarriage, they are usually offered to women with a risk of having a chromosomally abnormal fetus greater than 1 in 200. Generally this applies to women above age 35 at expected delivery date, although the newer screening methods (MSS and measurement of nuchal translucency) may change this indication. Prenatal diagnosis is offered to mothers who have had a previous child (live-born or stillborn) with a chromosomal aneuploidy. For women under age 30, the risk of a second event is about 1 in 100. The same risk probably applies to women between 31 and 35 years of age. For women above the age of 35, the risk remains at their age-related risk. In a dizygotic pregnancy, the risk for having a baby with a chromosomal abnormality doubles; thus fetal karyotyping is indicated at a maternal age of 30 and older at expected delivery date. When the aneuploidy involves the sex chromosomes, the recurrence risk is

Table 3 Ages

Risks of Down Syndrome and All Chromosome Abnormalities at Different Maternal

Maternal age at delivery (years) 25 30 35 36 37 38 39 40 41 42 43 44 45

Risk of Down syndrome

Risk of all chromosome abnormalities

1/1270 1/970 1/330 1/255 1/205 1/155 1/125 1/95 1/73 1/55 1/45 1/35 1/28

1/480 1/390 1/180 1/150 1/125 1/100 1/80 1/65 1/50 1/40 1/30 1/24 1/19

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considered to be small (5). It is interesting to note that an aneuploid spontaneous abortion (miscarriage) is not associated with an increased risk (6). As about half of all recognized losses in the first trimester of pregnancy are chromosomally abnormal (7), this is an important consideration. Couples where one member is a carrier of a significant chromosomal rearrangement are at high risk of having a chromosomally unbalanced child. The actual risk depends on the chromosomes involved, the type of rearrangement, whether it is maternally or paternally derived, and the mode of ascertainment of the family (8). When the ascertainment is through recurrent miscarriages, the risk for having a live-born child with an unbalanced chromosome rearrangement is 1.5–3%. When the ascertainment is through an affected newborn, the risk for having an affected child is 20–50%. When fetal anomalies are detected by ultrasound, chromosome analysis is indicated (9). Single abnormalities have an association with specific chromosomal abnormalities; these include cystic hygroma (Turner syndrome, trisomy 21, 13, and 18), duodenal tresia (trisomy 21), nuchal translucency (trisomy 21, 13, 18, and 45,X) and holoprosencephaly (trisomy 13); however, none are considered pathognomonic. The incidence of chromosomal abnormalities in fetuses with two or more detectable defects is 10–20% (10–12). Chromosomal analysis is indicated for those at risk of having children with singlegene disorders associated with increased chromosome breakage or other cytogenetic markers, including Fanconi’s anemia (13), Bloom syndrome, ataxia telangiectasia (14), xeroderma pigmentosum, and Robert syndrome (15). Mutation or linkage analysis for Bloom syndrome (16), ataxia telangiectasia (17), and some forms of Fanconi’s anemia is currently available. Fetal chromosome analysis using FISH analysis for a specific segmental aneuploidy carried by a parent [i.e., del(22)(q11.2)] is also indicated. Sex determination for X-linked conditions not diagnosable by molecular techniques may still occur, although for many of these the gene responsible is cloned and mutation or linkage analysis is available. In cases where either member of a couple has had therapeutic levels of radiation or cytotoxic drugs in the months prior to conception, fetal karyotyping may be warranted. Increased Risk for Single-Gene Disorders Diagnosable by DNA Analysis Any fetal sampling technique may be used. Many dominant, recessive, and X-linked disorders can now be prenatally diagnosed using either linked DNA markers, intragenic probes, or direct mutation analysis. Historically, individuals from such families often had to accept their a priori risk of transmission of a disorder, although sex determination by chromosome analysis for families with X-linked conditions has been available for some time. Often family studies are required for ascertainment of phase of the disease with linked markers; in such cases, the accuracy of diagnosis is not absolute. The fetus is placed at either a high or low risk of having inherited the ‘‘at-risk’’ chromosome. Increasingly, the genes themselves are cloned and the mutations identified, which allows direct gene analysis with no necessity for family studies and linked markers. In some instances the result can provide prognostic information (18); in others the prognostic indications are of value within families rather than between families (15). For those with an a priori pedigree risk of 25 or 50%, the advent of this technology has meant the possibility of having disease-free children. In all cases, however, the sequel to a positive result is for the pregnancy (if desired by the

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parents) to be terminated. Recent impetus has been toward preimplantation diagnosis (20). This technique utilizes a single cell obtained by biposy of a fertilized egg, obtained through in vitro fertilization (IVF), at the eight-cell stage. The DNA contained within the cell is amplified using PCR (21). Both sex determination and the successful diagnosis of a variety of autosomal recessive autosomal dominant and X-linked disorders—including cystic fibrosis, Tay-Sachs, hemophilia A and B, Alport syndrome, Marfan syndrome, and myotonic dystrophy, among others—have been reported (22–24).

Increased Risk for Single-Gene Disorders not Diagnosable by DNA Analysis The diagnosis of many inborn errors of metabolism relies upon biochemical studies of the cell-free amniotic fluid or of the cells themselves. Tay-Sachs disease and mucopolysaccharidosis are two conditions diagnosable in this way (25). Prior to the advent of DNA analysis for cystic fibrosis, microvillar intestinal enzymes were measured in the amniotic fluid (26). Histopathological studies of amniocytes can also be used in the diagnosis of neuronal ceroid lipofuscinosis (27) and mucolipidosis IV (28).

Increased Risk for Fetal Abnormalities Associated with Maternal Serum Screening In cases where the maternal serum α-fetoprotein (MSAFP) is high, the increased risk of having a child with a neural tube defect (NTD), ventral wall defect (VWD), Finnish type congenital nephrosis (29,30), or other problems warrants further investigation. Both ultrasonography and analysis of α-fetoprotein and acetylcholinesterase in the amniotic fluid refine the risk. For low MSAFP, the risk of Down syndrome increases. This risk is refined further by other biochemical markers (see ‘‘Screening for Down Syndrome,’’ below).

METHODS OF PRENATAL DIAGNOSIS Amniocentesis The aspiration of amniotic fluid from the amniotic cavity continues to be the most widely used procedure in prenatal diagnosis. It was performed as a technique for the management of oligohydramnios as long ago as the eighteenth century (31,32) but did not gain wide acceptance until the mid-nineteenth century, when it was successfully used in the management of erythroblastosis fetalis (33). The diagnosis of metabolic disorders became possible (34,35), and in 1966, Steele and Berg (36) successfully cultured and karyotyped amniotic fluid cells, leading to the first antenatal diagnosis of Down syndrome (37). Amniocentesis is carried out at 15–17 weeks’ gestation. Gestational age is confirmed by ultrasound (measuring the fetal biparietal diameter and femur length), which also determines zygosity, placental position, cardiac activity, structural normality of the fetus, and the optimal position for needle insertion. Once this is determined, a 20-gauge (or smaller) spinal needle is inserted transabdominally into the uterine cavity, through which a 10–20-mL sample

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of amniotic fluid is drawn (Fig. 1). Some centers infiltrate the subcutaneous area with lidocaine prior to needle insertion, although this is not considered necessary. The first few milliliters of the sample are discarded to minimize contamination by maternal cells, after which the greater part of the sample is used for cell culture. A small amount of cell-free amniotic fluid is referred to determine the α-fetoprotein (AFP) levels and, when indicated, acetylcholinesterase (AChE) is assayed. Failure to obtain amniotic fluid rarely occurs, although this was common historically, without the aid of ultrasound (38). Amniotic fluid cells are heterogeneous and derive from fetal skin, the inner epithelial surfaces of the respiratory and genitourinary tracts, and uterine membranes. They can be used for biochemical and molecular genetic studies in addition to the more usual cytogenetic studies. Culture time varies considerably, depending on the type and number of viable cells and other less easily classifiable variables. Most centers have results in less than 3 weeks. Culture failure is rare, and maternal cell contamination is considered to be less than 0.5% (39). As with all invasive prenatal testing, there is compromise between accurate information and harm to an otherwise normal fetus. The impetus over the last three decades has been to assess the possible disadvantages of each method to both the fetus and the mother. There is still uncertainty about the exact fetal loss rate due to amniocentesis, although the background rate is well established (40). It bears some relation to the number of needle insertions (41), the recommendation being that two attempts to obtain fluid at any one procedure be considered maximum. Although the figure quoted for fetal loss above the background rate is 1 in 200 (0.5%) (41,42), the actual risk is difficult to ascertain and is possibly lower (43). Fetal trauma is rare, while maternal risks are negligible. The timing of the procedure and the cell culture requirements mean that chromosome results are not available much before 19 weeks of pregnancy. For a couple found to have an abnormal fetus, the emotional burden is great. In addition, there is an increase in morbidity and mortality associated with later termination of pregnancy. The need for earlier prenatal diagnosis led to the development of CVS and early amniocentesis as alternative methods. Both procedures became possible as fetal imaging technology improved.

Figure 1 Amniocentesis.

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Early Amniocentesis The smaller volume of amniotic fluid found in earlier pregnancy was thought to be a contraindication to this type of sampling. At 10–11 weeks there is 30–40 mL, which increases to 50–100 mL between weeks 12 and 14, with a volume of approximately 200 mL at 16 weeks (44). Since 1987, however, some centers have been offering amniocentesis prior to 15 weeks’ gestation (45,46). The procedure is the same as described for midtrimester amniocentesis, although the amount of amniotic fluid drawn is less. About 1 mL of fluid per week of gestation is considered a rule of thumb. The success rate of culture is high (47,48). However, early amniocentesis was found to be associated with higher fetal loss in comparison to midtrimester amniocentesis (7.6 vs. 5.9%; difference, 1.7%; onesided Cl 2.98%, p ⫽ 0.0001). There was also a significant increase in talipes equinovarus in the early-amniocentesis group compared with the midtrimester-amniocentesis group (1.3 vs. 0.1%, p ⫽ 0.0001) and a significant difference in postprocedural leakage of amniotic fluid (early amniocentesis, 3.5%, vs. midtrimester amniocentesis, 1.7%; p ⫽ 0.0007) (49).

Chorionic Villus Sampling CVS [the removal of a sample of chorionic (placental) tissue as a source of fetal cells] developed in response to the limitations of midtrimester amniocentesis. First suggested in the late 1960s (50), it became overshadowed in the 1970s by amniocentesis. With the advent of molecular genetic technology and the possibility of prenatally diagnosing genetic disorders with small amounts of tissue, interest in the procedure resurfaced, and in the early 1980s the technique was refined and came into more general use (51,52). The technique relies upon the biopsy of rapidly dividing cells in the first trimester. At 7–10 weeks postconception (9–12 weeks from the last menstrual period), the gestational sac does not yet fill the uterine cavity. The chorion surrounding the gestational sac is differentiated into the chorion laeve (smooth), which faces the uterine cavity and later degenerates and attaches to the uterine wall, and the chorion frondosum, attached to the uterine wall, which forms the future placenta and contains rapidly dividing cells. The transcervical method utilizes the space within the uterine cavity unfilled by the gestational sac and accessible by catheterization through the cervix into the chorion frondosum (Fig. 2). Before sampling, ultrasound determines the position of the gestational sac and the placenta. Gestational age is assessed; if necessary, the procedure is rescheduled. In older mothers especially, a discrepancy between dates and scan measurements may indicate an impending miscarriage. Once the chorion frondosum is recognized, a flexible catheter with a metal obturator is inserted under continuous ultrasound guidance. The metal obturator is removed and a 20-mL syringe containing media is attached. Negative suction is applied together with to and fro movements of the catheter, followed by withdrawal. The tissue is immediately assessed microscopically; usually 10–25 mg is obtained. If the first attempt fails to obtain sufficient tissue, up to three attempts (each with a new catheter) may be performed, although the risk of miscarriage appears to increase proportionally (53). Often the choice of method is determined as much by practitioner preference as clinical necessity. However, genital herpes, cervical polyps, infection, uterine abnormalities, or a pregnancy greater than 12 weeks’ gestation will render the transabdominal approach the one of choice. As with all methods described, ultrasound evaluation before

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Figure 2 Transcervical chorionic villus sampling.

and during the procedure is required. The transabdominal procedure most commonly used follows that of Brambati and colleagues (54), using an 18- to 20-gauge needle introduced through the maternal abdomen and uterine wall into the placenta. Negative suction is applied to the syringe with simultaneous movement of the needle tip. The advantage of this method over the former is that it can be performed at any stage of pregnancy if the placenta is in an accessible position. In cases where obtaining fetal cells by any other method is difficult, this may be an option. Complications related to the procedure are reported. Vaginal bleeding occurs in 15– 20% of women after trancervical CVS, while this finding is rare (⬍1%) in transabdominal CVS. The report of two life-threatening infections after transcervical CVS (55,56) led to the recommendation that a new catheter be used for each insertion. The overall incidence of chorioamnionitis after transcervical CVS, however, is 0.2% or less (57). Rupture of the membranes is a rare complication, with an incidence of 0.3% (58). The realization that MSAFP was elevated in the majority of women after CVS (regardless of method) led to the recommendation that every nonsensitized Rh-ve woman undergoing CVS (or any other invasive prenatal procedure) be given anti-D immunoglobulin. CVS in Rh-ve– sensitized women is contraindicated (59). Chorionic villi contain a mesenchymal core, a cytotrophoblast layer, and an outer single layer syncytiotrophoblast. Cells from all layers are used for extraction of DNA for molecular analysis, whereas cytogenetics utilizes cells from the cytotrophoblast and mesenchymal core. The cytotrophoblast contains dividing cells that are used for direct analysis, the results usually being available within days. The mesenchymal core cells are cultured, with results usually available within 2–3 weeks. Initial concern with CVS focused on maternal cell contamination; however, experience in dissociating maternal tissue from fetal tissue has lessened this problem. Other problems, however, became apparent. The ability to obtain earlier results was an advance over amniocentesis, but discrepancies were noted between results obtained through direct analysis and those obtained through long-term CVS culture, amniocentesis, or after birth. This, in addition to the fact that the quality of direct preparations was poorer, led many

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centers to stop direct analysis. It should be considered, however, if a chromosome aneuploidy is suspected based on fetal ultrasound findings. Mosaicism (that is, the presence of two or more cell lines in the same tissue) has been reported in most large CVS studies. It is found twice as frequently in direct preparations compared to cultured ones and is considered to have an incidence of between 0.6 and 1.0%. In about 75% of the cases, the mosaicism is confined to the placenta (53,60). Confined placental mosaicism is associated with intrauterine growth retardation and perinatal complications (61,62), probably as a result of placental dysfunction. In cases where mosaicism is found at CVS, a follow-up amniocentesis is usually recommended. The addition of this second invasive procedure is not thought to increase the risk of fetal loss (63). If the mosaicism involves a chromosome complement not known to result in a liveborn child, a detailed fetal ultrasound may be sufficient. In all cases the possibility of uniparental disomy (a rare but reported complication) not being detected during follow-up screening should be considered (64). Whether CVS places the fetus at higher risk than other sampling methods has been the subject of much debate. Randomized multicenter trials comparing CVS with midtrimester amniocentesis found little difference, with a figure from the Canadian study of 0.8% higher fetal loss rate after transcervical CVS compared to amniocentesis (60). The MRC European study (65) projected a grimmer prognosis, but the study was confounded. More recent controversy surrounds the issue of fetal damage with the report from the Oxford group (66) in the United Kingdom of an association between limb reduction defects and early (before 10 weeks gestation) CVS. Subsequent reports (67,68) seemed to confirm the finding. However, the World Health Organization (69) concluded that, in centers with extensive experience, the rate of limb-reduction defects following CVS was similar to that in the general population (6.0/10,000 vs. 5.4/10,000, respectively). Most cases so far reported have been with CVS performed before 9 weeks’ gestation. Discussion as to the possible etiology of the association has included vascular disruption, poor technique, and too early sampling, with a recommendation that CVS be performed after 10 weeks’ gestation. Percutaneous Fetal Blood Sampling Fetal blood sampling is used for both diagnostic and therapeutic purposes. Initially the procedure was performed by fetoscopy and the fetal loss was reported as 3–7% (70). This is now replaced by the safer ultrasound-guided transabdominal needle puncture of the cord insertion known as cordocentesis or percutaneous umbilical blood sampling (PUBS). Other sources of fetal blood include the heart (cardiac ventricles) and intrahepatic veins (71). As with all sampling techniques, an ultrasound evaluation of the fetus and uterus is mandatory. The procedure is performed by inserting a 20- to 25-gauge spinal needle through the maternal abdominal wall and uterine wall into the umbilical artery, 2–3 cm from the placental insertion site, and withdrawing 1–5 mL of blood. Other sites are directly sampled. It is important to always confirm that fetal blood has been aspirated (72). Unlike amniotic fluid cells, stimulated cultured lymphocytes can provide chromosome results within days. PUBS is indicated, therefore, when abnormalities detected by ultrasound indicate a possible chromosomal problem, both when termination is still an option and prior to delivery for obstetric guidance regarding management. It may also be indicated when mosaicism or pseudomosaicism is detected on amniocentesis or CVS.

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Intrauterine infections (such as toxoplasmosis and rubella) have been diagnosed using fetal blood, (73,74) as have several hematological disorders, including the hemoglobinopathies, hemophilia, and familial combined immune deficiency disorders (75). Many are now amenable to DNA diagnosis using other sampling methods. Other clinical indications for the use of PUBS include the diagnosis of rhesus disease and the measurement of acidbase balance in cases with symmetrical intrauterine growth retardation (76) and the number of platelets in cases of maternal alloimmune antiplatelet antibodies and TAR syndrome. Although PUBS is considered a higher-risk procedure than other methods at gestations under 20 weeks, with a fetal loss rate of 5% at 12–18 weeks’ gestation compared to 2.5% at 19–21 weeks (77), the risks compared to the benefits are considered to be low. Other Fetal Tissue-Sampling Techniques Skin biopsies are indicated for the prenatal diagnosis of inherited congenital skin disorders, which include epidermolysis bullosa lethalis (78), epidermolysis bullosa dystrophica (79), epidermolytic hyperkeratosis (80), and harlequin ichthyosis (81). Live biopsy was used to diagnose rare inherited metabolic disorders where the enzyme is formed only in the liver, including ornithine carbamyl transferase deficiency, carbamyl phosphate synthetase deficiency, glucose-6-phosphatase deficiency, and alanine glyoxalate aminotransferase deficiency (82). However, mutation or linkage analysis is currently available for most of these conditions. Other organs such as lungs, kidneys, and muscle (83) have been biopsied for prenatal diagnosis of disorders detectable histopathology.

NONINVASIVE PRENATAL TECHNIQUES The most widely used technique for assessing the well-being of the fetus for most pregnant women is ultrasound. Other techniques for visualizing fetal structure are x-rays, magnetic resonance imaging (MRI), and echoplanar imaging (EPI). Fetal Ultrasonography Obstetric ultrasound imaging involves the transmission of sound waves with a frequency between 2 and 7.5 MHz into the pregnant abdomen and recording the echoes from the tissues in the path of the beam. This allows analysis of fetal structure. The lower frequencies have greater penetration, while the higher frequencies allow for better resolution of the image. Ultrasound has been used as a technique in obstetrics since the early 1960s. Initially the pictures were static and fuzzy, but the development of gray-scale ultrasonography and real-time imaging in the last 20 years has markedly increased the ability to identify fetal abnormalities. Ultrasound may be performed at any stage of gestation. In the first trimester, it is used to assess viability of the pregnancy and gestational age (by measuring crownrump length). Later in pregnancy, fetal structure may be examined more closely. The American College of Obstetrics and Gynecology therefore addressed the issue of different levels of fetal ultrasound examination (84). They suggested a basic and a targeted level and minimal requirements for each. The basic examination is considered appropriate for routine obstetric patients and includes determination of gestational age (using at least two parameters), zygosity, viability and presentation, placental localization, and amniotic fluid

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volume. The fetal head and spine, four-chamber heart, gastrointestinal tract, kidney and bladder, umbilical cord insertion, extremities, and genitalia should be adequately visualized and assessed. The delineation of abnormalities detected on a basic ultrasound resembles the postnatal physical examination; most are unexpected. Once an abnormality is detected, however, a targeted fetal ultrasound is recommended. Other indications include (among many) maternal diabetes mellitus [with an increased risk of NTD, congenital heart defect (CHD) and sacral agenesis], maternal systemic lupus erythematosus (congenital heart block), and maternal myasthenia gravis (arthrogryposis). Exposure to potential teratogens such as antiepileptic medications (an increased risk for NTD) or vitamin A congeners (hydrocephally, microcephaly, and cardiac defect) would warrant further investigation. In all cases a detailed family and pregnancy history is invaluable in determining pertinent risks. The technique is not perfect. Even with modern high-resolution equipment and experienced operators, abnormalities may be missed. Technical difficulties such as maternal obesity or oligohydramnios may hamper diagnostic ability. In addition, variations in structure may be seen about which little is known, and both diagnostic and prognostic information may be difficult to assess. The ability to detect subtle findings on fetal ultrasound (85) coupled with the fact that most women have at least one fetal ultrasound during a pregnancy led to the suggestion of using ultrasound as a screening test for Down syndrome. A relationship between shortened femurs and Down syndrome is known (86–88). Other features include nuchal folds, hypoplastic middle phalanx of the fifth digit, cardiac defects (89), mild dilatation of the cerebral ventricles, and hyperechogenic bowel (90). Detection of up to 75% of fetuses with Down syndrome may be possible (91). Ultrasound is both a diagnostic and a screening test; as the latter, it detects individuals in an otherwise normal population at higher risk who are then offered further investigations. As the former, it diagnoses fetal abnormality directly.

SCREENING METHODS IN PRENATAL DIAGNOSIS Screening for Neural Tube Defects (NTDs) Biochemical screening for open neural tube defects (ONTDs) between 16 and 18 weeks of gestation has been available since the 1970s. The screening test ascertains the level of AFP in the maternal serum. With improvements in ultrasonography, severe ONTDs are often diagnosed directly; anencephaly is almost always diagnosed before 16 weeks. AFP is a glycoprotein found in high concentrations in fetal serum and consequently amniotic fluid through fetal urination. It is synthesized initially by the yolk sac, then by the fetal liver and gastrointestinal tract. Peak concentrations of amniotic fluid AFP (AFAFP) occur at 12–14 weeks’ gestation, then steadily decline. Levels of AFP in maternal serum are an order of magnitude lower. The interchange between mother and fetus probably occurs directly via the placenta and indirectly via the amniotic fluid and the fetal membranes. The association between raised AFAFP and NTDs was reported in the early 1970s (92), when stored amniotic fluid samples from NTD pregnancies were retrospectively studied and found to have levels of AFP far in excess of normal levels. The increase is assumed to be due to leakage of AFP from fetal sera or cerebrospinal fluid. As leakage will occur from other anatomical defects, AFP levels are not specific for NTDs. The introduction in the late 1970s of both a quantitative and qualitative assay for acetylcholin-

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esterase (AChE), an enzyme synthesized in the central nervous system (CNS) and present in the cerebrospinal fluid (CSF), was an improvement (93,94). The leakage of CSF into the amniotic fluid when there is an ONTD results in a marked rise in AChE levels. The assessment of AChE uses the qualitative method of polyacrylamide gel electrophoresis (PAGE), where fluid from unaffected pregnancies produces a single band of pseudocholinesterase, while ONTDs have a faster second band of AChE. A second band is not specific for NTDs and can also be present with ventral wall defects. AChE is not present in cases of high AFP related to congenital nephrosis, an autosomal recessive condition prevalent in the Finnish population. False positives can occur with either assay if fetal blood is present in the sample. Where there is doubt, a Kleihauer-Betke test should be applied. The detection of open NTDs by measuring AFP and AChE in amniotic fluid was an improvement; it related, however, to a small subsection of the population undergoing amniocentesis. The use of MSAFP allowed for all pregnant women to be screened. However, unlike the case with AFAFP, there is considerable overlap between normal and abnormal pregnancies; at between 16 and 18 weeks, the separation of the two distributions is most distinct, although the remaining overlap makes optimum cutoff levels difficult to ascertain. The final value is ultimately a compromise between ascertaining all abnormal gestations and subjecting too many women to invasive tests with consequent risks and costs to the care providers. A cutoff level of 2.5 multiples of the median (MoMs) of MSAFP is used, which is considered to have a pickup rate of approximately 75% of ONTDs and about 3% false positives (95). It will not, by definition of being a screening test, pick up all ONTDs or ventral wall defects. Causes other than anatomical defects resulting in leakage of AFP into the amniotic fluid are known to cause a rise in MSAFP. These include incorrect gestation at the time of sampling (as the normal values are gestation-based); multiple pregnancy; conditions that cause oligohydramnios (renal agenesis and urethral obstruction); those which interfere with kidney resorption [congenital nephrosis (29,96)], polycystic kidneys, and fetal death, with its consequent autolysis of tissues. If the MSAFP is raised for no apparent reason, there is an associated high risk of fetal death, intrauterine growth retardation (IUGR), and prematurity (97). Syndromes associated with NTDs or VWDs (ventral wall defect) may be detected, and it is thought that the risk of having a significant chromosome abnormality with a raised MSAFP beyond the second trimester is in the region of 1% (98,99). The high concentration gradient between amniotic fluid and maternal serum means that any placental abnormalities (for example, an intrauterine infection or maternal lupus anticoagulant) may result in a rise in MSAFP (100). Other findings linked to raised MSAFP include fetal cardiovascular defects (101), maternal hepatic tumor, ovarian cysts, and prior fetal reduction. Whatever the cause, a raised MSAFP should prompt further investigation. If no obvious cause is ascertained, regular surveillance of the pregnancy should occur and amniocentesis be considered. Screening for Down Syndrome Prior to the possibility of screening for defects by ultrasound, the only marker for Down syndrome was maternal age. The majority of Down syndrome babies therefore remained undetected and a large number of invasive tests were performed unnecessarily. With the introduction of midtrimester MSAFP screening for NTDs came the unexpected correlation between low levels of AFP and Down syndrome pregnancies (102). Subsequently, other maternal serum markers were found to be associated with an increased risk for Down

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syndrome. These include human chorionic gonadotropin (hCG) (103), unconjugated estriol (104), pregnancy-specific β1-glycoprotein (105), inhibin, and PAPP-A (106). The four principal markers used in most screening programs are maternal age, α-fetoprotein (AFP), unconjugated estriol (uE3), and hCG. Pilot studies using MSAFP alone for the detection of Down syndrome among women below age 35 revealed that 26% of the Down syndrome gestations expected were detected, compared to 10–20% detected by fetal karyotyping in women 35 years of age or older (108). In a Canadian study, the mean second-trimester MSAFP level found in pregnancies that resulted in a Down syndrome baby was 0.79 MoMs. Estriol is a steroid hormone produced by the syncytiotrophoblast from fetal precursers. The fetal liver produces dehydroepiandrosterone sulfate (DHEAS), which is converted to 16α-OH-DHEAS. The sulfate is deconjugated by sulfatase in the placenta and forms unconjugated estriol. Its presence in the maternal serum was found to be discriminatory for Down syndrome, with a geometric mean for affected pregnancies of 0.73 MoMs— a concentration 25% lower than normal. Human chorionic gonadotropin is a glycoprotein hormone consisting of α and β subunits. The α subunit is identical to the α subunit of luteinizing hormone, folliclestimulating hormone, and thyrotropin-stimulating hormone; its specifity is determined by its unique β subunit. It is excreted by the syncytiotrophoblast and appears in the maternal circulation shortly after implantation. It rises rapidly to a peak at 9–10 weeks’ gestation, after which it declines steadily to a plateau at 18 weeks, where it remains until delivery. Both retrospective and prospective studies have shown a strong correlation betwen elevated midtrimester hCG and Down syndrome. Median hCG maternal serum values from Down syndrome pregnancies between 15 and 19 weeks’ gestation were above the 95th percentile compared to unaffected pregnancies. In a retrospective study, 64% of Down syndrome pregnancies were detected based on a single hCG assay (103). Prospective studies confirmed results and showed that the average maternal serum concentration of hCG was at least twice that of normal pregnancies (109). Interestingly, a low midtrimester MShCG was found to be associated with trisomy 18 pregnancies (110) and was used in their detection (111). In a prospective study using all three maternal serum markers in combination with maternal age, more than 60% of Down syndrome fetuses were detected, with a falsepositive rate of 5% (102). When all three biochemical markers were low, the detection of fetuses with trisomy 18 was as high as 80%. Confounders exist that render the test less efficient. An inaccurate gestational age will skew the results, as the normal levels are gestation-based. Maternal obesity decreases the concentration of all three serum markers, as does insulin dependent diabetes mellitus, while twin pregnancies increase the levels. A correction factor exists for the last two scenarios (112,113). Smoking in pregnancy increases MSAFP levels while reducing both hCG and uE3 (114). An adjustment factor is not considered necessary. Recently, biochemical markers were used for detection of Down syndrome at 10–14 weeks; the markers of choice at this point and at this stage of the pregnancy are AFP, uE3, free β-hCG, and PAPP-A (115). Another method used in first-trimester screening for fetal aneuploidy is the combination of maternal age and nuchal translucency measured at 10–14 weeks’ gestation (116). The use of a neural tube thickness of 3 mm and more in association with maternal age can detect about 85% of the fetuses with trisomy 21. Many consider that serum screening for Down syndrome should be carried out on women regardless of age and that the automatic offer of invasive procedures to all women above the age of 35 should be reconsidered. This may allow women previously given a

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high risk to avoid invasive testing and the inherent risks. Meanwhile, the refining of screening tests continues. The possibility of isolating fetal cells from the maternal serum and using them as a source of tissue for prenatal testing was first suggested in 1969 (117), when lymphocytes in the maternal serum were detected containing a Y chromosome from a male fetus. Subsequent reports, however, failed to confirm the findings (118,119). The PCR technique revived interest in the possibility of assessing small amounts of fetal cells in maternal blood, and it has been used successfully in the determination of fetal sex (120). The amount of fetal blood present in the maternal circulation for it to be detectable as well as the type of fetal cells and the optimum time of gestation for testing are questions that have been addressed by several authors (121,122). Recently, the nucleated fetal red cell (erythroblast) has been the focus of intensive research by some groups (123). Bianchi et al. were the first to focus on this cell with flow-sorting technique, using the transferrin receptor (CD71). PCR was used to amplify the Y sequences. Of eight samples showing the Y sequence, six were derived from pregnancies in which the woman was carrying a male fetus. Since the transferrin receptor alone was found ineffective, the sorting for fetal nucleated erythrocytes is currently based on four criteria: cell size, cell granularity, CD71 receptor, and glycophorin A. Fetal aneuploidy, using fetal erythroblasts isolated from maternal blood, will require FISH analysis and thus can be used as a screening for the most common fetal chromosomal abnormalities and not as a conclusive test (125). SUMMARY This chapter has focused on techniques and methods used in prenatal diagnosis; other facets (such as sequelae to an abnormal result, fetal therapy, and legal and ethical aspects) are covered by references cited in the bibliography. The discipline itself is relatively new in medicine and the issues become more complex as more tests become available. Concerns exist regarding the provision of services and the availability of accurate counseling. The techniques alone cannot replace accurate risk estimation based on family history and ethnic background, nor can they deal with the complexity of the decision-making process in which couples are often involved. The Royal College of Physicians in London attempted, in 1989, to address ths issues; it recommended that both genetic screening and prenatal diagnosis should be recognized as intrinsic components of maternal and child health services. It stated: ‘‘While prenatal tests should not be pressed upon everyone, they should be made available, even to women who are completely opposed to abortion, since testing may provide welcome reassurance, or an informed choice to care for a child with a known handicap, or allow the option of abortion to be reconsidered on the basis of known facts’’ (126). Whatever the future holds, the push for earlier and safer noninvasive methods of prenatal diagnosis and the debate surrounding the efficient assessment of the unborn will continue. REFERENCES 1. MacMahon B. Etiology of congenital defects. N Engl J Med 1972; 287:514–515. 2. Barch MJ, ed. ACT Cytogenetics Laboratory Manual, 2nd ed. New York: Rowan Press, 1991.

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3. Jauch A, Daumer C, Lichter P, Murken J, Schroeder-Kurth TM, Cremer T. Chromosomal in situ suppression hybridization of human gonosomes and autosomes in its use in clinical cytogenetics. Hum Genet 1990; 85:145–150. 4. Hook EB. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 1981; 58:282–285. 5. Harper PS. Practical Genetic Counselling, 5th ed. Boston: Butterworth Heinemann, 1998. 6. Warburton D, Kline J, Stein Z, Hutzler M, Chin A, Hassold T. Does the karyotype of a spontaneous abortion predict the karyotype of a subsequent abortion? Evidence from 273 women with two karyotyped spontaneous abortions. Am J Hum Genet 1987; 41:465–483. 7. Carr DH, Gedeon M. Population cytogenetics of human abortuses. In: Hook EB, Porter IH, eds. Population Cytogenetics: Studies in Human Reproduction. New York: Academic Press, 1977. 8. Daniel A, Hook EB, Wolf G. Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements: data from United States and Canadian laboratories. Am J Med Genet 1989; 33:14–53. 9. Eydoux P, Choiset A, Le Porrier N, Thepot F, Szpiro-Tapia S, Alliet J, Ramond S, Viel JF, Gautier E, Morichon U, et al. Chromosomal prenatal diagnosis: study of 936 cases of intrauterine abnormalities after ultrasound assessment. Prenat Diagn 1989; 9:255–268. 10. Hentemann M, Rauskolb R, Ulbrich R, Bartels I. Abnormal pregnancy sonogram and chromosomal anomalies: four years’ experience with rapid karyotyping. Prenat Diagn 1989; 9: 605–612. 11. Wilson RD, Kendrick V, Wittmann BK, McGillvray C. Spontaneous abortion and pregnancy outcome after normal first-trimester ultrasound examination. Obstet Gynecol 1985; 67(supp): 352–355. 12. Nicolaides KH, Snijders RJ, Gosden CM, Berry C, Campbell S. Ultrasonographically detectable markers of fetal chromosomal abnormalities. Lancet 1992; 340(8821):704–707. 13. Auerbach AD, Sagi M, Adler BA. Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics 1985; 76:794–800. 14. Shaham M, Voss R, Becker Y, Yarkoni S, Ornoy A, Kohn G. Prenatal diagnosis of ataxia telangiectasia. J Pediatr 1982; 100:134–137. 15. Stanley WS, Pai GS, Horger EO. 3rd, Yan YS, McNeal KS. Incidental detection of premature centromere separation in amniocytes associated with a mild form of Roberts syndrome. Prenat Diagn 1988; 8:565–569. 16. Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 1995; 83:655– 666. 17. Crawford TO. Ataxia telangiectasia. Semin Pediatr Neurol 1998; 5:287–294. 18. Sutherland GR, Richards RI. Fragile-X syndrome. In: Brock DJH, Rodeck CH, FergusonSmith MA, eds. Prenatal Diagnosis and Screening. New York: Churchill Livingstone, 1992, pp 393–403. 19. Hunter A, Tsilfidis C, Mettler G, Jacob P, Mahadervan M, Surh L, Korneluk R. The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet 1993; 29:774–779. 20. Monk M. Preimplantation diagnosis—a comprehensive review. In: Brock DJH, Rodeck CH, Ferguson-Smith MA, eds. Prenatal Diagnosis and Screening. New York: Churchill Livingstone, 1992, pp 627–638. 21. Childs B, Holtzman NA, Kazazian HH, Valle DL, eds. Molecular Genetics in Medicine: Progress in Medical Genetics. New series. Vol 7. New York: Elsevier, 1988. 22. Handyside AH, Kontogianni EH, Hardy K, Winston RML. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990; 344:768– 770. 23. Handyside AH, Lesko JG, Tarin JJ, Winston RML, Hughes MR. Birth of a normal girl after

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34 Fetal Malformations Associated with Drugs and Chemicals Visualization by Sonography Irena Nulman, Dionne Laslo, Shawn Fried, David Chitayat, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Benjamin Bar-Oz Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel

Clinical Case You are following the pregnancy of a woman who is being treated with carbamazepine for neuralgia. Attempts to discontinue the drug have resulted in reappearance of severe pain. The woman wants to know whether a fetal ultrasound examination will help to detect fetal abnormalities associated with exposure to carbamazepine.

INTRODUCTION The ability to detect fetal malformations antenatally is important both in order to allow families to terminate affected pregnancies if they so wish and to plan for optimal fetal/ neonatal management if pregnancy continues. Since the thalidomide disaster in the 1950s, an increasing number of drugs and chemicals have been incriminated as causing teratogenicity or fetal toxicity. As the majority of pregnant women are exposed to at least one medication during pregnancy, either before or after realizing that they are pregnant (1), the need to determine the relative risk for fetal malformations associated with pregnancy exposure is of the utmost importance. Data on chemically induced teratogenic risk are derived from animal studies, human case reports, and epidemiological studies. While such information is essential for assigning a relative risk to a potential teratogen, it may be of little help for drug therapy in a specific case. Sonography has emerged as a powerful tool for antenatal detection of structural fetal anomalies. It is conceivable, therefore, that more and more pregnant women exposed to drugs and chemicals will be referred for fetal ultrasound to rule out or diagnose fetal abnormalities associated with exposure to these agents. Text continues on p. 695

673

Drugs and Chemicals Associated with Fetal Malformationsa Drug

1

674

Table 1

Central nervous system

Cardiovascular

3

Acetazolamide

4 5 6 7

Acyclovir Albuterol Alprazolam Amantadine

8 9

Amiloride Aminopterin b

10

Amiodarone

11

Amitriptyline

Hydrocephaly, microcephaly

12

Amobarbital

NTD

Cardiac defects

13 14

Amoxicillin Amphetamine

Brain abnormalities, intracranial hemorrhage, microcephaly, NTD, porencephaly

15

Ampicillin

Skeleton

Craniofacial anomalies

Extremities

Gastrointestinal

Genitourinary

Miscellaneous

CPP CR SS

Clubfoot, digital anomalies, polydactyly

Sacrococcygeal teratoma

CR Hypospadias

NTD

Tachycardia

Polydactyly Clubfoot Limb-reduction defects

Cardiac defects

Oral clefts

Hypospadias Brachycephaly, hydrocephaly, NTD

Cranial anomalies, incomplete skull ossification

Bradycardia, cardiac defects Cardiac defects

Hypoplasia of thumb and fibula, short forearms, syndactyly, talipes

Feet deformities, limb-reduction defects, polydactyly Clubfoot, polydactyly, severe limb deformities

Ambiguous genitalia, hypospadias

Cardiac defects, tachycardia

Limb deformity

Genitourinary malformations

Cardiac defects

Polydactyly

Hypospadias

Anomalous mandible

Source

Genitourinary malformations, hypospadias

SS CR CS SS CR MA CR SS

IUGR Low-set ears

CR SS CR

Goiter, hypertelorism, IUGR Anopthalmia, oral clefts

CR CS

Accessory auricle, nuchal edema, oral clefts Oral clefts Eye abnormalities, IUGR, oral clefts

CPP SS

CR SS

SS CR PS RS

RS SS

Nulman et al.

2

Acebutolol (see atenolol) Acetaminophen

Aspirin

17

Atenolol

18

Atropine

19

Azatadine

20

Azathioprine b

21 22

Beclomethasone Belladonna

23

Benazepril (see captopril) Benzthiazide (see chlorothiazide, hydrochlorothiazide) Benztropine

24

25 26 27 28 29 30 31 32

Intracranial hemorrhage

Cardiac defects Bradycardia, cardiac defects

NTD

Plagiocephaly

Cardiac defects

Limb-reduction defects Limb-reduction defects, polydactyly Limb-reduction defects Pes equinovarus, polydactyly

Cardiac defects

Betamethasone b Betaxolol (see atenolol) Bismuth subsalicy- Intracranial hemorlate rhage Bisoprolol (see atenolol) Bretylium Macrocephaly, miBromides crocephaly Bromocriptine Hydrocephaly, microcephaly Bumetanide Busulfan

Myeloschisis

35

Butoconazole

NTD

Cardiac defects

IUGR

RS SS

Hypospadias

IUGR, oral clefts

PS SS CR SS

Oral clefts

SS

Hypospadias

IUGR

CR SR

Hypospadias

Oral clefts MA Eye and ear anoma- CPP lies

Gastrointestinal anomalies

Clubfoot, polydactyly Limb-reduction defects

CR SS

Gastrointestinal anomalies Renal agenesis

Cardiac defects Hepatic subscapular calcification

Absent kidney, hydronephrosis, hydroureter

Oral clefts

MA

IUGR

CPP CS

IUGR

PI CPP CR

Hypospadias, oral cleft, single umbilical artery

RS

SS IUGR, microphthal- CR CS mia, oral clefts SS

675

33 34

Bradycardia Cardiac defects

Hypospadias

Drugs, Chemicals, and Fetal Malformations

16

Continued Drug

36

676

Table 1

Central nervous system

Cardiovascular

37

Butriptyline (see imipramine) Caffeine

38

Captopril

Microcephaly, NTD

Cardiac defects, pulmonary hypoplasia

39

Carbamazepine b

Microcephaly, NTD

Cardiac defects

40 41

Carbenicillin Carbimazole (see methimazole) Carbon monoxide b

42

43 44 45 46 47 48 49

Carisoprodol Carteolol (see atenolol) Casanthranol Cefaclor Cefadroxil

Tachyarryhthmias

Cerebral atrophy, hydrocephaly, microcephaly

NTD NTD

Skeleton

Extremities

Musculoskeletal defects Clinodactyly, limbAcrania reduction defects, polydactyly Polydactyly, talipes Hypertelorism

Gastrointestinal

Omphalocele

Genitourinary

Miscellaneous

Hydronephrosis

IUGR, tumors

CPP CR CS

Hypospadias, renal defects

IUGR, low set ears, oligohydramnios

CR SS

Genitourinary defects

IUGR, oral clefts

CR PS RS SS

Cardiac defects

SS

Bradycardia

CR PS

Cardiac defects Cardiac defects

Oral clefts

SS

Oral clefts

SS SS SS

Polydactyly Limb-reduction defects

Cardiac defects Cardiac defects Cardiac defects

53 54

Chlordiazepoxide Chloroquine

Cardiac defects Cardiac defects

Cardiac defects

SS

Oral clefts Unilateral agenesis of kidney and ureter (in male fetuses) Polydactyly

Duodenal atresia

IUGR

SS SS CR PS RS

Oral clefts Wilms’ tumor

CCS SS CR CS

Nulman et al.

50 51 52

Ceftriaxone Celiprolol (see atenolol) Cephalexin NTD Cephradine Chlorambucil

Microcephaly

Source

56

Chlorothiazide (see hydrochlorothiazide) Chlorpheniramine

Hydrocephaly

Polydactyly

57

Chlorpromazine

Microcephaly

58

Chlorpropamide

Microcephaly

Brachymesophalangy, clinodactyly, clubfoot/hand, syndactyly Limb anomalies

59 60 61

Chlortetracycline (see tetracycline) Chlorzoxazone Cholestyramine

62 63

Cimetidine Ciprofloxacin

64

Clarithromycin

NTD

65

NTD

66

Clavulanate potassium Clemastine

67 68

Clindamycin Clomiphene

NTD Hydrocephaly, microcephaly, NTD

69

Clomocycline (see tetracycline) Clonazepam Clonidine

70 71

Hypospadias

Cardiac defects

Vertebral anomalies

SS

Gastrointestinal Malformation of fe- Eye and ear defects anomalies male genitalia Abdominal wall defect

CPP SS

Bowel obstruction

CR CS

Facial and auricular anomalies

Cardiac defects

SS CR

Hydrocephaly, intracranial hemorrhage Cerebellar hypoplasia

Cardiac defects Cardiac defects

Cardiac defects

Skeletal defects

Amputation of right forearm, femur aplasia

SS PS RS

Urethral atresia/stenosis

Absent clavicles, craniofacial anomalies

Oral clefts

CR

Oral clefts

SS

Limb-reduction defects, limb abnormalities

NTD

Cardiac defects

Cardiac defects Cardiac defects

CPP

Clubfoot, polydactyly, syndactyly

Drugs, Chemicals, and Fetal Malformations

55

SS

Absent kidney, hypospadias

Oral clefts

Oral clefts

SS CR SS

MA SS SS

677

678

Table 1

Continued Drug

Central nervous system

72

Clorazepate

73 74 75

Clotrimazole Cloxacillin Cocaine b

76

Codeine

Absence of septum pellucidum, brain lesions, cerebral hemorrhage, hydrocephaly, microcephaly Hydrocephaly

77

Cortisone/ corticotropin b Coumarin derivatives b

Cyclopia, hydrocephaly Brain structural defects

78

Cromolyn sodium Cyclacillin Cyclophosphamide b

82

Cyclosporine

Cardiac defects

NTD

Microcephaly

Cardiac defects Cardiac defects Bradycardia, cardiac defects, tachycardia

Cardiac defects

Skeleton Deformities of the lumbosacral vertebrae

Clubfoot, digital abnormalities, limb-reduction defects, polydactyly

Musculoskeletal malformations

Limb reduction, polydactyly Clubfoot

Absence of nasal septum, scoliosis, stippled epiphyses

Cardiac defects Cardiac defects

Osseous malformation

Gastrointestinal

Genitourinary

Miscellaneous

Absence and abnor- Genital abnormalimalities of finties gers and feet, shortened thigh, underdeveloped femur Polydactyly

Hypertelorism

Cardiac defects Cardiac defects

Extremities

Bradydactyly, finger hypoplasia, hypoplasia of extremities, polydactyly Polydactyly Hypoplastic midphalanx fifth finger, missing toes and fingers, syndactyly Hypoplasia of leg

Intestinal defects

Source CR

Hypospadias Genitourinary abnormalities, hydronephrosis, hypospadias

Genitourinary abnormality Gastroschisis Single kidney

IUGR, oligohydramnios, oral clefts

SS SS CR PS RS

Oral clefts, tumors

CPP RS SS

Oral clefts

CPP

Agenesis of diaphragm, eye defects, IUGR

CR CS RS SS

Oral clefts

SS SS CR

Abnormally shaped, low-set ears, eye defects, IUGR, oral clefts IUGR

CR

Nulman et al.

79 80 81

Cardiovascular

84 85

Cyclothiazide (see chlorothiazide, hydrochlorothiazide) Cyproheptadine Cytarabine

86

Danazol

87 88

Daunorubicin b Demeclocycline (see tetracycline) Dexamethasone b Dextroamphetamine (see amphetamine) Diazepam b

89 90

91

92 93

94

95 96

Cardiac defects (paternal use)

Oral clefts Ear abnormalities, IUGR

Ambiguous genitalia Anencephaly

CNS abnormalities, microcephaly, NTD

Dibenzepin (see imipramine) Diclofenac

Cardiac defects

Craniofacial defects, hypertelorism, hypoplastic mandible

Limb deformity

CR CS

Urogenital abnormalities

Oral clefts

MA

IUGR, oral clefts

CR MA PS RS

Premature closure of ductus arteriosus

CR SS

Clubfoot, polydactyly

Diaphragmatic hernia

Testicular tumors Oral clefts Cardiac defects

SS CR

CR RS

Syndactyly

Cardiac defects

Dicumarol (see coumarin derivatives) Dicyclomine Macrocephaly Dienestrol (see estrogen) Diethylstilbestrol Diflunisal Diltiazem

Ectrodactyly, lower limb abnormalities, missing and malformed fingers, missing toes, syndactyly (paternal use)

CPP SS

CR SS SS

679

97 98 99

Hypospadias Anencephaly (paternal use)

Drugs, Chemicals, and Fetal Malformations

83

680

Table 1

Continued Drug

100 101

103

Diphenoxylate

104

Disulfiram

105

109 110

Dothiepin (see imipramine) Doxepin Doxorubicin Doxycycline (see tetracycline) Doxylamine Droperidol

111 112

Dyphylline Enalapril

113 114 115

Enoxacin (see ciprofloxacin) Ephedrine Epinephrine

116

Epoetin alfa

106 107 108

Cardiovascular

Skeleton

Extremities

Gastrointestinal

Genitourinary

Miscellaneous

Cardiac defects

Hydrocephaly, hypoplasia of cerebral hemisphere

Cardiac defects

NTD

Cardiac defects

CPP

Clubfoot, polydactyly

Hypertelorism

Vertebral fusion

Cardiac defects

Hypospadias and other genitourinary abnormalities Hypospadias

Limb-reduction defects, polydactyly Clubfoot, phocomelia of lower extremities, radial aplasia

Polydactyly

Eye and ear anoma- CPP CR PS SS lies, oral clefts

CR

CR

Bowel obstruction

Oral clefts

CR SS CR CR SS

Oral clefts

CR PS CR

Microcephaly NTD Cardiac defects

Skeletal defects

Brain hypoplasia, hydrocephaly Cardiac defects Pulmonary hypoplasia

Bradycardia

Source

Calvarial hypoplasia, craniofacial defects

Polydactyly Polydactyly, short limbs

Kidney defects

IUGR

Clubfoot

SS CR SS

CPP CS SS

Intracranial hemorrhage IUGR

CR

Nulman et al.

102

Dimenhydrinate Diphenadione (see coumarin derivatives) Diphenhydramine

Central nervous system

Ergotamine

118

Erythromycin

119

Esmolol (see atenolol) Estradiol Estrogens, conjugated

120 121

Hydrocephaly, lissencephaly, microcephaly, NTD, ventriculomegaly

Cardiac defects

Cardiac defects

Cardiac defects Cardiac defects

122

Ethanol b

123 124

Ethinyl estradiol Cardiac defects Ethisterone (see hydroxyprogesterone) Ethoheptazine Ethosuximide b Hydrocephaly Ethotoin Ethyl biscoumacetate (see derivatives) Ethynodiol (see oral contraceptives) Etodolac (see indomethacin) Etoposide Etretinate b Cerebral abnormali- Cardiac defects ties, microcephaly, NTD

125 126 127 128

129

130 131 132

Sacral or coccygeal agenesis

Agenesis of corpus callosum, microcephaly, NTD

Cardiac defects

Vertebral and chest abnormalities

Absent tibia, bowed fibulae, polydactyly Limb and finger abnormalities

Absence of terminal phalanges, limb reduction defects and abnormalities, syndactyly

Bowel obstruction

Hypospadias, genital abnormalities, multicystic dysplastic kidneys Hypospadias

Oral clefts

CR RS SS

IUGR, oral clefts

CS SS

Hypospadias

Eye and ear CPP SS Eye and ear anoma- CPP lies, oral clefts

Kidney and urinary defects

Eye and ear anoma- CR CS PS RS lies, IUGR Eye and ear

CPP

Umbilical hernia Oral clefts Oral clefts

CPP CR CR

IUGR Low-set ears, oral clefts

CR CR

681

Abnormalities of skull and cervical vertebrae, facial abnormalities, skeletal anomalies

Bilateral talipes equinovarus, digital and limb hypoplasia, polydactyly Absence of tibia, limb reduction, polydactyly

Drugs, Chemicals, and Fetal Malformations

117

Continued Drug

133 134

Famotidine (see cimetidine) Fenfluramine

135

Fluconazole

136

138

Flucytosine (see fluorouracil) Flunitrazepam (see diazepam) Fluorouracil

139

Fluoxetine

140

Fluphenazine

141

Flurazepam (see diazepam) Flurbiprofen (see indomethacin) Folic acid deficiency b

137

142 143

144

150

Cardiovascular

Skeleton

Cardiac defects Hydrocephaly

Cardiac defects

Anencephaly, hydrocephaly

Cardiac defects

Craniofacial abnormalities, thin clavicles and ribs

Extremities

Cardiac defects

Genitourinary

Clubfoot, limb abnormalities Upper and lower limb

Absence of thumbs and fingers, radial aplasia

Cardiac defects Enlarged ventricles

Gastrointestinal

Miscellaneous

CR WHO

Duodenal atresia

Low-set ears, oral clefts

CR

Single umbilical artery

CR

Abdominal wall defect

CR Hypospadias

Hypertelorism, poor ossification of skull bone

IUGR, oral clefts

Polydactyly IUGR

CR

IUGR, placental abruption, placenta previa

CR PS RS

Hypospadias

Cardiac defects

Cardiac defects

CR SS

SS

NTD

Fosinopril (see captopril) Furosemide Gabapentin Holoprosencephaly Gemfibrozil Glyburide Gold sodium thiomalate Griseofulvin

Source

Cyclopia Oral clefts Ear defects IUGR

SS CR SS CS SS CR CS

Conjoined twins

CCS CR

Nulman et al.

145 146 147 148 149

Central nervous system

682

Table 1

Guaifenesin Haloperidol

Cardiac defects Cardiac defects

153 154 155

Heparin b Heroin Hexachlorophene

Cardiac defects

156 157

162

Hexamethonium Hydrochlorothiazide (see chlorothiazide) Hydrocodone Hydroflumethiazide (see chlorothiazide, hydrochlorthiazide) Hydroxychloroquine (see chloroquine) Hydroxyprogesterone Hydroxyzine

163

158 159

160

161

NTD

Cardiac defects

Polydactyly Limb abnormalities, limbreduction defects Polydactyly

CPP SS CR SS

Hypospadias

Foot anomalies, limb-reduction defect, polydactyly

Hypospadias, kidney defects

IUGR Microphthalmia, oral clefts

Bowel obstruction

164

Imipramine

NTD

165

Indigo carmine

Hydrocephaly

166

Indomethacin

Intraventricular hemorrhage

167 168

Iodinated glycerol Iodine (see potassium iodide)

Cardiac defects

CR SS

Cardiac defects

SS

Cardiac defects

Absence of thumbs

Cardiac defects Cardiac defects

Limb-reduction defects Polydactyly

Cardiac defects

Bilateral amelia

Cardiac defects, tricuspid regurgitation

Clubfoot, syndactyly Limb-reduction defects Polydactyly

Ambiguous genitalia, hypospadias

Intestinal atresia

Hypospadias, renal cystic dysplasia Urethral obstruction sequence

CPP CS CSr Oral clefts

CPP CS

Oligohydramnios, oral clefts, microphthalmia Adrenal hypoplasia, oral clefts

CR SS VR

CR CS SS CR CS

Hydrops, oligohydramnion, oral clefts

CR SS

SS

683

Ibuprofen

Hydrocephaly, NTD Hydrocephaly, NTD NTD

CR SS CR CS CS

Drugs, Chemicals, and Fetal Malformations

151 152

684

Table 1

Continued Drug

Central nervous system

169

Ipratropium

170

Iprindole (see imipramine) NTD Isoniazid Isoproterenol Isotretinoin b Brain structural abnormalities, hydrocephaly, microcephaly, NTD

171 172 173

174 175 176 177 178

Itraconazole Ketoconazole Ketoprofen Ketorolac (see indomethacin) L-hyoscyamine

179 180

Labetalol Lamotrigine

181

Levofloxacin (see ciprofloxacin) Levothyroxine Lidocaine

182 183

186

Lindane Liotrix (see levothyroxine) Lisinopril (see captopril)

Skeleton

Extremities

Gastrointestinal

Genitourinary

Miscellaneous

Urinary tract obstruction

Hydrocephaly, NTD

Cardiac defects

Absence of clavicle and scapula, hypertelorism

Bradycardia Cardiac defects

Hypospadias Hydroureter, hypospadias, multicystic dysplastic kidneys

Oral clefts Anotia, low-set ears, microphthalmia, microtia, oral clefts, single umbilical artery

CR CR SS

Limb-reduction defects, polydactyly

SS

Polydactyly

Acrania

CPP CR RS SS CR CPP SS CR RS SS

Limb abnormalities Limb abnormalities Polydactyly

IUGR

CS SS VR

Goiter Respiratory tract anomalies, tumors Oral clefts

CS PS SS CPP CS SS

Clubfoot, polydactyly

Cardiac defects

Cardiac defects

Polydactyly, talipes Clubfoot Limb-reduction defects, syndactyly

Source CR SS

Hypospadias

SS

Nulman et al.

184 185

Cardiovascular

Lithium b

188

Lomefloxacin (see ciprofloxacin) Loperamide Loratadine

189 190

191 192

Lorazepam (see diazepam) b Lovastatin

Aqueduct stenosis, hydrocephaly, NTD

Bradycardia, cardiac defects

194 195 196

Lysergic acid dieth- Brachycephaly, hyylamide drocephaly, NTD Maprotiline Marijuana Porencephaly Mebendazole

197

Mechlorethamine

198

Meclizine

199

Meclofenamate (see indomethacin) Medroxyprogesterone Mefenamic acid (see indomethacin) Melphalan Meperidine Mephenytoin (see phenytoin)b Mepindolol (see atenelol)

201

202 203 204 205

Diaphragmatic hernia, microphthalmia, oral clefts

Limb abnormalities

Renal dysplasia

Cardiac defects

Limb deformities, limb-reduction defects

Urinary tract defects

Cardiac defects

Syndactyly Limb-reduction defects Limb abnormalities

Intracranial hemorrhage

Vertebral anomalies

Renal hypoplasia

Hypoplastic left heart sequence

CR PS RS

SS CR

CR RS Neuroblastoma, oral clefts, ocular defects Oral clefts IUGR

IUGR

CR CS

SS CR CS SS CR

Eye and ear anoma- CPP PS lies

Cardiac defects

Hypospadias

CPP CR SS

IUGR Polydactyly

Hypospadias

CR CPP SS

685

Cardiac defects

200

Bilateral renal agen- Microtia, polyhyesis dramnios, single umbilical artery

Cardiac defects Cardiac defects

Holoprosencephaly

193

Hypoplasia of max- Bilateral talipes equivovarus, illa clubfoot, polydactyly

Drugs, Chemicals, and Fetal Malformations

187

686

Table 1

Continued Drug

Central nervous system

Cardiovascular

Meprobamate

207

Mercaptopurine

208

213

Mestranol (see estrogen, estradiol) Metaproterenol Methacycline (see tetracycline) Methamphetamine (see amphetamine) Methazolamide (see acetazolamide) Methenamine

214

Methimazole

215

Methocarbamol

216

Methotrexate b

NTD

Cardiac defects, tachycardia

217 218

Methotrimeprazine Methyclothiazide (see chlorothiazide, hydrochlorothiazide) Methyl mercury b Methyldopa

Hydrocephaly

Cardiac defects

Microcephaly Microcephaly

Cardiac defects

209 210 211

212

219 220

Cardiac defects, ectopia cordis Hydrocephaly, NTD

Extremities

Gastrointestinal

Genitourinary

Deformed elbows and joints, polydactyly

Miscellaneous Oral clefts

Cardiac defects

CPP CS SS

IUGR, microphthal- CR mia, oral clefts

Polydactyly

NTD

Source

Cardiac defects, tachycardia

Multiple anomalous ribs, skull and facial bone abnormalities

Limb-reduction defects Adactyly, polydactyly Bilateral equinovarus Absence of digits on feet, long webbed fingers, talipes equinovarus

SS

Hypospadias

Oral clefts

SS

Goiter

CR CS SS CPP CS SS

IUGR, low-set ears

CR CS

PS

Hypospadias, renal agenesis

Oral clefts

CR CPP CR SS

Nulman et al.

206

Skeleton

Methylene blue Methylphenidate Metoclopramide

224

226

Metolazone (see chlorothiazide, hydrochlorothiazide) Metoprolol (see atenolol) Metronidazole

227 228

Miconazole Mifepristone

229 230

Minocycline (see tetracycline) Minoxidil

Cardiac defects

231

Misoprostol b

Cardiac defects

232

238

Nabumetone (see indomethacin) Nadolol (see atenolol) Nalidixic acid Nicoumalone (see coumarin derivatives) Nifedipine Nonoxynol-9/ Octoxynol-9 Norethindrone

239 240

Norethynodrel [entry deleted]

225

233 234 235

236 237

Bowel obstruction

CR CS SS CR

Cardiac defects Brain hypoplasia, Hydrocephaly

Brain defects

Cardiac defects

Craniostenosis, midline facial defects

Cardiac defects

Limb abnormalities

Polydactyly Fused lower limbs

Anomalies of cranium, hypertelorism

Bilateral fifth finger, clinodactyly Limb abnormalities

Genital defects, hypospadias, obstructive uropathy Absence of stomach

Renal agenesis

Omphalocele

Oral clefts

CPP CR SS

Oral clefts Absence of amniotic sac, oral clefts

SS CR

Low-set ears

CR

Oral clefts

CR LACS PS SS

Hydrocephaly

CR

Cardiac defects

IUGR

CR SS CCS

Oral clefts

CPP SS

Limb-reduction defects Hydrocephaly, NTD

Drugs, Chemicals, and Fetal Malformations

221 222 223

Hypospadias

Cardiac defects

Hypospadias

CPP

687

Cardiac defects

688

Table 1

Continued Drug

241

Norfloxacin

242

Norgestrel (see oral contraceptives) Nortriptyline Ofloxacin

243 244 245

246 247 248 249 250 251

252 253

255 256

Opipramol (see imipramine) Oral contraceptives Oxazepam (see diazepam) b Oxprenolol (see atenelol) Oxyphenbutazone (see phenylbutazone) Oxytetracycline (see tetracycline) Para-amino salicylic acid Paramethadione (see trimethadione) Paroxetine Penbutolol (see atenolol)

CNS calcification, NTD

Hydrocephaly, NTD

Cardiovascular

Skeleton

Extremities

Cardiac defects

Gastrointestinal Abdominal wall defect

Cardiac defects Cardiac defects

Genitourinary Hypospadias, renal agenesis

Dwarfism ectopia cardis

Hypospadias

IUGR

Talipes

Hydranencephaly, NTD

Cardiac defects

Vertebral malformations

Miscellaneous

Source PS RS

SS PS RS

CR

Limb-reduction defects

Renal malformations

CR CS

Limb-reduction defects

Hypospadias

CPP

Cardiac defects

CR CS

Clubfoot

CR

Nulman et al.

254

Olsalazine (see para-amino salycilic acid) Omeprazole

Central nervous system

Penicillamine

258 259 260 261 262 263

Penicillin V Pentamidine Pentazocine Pentoxifylline Perphenazine Phenacetin

264 265

267

Phenazopyridine Phendimetrazine (see amphetamine) Phenindione (see coumarin derivatives) Pheniramine

268

Phenobarbital b

269

Phenprocoumon (see coumarin derivatives) Phenylbutazone NTD Phenylephrine

266

270 271 272 273 274 275 276

Phenylpropanolamine Phenytoin b Phytonadione Pindolol (see atenolol) Piperazine

Bilateral talipes

Intraventricular hemorrhage, hydrocephaly NTD

NTD Microcephaly Craniosynostosis

Meconium peritonitis

IUGR

Polydactyly Cardiac Cardiac Cardiac Cardiac

defects defects defects defects

IUGR IUGR

Polydactyly Foot deformities

Oral clefts Hydronephrosis, hypospadias

Musculoskeletal defects

Cardiac defects

Microcephaly, NTD

Microcephaly, NTD NTD

Cardiac defects

SS CR CS SS CPP CR SS CPP SS SS

Eye and ear anoma- CPP lies, respiratory tract malformations IUGR CPP CR SS

Cardiac defects

Cardiac defects Bradycardia

CR

Musculoskeletal de- Clubfoot, syndacfects tyly Polydactyly Hypoplasia of distal phalanx

Cardiac defects

Limb abnormalities

Hypospadias

Drugs, Chemicals, and Fetal Malformations

257

SS Eye and ear anoma- CPP lies Eye and ear anoma- CPP lies Hypertelorism, CR PS RS SS IUGR, oral clefts SS

Anophthalmia, oral clefts

CR

689

690

Table 1

Continued Drug

Central nervous system

277

Piroxicam

278 279

Podophyllum Polychlorinated bi- Microcephaly phenyl b Polythiazide (see chlorothiazide, hydrochlorothiazide) Potassium iodide Povidone-iodine (see potassium iodide) Prednisolone Prednisone (see prednisolone)b Primidone (see phenobarbital)b Probenecid Procarbazineb Intracranial hemorrhage Prochlorperazine

280

281 282

283 284 285 286 287 288

289

292 293

Skeleton

Premature closure of ductus arteriosus Cardiac defects

Extremities

Gastrointestinal

Genitourinary

Polydactyly

Miscellaneous Oral clefts

SS

IUGR

CR PS

Goiter

CR

Hypospadias

Oral clefts Oral clefts

MA SS SS

Malformed kidneys

IUGR

SS CR

Oral clefts

CPP CR

Absent thumb

Cardiomegaly

Cardiac defects Cardiac defects

Cardic defects Cardiac defects Cardiac defects

Skeletal defects

Limb abnormalities, oligodactly Limb abnormalities, limbreduction defects

Progesterone (see hydroxyprogesterone) Promethazine Propoxyphene Microcephaly

Cardiac defects Cardiac defects

Arthrogryposis

Polydactyly Limb reduction and abnormalities

Propranolol (see atenolol) Propylthiouracil

Cardiac defects

Finger/toe abnormalities

Source

Omphalocele

Anopthalmia, microphthalmia

Hypospadias

Goiter

CPP SS CPP CR SS

CR SS

Nulman et al.

290 291

NTD

Cardiovascular

Pseudoephedrine Pyridoxine Quazepam Quinacrine

298

Quinapril (see captopril) Quinethazone (see chlorothiazide, hydrochlorothiazide) Quinine

299

300 301

Clubfoot Phocomelia/amelia

Oral cleft Hydrocephaly, NTD

CNS anomalies, hy- Cardiac defects drocephaly

302 303

Ramipril (see captopril) Ranitidine NTD Reserpine Microcephaly

304

Retinoic acid b

305

Rifampin

306 307

Secobarbital (see phenobarbital) Sertraline

308 309

Simethicone Simvastatin

310

Sodium iodide (see potassium iodide) Sotalol (see atenolol) Sparfloxacin (see ciprofloxacin) Spermicides

311 312 313

Gastroschisis

Brain defects, hydrocephaly, microcephaly Hydrocephaly, NTD

Vertebral anomaly

Limb deformities

Megacolon

Hydronephrosis, renal agenesis

Gastrointestinal anomalies

Genitourinary abnormalities

CR SS

Cardiac defects

SS CPP

Hydronephrosis, hydroureter Cardiac defects

Malformations of cranium, ear, ribs

Microphthalmia

Limb abnormalities

NTD

Renal defects

PS RS

CR

Abdominal wall defect Cardiac defects

CPP SS CR MA CR

Drugs, Chemicals, and Fetal Malformations

294 295 296 297

CR Hypospadias

Limb abnormalities, limbreduction defects

Hypospadias

Oral clefts

SS PS RS

CR PS RS

691

Polydactyly Clubfoot, polydactyly

692

Table 1

Continued Drug

Central nervous system

Cardiovascular

Skeleton

314 315 316

Spironolactone Sucralfate Sulfasalazine

317

Sulfonamides: sulfisoxazole and sulfabenzamide

Cardiac defects

318

Sulindac

Premature closure of ductus arteriosus

319

Sumatriptan

320

Tamoxifen

321 322 323

Temazepam Terconazole Terfenadine

Cardiac defects Cardiac defects

324 325

Terpin hydrate Tetracycline

Cardiac defects

Clubfoot

326

Thalidomide b

Cardiac defects

Spine defects

327

Thioguanine

Hydrocephaly, macrocephaly

Extremities

Polydactyly Talipes equinovarus Clubfoot, hypoplasia of limb or part of it, miscellaneous foot defects

Cardiac defects

Gastrointestinal

Genitourinary

Polycystic or absent kidney Urethral obstructions

Miscellaneous SS SS CR

Oral clefts

CR CPP PS SS

CR SS

Absence of hands, clubfoot, phocomelia, reduction of lower limbs

Absent corpus callosum, holoprosencephaly

Absent kidney

Diaphragmatic hernia, oral clefts

Ambiguous genitalia

Cardiac defects (paternal use)

Limb-reduction defects, polydactyly Clubfoot Hypoplasia of limbs, limbreduction defects, polydacyly Limb/digit reduction and abnormalities Finger/toe abnormalities (paternal use)

PS RS SS

CR Oral clefts

SS SS SS

Benign tumors Hypospadias

CPP CPP CR CS SS

Hypospadias

CR PS

IUGR

CR

Nulman et al.

Anecephaly (paternal use)

Source

Oral clefts Oral clefts Oral clefts

333 334 335

Thiopropazate (see chloropromazine) Thiothixene Thyroid Timolol (see atenolol, propranolol) Timolol (see atenolol) Tobacco Tolazamide Tolbutamide

336

Tolmetin

337

338

Tretinoin (see etretinate, isotretinoin) b Tretinoin (topical) b

339 340

Triamcinolone Triazolam

341

342

Trichlormethiazide (see chlorothiazide, hydrochlorothiazide) Trifluoperazine b

343

Trimethadione b

Microcephaly

Cardiac defects

344 345

Trimethoprim Triprolidine

Holopresencephaly

Cardiac defects Cardiac defects

329 330 331 332

Cardiac defects Cardiac defects

Cardiac defects

Premature closure of ductus arteriosus

SS SS

Hand and foot anomalies, talipes Polydactyly

Gastrointestinal anomalies

Supraumbilical exomphalos

Holoprosencephaly, microcephaly

Cardiac defects

Upper limbreduction defects

Hydrocephaly

Cardiac defects

Polydactyly

Cardiac defects

Limb-reduction defects Clubfoot, malformed hand

Renal anomalies

IUGR Ear defect External ear defect

PS CR CR CS SS

SS

Kidney malformations

Abnormal ear, IUGR

CR

IUGR, oral clefts IUGR, oral clefts

CR MA SS VR

Drugs, Chemicals, and Fetal Malformations

328

CR SS

Oral cleft

Genitourinary abnormalities Hypospadias

Abnormal ears, IUGR, oral clefts

CS CR SS SS

693

694

Table 1

Continued Drug

346

Valproic acid b

347

Vinblastine (see vincristine) Vincristine (during gestation or up to one year after treatment) Vitamin A

348

349

350

351

352

Warfarin (see coumarin derivatives) b Zidovudine

Central nervous system

Skeleton

Extremities

Chest and rib abnormalities, vertebral defects

Limb, finger, and toe abnormalities

Genitourinary abnormalities

Ear defects, oral cleft

CR CS SS

Cardiac defects

Talipes

Malformed kidneys (reduced size and malpositioned)

IUGR

CR CS

Cardiac defects

Limb-reduction defects

Micro/ anophthalmia, oral clefts

CR

Cardiac defects

Clubfoot, polydactyly

Diaphragmatic hernia, IUGR, microphthalmia, oral clefts

PS RS

Cardiovascular

Hydrocephaly, microcephaly, NTD

Cardiac defects

NTD

NTD

Gastrointestinal

Genitourinary

Hydronephrosis, polycystic kidney, renal agenesis

Miscellaneous

Source

Zuclopenthixol (see chlorpromazine)

CNS: central nervous system; HCS: historic cohort study; CPP: collaborative perinatal project; CCS: case-control study; SS: surveillance study; CR: case report; PS: prospective study; RS: retrospective study; SR: sporadic reports; NTD: neural tube defect; IUGR: intrauterine growth retardation; MA: meta-analysis; CS: cohort study; WHO: World Health Organization; LACS: Latin American Collaborative Study; M: manufacturer; CSr: case series reports; VR: voluntary reports.

Since only malformations that can be visualized by current ultrasonographic techniques are listed, the guide cannot be used as a complete list of drug-induced teratogenicity. Proved to be teratogenic. Source: Koren G, et al. (Am J Obstet Gynecol 1987; 156:79–85), with the permission of CV Mosby Company. b

Nulman et al.

a

Drugs, Chemicals, and Fetal Malformations

695

Currently, pregnant women who attend the Motherisk Clinic for antenatal counseling of drug-chemical exposure are scheduled for a detailed fetal ultrasound at 18–19 weeks of pregnancy if there is an increased risk for malformations. This guide aims at providing the sonographer with a practical list of malformations that have been described in association with specific drugs or chemicals. It is an updated version of our original publication several years ago (1). METHODOLOGICAL CONSIDERATIONS Two groups of agents are included (1). Common drugs and chemicals that have been associated with malformations are listed. In many cases the incriminating data are controversial; hence the inclusion of a certain malformation in this guide by no means suggests that we are convinced that the agent is a teratogen. Because of the heterogeneity of the data, the source of information is mentioned (for instance, case reports, retrospective or prospective studies) (2). Drugs and chemicals that have been proven beyond doubt as teratogens are noted (see Table 1). Table 1 includes only malformations that can be visualized by current ultrasonographic techniques and cannot be used as a complete list of drug-induced teratogenicity. The data in this guide have been extracted from currently available literature (2–9). Certain points with respect to the ultrasound examination itself should be stressed. It is possibly best carried out by a physician ultrasonographer who has had significant experience in looking at fetuses. A very meticulous technique and high-resolution, realtime equipment should be used. The examination is best recorded on videotape so that it can be reviewed as needed. A great deal of patience is required in this type of study, especially when one is examining the face, digits, and heart. At the outset of the examination, it should be explained to the patient that the assessment may take some time to complete and that more than one sitting may be required. Clinical Case Answer It is estimated that about 1% of carbamazepine users will have babies with neural tube defects (a relative risk of around 10 compared to the general population). Detailed ultrasound examination and maternal serum α-fetoprotein can detect most cases of neural tube defects. REFERENCES 1. Koren G, Brill Edwards M, Miskin M. Fetal malformations associated with drugs and chemicals: visualization by sonography. In: Koren G, ed. Maternal-Fetal Toxicology, 1st ed. New York: Marcel Dekker, 1990, pp 297–307. 2. Schardein J. Chemically Induced Birth Defects. New York: Marcel Dekker, 1985. 3. Fabro S. Reproductive toxicology: a medical letter. Washington, DC: Reproductive Toxicology Center, 1984. 4. Mattison DR. Reproductive Toxicology. New York: Alan R Liss, 1983. 5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, 4th ed. Baltimore: Williams & Wilkins, 1994. 6. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: PSG Publishing, 1977.

696

Nulman et al.

7. Shepard TH. Catalog of Teratogenic Agents, 6th ed. Baltimore: John Hopkins University Press, 1989. 8. Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Chichester, England: Ellis Horwood, 1984. 9. Berglund F, Flodh H, Lundborg P, Prame B, Sannerstedt R. Drug use during pregnancy and breast-feeding: a classification system for drug information. Acta Obstet Gynecol Scand Suppl 1984; 126:1–55. 10. Eller D, Patterson CA, Webb G. Maternal and fetal implications of anticonvulsive therapy during pregnancy. Obstet Gynecol Clin North Am 1997; 24:523–534. 11. Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clin North Am 1997; 24:499–521. 12. Diket AL, Nolan TE. Anxiety and depression: diagnosis and treatment during pregnancy. Obstet Gynecol Clin North Am 1997; 24:535–557. 13. Briggs GG, Freeman RK, Sumner JY. Drugs in Pregnancy and Lactation, 5th ed. Baltimore: Williams & Wilkins, 1998.

35 Maternal Disorders Leading to Increased Reproductive Risks Ruthie Geist and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A young Type I diabetic woman, known to your clinic for many years, is in the first trimester of her first pregnancy. She is concerned that her daily injections of insulin may adversely affect the baby.

INTRODUCTION When pregnancy and maternal medical disease coexist, there may be serious consequences for mother, fetus, and child. For example, maternal risks include preeclampsia in the hypertensive woman, increased vaso-occlusive crises in the presence of sickle cell disease, and functional deterioration in cardiac patients. The fetus or neonate is predisposed to congenital anomalies if the mother has diabetes; to haemorrhage if she suffers from autoimmune thrombocytopenia; and to heart block in the presence of maternal lupus. In later years, the child may exhibit manifestations of genetic transmission, as with thalassemia or Marfan’s syndrome, and in addition is subject to the potential repercussions from growing up in an environment rendered less secure by the mother’s medical condition. Aside from events that relate directly to the interaction between maternal health and pregnancy, there are risks arising from the treatment of several underlying medical disorders. For example, warfarin (in a woman with a prosthetic heart valve) and valproic acid (in the treatment of seizure disorders) are known teratogens. Propylthiouracil, used in the management of hyperthyroidism, can result in fetal goiter and hypothyroidism. Other drugs, such as the anticancer chemotherapeutic agents and posttransplant immunosuppressants, are potentially dangerous and require further evaluations. Finally, certain maternal factors that relate primarily to lifestyle carry increased reproductive risks. Aside from the obvious disadvantages to maternal health brought on by alcohol, drug abuse, and dietary extremes, there are recognized corresponding fetal and neonatal hazards such as fetal alcohol syndrome, placental abruption, and stillbirth.

697

698

Table 1

Maternal Disease and Pregnancy Outcome

Condition a

AIDS (1–5)

Epidemiology/incidence

Effects of pregnancy on the disease

Vertical transmission averages 14–33% in industrialized countries. Transmission occurs prenatally as well as intrapartum and postpartum via breast feeding. Vertical transmission may result in intrauterine growth retardation, increased risk of postpartum endometritis, neonatal AIDS. Perinatal complications have not been clearly defined.

No adverse impact of pregnancy on disease progression.

Practice points Pregnant women who are HIVpositive should be counseled regarding the risks for the newborn. Zidovudine and other antiretroviral treatment during pregnancy can markedly reduce the rate of vertical transmission. The efficacy of cesarean section for the prevention of vertical transmission has been suggested but not proven. Mouth-suction devices for clearing the newborn’s airway should be avoided. In the industrialized world, HIV-positive women should refrain from breast-feeding.

Geist and Koren

Current seroprevalence of AIDS in the US: 3.8/100,000 in whites 59.2/100,000 in blacks 61.9/100,000 in Hispanic. HIV seroprevalence in all reproductive age women: 1.1–1.4/1000. In parts of Central Africa and Haiti it may be 10–30%. High-risk women: younger, prostitutes, IV drug abusers, women living outside major population centers. 70% of adult infection result from heterosexual transmission. In the 1990s, the rate of increase of incidence was threefold in women compared to men.

Effects of the disease on pregnancy

Maternal and perinatal outcomes differ markedly between different etiologies of anemia. Please refer to specific type.

Significant maternal complications with Hgb ⬍ 6g/dL (60g/L).

Iron supplementation needed from second trimester even if Hgb not measured.

Antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodiesb (1,6–8)

3–5% of general obstetrical population.

Increased rate of recurrent abortions, fetal wastage, growth restriction, and early-onset preeclampsia. High incidence of venous and arterial thromboses, cerebral thrombosis, hemolytic anemia, thrombocytopenia, and pulmonary hypertension.

Sometimes symptomatic disease only during pregnancy.

IgG anticardiolipin antibodies are with clinical significance, not IgM. No consensus as to the efficacy of corticosteroids, aspirin or heparin therapy. In women with high-titer antibodies and a history of recurrent early pregnancy loss or previous unexplained secondor third-trimester fetal death, therapy with anticoagulation with or without steroids or aspirin should be initiated at diagnosis of pregnancy. Women with a history of thrombosis due to antiphospholipid antibodies should be treated with therapeutic anticoagulation during pregnancy and the puerperium. In absence of clinical manifestations, positive antiphospholipid antibodies do not require therapy.

699

Most frequent maternal complication during pregnancy. Using WHO definition of hemoglobin (Hgb) ⬍ 13g/dL (130 g/L), 50% of all U.S. gestations are complicated by anemia. However Hgb ⬍ 10g/dL (110g/ L) is the usual clinical definition of anemia during pregnancy and the puerperium.

Maternal Disorders and Reproductive Risk

Anemia (1,2)

Table 1

Continued

a

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Practice points

1–4% of pregnancies.

Significant relationship exists between level of chronic asthma control and infant gestational age, intrauterine growth retardation, and perinatal mortality. Increased risk of eclampsia with suboptimal control of disease.

Course unpredictable for first pregnancy, but severe asthma prior to pregnancy often associated with worsening during pregnancy; exacerbation usually between 28 and 36 weeks. In 60% of women, the course of asthma is similar in subsequent pregnancies. In 10%, asthma is exacerbated during labor and delivery; this is more frequent following cesarean section.

Therapy should be guided by objective measures of airway obstruction, as subjective complaints are unreliable. Considered safe in pregnancy: inhaled β2-selective agents, steroids, disodium chromoglycate, ipratropium. When needed IV/PO steroids can be safely administered. Inhaled β2 agonists should be used sparingly near labor as they suppress uterine contractions. For analgesia, prefer non–histamine-releasing narcotic (fentanyl) to meperidine or morphine. Epidural analgesia is ideal for labor. For postpartum hemorrhages, use PGE2 and not PGF2α, as the latter can cause bronchospasm and O2 desaturation.

Vitamin B12 deficiency (1,2)

Very rare. More likely encountered following partial or total gastric resection, Crohn’s disease, ileal resection, and bacterial overgrowth in the small bowel.

Pernicious anemia may be associated with infertility. Except in transcobalamine 2 deficiency, fetus is protected from deficiency because of efficient placental transfer. Breast-fed neonates whose mothers have B12 deficiency may develop severe deficiency 4– 12 months after birth.

Maternal levels of vitamin B12 fall progressively during gestation to intermediate levels (80–120 g/mL), because of decreased concentration of transcobalamins.

Treatment necessary for vitamin B12 ⬍ 50 pg/mL. Breast-feeding not recommended until deficiency corrected.

Geist and Koren

Asthma (1,9,10)

700

Condition

Increased risk of spontaneous abortion, premature deliveries, and stillbirths. Increased risk of maternal bleeding and infection if peripheral blood counts are suppressed by chemotherapy. Chemotherapy increases risk of fetal abnormalities; congenital malformations occur in 2– 10% of cases. There are case reports of congenital leukemia in the newborns of women with leukemia.

Pregnancy does not adversely affect course or prognosis of disease. Overall, complete remission rate for standard induction chemotherapy is comparable to that in general population (50– 80%). Suboptimal treatment and delay of therapy in attempt to protect the fetus may adversely affect chances of remission/ cure.

Once the diagnosis of acute leukemia has been made, treatment with multiagent chemotherapy should not be delayed. Tretinoin should be avoided during pregnancy. Therapeutic abortion may be considered if disease is diagnosed in first trimester because of poor maternal prognosis and the effects of multidrug chemotherapy on the fetus. If chemotherapy is administered close to time of delivery, neonatal hematological status should be assessed.

Breast cancera (1,2,11)

The second most common malignancy during pregnancy. 10– 30/100,000 pregnancies.

Teratogenic risk when chemotherapy is used during first trimester (10%). Breast cancer is not transmitted vertically. Potential unproven risk for later development of malignancy in offspring due to exposure to cytotoxic drugs in utero. The effect of gestational exposure to chemotherapy on female fetuses is of concern because ova are formed during gestation. Mutations/chromosomal aberrations produced in such gametes could result in embryopathology in the next generation; recessive mutations might not become manifest until subsequent generations.

Stage-for-stage survival similar in pregnant and nonpregnant women, but diagnosis and treatment may be delayed by pregnancy, worsening prognosis. Pregnancy may affect the course of breast cancer by altering the incidence, altering the ability to diagnose, or limiting therapeutic options.

The risk of mammography is negligible for the fetus if appropriate shielding is used. Therapeutic abortion does not improve prognosis, therefore it should not be offered unless it is necessary to initiate chemotherapy in the first trimester. Radiotherapy is not recommended during pregnancy because fetal radiation exposure is substantial even with shielding. Surgical and chemotherapeutic treatment as in nonpregnant women.

701

0.9–1.2/100,000 pregnancies.

Maternal Disorders and Reproductive Risk

Cancer, acute leukemia (1,2)

702

Table 1

Continued

Condition

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Practice points

In situ: 0.13% Invasive: 0.05%

Conization can cause hemorrhage, abortion, rupture of membranes, and preterm delivery. Fetus is not affected.

Survival not influenced by pregnancy. Mode of delivery does not alter prognosis; however, there is theoretical concern of implantation of cancer cells along the vaginal tract during vaginal delivery.

Treatment of invasive cervical cancer in pregnancy depends on the stage of disease at diagnosis: with microinvasion, treatment may be deferred until fetal maturity when cesarean section and hysterectomy are performed. Pregnancy termination may be advisable with more advanced stages when diagnosed before 24 weeks’ gestation. After 24 weeks’ gestation, consideration may be given for postponing treatment until lung maturity.

Hodgkin’s lymphoma (1,2,12)

1/6000 pregnancies

Disease does not affect pregnancy outcome; however, during the first trimester, diagnostic and/or therapeutic radiological procedures may be hazardous to the fetus. Radiation doses ⬎ 10 rads or full doses of chemotherapy during the first trimester can be deleterious to fetal health.

Pregnancy does not affect course or prognosis. Limitation in application of radiographic studies for staging.

MRI should be considered instead of CT scan in the process of staging. Therapeutic abortion may be advised if disease is diagnosed during the first trimester because of chemotherapy, irradiation, or aggressive/advanced disease. If the disease is asymptomatic and diagnosed during second or third trimester, it can be followed without treatment until early delivery is carried out.

Geist and Koren

Cervical cancera (1,2)

0.14–2.8/1000 live births

Generally, no adverse effects. Metastases of maternal cancer to fetus and placenta are extremely rare, but several cases of neonatal melanomas have been reported. They represent one-third of reported cases of metastases of fetus.

Thicker skin tumors in pregnant patients. Stage-for-stage survival rates similar.

Primary lesion should be treated surgically as soon as diagnosis is made. Prophylactic chemotherapy or immunotherapy should be avoided during pregnancy. In case of active disease, chemotherapy should be given as indicated.

Ovarian cancer (1,2,12)

1/25,000 deliveries. 1/1000 pregnant patients undergoing surgery for adnexal mass. About 5% of adnexal neoplasms in pregnancy are malignant.

Fetus usually not affected. Increased rate of abortion and preterm deliveries due to torsion and rupture. In advanced malignancy, fetal growth retardation may occur. Possible virilization of a female fetus due to androgens produced by ovarian stromal tumors.

Prognosis not altered by pregnancy. Pregnancy does not promote/predispose to ovarian cancer but rather is considered protective to subsequent ovarian cancer.

Exploratory laparotomy with staging procedure to evaluate an adnexal mass detected early in pregnancy should not be delayed. 12% of ovarian masses may present as an acute surgical abdomen not allowing for planned surgery. In advanced cases, hysterectomy with bilateral adnexectomy is indicated, but in certain circumstances it is justified to remove the tumor and wait for lung maturity while giving chemotherapy. Postoperative therapy should be given in nearly all instances. Serum markers should be followed, as they indicate tumor progression (e.g., αfetoprotein, hCG, LDH, CA125).

Maternal Disorders and Reproductive Risk

Melanomaa (1,2,12)

703

704

Table 1

Continued

Condition

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Practice points

Prevalent in young women of lower economic status. Cultured from up to 25% of women attending prenatal clinics, many of whom are asymptomatic.

Vertical transmission intrapartum in at least 50% of infected women. In infants of untreated mothers, ophthalmia neonatorum occurs in one-third and 10% develop pneumonia. May increase risk of premature rupture of membranes, premature deliveries, and perinatal death, moreso with recent infection. Late postpartum endometritis is increased.

Pregnancy does not alter the course of the disease.

Infected pregnant women should be treated with erythromycin. The efficacy of eye prophylaxis with silver nitrate, erythromycin, or tetracycline in the prevention of chlamydia conjunctivitis is not clear.

Cystic fibrosisb (1)

80% of females survive to adulthood; 4% become pregnant each year in the United States.

Increased maternal and perinatal mortality related to degree of hypoxia and pulmonary infections. Perinatal mortality—14%. Increased rate of preterm deliveries (20%) and cesarean deliveries. Increased development of gestational diabetes mellitus.

Maternal mortality, 14%. Cor pulmonale is common. 13% develop heart failure.

Prepregnancy counseling is mandatory. Follow-up with serial pulmonary function tests, also surveillance for infection, diabetes, and heart failure. Treatment as in nonpregnant. Mode of delivery is decided upon according to obstetrical guidelines. Epidural analgesia is recommended during delivery or cesarean section.

Geist and Koren

Chlamydia trachomatis infection (1,2)

Primary infection in 1–4% of pregnancies. Seropositivity is more prevalent in lower socioeconomic class (85 vs. 55% in mid–upper class). Most common cause of perinatal infection. Evidence for fetal infection in 0.5–2% of all neonates.

⬎90% of primary infections and almost all recurrent infections are asymptomatic. Vertical transmission during pregnancy occurs in 40–79% of infected gravidas with primary infection and in less than 1% after recurrent infection. Congenital CMV includes small-for-gestational-age newborns, microcephaly, intracranial calcifications, chorioretinitis, sensorineural hearing loss, hepatosplenomegaly, jaundice, petechiae or purpura and thrombocytopenia. There is also an increased rate of spontaneous abortion and later fetal loss. Approximately 1% (0.2–2.5%) of all newborns are congenitally infected. Infected fetus is more likely if maternal infection was in the first half of pregnancy; however, sequelae can occur with infection at any stage of gestation.

No change in incidence/severity of maternal disease.

Screening is not really worthwhile except for warning seronegative women to avoid contact with susceptible people or places. Culture of amniotic fluid by amniocentesis not 100% sensitive. Prophylactic cesarean section not necessary. Breast-feeding not contraindicated.

Maternal Disorders and Reproductive Risk

Cytomegalovirus (CMV) infectiona (1,13)

705

706

Table 1

Continued

Condition Diabetes mellitus (10,11) Overt

Epidemiology/incidence Type I DM: 1% pregnancies. Gestational diabetes (GDM): 3% pregnancies.

Effects of pregnancy on the disease

Maternal Increased in frequency: chronic hypertension, probably pregnancy-induced hypertension in Type I DM, polyhydramnios, maternal mortality (ⱕ0.11%). Fetal/neonatal Type I DM; rate of congenital malformations increased 2–6fold (7.5–12.9%) Preconceptional counseling recommended, as preconception hemoglobin A1C (glycosilated hemoglobin) within 1% of upper limits of normal (6– 7%) has decreased rate of malformations almost to levels seen in nondiabetic patients (2–3%) Cardiac and neural tube defects most common, followed by skeletal, GI, urinary tract abnormalities. Increased perinatal mortality and morbidity (macrosomia, cesarean delivery, birth trauma, respiratory distress syndrome, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia) that may be decreased by good glycemic control.

Insulin requirements increase progressively during pregnancy. Type I DM: diabetic retinopathy: nonproliferative usually does not progress; proliferation may progress during pregnancy. Diabetic nephropathy: proteinuria usually increases during pregnancy, whereas creatinine clearance may decrease in up to one-third of patients. However, most values return to normal postpartum, following same rate of progression thereafter as in men.

Practice points Excellent preconceptional control and in early pregnancy may reduce risk of fetal malformations. Diabetic diet should be reviewed with a dietitian. Type I DM should be managed by an endocrinologist for intensive insulin therapy and monitoring; have basic ophthalmologic assessment, and 24-hour urine collection for protein and creatinine clearance (the latter to be repeated every trimester. Level II ultrasound and serum α-fetoprotein recommended in midsecond trimester. Cesarean delivery for obstetrical indications only.

Geist and Koren

Effects of the disease on pregnancy

Two- to threefold increase in fetal malformations, especially facial clefts, cardiac malformations, and neural tube defects, probably due both to disease itself and to antiepileptic medications. Increased risk of preeclampsia, preterm labor, IUGR, cesarean delivery, and perinatal mortality. Increase in cerebral palsy, seizures, and mental retardation in the offspring.

Variable effect on pregnancy in seizure frequency; increased in 45%, unchanged in 50% and decreased in 5%.

Folic acid deficiency (1,15)

Frank megaloblastic anemia in 1/70–1/250 pregnancies. WHO report 1 in 3 women worldwide suffer from folic acid deficiency. 30–69% U.S. women in low socioeconomic class have this deficiency.

Prospective human studies show a cause-and-effect relationship between folate deficiency and increased risk for neural tube defects (both in normal population and high-risk families). The fetus and placenta extract folate from the maternal circulation so efficiently that the fetus is not anemic even when the mother is severely so.

Pregnancy aggravates folic acid depletion.

1 mg of supplemental folate is adequate for prophylaxis and overt folate deficiency. Treatment should include iron as well. Folate supplementation periconceptually and prenatally has been reported to reduce the risk for neural tube defects in the newborn.

Gonorrhea (1,2,12)

Up to 7% of prenatal patients in North America have endocervical gonorrhea; 75–90% are asymptomatic. In 40% there is concomitant chlamydia infection.

Vertical transmission occurs by ascending infection in the presence of ruptured membranes or by delivery through an infected birth canal. Higher incidence of premature rupture of membranes, preterm labor and delivery, intrauterine growth retardation, and chorioamnionitis in untreated cases. Newborn infection may involve eye, ear canal, oropharynx, stomach, anorectal mucosa, or hematogenous dissemination.

Risk of noncervical infection and disseminated infection increase in pregnancy.

Since most women are asymptomatic, routine endocervical cultures are essential in early pregnancy and again at 28 weeks gestation. Treatment of the mother with ceftriaxone and topical application of 1% silver nitrate or erythromycin to the newborn’s eyes dramatically decrease neonatal infection and ophthalmia neonatorum. Screening for syphilis and chlamydia should always precede treatment.

707

0.3–0.5% of pregnancies

Maternal Disorders and Reproductive Risk

Epilepsy (1,2,12)

708

Table 1

Continued

Condition

Epidemiology/incidence a

Heart disease (1,16)

Heart disease complicates 1–4% of all pregnancies. Congenital and rheumatic etiologies most common.

Effects of pregnancy on the disease

Practice points

Poor cardiovascular status associated with spontaneous abortions, intrauterine growth retardation, and premature labor. Women with congenital heart disease (CHD) have a 3–10% risk of having a baby with CHD, especially in the presence of obstruction to left ventricular outflow. Critical period of exposure for causing fetal warfarin syndrome is between 6–12 weeks’ gestation, when 25% of babies are affected. Fetal warfarin syndrome includes nasal hypoplasia and stippled epiphyses. Intrauterine growth retardation, developmental retardation, eye defects, and hearing loss have also been described. Exposure to warfarin after the first trimester may present a risk of CNS damage and stillbirth due to hemorrhage; however, degree of risk unclear and must be balanced against risk to the mother (e.g., of stroke in the case of mechanical heart valves).

Cardiac output increases during pregnancy by 40%, peaking by the end of the second trimester. The vast majority of patients can be safely managed to term. Maternal mortality is 0.4% with New York Heart Association (NYHA) class I or II but increases to 4–7% with class III or IV. Pregnancy not recommended with high-risk cardiac lesions: any cardiac disease with class III or IV symptoms, unrepaired cyanotic CHD, critical aortic stenosis, primary pulmonary hypertension, Eisenmenger’s syndrome, Marfan’s syndrome, or peripartum cardiomyopathy in previous pregnancy with persistent cardiomegaly. Maternal complications include congestive heart failure and risk of aortic rupture in Marfan’s syndrome or coarctation of aorta (even repaired).

Management in high-risk obstetrical center recommended. Rest, reassurance, and monthly examination are mainstays of therapy. Patients with class III or IV should be hospitalized. Warfarin should be changed to SC heparin either prior to conception or certainly before 6 weeks’ gestation. Digoxin, β-adrenergic blockers, calcium channel blockers, and heparin are not teratogenic. Arigiotensin-converting enzyme inhibitors should not be used during pregnancy. Fetal echocardiography recommended at 18–20 weeks gestation to rule out CHD. Delivery mode dictated mainly by obstetrical considerations. Deterioration can occur in labor and especially postpartum. American Heart Association does not consider delivery in either mode an indication for antibiotic prophylaxis.

Geist and Koren

Effects of the disease on pregnancy

Hepatitis (viral)b (1,17–19)

0.2% of pregnant women. However, 1–5% of adults may develop chronic infection and persistent viremia, depending on the pathological agent. Hepatitis C virus infection prevalence in pregnant women: 1.5–5.2%.

No vertical transmission of hepatitis A (HA). Significant risk of vertical transmission of hepatitis B (HB) from mother with acute or chronic hepatitis and from asymptomatic carriers. If maternal HBe antibody positive or HBe antigen negative, there is a 10–20% risk of perinatal infection. If maternal HBe antigen positive, the risk is 80–90% for either infantile hepatitis or carrier state. Risk of vertical transmission of hepatitis C (HC) exists but is lower than that for HB. Transmission does not occur before third trimester.

The course of HA, HB, and HC viral diseases is unaltered by pregnancy; thus risk of fulminant hepatitis is well below 2%. Hepatitis E may be fulminant during pregnancy, with high mortality rates in third trimester (20%).

Pregnant women in contact with HAV infective cases should receive immune globulin (0.02 mL/kg) as soon as possible. Pregnant women exposed to HBV should receive HBIg (0.04–0.07 mL/kg) and the first of three 1-mL HBV vaccines as soon as possible, the second and third vaccines given 1 and 6 months later. Prevention of HBV transmission currently dependent on identification of HB surface antigen (HbsAg) and HbeAg carriers among pregnant women and the recognition of acute HBV infection in the latter half of the pregnancy/postpartum period.

Maternal Disorders and Reproductive Risk

Successful pregnancies after heart transplantation have been described; these women, however, suffer more hypertension, preeclampsia, intrauterine growth retardation, and preterm labor. Immunosuppressive drugs used in heart transplant patients are potentially teratogenic. However, there is good experience with those drugs in renal transplant patients.

709

710

Table 1 Condition

Continued Epidemiology/incidence

Effects of the disease on pregnancy

Practice points Newborns of HbsAg-positive women should receive HBIg (0.5 mL within 1 hour and 0.5 mL HBV within a week of birth). Test infants for HbsAg and anti HBc at 1 year to determine treatment success. The presence of HbsAg ⫾ IgM anti HBc indicates treatment failure, since the infant is actively infected. Anti HBs alone suggests that vaccine-induced immunity can last approximately 5 years. Boosters needed every 5 years for continued protection. Immune globulins are ineffective for prevention or treatment of HCV. There is no vaccine yet.

Geist and Koren

In third-trimester maternal disease, there is a 45–87.5% risk of transmission. One-third of infants will become chronic asymptomatic carriers. No teratogenic effect of HC is known. Hepatitis E (HE) virus disease increases fetal mortality. Prematurity is two to three times higher with maternal viral hepatitis. In fulminant hepatitis, fetal wastage is ⬎70%.

Effects of pregnancy on the disease

20–50% of primary infections are due to herpes simplex virus type 1 (HSV-1), but ⬎80% of recurrent infections are due to HSV-2. HSV can be isolated from 0.2– 2% of pregnant women at delivery. Women may shed virus in absence of clinical history of HSV infection. Only 0.25–0.33% of women who deliver a neonate with HSV infection are symptomatic at the time of delivery.

True congenital infections with HSV are rare (5%) and are mainly associated with primary maternal infection during pregnancy. Primary infections that occur in first trimester are not indications for therapeutic abortion, since malformations usually not consistent with life; later infections may increase incidence of preterm labor. Neonatal infections can 1. Be localized with skin, eye, and mouth manifestations 2. Have CNS involvement 3. Be disseminated Recurrent infections during pregnancy are a reservoir for neonatal infections but do not contribute significantly to fetal morbidity and mortality. Perinatally acquired infections occur in 1/3000–1/7000 births in the United States, especially with preterm birth. Such risk is still present in absence of maternal symptoms or lesions.

Primary maternal infection during pregnancy associated with greater risk of recurrence and viral excretion during labor. Recurrences tend to increase in frequency as pregnancy progresses. Overriding concern is transmission to baby, since maternal infection usually follows self-limited course.

Consideration can be given to oral acyclovir treatment for frequent recurrences of HSV, since reported use to date has failed to reveal significant increases in congenital malformations. Pregnant women with history of HSV and no lesions or prodromal symptoms at the time of delivery can undergo vaginal delivery; however, they should also have cultures of previously affected areas and cervix done to document possible neonatal exposure. Risk of neonatal infection estimated to be 1/1000. Women with genital lesions or prodromal symptoms should be delivered by cesarean section as soon as possible after membrane rupture/onset of labor, ideally, within 4–6 hours.

Maternal Disorders and Reproductive Risk

Herpes simplexa (1,20,21)

711

Table 1

Continued Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

712

Condition

Practice points

1–3% of all pregnancies. 70% have preeclampsia/eclampsia, 25% essential hypertension, 5% gestational hypertension. Results in 20% of all maternal deaths.

In preeclampsia, increased rate of the following proportional to degree of hypertension: spontaneous abortions, intrauterine growth retardation and fetal death, abruptio placentae, prematurity, operative delivery, perinatal morbidity and mortality. In chronic hypertension, increased rate of intrauterine growth retardation (IUGR) abruptio placentae, and perinatal death.

Incidence of chronic hypertensive complications unchanged. Acute hypertension (BP ⬎ 170/ 110) associated with increase in maternal stroke. Superimposed preeclampsia in 20% of chronic hypertension.

Blood pressure usually decreases in first trimester (through 20 weeks), reaching previous levels by term. Decreased maternal stroke is the only consequence of treating hypertension in pregnancy other than possible decrease in fetal loss with treatment of essential hypertension in first trimester with methyl-dopa. BP ⬎ 160/100 should be treated. Goal of treatment: diastolic BP, 90 mm Hg. Methyldopa drug of choice during pregnancy.

Hyperthyroidism (26)

Rare, 1:2000 pregnancies. Graves’ disease most common etiology.

In untreated women there is increase in rate of stillbirths, low birth weight, neonatal death, premature birth, preeclampsia, and heart failure. Graves’ disease due to thyroid-stimulating IgG (TSAb) occurs in 1–2% of cases, especially with history of previously affected child. However, even presence of IgG TSAb confers a low risk of neonatal Graves’. Long-standing antithyroid treatment can cause neonatal hypothyroidism. However, no adverse effects in subsequent growth and development.

Tendency for increased activity of disease in first trimester and postpartum. No change in natural history of disease. TSAb activity in Graves’ disease usually declines during pregnancy. Chemical remission in almost all pregnancies with Graves’ disease.

TSAb may be present even after treatment for Graves’ hyperthyroidism; should be measured in all patients with history of Graves’. Treatment in pregnancy decreases risk of thyroid storm. Propylthiouracil (in lowest possible dose) is the drug of choice in pregnancy. Thyroidectomy can be safely carried out if needed.

Geist and Koren

Hypertensive disorders (1,22–25)

6/1000 women who carry pregnancy ⬎ 20 weeks.

Decreased fertility. Possibly increased fetal loss, adverse fetal and perinatal outcomes. When hypothyroidism is caused by iodine deficiency, cretinism may develop with no replacement therapy.

20% require higher replacement dose of thyroid hormone during pregnancy.

Treatment improves fertility and probably pregnancy outcome. TSH should be repeated every trimester; a rise warrants increase in thyroid hormone. Subclinical hypothyroidism should be treated during pregnancy.

Immune thrombocytopenia purpura (ITP)a (1,2)

Not uncommonly associated with or occurring during pregnancy. Etiology: autoimmune or alloimmune mechanisms. Alloimmune: 1:2000–5000

Maternal If platelets ⬍ 20,000/mm3, blood loss may be increased during delivery. No increase in maternal mortality. Fetal Increased fetal loss with fetal mortality of 15–25% (most common causes are spontaneous abortion and hemorrhage); 50% fetal deaths occur before the onset of labor, most due to alloimmune mechanisms. Incidence of neonatal thrombocytopenia (NATP) is 30–40% but severe NATP (i.e., platelets ⬍ 50/mm3) occur in 10– 20% at delivery or in the first 3–5 days postpartum. 1–4% of babies with NATP suffer from cerebral hemorrhage. There is no correlation between maternal and fetal platelet count!

Symptoms of ITP tend to worsen. Ideally, pregnancy should be postponed until remission.

Treatment is as in nonpregnant state (i.e., steroids are firstline treatment, with IV IgG as second line, and splenectomy as last resort). Maternal steroid treatment is of unproven benefit in increasing fetal platelet count; trial of maternal (and neonatal) IV IgG are ongoing. Goal of therapy; maternal platelets ⬎ 100/mm3, or cessation of serious bleeding. These pregnancies are best managed in a high risk obstetric center. Cordocentesis advised in case of alloimmune thrombocytopenia or presence of facts that indicate high risk for NATP. Cesarean section reserved for obstetrical indications unless the fetus is shown to be severely thrombocytopenic (i.e., by cordocentesis).

Maternal Disorders and Reproductive Risk

Hypothyroidism (27)

713

714

Table 1

Continued

Condition

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Factors that indicate a high risk of NATP are controversial but include women with a previous history of ITP (especially of splenectomy), acute or chronic ITP with platelets ⬍ 100/mm3, or a previous infant with NATP. These have a 20% risk of severe NATP. Inflammatory bowel disease, (IBD) Crohn’s disease (28,29)

Not rare in pregnancy. Prevalence of inflammatory bowel disease in the US ranges 1–2 million people: with peak incidence at 15–30 years.

The effects on pregnancy outcome are unclear. There are controversial data. Most report no effect of disease—no increase in adverse pregnancy outcome.

Practice points In other circumstances, it is of unproven benefit in decreasing rate of neonatal cerebral hemorrhage.

Infertility is reversed with appropriate drug therapy resulting in remission. Management of active disease should be similar to nonpregnant patients. Safe: corticosteroids, sulfasalazine and its 5-aminosalicylic component (5-ASA), and antibiotics. 6-Mercaptopurine and azathioprine should best be avoided. Limited radiological investigations should not be postponed if results are likely to alter management.

Geist and Koren

Disease not adversely affected by pregnancy per se; disease remains quiescent in about 70% of pregnant women if in remission at time of conception. 30% relapse during pregnancy if in remission at time of conception. Highest risk of exacerbation in first trimester and puerperium. Onset of Crohn’s disease during pregnancy is associated with a poorer prognosis.

No effect on fertility. Incidence of live births, congenital anomalies, spontaneous abortions, and stillbirths not increased except for a high incidence of spontaneous abortions (44%) in women with severe disease requiring surgery during pregnancy.

Overall risk of exacerbation same as in nonpregnant women (50%). If disease quiescent at conception, only 33% will relapse in pregnancy. If disease active at time of conception, about 50% will improve and 33% will worsen. If disease begins in pregnancy, it may be more severe with high attack rates.

In general, treatment same as in the nonpregnant patient.

Iron deficiency anemia (IDA) (1)

75–80% of pregnant women with low hemoglobin have IDA.

Severe IDA may be associated with increased risk of preterm birth, intrauterine growth retardation, stillbirths, and maternal deaths in the third world.

There is a 50% increase in plasma volume during pregnancy, therefore there is delusional anemia. Iron requirements are elevated in pregnancy. If iron depletion present, without signs of deficiency, frank IDA may develop during/ after gestation.

IDA during pregnancy is primarily the consequence of plasma volume expansion without normal expansion of maternal hemoglobin mass. Since demand for iron in pregnancy cannot be met by dietary iron alone, supplemental iron recommended (30–60 mg/day in non-IDA and 200– 300 mg/day in IDA states).

Malaria (1)

Approx. 1000 cases of malaria in United States per year. 13 cases of congenital malaria in United States/year, but 0.3% in immune mothers and 1–4% in nonimmune mothers in endemic areas.

Majority of malarial infections caused by Plasmodium falciparum. Severe maternal disease causes increased fetal wastage. Malaria can cause intrauterine infection, placental insufficiency, intrauterine growth retardation, prematurity, abortion, low birth weight, and stillbirth.

Pregnancy enhances the severity of falciparum malaria.

Antimalarial prophylaxis advocated for mothers living in endemic areas. May prescribe chloroquine or mefloquine as prophylaxis or for treatment.

715

Peak incidence is at 20–35 years.

Maternal Disorders and Reproductive Risk

Ulcerative colitis (28,29)

716

Table 1

Continued

Condition

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Practice points

10–75/100,000 pregnancies (same as general population).

Uncomplicated MS has no effect on pregnancy. Exacerbation episodes tend to occur in the first trimester and mainly in the puerperium (30–40%).

Relapse rate approximates that of nonpregnant state. Women with severe debilitation may experience an increase in infections, fatigue, and pulmonary problems.

Rest is an important component of optimal care in pregnancy. Urinary tract infection should be screened for and treated promptly.

Myasthenia gravisa (1)

2–4/100,000 pregnancies (same as general population).

Neonatal myasthenia gravis occurs in 10–20% of newborns. Newborn disease is more likely if the mother produces antibodies against embryonic acetylcholine receptors. Newborn disease resolves in 2– 6 weeks. No adverse perinatal effects.

One-third improve, one-third worsen, and one-third remain stable. If diagnosed during pregnancy, mother is prone to more severe form of disease. Exacerbations tend to occur in first trimester and puerperium, with improvement in second and third trimesters.

Agents that potentiate neuromuscular blockade, such as curare, muscle relaxants, magnesium sulfate, or aminoglycosides should be avoided. Regional anesthesia preferred. Narcotics must be used with care. Mode of delivery is according to obstetrical considerations. Might consider forceps during second stage to overcome lack of maternal expulsion forces.

Parvovirus B19 (30)

35–55% of women of childbearing age are seropositive.

Vertical transmission: In the first half of pregnancy, 16%. Above 20 weeks gestation, 35%. A rare cause of fetal hydrops fetalis. Case reports of association with congenital birth defects, but no epidemiological studies. May increase fetal loss.

No effect on natural history of disease.

Routine exclusion of pregnant women from work if a case of B19 parvovirus is found is not recommended since low risk of adverse fetal outcome.

Geist and Koren

Multiple sclerosis (MS) (1)

Renal diseasea (1,31,32)

Patients should be seen every 2– 4 weeks for serial 24-hour urine collections for protein and creatinine clearance and BP control to rule out asymptomatic bacteriuria and treat it. Criteria of hypertension and proteinuria are unreliable for diagnosis of preeclampsia. When renal biopsy is considered for diagnosis, it should be postponed until after pregnancy.

717

Mild renal impairment (serum creatinine ⬍ 1.4 mg/dL (124 µM): even with preserved renal function, pregnancy termination should be considered in women with renal PAN or renal scleroderma. Natural history of other renal diseases not affected, except possibly IGA nephropathy, focal glomerulosclerosis (FGS), membranoproliferative glomerulonephritis, and reflux nephropathy. Most show increase in glomerular filtration rate, but 15% decrease near term is permissible. Increased/appearance of proteinuria (may be nephrotic) common, up to 60% of patients. Moderate renal impairment (creatinine 1.5–2.0 mg/dL ⫽ 133–265 µM): may suffer unpredictable, and at times irreversible, loss of function during/after pregnancy. Up to 50% develop hypertension. High rates of preterm deliveries. Severe renal impairment (creatinine ⬎ 3 mg/dL ⫽ 265 µM): pregnancy should be discouraged because of risk of severe maternal complication— chronic hypertension, anemia, preeclampsia, high-grade proteinuria, and need for dialysis. In the absence of superimposed preeclampsia or severe placental abruption, long-term deterioration of renal function is not accelerated by pregnancy.

Maternal Disorders and Reproductive Risk

Fertility decreased with chronic renal impairment. Uneventful pregnancy unusual when serum creatinine ⬎ 3.0 mg/dL (265 µM), even in absence of maternal symptoms. Outcome is usually successful when serum creatinine ⬍ 1.5–2.0 mg/dL (133– 177µM), hypertension is absent, and underlying renal disease is not scleroderma or polyarteritis nodose (PAN). Pregnancy outcome depends on the degree of associated hypertension and renal insufficiency. Increased risk of pre-eclampsia and perinatal morbidity and mortality. Acute glomerulonephritis—high rate of fetal loss, preterm deliveries, intrauterine growth retardation. With nephrotic syndrome, huge vulvar edema may develop.

718

Table 1

Continued

Condition

Epidemiology/incidence b

Renal transplantation (1,31)

Prevalence increases as more successful outcome and prompt return of ovulation in most women.

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Successful outcome if pregnancy survives beyond first trimester, otherwise high rate of spontaneous and therapeutic abortions. Increased premature rupture of membranes and preterm labor.

Glomerular filtration rate usually increases, as in healthy women.

Practice points

Geist and Koren

At least 2 years of good general health without hypertension required before conception. Prednisone and azathioprine should be continued. The evidence concerning cyclosporine use during pregnancy is inconclusive, but there is no report to link its use to teratogenicity or mutagenicity. There is still concern about the possibility of late effects of immunosuppression on the offspring (e.g., malignancy, germ-cell dysfunction, and malformations in the offspring’s children).

RA affects 1–2% of women of childbearing age and may present during pregnancy.

Anti-Ro antibodies are present in 5% of women with RA, but in 50% of RA patients who also have Sjo¨gren’s syndrome; this antibody has been associated with congenital heart block, but the risk is very low. Fetal echocardiogram at 20 weeks’ gestation is recommended when maternal AntiRo is present. Otherwise, no adverse effects on fetal outcome.

75% of patients improve; most do so in the first trimester, but may not improve until the third. 25% worsen and may develop new joint lesions. Relapse often occurs, usually within 2 months of delivery. Course during last pregnancy is predictive of course in current pregnancy.

Many patients are able to stop nonsteroidal anti-inflammatory drugs and disease-remitting agents during pregnancy and are often managed with analgesics. ASA is drug of choice for treatment of joint inflammation, although this may cause maternal complications (prolonged gestation and labor, ante- and postpartum hemorrhage) or neonatal pulmonary hypertension secondary to premature closure of ductus arteriosus. If needed, gold salts and chloroquine can be used (risk category C). Corticosteroids are safe to use during pregnancy. When cervical spine involvement exists, subluxation is common, more so during pregnancy. Delivery mode is according to obstetrical considerations.

Maternal Disorders and Reproductive Risk

Rheumatoid arthritis (RA) (1)

719

720

Table 1

Continued

Condition Rubella infection (1,33)

Epidemiology/incidence Even with current vaccination procedures, 6–25% of young adults are susceptible.

Effects of pregnancy on the disease

Effects depend on gestational age at infection: First trimester: 20% congenital rubella syndrome (CRS). CRS includes one or more of the following: 1. Eye lesions 2. Heart disease 3. Sensorineural deafness 4. CNS defects 5. IUGR 6. Thrombocytopenia, anemia 7. Liver problems 8. Pneumonitis 9. Osseous changes 10. Chromosomal abnormalities 85% defects at 4 years of age (e.g., hearing defects both peripheral and central) associated with impaired language development, subretinal neovascularization, autism, developmental defects (motor, intellectual and behavioral, a subacute progressive panencephalitis, and various endocrine abnormalities, including diabetes mellitus).

Course of disease is unchanged by pregnancy. Maternal disease is usually mild.

Practice points Vaccination of seronegative women advised 48–72 hours postpartum. Vaccine virus excreted in breast milk, but no contraindication to breast-feeding. Pregnancy should be deferred for 3 months after vaccination, but there is no documented increased risk of CRS with inadvertent vaccination during pregnancy.

Geist and Koren

Effects of the disease on pregnancy

Sickle cell disease (34–36)

Incidence in black Americans: sickle cell trait—1 in 12. HbS-S—1 in 576 HbS-C—1 in 2000 HbS-β—1 in 2000

⬎30% overall fetal wastage with increased risk of spontaneous abortions, infertility, prematurity, intrauterine growth retardation, and perinatal death. Prior to 1970 maternal mortality was as high as 10–12% and maternal morbidity up to 80– 90%. Fetal loss up to 50–60%. These figures have been markedly reduced as a result of improved obstetric and prenatal care; maternal mortality nowadays in the Western world is around 1%.

Vaso-occlusive crises increase, especially in the third trimester, labor, and puerperium. Increased incidence of congestive heart failure (2–20%), pneumonia (3–15%), pyelonephritis (5–12%), pulmonary embolism (20–40%) and cholelithiasis (25% vs. 10% in nonpregnancy).

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Sickle-cell screen in early pregnancy is recommended for all black women. Prenatal diagnosis by amniocentesis, cordocentesis, or chorionic villus sampling is recommended. Early and frequent prenatal assessment of pregnant women with this condition. Supplemental folic acid useful to promote erythrocyte production. Painful crises treated as in nonpregnant states. Transfusions increase risk of allosensitization. Exchange transfusions by manual/erythrocytophoresis techniques may be used for specific crises; not recommended prophylactically.

Maternal Disorders and Reproductive Risk

Second and third trimester: 10% defects at 4 years of age with infection after 20 weeks gestation. Maternal infection confirmed by rubella-specific IgM or fourfold rise in rubella-specific IgG (by hemagglutination) OR probably by presence of rubella-specific IgG by complement fixation technique. In utero infection diagnosed by rubella-specific antibody in cord blood.

722

Table 1

Continued

Condition

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

1.8:1000 live births GBS is present in urogenital tract of 15– 25% of pregnant women.

Increased rate of preterm premature rupture of membranes, preterm deliveries, postpartum endometritis and chorioamnionitis. Invasive infant GBS disease with 5–20% mortality rate in early-onset disease.

Usually asymptomatic infection.

Syphilis (1,40–42)

Approximately 100,000 cases of syphilis diagnosed annually in United States. 350 cases of congenital syphilis per year. Increase in prevalence in the late 1980s and 1990s.

Vertical transmission can occur in any trimester; most severe fetal disease results from syphilis in early pregnancy. In untreated early disease, 80% infantile mortality and morbidity. 50% of infants born to women with untreated primary/secondary syphilis will have congenital infection at birth.

The course of syphilis is not altered by pregnancy.

Screen for vaginal and rectal GBS at 35–37 weeks’ gestation. Intrapartum penicillin when: —Previous infant with GBS infection. —GBS bacteriuria in current pregnancy. —Premature labor. —Positive screening at 35–37 weeks. When screening not done: —Intrapartum fever ⬎ 38°C. —Membrane rupture ⬎ 18 hours. Pregnancy is commonly listed as an etiology for false-positive serology but recent studies do not show increased rate of such results in gravidas. HIV-coinfected adults show extremely high titer or paradoxically negative titers with secondary syphilis. Confirmatory tests as in nonpregnant state.

Geist and Koren

Streptococcus group B (GBS)b (37–39)

Practice points

Systemic lupus erythematosus (SLE)a (1,43)

1:500 as in nonpregnant state.

Increased rate of stillbirths, IUGR, preterm deliveries and perinatal mortality with active disease at conception and positive maternal antibodies (especially antiphospholipid). With lupus nephropathy, increased risk of preeclampsia. Positive anti-Ro antibody present in 20–80% of SLE patients and is associated with neonatal lupus syndrome (NLS). Risk of NLS ⬍ 5%. Risk of congenital heart block ⬍ 3%.

A penicillin-allergic patient may be treated with erythromycin; However, penicillin should be used to treat the neonate, since fetal erythromycin levels are not adequate. Titers of VDRL do not fall rapidly enough to indicate an adequate response to treatment. Breast-feeding is not contraindicated unless an infectious lesion is present on the breast. Conflicting data. Most agree that pregnancy has no adverse effect on the course of disease. No evidence for increased exacerbation postpartum.

Should be followed in high-risk obstetrics unit, where fetal survival is ⬎80%. Treatment is generally the same as in nonpregnant. Prednisone is drug of choice for therapy, but no prophylactic treatment or increase in dosage recommended. If immunosuppression needed, azathioprine is preferred to cyclophosphamide. Decreasing C3 or C4 levels useful for distinguishing preeclampsia from SLE flare.

Maternal Disorders and Reproductive Risk

This includes, IUGR, stillbirth, hepatosplenomegaly, abnormal skeletal development including development of teeth, eye involvement, CNS problems, and dermatitis. Increased rate of spontaneous abortions, stillbirth, nonimmune hydrops, premature delivery, and perinatal death. Antepartum infection in the last week of pregnancy may be asymptomatic.

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Table 1

Continued

Toxoplasmosis (1,44)

Epidemiology/incidence 50–60% of women of childbearing age susceptible. Acute toxoplasmosis complicates 1–5/1000 pregnancies. Congenital infection in 1–2/ 1000 live births in United States.

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Transmission to fetus possible at any time during pregnancy but less likely during first trimester; overall, congenital infection in 40–60% of cases. Most severe sequelae with transmission before 20 weeks gestation. Spontaneous abortion, stillbirth, and severe congenital infection occur exclusively with maternal infection in early pregnancy. Congenital toxoplasmosis includes IUGR, hepatosplenomegaly, icterus, anemia, convulsions, intracranial calcifications, hydrocephalus or microcephalus, and mental retardation. Asymptomatic/subclinical infection occurs in the majority of babies infected.

Pregnancy does not alter course of disease.

Practice points

Geist and Koren

Preconception serology of highrisk women is key (i.e., women who have recently acquired cats, who handle kitty litter, eat raw/undercooked meat, or have had a recent mononucleosis-like illness). Seronegative individuals should avoid high-risk situations (as detailed above); serial serology should be performed throughout pregnancy. Diagnosis made by serology: rising IgM indirect fluorescent antibody titer or absolute titer of ⬎1:512 is a good indicator of active recent infection; false positives do occur. Treatment can decrease risk of congenital infection, but risk still remains substantial and there is no proof that the severity of congenital infection is modified. Ultrasound is not sensitive enough to diagnose all cases of congenital infection. Amniocentesis/cordocentesis/ PCR assay are performed in some centers when acute infection occurs during pregnancy and therapeutic abortion is an option; treatment with spiramycin recommended while awaiting the procedure.

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Condition

Tuberculosisa (45)

Intrauterine fetal infection very unusual but can be fatal (mortality close to 50%), mainly due to the failure to diagnose correctly.

No increase in risk of progression to active disease; risk of such still greatest in the 1–2 years after infection. Presentation and natural history of disease unchanged in pregnancy.

725

Pregnant women generally react to purified protein derivative testing in manner similar to general population. Isoniazid prophylaxis is not recommended during pregnancy. It is recommended as treatment for women who have been recently infected (within the last 2 years), women who recently converted in PPD test, and HIV-positive patients. Isoniazid, rifampin, and ethambutol have not been found to be teratogenic. Give pyridoxine with isoniazid. Prophylactic treatment of the neonate with vitamin K recommended because of possible complication of hemorrhagic disease of the newborn. Neonate born to a mother with active TB should be treated with isoniazid for the first 2– 3 months of life or at least until the mother is known to be smear- and culture-negative. The treatment is so effective that separation of mother and child is no longer mandatory. Isoniazid treatment could be given to the neonate with or without BCG vaccination. Treatment with four drugs should be initiated if infant’s skin test is positive or there is evidence of clinical disease. There are reports on isoniazidinduced postpartum hepatitis; withhold treatment until 3–6 months postpartum.

Maternal Disorders and Reproductive Risk

Prevalence increasing since 1985 as a result of HIV infection in population and considerable immigration from endemic areas.

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Table 1

Continued

Condition Urinary tract infection (UTI)a

Epidemiology/incidence

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Asymptomatic bacteriuria (ASB) occurs in 2–7% of women during pregnancy, most of whom have positive urine cultures at first antenatal visit. 25% of untreated gravidas with ASB will develop acute UTI. Pyelonephritis complicates 1– 2% of pregnancies.

Association of ASB with preeclampsia, anemia, prematurity, and fetal loss unproven. Acute UTI can mimic/precipitate premature labor; role in etiology of intrauterine growth retardation, fetal death, or congenital abnormalities controversial.

Pregnancy does not predispose women to ASB. However, urinary stasis does. 1–2% of gravidas with pyelonephritis develop respiratory complications, sometimes ARDS.

Practice points

Geist and Koren

All women should be screened for ASB at first antenatal visit. Treatment of ASB prevents most of acute UTI cases. Treatment can proceed with nitrofurantoin (for 10 days), ampicillin, or cephalexin. There are also single-dose and 3-day regimens. One-third of women treated for ASB will have persistence/recurrence of infection; suppressive therapy should be considered in such women if close follow-up and treatment not possible. Acute UTI usually caused by gram-negative bacteria. Treatment of pyelonephritis in pregnancy requires hospitalization and intravenous ampicillin and gentamicin or cephalosporins.

Increase in symptomatic urinary tract infection; otherwise, course and outcome of pregnancy unchanged.

Pregnancy has no effect on progression of nephrolithiasis. Increased rate of spontaneous stone passage (70%). Pregnant women have fewer symptoms and pass stones more easily.

Hydronephrosis (usually greater on right side) diagnosed by ultrasound is an unreliable sign for urethral obstruction. Calcium oxalate stones are the most common in pregnancy. The stones can usually be visualized by ultrasound, but if there is a diagnostic dilemma, radiography should be done. Radiation from most IVPs is less than 1100 mrads, which is well below the dose that is required to increase congenital malformation risk. Must be distinguished from acute pyelonephritis.

Varicellaa (1,48,49)

5–7 100,000 pregnancies.

Congenital varicella syndrome (CVS) is characterized by intrauterine growth retardation, limb hypoplasia, brain atrophy, cicatricial scars, mental retardation, and ocular lesions. Risk for CVS only if encountered before 20 weeks gestation. 2% above baseline risk for birth defects. Before 13 weeks reduced risk (app. 0.5%). Otherwise, no increase in pregnancy complications. Varicella near term can cause disseminated varicella in newborn with high complication rate.

It is not clear whether chickenpox during pregnancy has a higher complication rate than in adults in general. However, maternal mortality rate of 41% has been reported due to chickenpox pneumonia.

Exposed pregnant women should receive varicella zoster immune globulin (VZIG) within 96 hours of exposure. VZIG has been shown to reduce maternal complication rate, but its efficacy in reducing vertical transmission has yet to be proven. Infants born to mothers who had chickenpox 5 days prior to delivery to 2 days postpartum are at greatest risk of varicella of newborn; VZIG should, therefore, be given to the newborn.

727

Complicates 0.05% of pregnancies.

Maternal Disorders and Reproductive Risk

Urolithiasisa (46,47)

728

Table 1

Continued

Condition Venous thromboembolisma (50,51)

Epidemiology/incidence Deep venous thrombosis (DVT) of lower extremities in 0.0004–0.007% of pregnancies antepartum, but up to 3% postpartum. Pulmonary embolism (PE) occurs in 1:2700 to less than 1:7000 pregnancies. Increased risk associated with operative delivery, preeclampsia, and hypercoagulable states (e.g., antiphospholipid antibodies, deficiencies of antithrombin III, protein C, protein S, plasminogen or resistance to activated protein C).

Effects of the disease on pregnancy

Effects of pregnancy on the disease

Only a problem when maternal hemodynamic integrity is compromised. No fetal effects unless oral anticoagulants are given. Thrombophilias may increase risk of fetal wastage.

Pregnancy is a hypercoagulable state. Diagnosis of DVT best made using combined ultrasoundDoppler technique. Clinical suspicion of PE should lead to V/Q scanning, since radiation exposure is far below permissible dose in pregnancy.

Practice points

Geist and Koren

Warfarin should not be used between 6 and 12 weeks’ gestation, since it has been shown to be teratogenic. It is best avoided throughout pregnancy as it can cause CNS problems due to intrauterine bleeding. Prophylactic heparin (5000 U SC q12h starting at 12 weeks gestation) recommended for history of unexplained DVT in previous pregnancy, antiphospholipid antibodies, or other hypercoagulable states. Heparin should be discontinued at onset of labor and restarted 2 hours postpartum (when hemostasis achieved). Anticoagulation should be continued for 6 weeks postpartum, or until 3 months of treatment achieved when DVT occurred in index pregnancy; warfarin is safe for breast-feeding.

Maternal Disorders and Reproductive Risk

729

During the past three decades, we have witnessed an explosion of activity directed toward the identification of the fetus at risk, the management of preterm labor, and the intensive care of the prematurely born neonate. These efforts have been accompanied by significant reductions in perinatal mortality and morbidity. More recently, the component of high risk pregnancy arising from compromised maternal health has acquired a growing, if not novel importance, as evidenced by a proliferation of scientific articles as well as new and revised editions of textbooks addressing this theme (1–43). There are several good reasons for intensified interest in the influence of maternal factors on reproductive risks. First, advances in medical and surgical care have made pregnancy feasible in a variety of conditions in which previously the mother’s life was seriously threatened and perinatal results were disastrous. Examples include surgical correction of congenital heart disease, renal transplantation, and the medical management of systemic lupus erythematosus. Second, societal factors are altering the composition of the population at risk. For example, growing immigration from Asia has resulted in an increase in the incidence of hepatitis and some of the hemoglobinophathies. In the adolescent population, intravenous drug abuse has become more prevalent, and there are already many documented cases of pregnant women with acquired immune deficiency syndrome (AIDS) and vertical transmission to the neonate. With the advent of in vitro fertilization and the expansion of career options for women, many have delayed childbearing (comforted by the availability of prenatal diagnosis for advanced maternal age); thus, it is likely that we will increasingly see during pregnancy certain conditions that occur with aging, such as hypertension and diabetes. Third, with the heightened awareness by members of the medical profession, as well as legislators and consumers, of the importance of preventive medicine and quality of life, it is no longer sufficient merely to see a woman affected with a medical disorder safely through pregnancy and delivery. Rather, it is important to adopt a more global approach, which in an interdisciplinary fashion encompasses prepregnancy counseling and obstetrical care and, in addition, addresses the medical and social factors that might influence the well-being of the child, the mother, and the family.

MEDICAL DISEASES IN PREGNANCY In this chapter, we have summarized the interrelationship between pregnancy outcome and a variety of maternal medical diseases. Reproductive risks associated with maternal lifestyle and various specific medical therapies are dealt with in other chapters. Table 1 addresses the two essential questions one asks when a woman with a medical disease becomes pregnant: 1. What is the effect of the disease on pregnancy? 2. What is the effect of pregnancy on the disease? The first question deals with pregnancy loss (abortion, stillbirth, neonatal death), congenital malformations, fetal and neonatal morbidities, and maternal complications peculiar to pregnancy, such as abruptio placentae, and preeclampsia. In the second question, we are asking whether pregnancy per se alters the course and prognosis of the disease, and to what extent and in what manner.

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For the purposes of this chapter, we have limited ourselves to medical disorders that are relatively common in pregnancy and to those that are not common but are associated with specific reproductive risks. Clearly, a complete list of medical conditions in pregnancy could not be incorporated into a single chapter, and the reader is referred to the References for further information. The final column of Table 1 is headed ‘‘Practice points.’’ Again, the details of management and the adjustments in medical care necessary during pregnancy are numerous. We have tried to highlight a few key points for each condition that may serve as valuable clinical tips. Clinical Case Answer Women with diabetes mellitus have higher rates of fetal malformations, mainly sacral agenesis or cardiac anomalies. In addition, the baby may suffer from macrosomia, neonatal hypoglycemia, and a variety of other perinatal complications. Recent research suggests that tight glycemic control substantially decreases the risk for both malformations and perinatal complications. Some studies, however, have not shown a correlation between glycemic control and rates of major malformations. In any case, your patient’s anxiety about the effects of insulin is not justified. In fact, she may end up needing more insulin during pregnancy. REFERENCES 1. Cunningham FG, MacDonald PC, Gant NF et al. Williams Obstetrics. Stamford, CT: Appleton & Lange; 1997. 2. Gleicher N, ed. Principles of Medical Therapy in Pregnancy. Norwalk, CT: Appleton & Lange, 1992. 3. Mofenson LM. Reducing the risk of perinatal HIV-1 transmission with zidovudine: results and implications of AIDS Clinical Trials Group protocol 076. Acta Paediatr Suppl. 1997; 421: 89–96. 4. Minkoff HL. HIV disease in pregnancy. Obstet Gynecol Clin North Am 1997; 24(4):xi–xvii. 5. Lindsay MK, Nesheim SR. Human immunodeficiency virus infection in pregnant women and their newborn. Clin Perinatol 1997; 24(1):161–180. 6. Branch SW. Antiphospholipid antibodies and pregnancy: maternal implications. Semin Perinatol 1990; 14:139–146. 7. Infante-Rivard C, David M, Gauthier R, et al. Lupus anticoagulants, anticardiolipin antibodies and fetal loss. N Engl J Med 1991; 325:1063–1063. 8. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus and in non-SLE disorders. Ann Intern Med 1990; 112:682– 698. 9. Mabie WC. Asthma in pregnancy. Clin Obstet Gynecol 1996; 39(1):56–69. 10. Wendel PJ, Ramin SM, Barnett Hamm C, Rowe TF, Cunningham FG. Asthma treatment in pregnancy: a randomized controlled study. Am J Obstet Gynecol 1996; 175(1):150–154. 11. Drukker BH, Sauer H. Diseases of the Breast. Part XVII. 1991, pp 1142–1156. 12. Abrams RS, Wexler P, eds. Medical Care of the Pregnant Patient. Little, Brown, Boston, 1983. 13. Nelson CT, Demmler GJ. Cytomegalovirus infection in the pregnant mother, fetus and newborn infant. Clin Perinatol 1997; 24(1):151–160. 14. Reece EA. Diabetes in pregnancy. Obstet Gynecol Clin North Am 1996; 23(1):29–45. 15. Holmes L, Harris J, Oakley GP, et al. Teratology society consensus on use of folic acid to reduce the risk of birth defects. Teratology 1997; 55(6):381.

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16. Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: Saunders, 1992. 17. Centers for Disease Control, Immunization Practices Advisory Committee. Prevention of perinatal transmission of hepatitis B virus: prenatal screening of all pregnant women for hepatitis B surface antigens. MMWR 1988; 37:341. 18. Ohto H, et al. Transmission of Hepatitis C Virus from mothers to infants. N Engl J Med 1994; 330:744–750. 19. Kane MA. Hepatitis viruses and the neonate. Clin Perinatol 1997; 24:181–92. 20. Kohl S. Neonatal herpes simplex virus infection. Clin Perinatol 1997; 24(1):129–150. 21. Kulhanjian JA, et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med 1992; 326(14):916–920, 946– 947. 22. CLASP Collaborative Group. CLASP: a randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. Lancent 1994; 343:619– 629. 23. Cunningham FG, Lindheimer MD. Hypertension in pregnancy. N Engl J Med 1992; 326(14): 927–932. 24. Sibai BM, Treatment of hypertension in pregnant women. N Engl J Med 1996; 335(4):257– 265. 25. Kaplan PW, Repke JT. Eclampsia. Neurol Clin 1994; 12(3):565–582. 26. Lazarus JH, Othman S. Thyroid diseased in relation to pregnancy. Clin Endocrinol 1991; 34: 91–98. 27. Mandal SJ, et al. Increased need for thyroxine during pregnancy in women in primary hypothyroidism. N Engl J Med 1990; 323:91–96. 28. Kirsner JB, Shorter RG. Recent developments in non-specific inflammatory bowel disease. N Engl J Med 1982; 306:837. 29. Mayberry JF, Weterman IT. European survey of fertility in women with Crohn’s disease: a case controlled study by a European collaborative group. Gut 1986; 27:821. 30. Keyserling HL. Other viral agents of perinatal importance: vericella, parvovirus, respiratory syncytial virus, and enterovirus. Clin Perinatol 1997; 24(1):193–212. 31. Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996; 335(4):226–232. 32. Abe S. An overview of pregnancy in women with underlying renal disease. Am J Kidney Dis 1991; 17:112–115. 33. Rubella vaccination during pregnancy—United States, 1971–1988. MMWR 1989; 38:289– 293. 34. Akinyanju OO, Nnatu SNN, Ogendengbe OK. Antenatal iron supplementation in sickle cell disease. Int J Gynaecol Obstet 1987; 25:433. 35. Charache S, Neibyl JR. Pregnancy in sickle cell disease. Clin Haematol 1985; 14:729. 36. Morrison JC, Schneider JM, Whybrew WD, et al. Prophylactic transfusion in pregnant patients with sickle cell disease: a randomized cooperative study. N Engl J Med 1988; 319:1447. 37. Schuchat A, Whitney C, Zanfwill K. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR 1996; 45:1. 38. Hannah ME, Ohlsson A, Wang EEL, et al. Maternal colonization with group B Streptococcus and prelabor rupture of membranes at term: The role of induction of labor. Am J Obstet Gynecol 1997; 177:780–785. 39. Baker CJ. Group B Streptococcal infections. Clin Perinatol 1997; 24(1):59–70. 40. Moore JE, Mohr CF. Biologically false positive serologic tests for syphilis. JAMA 1952; 150: 467. 41. Centers for Disease Control. Recommendations for diagnosing and treating syphilis in HIVinfected patients. MMWR 1988; 37:600. 42. Sanchez PJ, Wendel GD. Syphilis in pregnancy. Clin Perinatol 1997; 24(1):71–90.

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43. Ramsey-Goldman R. Pregnancy in systemic lupus erythematosus. Rheum Dis Clin North Am 1988; 14:169–185. 44. Jeannel D, et al. What is known about the prevention of congenital toxoplasmosis? Lancet 1990; 336:359–361. 45. Starke JR. Tuberculosis: An old disease but a new threat to the mother, fetus, and neonate. Clin Perinatol 1997; 24(1):107–128. 46. Wait RB. Urinary tract infection during pregnancy. Postgrad Med 1984; 75:153–161. 47. Coe FL, Parks JH, Lindheimer MD. Nephrolithiasis during pregnancy. N Engl J Med 1978; 288:324–326. 48. Pastuszak AL, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994; 330:901–905. 49. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 1994; 343:1543–1550. 50. Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Eng J Med 1996; 335(2): 108–114. 51. Kittner SJ, Stern BJ, Feeser BR, et al. Pregnancy and the risk of stroke. N Eng J Med 1996; 335:768–774.

36 Teratogen Information Services Around the World Antonio Addis and Maurizio Bonati Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

Lavinia Schu¨ler Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Myla E. Moretti and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION The worldwide publicity given to the thalidomide disaster revolutionized the way pharmacotherapy is applied during pregnancy. Although many drugs and chemicals and a multitude of environmental factors were said to be human teratogens, only a very limited group of agents have been conclusively associated with an increased risk of congenital malformations (1). Nevertheless, during the last decades, health professionals in the area of maternal-fetal toxicology have been approached by an increasing number of pregnant women and their physicians for available information on the safety or risk of drugs, chemicals, and radiation. Several factors can account for the requests for information on exposures during pregnancy, namely: It has been estimated that about half the pregnancies in North America (2) are unplanned; therefore numerous pregnant women expose their fetuses to substances taken for a variety of indications before they actually know about their pregnancy status. The use of drugs during pregnancy is not a rare event. International surveys have shown that 85% (3) of pregnant women are exposed to an average of 2.5 medications during the gestational period. For both ethical and methodological reasons, pregnant women are usually not included in premarketing drug investigations. Consequently, most drugs cannot be labeled for use during pregnancy. Moreover, a typical statement found in the Physicians Desk Reference and in similar sources may read, ‘‘Do not use during pregnancy’’ (1).

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Table 1

Teratogenic Information Services in North America

Organization Teratogenic Information Service (OTIS) 1 Pregnancy Environmental Hotline 2 Connecticut Pregnancy Exposure Info 3 Pregnancy Safety Hotline 4 North Dakota Teratogen Project 5 Centers for Disease Control 6 Indiana Teratogen Information Service 7 Teratogen Information Service—USFI 8 Motherisk 9 TERAS 10 Genetic Services—WMC 11 Arkansas Genetic Program 12 Reproductive Hazard in the Workplace 13 Nebraska Teratogen Project 14 Pregnancy Risk Line 15 California Teratogen Information Service 16 Regional Medical Genetics Center 17 Reproductive Toxicology Center 18 Teratology Information Service WNY 19 Pregnancy Healthline 20 Northwestern 21 Florida Teratogen Information Service 22 Vermont Pregnancy Risk Information 23 CARE Northwest 24 Food and Drug Administration

City/State

Service began

Number of calls (1996)

% professional

% patients

Follow-up

Waltham, MA Farmington, CT Pittsburgh, PA Grand Forks, ND Atlanta, GA Indianapolis, IN Tampa, FL Toronto/Ontario, Canada Boston, MA Wichita, KS Little Rock, AR Madison, WI Omaha, NE Salt Lake City, UT San Diego, CA Valhalla, NY Washington, DC Cheektawaga, NY Philadelphia, PA Chicago, IL Miami, FL Burlington, VT Seattle, WA Washington, DC

— 1985 1986 1989 1970 1989 1988 1985 1995 1978 1988 1986 1987 1984 1979 — 1981 — 1994 1985 1987 1994 1994 1979

7,500 1,788a 1,626a 13 700a 200 1,469 23,000 250 120 16 167 1,200 9,628 — 359 200 573a — 500a 445a 572a 706 4,000

30 10 11 100 50 50 89 30 10 100 100 — 90 30 50 25 100 25 25 32 65 25 47 50

70 90 83 0 50a 50 11 60 90 0 0 — 10 70 50 69a 0 60a 75 68a 35a 75a 53 50a

— Y — Y N — Y Y — — — Y Y Y Y — — Y Y Y Y — — —

1996 1990 —

— 347 160

— 70 95

— 30 5

Y — N

(ENTIS) Graz, Austria Linz, Austria Vienna, Austria

Addis et al.

European Network of Teratogenic Information Services 1 Fetal Maternal Medicine 2 Teratogenic Information Service Linz 3 Dept. Obstetrics and Gynecology, University Hospital of Vienna

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Center Name

CZTIS Va¨esto¨liitto TIS Centre Anti poisons/Info Agents Teratog. Teratogenic Information Services Lyon Teratogenic Information Services Lyon 2 Centre Rens. sur les Agents Te´r. (CRAT) Centre de Pharmacovigilange (HSVP) Service de Ge´ne´tique Me´dicale Beratungsstelle fu¨r Embryonaltoxikologie Frauenklinik/Staadt Kliniken Ander Rosenhohe Department of Obstetrics Beratungsstelle fu¨r Medik. in der Schwan. Teratology Information Service Kentro Enimerosis Teratogonu Drasis Pharmakon Israel Teratogenic Information Service Beilinson Teratology Information Service Telefono Rosso ASM Milano C.R.I.F-IRFM Servizio Informazione Teratologica (SIT) Telefono Rosso ASM Roma Telefono Rosso ASM Firenze Informacija apie Teratogenus/INFOTERA Teratologie Information Service SITTE Swiss Teratogen Information Service The National Teratology Information Service C.I.A.Te. S.I.A.T. S.R.I.T Rio de Janeiro

1996 1994 1991 1985 1979 1980 1975 1989 1988 1996 1991 1979 1990 1987 1985 1988 1975 1989 1988 — 1996 1978 1991 1990 1985 1995 1990 1992 1996

— 330 120 237 611 1,570 700 211 2,586 — 540 2,300 648 835 2,904 514 1,505 2,272b 294 12,519 — — 2,310 2,079 216 2,844 210 261 238 —

— 28 65 97 87 100 100 98 65 — 90 90 40 12 71 32 18 35 93 14 — — 94 40 — 99 10 48 24 —

— 72 35 3 13 0 0 2 35 — 10 10 60 88 29 68 82 65 7 86 — — 6 60 — 1 90 52 76 —

— Y Y Y Y Y Y Y Y — — Y Y Y Y Y Y Y — Y Y — Y Y Y Y Y Y Y —

735

Abbreviations: Y ⫽ yes; N ⫽ no. a Data from 1995. b Data from 1996.

Prague, Czech Rep. Helsinki, Finland Lille, France Lyon-IEG, France Lyon-SPV, France Paris, France Paris, France Strasbourg, France Berlin, Germany Bielefeld, Germany Jena, Germany Ulm, Germany Athens, Greece Thessaloniki, Greece Jerusalem, Israel Tel Aviv, Israel Milan, Italy Milan, Italy Padua, Italy Rome, Italy Florence, Italy Vilnius, Lithuania Bilthoven, Netherlands Madrid, Spain Lausanne, Switzerland Newcastle, U.K. Buenos Aires, Argentina Porto Alegre, Brazil Rio De Janerio, Brazil Kandy, Sri Lanka

Teratogen Information Services

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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As a consequence of the fact that the field of maternal-fetal toxicology is an orphan of research, few data are available on drug use during pregnancy. Most information is based on animal, anecdotal, or retrospective reports. In light of these issues, many drug information services over the past few decades found the need to become more oriented toward the evaluation of drugs as it related to teratogenic risk. Hence the creation or development of what is today called the Teratology Information Services (TIS) (1). TIS have been implemented in various states, provinces, and countries around the world. As of 1995, several dozen TIS were operational in North America and Europe (Table 1). This chapter reviews the structure and activities of these original services and their unprecedented potential to advance our knowledge on human teratogenesis. The analysis of these activities is presented by dividing the two principal types of services provided by the TIS: passive information and proactiveinformation. Passive information is simply defined as the dissemination of information in the form of consultation. Proactive information is the production of original data in the field, which then provides the basis for consultation. PASSIVE INFORMATION Structure and Function of Teratogen Information Services Most TISs operate as question/answer services, mainly by phone and with the aim to respond to questions posed by consumers or professionals. Typically, all TISs document incoming calls on specially designed forms. Although various TISs differ slightly in the data collected during the telephone interview, all services aim to review the relevant information needed to address the safety/risk for a particular case. The TISs are operated by health professionals drawn from different medical fields, including genetic counselors, nurses, toxicologists, and pharmacists. Virtually all services are directed by physicians, most commonly geneticists but also clinical pharmacologists/ toxicologists, epidemiologists, and obstetricians. Frequently they are made up of multidisciplinary teams, providing a broader scope of knowledge. The training of health professionals for their task as teratogen information specialists varies substantially among the TISs, probably because at present no formal process for such training exists. Figure 1 shows a scheme displaying the way most TISs work. While some TISs postpone the reply to the caller by several days, most tend to answer as soon as possible. In the best case, replies occur within the initial call. Many TISs record all contacts and queries to the service in a specialized database, and a selected number will perform followup activity after pregnancy to obtain information on the health of the mother and newborn and other details pertaining to the pregnancy and its outcome. In some programs the information given to women or health professionals over the telephone is followed by a letter, while in other programs no such letters are sent. Furthermore, selected patients may need to be referred to geneticists, obstetricians, or to other medical specialists as the case demands. Sources of Information Typically there are three main kinds of sources from which TISs retrieve the information necessary to answer queries on the risk and safety of drug exposure during pregnancy.

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Figure 1 Working method of Teratogen Information Services

Primary Source of Information All TISs have access to library data services (e.g., Medline, Embase, Current Contents, etc.). Using appropriate search strategies, one is able to identify the most recent literature published on issues pertaining to specific questions. The use of these systems or other sources (hospital or university medical library) simplifies the task of answering a query with the most up-to-date data. Classifications and storage systems for the retrieved literature have been implemented in several TISs. The information is organized by drug or keyword and therefore is readily available. Secondary Source of Information Most TISs use one or more database programs specifically focused on reproductive toxicology, such as ReproTox, Teris, or Reprorisk. All programs contain summarized texts in the area of clinical teratology and related fields, such as diseases in pregnancy, drug abuse toxicology, and infectious diseases. Tertiary Source of Information Unpublished reports of studies or reviews related to exposures in pregnancy. This is frequently ascertained by contacting colleagues in the area who may currently be conducting studies and for which preliminary results may be available. One may also review abstracts of studies presented at various meetings. Tertiary sources may also include registries maintained by the manufacturer as well as reports to several regulatory bodies, including the

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FDA, and also prescription surveillance methods (e.g., Michigan Medicaid and British Prescription Event Monitoring). Proactive Information Problem-oriented drug information centers, such as the TIS, are the obvious place where doubts and misperceptions converge. It follows logically that the TIS may be the ideal observatory for the informational needs in the area of maternal and fetal toxicology. These needs have been attended to in recent years, since epidemiological methods—such as meta-analysis or prospective observational studies—have been increasingly applied to better investigate the risks after exogenous exposures. Typically, when a TIS must reach an informed opinion concerning the possibility of teratogenic effects of a given therapeutic modality, it often faces contradictory and sometimes controversial results generated by different studies and study methodologies. For a TIS, it is vital to deliver the most updated and objective summary of the literature. In this context the meta-analytical approach offers an important opportunity for a better understanding of risk or safety after exposure to drugs or other agents during pregnancy. On the other hand, the increasing number of women who contact TISs around the world each day are becoming an important cohort. If observed prospectively and when compared to adequate controls, they may serve as an original epidemiological point of view providing optimal knowledge on the safety of different agents used during pregnancy. The TIS has the ability to perform pharmacoepidemiological studies uniquely by approaching a problem from two sides. On one hand, by starting from the summary of literature used to answer to the queries, and on the other hand, starting from data collected from the patients exposed to particular agents during pregnancy, the TIS has become an important proactive subject in the production of new data regarding maternal-fetal toxicology. The Meta-analysis Each answer that the TIS produces requires a summary of the literature. However, the problem of how to analyze the literature in order to arrive at an overall conclusion concerning the relationship of a drug and a given outcome is not a new one. Meta-analysis is a well-established strategy useful in clarifying the status of therapeutic modalities because it objectively combines and quantifies the data regarding risk or efficacy of drug (or other) exposures from a number of epidemiological studies. Because most studies investigating teratogenic risk are limited in size, the meta-analysis of studies of similar design is becoming increasingly employed to clarify potential risks. Table 2 shows a list of meta-analyses produced by the Motherisk Program, one of the TISs that have used this method systematically. It is important to note that some metaanalyses have been crucial in establishing or reestablishing the correct risk levels for some common exposures (e.g., spermicides, Bendectin) initially thought to be associated with a ‘‘high risk’’ of teratogenicity. The Collaborative Multicenter Study In the past, most of the data regarding the use of drugs or any other agents during pregnancy came from animal models or retrospective analysis. With the exception of isotreti-

Meta-analyses on Teratogenic Risk of Exposures During Pregnancy

Drugs Bendectin Spermicides Metronidazole Antihistamines Sex hormones Cocaine Benzodiazepines Fluoxetine Alcohol (Moderate use) Organic solvents Corticosteroids a b

Studies retrieved

Studies included in the meta-analysis

25 26 32 109 86 45 74

17 9 7 24 14 20 23

31 61 10 10

4 7 5 6 4

Overall odds ratios for major malformations (C.I. 95%) 1.01 1.02 0.93 0.76 1.09 4.08 0.90 3.01 1.33 1.01 1.64 3.03 3.35

(0.66–1.55) (0.78–1.32) (0.73–1.18) (0.60–0.94) (0.90–1.32) (0.70–23.6) (0.61–1.35) a (1.32–6.84) b (0.49–3.58) (0.94–1.08) (1.16–2.3) (1.08–8.54)a (1.97–5.69)b

References Einarson et al., 1988 (4) Einarson et al., 1990 (10) Burtin et al., 1995 (11) Seto et al., 1997 (12) Raman-Wilms et al., 1995 (13) Lutiger et al., 1989 (14) Dolovich et al., 1998 (15)

Teratogen Information Services

Table 2

Addis et al., 2000 (16) Polygenis et al., 1998 (17) McMartin et al., 1998 (18) Park-Wyllie et al., 2001 (Chap. 11)

Combined effect only for cohort studies. Combined effect based only on case-control studies.

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noin, animal studies have frequently been unable to accurately predict agents identified as teratogenic in humans, including thalidomide initially. Moreover postmarketing studies based on retrospective analysis suffer greatly from the human ‘‘recall bias.’’ That is, women treated with drugs for chronic illness or mothers who give birth to malformed children may be more likely to recall their treatment better than women who took an overthe-counter drug or those who had a healthy baby. Finally, premarketing studies cannot be expected to provide information regarding a drug’s teratogenic potential, because samples are of limited size and inclusion of pregnant women is prohibited due to obvious ethical considerations. With the international development of TISs, a new source of data for prospective observational research has emerged. Pregnant women taking prescription or over-thecounter drugs voluntarily call the TIS for risk-assessment counseling, usually during the first trimester. Since the exposure data are recorded prospectively, the probability of recall bias is reduced and follow-up of exposed pregnancies can extend well beyond parturition. Furthermore, contact with relevant physicians and direct examination of the child at centers in a hospital/patient-care setting provides both adequate and accurate information on the outcome of a particular case. Some of the most well established TISs, which by now have accumulated impressive cohorts of patients, have begun doing follow-up analyses on several drug exposures during pregnancy. Table 3 highlights some of the collaborative studies performed using the databases from different TISs around the world. Each woman exposed to a particular drug during pregnancy was compared to at lease one control case. Nonteratogenic controls (NTC), are matched for maternal age (⫾2 years), smoking habits, and alcohol consumption. A NTC was defined as a medical or environmental substance that was proven not to increase the baseline risk for major malformations. Studies frequently also include a group of disease-matched controls (DMC), matched according to the indication of drug use. The DMCs are recruited based on the presence of a disease similar to those present in the investigation group, but are either exposed to agents which do not pose a teratogenic risk or not having any exposure at all for that specific indication.

Disseminating Information As part of proactive service, several TIS are involved in the production of material for widespread dissemination of information on risk and safety after environmental or therapeutic exposures during pregnancy. Recently, the Motherisk Program (a Canadian TIS) developed a pregnancy wallet card on the risks and safety of some commonly used agents during pregnancy. This is a handy fold-out pamphlet with answers to the questions most frequently asked by pregnant women, such as how may tobacco and alcohol or painting and video-display-terminal exposures during pregnancy increase the risk of teratogenicity for the newborn? The wallet card attempts to answer all these and other common questions in a concise and easy to understand manner. The Motherisk Program has also created a pamphlet summarizing the facts on folic acid prophylactic use. The aim of this brochure is to make known the ‘‘why, when, and how’’ to use folic acid in the prevention of neural tube defects. Other examples of information pamphlets produced by TISs are those produced by the Telefono Rosso program. With financial support by the Italian Association for the Study of Malformations (ASM), this Italian TIS has produced a series of pamphlets on epilepsy and pregnancy and on the Tri-test (maternal triple serum screen). The North

Examples of Multicenter Prospective Cohort Studies Done by TIS on the Teratogenic Risk After Exposures During Pregnancy No. of TIS involved

Patients recruited

Nonteratogenic controls

Disease-matched controls

Relative risk (C.I.95%)

Fluoxetine

4

128

128

74

SSRIs Cisapride

9 10

267 129

267 129

— 129

Fluconazole Vitamin A (high doses) Omeprazole

3 11 4

226 354 113

452 659 113

— — 113

Quinolones Lithium Sumatriptan

4 4 4

200 138 96

200 148 96

— — 96

Clarithromycin Misoprostol Terfenadine

5 3 2

157 86 118

157 86 118

— — —

1.12 (0.2–7.8) a 1.86 (0.2–17.5)b 1.06 (0.43–2.62) 2.00 (0.5–7.7) a 1.20 (0.4–3.8) b 0.82 (0.3–1.9) 0.97 (0.5–1.9) 1.94 (0.4–10.4) a 1.44 (0.3–6.3) b 0.85 (0.2–3.5) 1.2 (0.2–5.7) 1.06 (0.26–4.26) a 1.05 (0.26–4.23) b 1.31 (0.63–2.7) 2.97 (1.12–7.88) 0.57 (0.06–5.39)

Drugs

a b

References Pastuszak et al., 1993 (19) Kulin et al., 1998 (20) Bailey et al., 1997 (21)

Teratogen Information Services

Table 3

Mastroiacovo et al., 1996 (22) Mastroiacovo et al., 1996 (23) Lalkin et al., 1998 (24) Loebstein et al., 1998 (25) Jacobson et al., 1992 (26) Shuhaiber et al., 1998 (27) Einarson et al., 1998 (28) Schu¨ler et al., 1999 (6) Loebstein et al., 1999 (29)

Versus nonteratogenic controls. Versus disease-matched controls.

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American Organization of Teratology Information Services (OTIS) has also produced several fact sheets on various agents in collaboration with all its members. The production of these materials is an important way to communicate and to become a more active source of information that can continuously be improved. Some TISs produce newsletters (e.g., The Motherisk Newsletter, ASM Notizie, etc.) with the aim of summarizing data on maternal fetal toxicology. The TIS may also secure space in drug therapeutic bulletins or medical journals (e.g., ‘‘Motherisk Update,’’ in the Canadian Family Physician journal; ‘‘Question/Answer’’ in Informazione sui Farmaci, etc.), in which they report the latest on issues regarding risk and safety of exposures during pregnancy.

TISs IN DEVELOPING COUNTRIES In South America, beginning in 1990, nine TISs were created; they are associated with the ECLAMC (Latin American Collaborative Study of Congenital Malformations), a hospitalbased birth defects registry operating since 1967. The social, political, and economic characteristics as well as the health needs in developing countries impose peculiar challenges for the establishment of TISs in these countries. These characteristics include low educational and economic level of the population at large, a high incidence of infectious and deficiency diseases, little financial support for health and research, poor drug-control measures, institutional and governmental instability frequently changing health policies, and a lack of legal means to obtain pregnancy termination. To illustrate, this scenario has led to situations such as frequent cases of congenital rubella syndrome or to the ongoing occurrence of thalidomide embryopathy after maternal misuse of thalidomide in regions where leprosy is still prevalent (5). One such situation recently investigated by the Brazilian TIS and by the Motherisk Program was the potential teratogenicity of misoprostol, a prostaglandin E1 analogue. In Brazil, where abortion is not a legal procedure, there is a widespread popular misuse of this drug as an abortifacient. As case reports of congenital malformations after maternal use of misoprostol began to appear in Brazil, two studies were conducted. One, a prospective study using information from 86 exposed and 86 nonexposed women ascertained by one of the Brazilian TIS, did not show differences in the rate of major or minor malformations between these two groups (6). On the other hand, a case-control study detected significantly higher exposure to misoprostol (49%) among the mothers of 96 children with Mo¨bius sequence compared to 96 mothers of children with neural tube defects (3%) (OR 38.8; 95% Cl 9.5–159.4) (7). These studies concluded that attempted abortion with misoprostol is associated with an increased risk of Mo¨bius syndrome, although the absolute risk is probably low. In this context, TIS play an essential and irreaplaceable role in both disseminating information and producing important data on drug safety during pregnancy.

NETWORK OF TISs During a recent meeting of the European and American organizations of TISs (ENTIS and OTIS), the need for a network system between TISs around the world was emphasized. The advantage of this is type of network is the increased ability for data exchange and

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facilitation of transfer of information as it relates to exposures during pregnancy. Geographic, economic, political and medical practice characteristics create different realities across countries, and frequently the dilemmas surrounding risks and safety during pregnancy also differ significantly. Teratogenic cases are rare events that require a large number of exposures before a single event is identified. Communication and collaboration across countries and centers may simplify this task. For example, it was the collaboration between different centers in Brazil and around the world that made it possible to share information regarding the teratogenicity associated with the use of misoprostol during the first trimester of pregnancy. There is an urgent need to diffuse information on the use of drugs on which there are no data regarding use during pregnancy. The mission of the new generation of TISs will be to contribute not only to the optimal dissemination of information but also to the production of original data on the risks and safety of therapies in pregnancy.

PERSPECTIVES ON THE FUTURE The number of TISs is increasing around the world. This is likely due to the vast need for such information and to the growing focus on maternal and pregnancy health as substantial medical entities. However, if establishing a new TIS is not so difficult, the undeniable challenge is to maintain the service’s life span and overcoming the difficulties in obtaining financial support. Although most TISs are underfunded, we believe that this kind of activity should increase. The TIS is the most simple, accessible, and direct way to obtain specialized information on maternal and fetal toxicology—probably much more useful and accurate than other means of providing information, such as leaflets, mass-media articles, and television programs. The cost-effectiveness of these services is evidenced by the prevention of unnecessary pregnancy termination (8) and major malformations by appropriate risk counseling (9). In the future, we hope that the access to TISs will become completely free of charge, with toll-free lines. Currently, there is already some experience in this direction, where TIS have set up a telephone line free of charge for specific problems (e.g., nausea and vomiting, folic acid, etc. See Chap. 38). The benefit to the patient is clear, but the benefits to the TIS is also present. The ability to collect data and provide information to selected underprivileged cohorts who may otherwise not pay to make a call to the service is unparalleled.

CONCLUSIONS During the past few years, there have been great changes in the infrastructures of several TISs. They have moved beyond a simple question-answer service ( passive information). TISs are now playing a principal role in the production of new data about maternal and fetal toxicology (active information). The originality of this new approach arises from the fact that hypotheses and studies investigating these hypotheses are generated in the same place where the doubts and queries of professionals and lay people accumulate. The TIS serves as an ideal model for those who search for the indisputable bridge between research and practice.

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REFERENCES 1. Koren G, Pastuszak A, Ito S. Drugs in pregnancy N Engl J Med 1998; 338:1128–1137. 2. Anonymous. Better news on population. Lancet 1992; 339:1600. 3. Collaborative Group on Drug Use In Pregnancy (CGDUP). Medication during pregnancy: an intercontinental cooperative study. Int J Gynecol Obstet 1992; 39:185–195. 4. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988; 22:813–824. 5. Castilla EE, Ashton-Prolla P, Barreda-Mejia E, Brunoni D, Cavalcanti DP, Correa-Neto J, Delgadillo JL, Dutra MG, Felix T, Giraldo A, Juarez N, Lopes-Camelo JS, Nazer J, Orioli IM, Paz JE, Pessoto MA, Pina-Neto JM, Quadrelli R, Rittler M, Rueda S, Saltos M, Sanchez O, Schu¨ler L. Thalidomide, a current teratogen in South America. Teratology 1996; 54:273– 277. 6. Schu¨ler L, Pastuszak A, Sanseverino MTV, Orioli IM, Brunoni D, Ashton-Prolla P, Silva da Costa F, Giugliani R, Couto AM, Brandao SB, Koren G. Pregnancy outcome after exposure to misoprostol in Brazil: a prospective, controlled study. Reprod Toxicol 1999; 13:147–151. 7. Pastuszak A, Schu¨ler L, Speck-Martins CE, Coelho KEFA, Cordello SM, Vargas FR, Brunoni D, Schwartz IVD, Larrandaburu M, Safattle H, Meloni VFA, Neto JC, Koren G. Use of misoprostol during pregnancy and Mo¨bius syndrome in infants. N Engl J Med 1998; 338:1881– 1885. 8. Koren and A. Pastuszak. Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical, and radiation exposure during the first trimester. Teratology 1990; 41:657–661. 9. Koren G, Graham K, Feigenbaum A, Einarson TR. Evaluation and counseling of teratogenic risk: the Motherisk approach. J Clin Pharmacol 1993; 33:405–411. 10. Einarson TR, Koren G, Mattice D, Schechter-Tsafriri O. Maternal spermicide use and adverse reproductive outcome: a meta-analysis. Am J Obstet Gynecol 1990; 162:655–660. 11. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995; 172:525–529. 12. Seto A, Einarson T, Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-Analysis. Am J Perinatol 1997; 14(3):119–124. 13. Raman-Wilms L, Tseng AL, Wighardt S, Einarson TR, Koren G. Fetal genital effects of first trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995; 85:141–149. 14. Lutiger B, Graham K, Einarson TR, Koren G. Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis. Teratology 1991; 44:405–414. 15. Dolovich LR, Addis A, Vaillancourt JMR, Power JDB, Koren G, Einarson TR. Benzodiazepines in pregnancy and major malformations or oral cleft: meta-analysis of cohort and casecontrol studies. BMJ 1998; 317:839–843. 16. Addis A, Koren G. Safety of fluoxetine during the first trimester of pregnancy: meta-analytical review of epidemiological studies. Psychol Med 2000; 30:89–94. 17. Polygenis D, Wharton S, Malmberg C, Sherman N, Kennedy D, Koren G, et al. Moderate alcohol consumption during pregnancy and the incidence of fetal malformations: a meta-analysis. Neurotoxicol Teratol 1998; 20(1):61–67. 18. McMartin KI, Chu M, Kopecky E, Einarson TR, Koren G. Pregnancy outcome following maternal organic solvent exposure: a meta-analysis of epidemiologic studies. Am J Ind Med 1998; 34(3):288–292. 19. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfield A, McCormack M, Leen-Mitchell M, Woodland C et al. Pregnancy outcome following first trimester exposure to fluoxetine. JAMA 1993; 296:2246–2248. 20. Kulin NA, Pastuszak A, Sage SR, Schick-Boshetto B, Spivey G, Feldkamp M, Ormond K, Mastsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G. Pregnancy outcome

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21.

22.

23.

24.

25.

26.

27. 28. 29.

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following maternal use of the new selective serotoninre uptake inhibitors: a prospective controlled multicenter study. JAMA 1998; 279:609–610. Bailey B, Addis A, Lee A, Sanghvi K, Mastroiacovo P, Mazzone T, Bonati M, Paolini C, Garbis H, Val T, DeSouza CFM, Matsui D, Schechtman AS, Conover B, Lau M, Koren G. Cisapride use during human pregnancy: a prospective, controlled multicenter study. Dig Dis Science 1997; 42:1848–1852. Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective assessment of pregnancy outcomes after first trimester exposure to fluconazole. Am J Obstet Gynecol 1996; 175:1645–1650. Mastroiacovo P, Mazzone T, Addis A, Elephant E, Carler P, Garbis H, Robert E, Bonati M, Ornoy A, Finardi A, Schaffer C, Caramelli L, Rodriguez-Pinilla E, Clementi M. High vitamin A intake in early pregnancy and major malformations: a multicenter prospective controlled study Teratology 1999; 59:7–11. Lalkin A, Loebstein R, Addis A, Ramesani-Namin F, Magee LA, Mastroiacovo P, Mazzone T, Vial T, Bonati M, Koren G. The Safety of omeprazole during pregnancy: a multi-center prospective controlled study. Am J Obstet Gynecol 1998; 179:727–730. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Moretti M, Lalkin A, Pastuszak A, Koren G. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicentre prospective controlled study. Antimicrob Agents Chemother 1998; 42:1336–1339. Jacobson SJ, Jones K, Johnson K, Donnenfeld AE, Rieder M, Kaur P, Ceolin L, Santelli R, Smythe J, Pastuszak A, Einarson TR, Koren G. Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester. Lancet 1992; 339:530–533. Shuhaiber S, Pastuszak A, Schick B, Reider M, Spivey G, Brochu J, Koren G. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998; 51:581–583. Einarson A, Phillips E, Mawji F, D’Alimonte D, Schick B, Addis A, et al. A prospective controlled study of clarithromycin in pregnancy. Am J Perinatol 1998; 15(9):523–525. Loebstein R, Lalkin A, Addis A, Costa A, Lalkin I, Bonati M, et al. Pregnancy outcome after gestational exposure to terfenadine: a multicenter, prospective controlled study. J Allergy Clin Immunol 1999; 104(5):953–956.

37 Teratogen Information Services Gideon Koren, Anne Pastuszak, and Myla E. Moretti The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case You have a patient with a potential teratogenic exposure you are not familiar with. You practice in central Florida. What should you do?

INTRODUCTION Since the thalidomide era 30 years ago (1), perinatal medicine has been practiced by physicians and their patients as if every drug were a potential human teratogen. In reality, relatively few xenobiotics have been proven beyond doubt to pose risk to the human fetus (2), while an ever-increasing number of agents have been found to be safe. It is estimated that about half the pregnancies in North America are unplanned, and thus a very large number of women expose their fetuses to prescribed and nonprescribed agents taken for a variety of indications. Moreover, the early weeks of unplanned pregnancies are more likely to entail uncontrolled consumption of cigarettes, alcohol, and drugs of abuse by women who otherwise would try to minimize their gestational exposures. During the last two decades, health professionals in the areas of teratology, genetics, pharmacology, toxicology, and obstetrics have been increasingly approached by pregnant women and their physicians for available information on the safety/risk of drugs, chemicals, radiation, and infections. This has led to the development of teratogen information services (TISs) in various states, provinces, and countries. Currently, several dozen TISs operate in North America and in Europe (Table 1). This chapter reviews the structure and clinical functions of these newly formed services, their research activities, and their unprecedented potential to advance our knowledge of human teratogens. Considering both the clinical endpoint and the research potential of the endeavor, TISs offer an exciting opportunity for clinicians and scientists, as well as an inexpensive, cost-effective way of achieving dramatic improvements in patient care.

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748 Table 1 International List of Teratogen Information Services (updated 2000) United States Alabama University South Alabama Department Medical Genetics 307 University Boulevard, Room 214, CC/CB Mobile, AL 36688-0002 (334) 460-7500, (800) 423-8324 Arizona Arizona Teratogen Information Program University of Arizona P.O. Box 245079 Tucson, AZ 85724-5079 (520) 626-3410, (888) 285-3410 Arkansas Arkansas Teratogen Information Service University of Arkansas for Medical Sciences Department of Obstetrics and Gynecology Arkansas Genetics Program 4301 West Markham/Slot 506 Little Rock, AR 72205 (501) 296-1700, (800) 358-7229 California California Teratogen Information Service and Clinical Research Program UCSD Medical Center, Department of Pediatrics 200 West Arbor Drive San Diego, CA 92103-8446 (619) 543-2131; in California, (800) 532-3749 Connecticut Connecticut Pregnancy Exposure Information Service Division of Human Genetics MC6310 University of Connecticut Health Center 270 Farmington Avenue/The Exchange Suite 160 Farmington, CT 06032 (860) 679-1502; in Connecticut, (800) 325-5391 District of Columbia Reproductive Toxicology Center Columbia Hospital for Women Medical Center 2440 M Street, NW, Suite 217 Washington, D.C. 20037-1404 (202) 293-5137

Koren et al.

Teratogen Information Services Table 1

Continued

United States Florida Florida Teratogen Information Service University of Florida Health Science Center Box 100296 Gainesville, FL 32610-0296 (352) 392-3050; in Florida, (800) 392-3050 Florida Teratogen Information Service University of Miami P.O. Box 016820 Miami, FL 33143 (305) 243-6464, 243-3919 Teratogen Information Service University of South Florida Birth Defects Center Department of Pediatrics 17 Davis Blvd. Tampa, FL 33606 (813) 233-2627 Illinois Illinois Teratogen Information Service Northwestern Memorial Hospital Division of Reproductive Genetics 333 East Superior, Suite 1543 Chicago, IL 60611 (312) 926-7441; in Illinois, (800) 252-4847 Indiana Indiana Teratogen Information Service Indiana University Medical Center Department of Medical and Molecular Genetics 1B130 975 West Walnut St. Indianapolis, IN 46202-5251 (317) 274-1071 Massachusetts Massachusetts Teratogen Information Service (MTIS) Pregnancy Environmental Hotline 40 Second Avenue, Suite 520 Waltham, MA 02451 (781) 466-8474; in Massachusetts, (800) 322-5014 Genetics and Teratology Unit, Pediatric Service Massachusetts General Hospital Warren Building 801 55 Fruit Street Boston, MA 02114 (617) 726-1742

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750 Table 1 Continued United States Michigan Michigan Teratogen Information Service 4160 John R Street, Suite 616 Detroit, MI 48201 (313) 966-9368, (877) 52-MITIS (64748) Minnesota MN Perinatal Physicians Abbott-Northwest Hospital 800 East 28th St. Minneapolis, MN 55407 (612) 863-4502 Missouri Missouri Teratogen Information Service University of Missouri Hospital and Clinics One Hospital Drive, DC058.00 Columbia, MO 65212 (573) 884-1345; (800) 645-6164 Nebraska Nebraska Teratogen Project University of Nebraska Medical Center 600 South 42nd Street Omaha, NE 68198-5440 (402) 559-5071 New Jersey Pregnancy Healthline Southern New Jersey Perinatal Cooperative 2500 McClellan Avenue/Suite 110 Pennsauken, NJ 08109-4613 (609) 665-6000 (New Jersey), (610) 222-9126 (Southeast Pennsylvania) New York Pregnancy Risk Network 976 Delaware Ave. Buffalo, NY 14209 (716) 882-6791 (then press 1); in New York, (800) 724-2454 (then press 1) PEDECS University of Rochester Medical Center Department of Obstetrics and Gynecology 601 Elmwood Ave. Rochester, NY 14642-8668 (716) 275-3638

Koren et al.

Teratogen Information Services Table 1

Continued

United States North Dakota North Dakota Teratogen Information Services UND School of Medicine and Health Sciences Department of Pediatrics/Medical Genetics P.O. Box 9037 Grand Forks, ND 58202-9037 (701) 777-6124 Texas Texas Teratogen Information Service UNT Department of Biology P.O. Box 305220 Denton, TX 76203-5220 (940) 565-3892, (800) 733-4727 Utah Pregnancy Riskline Utah Dept. of Health Box 2106 Salt Lake City, UT 84114-2106 (801) 328-2229 Vermont Pregnancy Risk Information Service Vermont Regional Genetics Center 1 Mill St., Box B-10 Burlington, VT 05401 (802) 658-4310 (Upstate New York and Vermont) Washington CARE Northwest Box 357920 University of Washington Seattle, WA 98195-7920 (900) 225-2273 ($8/call) Wisconsin Wisconsin Teratogen Project Wisconsin Clinical Genetics Center Madison, WI 53705-2280 (800) 442-6692

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752 Table 1 Continued Canada Motherisk Program Hospital for Sick Children 555 University Ave. Toronto, Ontario Canada M5G 1X8 (416) 813-6780 FRAME Children’s Hospital of Western Ontario 800 Commissioners’ Road East London, Ontario N4C 2V5 Canada (519) 685-8293 IMAGe: Info-Medicaments en Allaitement et Grossesse Pharmacy Department Ste Justine Hospital Montreal, Quebec H3T 1C5 Canada (514) 345-2333

Argentina Centro de Informacion sobre Agentes Teratogenicos (CIA Te) Hospital Italiano de Buenos Aires Potos 4135 1199 Buenos Aires Argentina 541-14-958-5800

Austria Fetal Maternal Medicine Department of Obstetrics and Gynecology University of Graz Auenbruggerplatz 14 8036 Graz, Austria 31-6-385-3209/3201 Fax 31-6-385-3199 TIS Linz Landesfrauenklinik Linz Ledergasse 47 4020 Linz Austria 43-732-7674 Fax 43-732-7674-1146

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Teratogen Information Services Table 1

Continued

Austria Department of Obstetrics and Gynecology University Hospital of Vienna Wohringer Gurtel 18-20 Austria 43-1-40400-2822 Fax 43-1-40400-2862

Brazil Sistema Nacional de Informac¸o¨es sobre Agentes Teratogeˆnicos (SIAT) SIAT – Unidade de Genetica Medica Hospital de Clinicas de Porto Alegre Av. Ramiro Barcelos 2350 90035-003 Porto Alegre – RS Brazil 55-51-330-2016 Fax 55-51-316-8010 Servicio e Registro de Informatio teratogenica do Rio de Janeiro Dept. de Genetica – Universidade Federal de Rio de Janeiro Caixa Postal 68.011 21 941-970 Rio de Janeiro Brazil 55-21-560-3432 Fax 55-21-560-3432, 280-0994/8043

Czech Republic CTZIS Institute of Histology and Embryology 3rd Faculty of Medicine Ruska 87 100 00 Praha 10 Czech Republic 42-02-67-10-2310 Fax 42-02-67-10-2311

Finland Vaestoliitto Teratology Information Service Department of Medical Genetics The Family Federation of Finland Kalevankatu 16 00 100 Helsinki, Finland 358-9-6162-2246 or 641-761 Fax 358-9-612-1211 or 645-018

753

754 Table 1 Continued France Centre anti Poisons/Info Agents Teratogenes Centre Hospitalier Regional Universitaire de Lille 5 Avenue Oscar Lambret 59037 Lille Cedex France 33-320-444444 Fax 33-320-445628 TIS-Lyon Institut Europeen des Genomutations 86 Rue Edmond Locard 69005 Lyon France 33-472-116997 or 33-472-116911 Fax 33-478-366182 TIS-Lyon2 Service de Pharmacovigilance et Centre Anti-Poisons Pavillon N/Hopital Edouard Herriot 69437 Lyon, Cedex 03 France 33-472-116997 or 33-472-116911 Fax 33-472-116985 CRAT-Centre Renseignement sur les Agents Teratogenes CHU St Antoine 27 Rue de Chaligny 75012 Paris France 33-1-4001-1462 Fax 33-1-4341-2622 Centre de Pharmacovigilance (F. Bavoux) Pharmacologie Hopital Saint-Vincent de Paul 82, Avenue Denfert Rochereau 75674 Paris, Cedex 14 France 33-1-4048-8213 Fax 33-1-4335-4670 Service de Genetique Medicale Hopital de Hautepierre Avenue Moliere 67098 Strasbourg, Cedex France 33-3-8812-8120 Fax 33-3-8812-8125

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Teratogen Information Services Table 1

Continued

Germany Beratungsstelle fur Embryonaltoxikologie Spandauer Damm 130 14050 Berlin Germany 49-30-3068-6719 Fax 49-30-3068-6721 Frauenklinik/Staadt. Kliniken An der Rosenhohe An der Rosenhohe 27 33647 Bielefeld Germany 49-521-943-8200 Fax 49-521-943-8299 Department of Obstetrics Universites Frauenklinik Bachstrasse 18 07740 Jena Germany 49-3641-633-190 Fax 49-3641-633-064 or 49-3641-933-986 Beratungsznetrum fur Reproduktionstoxikologie Kloster Roggenburg Klosterstr. 5 D-89297 Roggenburg Germany 49-0730-096-11-90 Fax 49-0730-096-11-99

Greece Teratology Information Service Children’s Hospital P.A. Kyrikou 11527 Athens Greece 30-1-7793777 Fax 30-1-7486114 Kentro Enimerosis Teratogonu Drasis Pharmakon 4th Dept. of Obstetrics and Gynecology Ippokration Hospital 54621 Thessaloniki Greece 30-31-851316 or 30-31-280767 Fax 30-31-851316 or 30-31-279891

755

756 Table 1 Continued Israel Israel Teratogen Information Service Faculty of Medicine Hadassah Medical School P.O. Box 1172 Jerusalem Israel 972-2-6758-430 or 972-2-6757-453 Fax 972-2-6758-430 Beilinson Teratology Information Service (BELTIS) Rabin Medical Center Beilinson Campus Petah-Tikva 49100 Israel 972-3-9377-474/3/2 Fax 972-3-9220-068

Italy Tossicologia Perinatale U.O. Tossicologia Medica Azienda Osperdaliera Careggi–Firenze Viale Morgagni 85 50134 Firenze Italy 39-55-427-7731 Fax 39-55-427-7925 Telefonao ASM-Milano c/o Clinica Obstetrica Ginecologica San Paolo Hospital Via a. Rudini 8 20142 Milano Italy 39-2-891-0207 Fax 39-2-813-5662 Regional Center for Drug Information Laboratory for Mother and Child Care Instituto di Ricerche Farmacologiche ‘‘Mario Negri’’ Via Eritrea 62 20157 Milano Italy 39-2-390-14511 Fax 39-2-355-0924

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Teratogen Information Services Table 1

Continued

Italy Servizio Infomazione Terologica (SIT) Genetica Midica/Departimento di Pediatria Via Giustiniani 3 35128 Padova Italy 39-49-821-3572 Fax 39-49-821-3513 Telefono Rosso Icaro – ASM Via Sabotino 2 00195 Rome Italy 39-6-370-1905/370-1898 Fax 39-6-370-1904

Lithuania Informacija apie Teratogenus /INFOTERA Vilnius University Hospital Human Genetics Center Santariskiu 2 Vilnius 2021 Lithuania 370-2-720-365 Fax 370-2-720-449

The Netherlands Teratologie Information Service National Institute of Public Health and Environment P.O. Box 1 3720 BA Bilthoven The Netherlands 31-30-274-2017 Fax 31-30-274-4460

Spain Espanol (SITTE) Facultad de Medicina Universidad Complutense 28040 Madrid Spain 34-1-394-1594 Fax 34-1-394-1592

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Table 1 Continued Switzerland Swiss Teratogen Information Service Division de Pharmacologie Clinique Beaumont 06-634 Centre Hospitalier Univers, Vaudois 1011 Lausanne Switzerland 41-21-314-4267 Fax 41-21-314-4266

United Kingdom The National Teratology Information Service Regional Drug and Therapeutics Centre Wolfson Unit, Claremont Place Newcastle upon Tyne, NE2 4HH United Kingdom 44-191-232-1525 Fax 44-191-232-7692

STRUCTURE AND FUNCTION OF A TERATOGEN INFORMATION SERVICE Most TISs operate as telephone services, mainly to respond to questions from the general public and from health professionals. All TISs document the incoming calls on specially designed forms. Although various TISs have slight differences in the data collected during the telephone interview, all services aim at assessing relevant information needed to address the safety/risk of the particular case. The TISs are manned by health professionals drawn from different medical fields. They include genetic counselors, nurses, toxicologists, and pharmacists. Virtually all services are directed by physicians, most commonly geneticists, but also clinical pharmacologists-toxicologists, epidemiologists, and obstetricians. The training of health professionals for their task as teratogen information specialists varies substantially among the TISs, probably because at present there is no formal process to acquire such training. In some programs, the information given to women or health professionals over the telephone is followed by a letter. In other programs, no such letters are sent, but selected patients are referred to geneticists, obstetricians, or other medical specialists. In Toronto, the Motherisk Program is presently dealing with 130–140 calls per day. Women are referred to the weekly Motherisk Clinic according to criteria presented in Table 2. At the clinic, the women are seen by a physician team member who collects data on the exposure in question and any other potential risk factors before communicating with the women the safety/risks of her exposure(s). The Motherisk physicians are pediatric pharmacologists/ toxicologists or trainees in our program, generally individuals who have already completed their specialty training in pediatrics, medicine, or emergency medicine.

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Indications for Motherisk Clinic Consultation

Exposure to known or suspected teratogens Exposure to new drugs Exposure to drugs of abuse Chronic maternal illness Chronic maternal drug therapy Occupation exposures Any woman who wants to be seen or whose physician wishes her to be seen

SOURCES OF INFORMATION Virtually all TISs use one or more on-line programs in reproductive toxicology, such as Reprotox or Teris. All programs obtain relevant texts in the area of clinical teratology and related fields, such as diseases in pregnancy, drug abuse toxicology, and infectious diseases. Moreover, most services continuously review new published studies in the area of teratology for their relevance to the human exposure. In Toronto, the Motherisk team meets weekly to critically review literature and to decide whether it should be included in our ‘‘statements.’’ The statement for each exposure is computerized to be included in all subsequent letters sent to physicians.

RESEARCH POTENTIAL In addition to the novel clinical component introduced by the TIS, these services open new horizons for much-needed research in the area of reproductive toxicology. In the past, many scientists have stressed the need for large prospective cohorts in the area of clinical teratology; however, these were difficult and expensive to collect. For example, the Collaborative Perinatal Project, funded by the U.S. National Institutes of Health in the 1960s, prospectively collected women and their offspring. More than 5 years were spent on the collection of 50,000 cases at a cost of many millions of dollars, yet most drug cohorts were too small to prove safety/risk. The TISs create a new reality because women call these services in real time about their exposures, thus obviating the problems of recall. Hence there are now on record hundreds of thousands of gestational exposures in North America that are a virtual gold mine for prospective research. However, there are also major issues in materializing this potential. For example, being clinical programs, many TISs do not have the infrastructure needed to conduct such research. At present, most TISs do not routinely follow up on the outcome of the pregnant women they counsel. A number of TISs follow up the outcome of a selected list of drugs of interest (e.g., new drugs, drugs for which no data exist, drugs known or suspected to be teratogenic). Yet some of the more established TISs, which by now have accumulated impressive cohorts of patients, have begun publishing their followup analyses. The San Diego program, headed by Dr. K. Jones, has published several peerreviewed studies in the last few years (3). Similarly, the Motherisk Program in Toronto has published a number of prospective studies based on its follow-up (4–6). An even more promising trend is the collaboration among TISs. We have published the prospective ascertainment of 149 first-trimester exposures to lithium in San Diego,

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Philadelphia, Toronto, and London, Ontario (7). Other examples of such collaborations are summarized in chapter 36. At present, most drug companies orphan pregnant women from drug use in pregnancy by labeling their products ‘‘not proven safe’’ in pregnancy. Yet, in many cases these companies are reluctant to support the collection of newly available data through the TIS. Because postmarketing collection of such data is not mandatory in either the United States or Canada, many manufacturers do not feel obligated to support its collection. When this attitude is coupled with the relatively small market for most medications in pregnancy, it can be seen that the incentive for many pharmaceutical houses is negligible. Yet, half the pregnancies in North America are unplanned; the refusal of manufacturers to participate in this data collection process may potentially lead to the exclusion of all women of reproductive age from the benefit of agents whose safety has not been proven. One author [AP] believes that only legislation will solve this example of abuse of women’s rights.

FUNDING At present TISs are funded though various sources at state, provincial, or municipal departments of health or through private agencies. Almost invariably these important services are underfunded, mainly because of the time needed to prove their effectiveness coupled with the present difficult economic times.

EFFECTIVENESS OF THE INFORMATION COUNSELING PROCESS To justify their functions, TISs must, like other clinical services, prove their impact on health care. This can be done in two separate dimensions: (1) proving the ability of TIS to prevent unnecessary pregnancy terminations and (2) calculating the impact of TIS on the prevention of major birth defects. We have analyzed, for this presentation, data on the effectiveness of the Motherisk Program in Toronto in these two dimensions. During the clinic visit we use a 10-cm visual analog scale (VAS) to assess each woman’s tendency to continue/terminate pregnancy (4). Briefly, 100 denotes an absolute intention to continue pregnancy and zero an absolute tendency to terminate the pregnancy. We validated this VAS recently by showing that the vast majority of women who left our clinic with a 50% or more tendency to terminate pregnancy eventually did so (7). This questionnaire is delivered once before any information is volunteered to the woman, and again after we have explained to her what is known about her exposures. Calculation of Cost-Effectiveness of Preventing Unjustified Pregnancy Terminations In an analysis of the first 516 VAS scores (8), we have shown that 24% of women selected to be seen in our clinic had a tendency of 50% or more or pregnancy termination prior to our intervention. Of these 24%, we reversed the tendency of 78% (18.7% of total cases) (7). For the following analysis, we have used these figures to calculate the yearly rate of prevention of unnecessary terminations.

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Presently we counsel in the clinic more than 400 women per year, which therefore would translate to prevention of at least 75 unnecessary pregnancy terminations. This calculation is very conservative, since it is likely that in some of the cases that are advised only by the telephone we also reverse the tendency to terminate pregnancy. However, because no VAS scores are available for these patients, we have not included them in the present analysis. The direct medical costs of pregnancy termination have been estimated at $2000 (8). We estimated that a woman loses on average 5 days of work directly and indirectly before, during, and after an elective abortion, adding another $1000; a husband’s loss was not calculated. Therefore, the cost of pregnancy termination was estimated at $3000. In some cases, first-trimester abortion may result in major complications (0.5%) and even mortality (0.03%) (9–12); however, we did not attempt to estimate these costs. Calculation of Cost-Effectiveness of Preventing Major Malformations Table 3 presents the rates per year of Motherisk patients exposed to known teratogens and the accepted rates of drug-induced major malformations known to occur in humans

Table 3 Estimated Number of Chemically Induced Malformations Prevented by Motherisk per Year (based only on patients seen in clinic; not including those advised over the telephone alone)

Agent Alcohol (high dose) Systemic retinoids Valproic acid Carbamazepine Phenytoin Severe carbon monoxide poisoning (grade 4–5) Warfarin Cancer chemotherapy Total a

Reported major malformations (%)

Mean number of cases per year based on Motherisk data-base for 1985–1990

Estimated % preventive procedures (definitive tests or terminations)

10

25

80a

2a

40

2

80b

0.64

2 1 8 50

8 25 21 1

100c 100c 40c 100d

0.16 0.25 0.67 0.5

16 10

4 8

50e 50

0.32 0.4

Estimated number of malformations prevented per year

The majority of heavy drinkers seen by us have chosen to terminate following the counseling. The majority tended to terminate. c The neural tube defect is detected antenatally in virtually 100%. d Women with severe poisoning (loss of consciousness) have chosen to terminate. e Half of cases terminate following our advice. b

4.94

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with these agents (2). Our analysis reveals that almost all our patients exposed to systemic retinoids terminate their pregnancy following our counseling and that virtually all those exposed to valproic acid and carbamazepine presently undergo tests that can rule out neural tube defects. Data regarding additional teratogens are presented in Table 3. For the calculation of societal burden from an undiagnosed major malformation, we chose a conservative estimate of lifelong costs of $1.5 million (the original figure was corrected for 1992 by adding cost of living) (13). We included in our analysis an estimated 100 women per year above the age of 35 who were advised by us for the first time on the risk of chromosomal aberrations associated with age, most of whom subsequently underwent amniocentesis. Based on a mean risk of 1% for Down’s syndrome in advanced age, this means that we counsel at least one Down’s mother per year. The annual prevention of 112 unnecessary pregnancy terminations, as a result of advising women that their exposures were not teratogenic and did not increase fetal risk (7), would result in a direct cost saving of $336,000. The rate of major complications (e.g., perforation, water intoxication, anesthetic complications) is 0.5% (9), which means that on average, every 2 years we would prevent one such case. With an estimated minimum annual prevention of five major malformations (Table 3), a saving of $7.5 million can be calculated. In addition, we prevent, by advising women over 35 years of age an estimated one case annually of Down’s syndrome, totaling another $1.5 million in lifelong costs. Summarizing all direct costs calculated above, Motherisk’s preventive impact results in a direct saving of $7,836,000 per year. In 1990 the operating budget of Motherisk totaled $201,395, and only $95,000 was paid by Ontario Ministry of Health, the rest being recovered mainly from research grants and fellowships. In performing the cost-effectiveness analysis presented in this study, we have chosen only a narrow portion of our activities. Not included are the thousands of patients counseled only over the telephone. In addition we did not calculate less well-defined endpoints such as decreasing levels of anxiety and increasing levels of well-being; we do have evidence that many women tend to have a more peaceful pregnancy after being reassured they have not endangered their fetuses. In addition, we made no attempt to quantify the educational impact of Motherisk. After each consultation, we send a letter summarizing the available data to the physician caring for the mother. This information helps educate physicians and health professionals and is consequently used by them for similar cases. In addition, Motherisk team members regularly lecture to physicians and health professionals on issues of the use of drugs and chemicals in pregnancy and lactation, thus further contributing to the educational goal. Finally, the Motherisk group has been initiating and publishing prospective studies on the reproductive safety/risk of drugs and chemicals, often as the first reports on issues such as carbon monoxide poisoning (5) or chloroquine use (6) in pregnancy. With the exponential increase in the cost of health care, the preventive role of counseling women on their teratogenic risk can decrease the load of major malformation while preventing numerous terminations of otherwise wanted pregnancies (14).

QUALITY ASSURANCE Since TISs are novel services, it is crucial to ensure that the standard of care they deliver meets high scientific and professional standards. The newly formed Organization of Te-

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ratogen Information Services (OTIS) is presently developing guidelines for accreditation of TISs based on their ability to deliver service using careful definitions for high levels of quality. There are no similar medical areas in which complicated information, which is very seldom clear-cut, is provided over the telephone to pregnant women, who are often at high levels of anxiety. Potentially this practice exposes the TIS to medicolegal liability. Because 1–3% of children will have major malformations, many callers of TISs who have been advised over the telephone that they do not have a risk higher than the baseline of 1–3% will, in fact, have malformed children. This makes the documentation of all information given to the caller most crucial. Since its inception in 1985, the Motherisk Program in Toronto has developed a quality assurance (QA) mechanism which is built into the system at various levels. We recognize that different TISs have a variety of functions; however, because Motherisk has telephone and clinic components as well as routine follow-up of pregnancy outcome and research arms, we believe our QA program may be helpful to other TISs. The next sections describe the various functions of the Motherisk Program with special focus on the QA aspects of each step.

RECRUITMENT AND TRAINING OF COUNSELORS The Motherisk counselors come from several sources: 1. Individuals who trained at the Pharmacology-Toxicology Specialty program at the University of Toronto and had their project course in Motherisk. This is a whole-year, 2-days-per-week exposure to the counseling experience, followed by a more intensive in-service training by the program’s coordinator. It includes a formal series of lectures and mostly practical work. Prior to the project course, these students had already had structured courses in the areas of experimental and clinical pharmacology, toxicology, and teratology. 2. Registered nurses with experience either in clinical medicine or research. Their initial training, which is provided ‘‘on the job,’’ includes reading assignments, instructions, and participation in the lectures series as in item 1 above. 3. Graduate students in pharmacology or pharmacy; their training is similar to that for registered nurses. All counselors participate in the weekly Motherisk rounds (on Fridays), featuring discussions of cases to be seen in the coming week, new literature, and research projects. As in the case of medical trainees and graduate students, each counselor makes a presentation in the ‘‘journal club’’ part of these rounds. We conduct an annual in-service examination, which includes case presentations. The test is attended by all counselors and physician-trainees serving in Motherisk and is administered without warning during one of our routine rounds. A week later we discuss the correct answers and their basis, and the director discusses areas of deficiencies with each counselor and medical trainee.

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QA OF THE COUNSELING PROCESS All inquiries are answered first by a counselor, who decides, according to known criteria, who should be referred to a clinic consultation and who should be answered via the telephone by the physician covering the service. During the initial months of the counselors’ work, both the coordinator and the assistant director of Motherisk monitor the counseling process and routinely discuss shortcomings or items that should be changed, either in style or in content. Bimonthly, the clinical fellows review a random sample of telephone and clinical consultation forms to assess the completeness of the recorded data and the appropriateness of the advice given. The finding of this analysis are discussed in a special team meeting in which we address deficiencies and suggestions for new policies, changes in the forms, and so on. Whenever a major deviation from Motherisk policy is found (e.g., a patient was not referred to a clinic visit despite meeting the criteria) the case is discussed personally with the counselor or physician who filled out the form.

QA OF THE CLINIC CONSULTATION Prior to counseling patients in clinic, all physician-trainees, who are already specialized in pediatrics or internal or emergency medicine, are instructed by the director about the steps and special features of this process. The forms filled out during the clinic visit are reviewed by the director when reviewing and signing the consultation letters. Any areas of deficiency are discussed with the trainee responsible. The consultation letter includes computerized statements about the various exposures the patient experienced. A new statement is constructed by the first team physician who had to address such exposure (e.g., fluoxetine), and existing statements are revised whenever new information becomes available and has been discussed by the team in its weekly meetings. All statements are stored in a computer to be used by the medical secretary typing the letters as well as by other team members. These statements are the basis for the answers given by the counselors to patients and health professionals.

RESEARCH While conducting follow-up of pregnancy outcome based on computerized patient data, we often identify items that should be corrected or improved either in the recording of the information or in its storage. The area of reproductive toxicology is characterized by a very rapid growth in the body of knowledge, coupled with difficult methodological issues in conducting and interpreting data on gestational exposures. This means that health professionals dealing with these issues have to be open minded, ready to continuously learn new information and adapt new concepts. Moreover, dealing with very anxious pregnant women over the telephone calls for a combination of compassion and scientific rigor. While it is possible that in the future a process will be created to accredit TIS counselors and maybe even programs, probably most of the burden of training and maintaining competence and quality of TISs will lie with the services themselves.

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Clinical Case Answer Call the Teratogen Information Service in Tampa [(813) 233-2627], one of more than 40 such services operating now in North America. The team there will give you up-to-date information. Services can also be located by contacting the national referral number (888) 285-3410 (http://orpheus.ucsd.edu/otis).

REFERENCES 1. McBrie WG. Thalidomide and congenital abnormalities (letter). Lancet 1961; 2:1358. 2. Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 1989; 320:1661–1666. 3. Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, et al. Weight gain in infants breastfed by mothers who take fluoxetine. Pediatrics 1999; 104(5):e61. 4. Lee A, Moretti ME, Collantes A, Chong D, Mazzotta P, Koren G, et al. Choice of breastfeeding and physicians’ advice: a cohort study of women receiving propylthiouracil. Pediatrics 2000; 106(1 Pt 1):27–30. 5. Khattak S, Moghtader G, McMartin K, Barrera M, Kennedy D, Koren G. Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study. JAMA 1999; 281(12):1106–1109. 6. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother 1998; 42(6):1336–1339. 7. Koren G, Pastuszak A, Pellegrini E. Prevention of unnecessary pregnancy termination by counseling women on drug, chemical and radiation exposure during the first trimester. Teratology 1990; 41:657–662. 8. Hook EB. Genetic counseling and prenatal cytogenetic services: Policy implications and detailed cost-benefit analysis of programs for the prevention of Down syndrome. In: Poster IH, Hood EB, eds. Services and Education in Medical Genetics. New York: Academic Press, 1979. 9. Rashbaum W. Complications of abortion. In: Hern WM, Andrikopoulos B, eds: Abortion in the Seventies. New York: National Abortion Federation, 1977, pp 33–54. 10. Atrash HK, McKay T, Hogue CJ. Ectopic pregnancy concurrent with induced abortion: Incidence and mortality. Am J Obstet Gynecol 1990; 162:726–730. 11. Lawson HW, Atrash HK, Franks AL. Fatal pulmonary embolism during legal induced abortion in the United States from 1972 to 1985. Am J Obstet Gynecol 1990; 162:986–990. 12. Kaali SG, Szgetvari IA, Bartfai GS. The frequency and management of uterine perforations during first trimester abortions. Am J Obstet Gynecol 1989; 161:406–408. 13. Schmid W. Economic aspects of prenatal genetic diagnosis. In: Hashem H, ed. Preventable Aspects of Genetic Morbidity, Vol II, Proceedings of the First International Conference of Preventable Aspects of Genetic Morbidity. Cairo. 1978, pp 168–173. 14. Koren G, MacLeod SM. Monitoring and avoiding drug and chemical teratogenicity. Can Med Assoc J 1986; 135:1079–1081.

38 Motherisk: The Toronto Model for Counseling in Reproductive Toxicology Myla E. Moretti and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION No doubt by this point you are well aware of the lessons that the thalidomide tragedy has taught us. The potential dangers of drugs, chemicals, and radiation and their abilities to disrupt normal fetal development have been well documented (1). For close to 40 years and nearly two generations, women and their health care providers have approached the issue of exposures in pregnancy with both hesitation and extreme caution. For women, the media (such as newspapers, books, and television), word of mouth, and physicians may all provide information about such exposures. Since the media have clearly shown their ability to skew the information they present (2) and physicians may not have the relevant literature available in their offices, the need for a service to provide accurate information about the effects of exposures in pregnancy has arisen. This highly specialized type of information service, known as a teratology information service (TIS), has appeared across Canada and the United States primarily over the last 10 to 15 years. In Europe, some services existed even before this, and today these services can be found around the world (see Chap. 36). The TIS functions mainly to provide information to health care providers and the public about the effects of drugs, chemicals, radiation, and infections in pregnancy on both the mother and her unborn child. Because patients may continue to have exposures while breast-feeding and since infant development continues into this postpartum period, many TISs will also provide information about these exposures in lactating patients. Services can be solely open to health care providers and to patients or they may provide information to the public at large. Depending on the nature or mandate of the service there may be a consultation involved, specific to each patient, rather than the simple dissemination of information in a generic fashion. The preceding chapter highlights specific features of how most TISs operate globally, while the purpose of this chapter is to describe the Motherisk Program, located at the Hospital for Sick Children in Toronto, Ontario, Canada. Special emphasis is placed on the day-to-day operations of the services that have evolved over the last 15 years.

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INCEPTION The Motherisk Program, originally a clinical consultation service, began its operation in September 1985 (3). Some 2 to 3 years later it expanded to include a telephone consultation service; this remains its largest component to date, averaging more than 150 calls per day from across the country. The most common calls to the program have not changed significantly over the years—namely, calls regarding antibiotics; analgesics and antipyretics; cough, cold, and allergy remedies; and cosmetic products continue to constitute a large proportion of the inquiries to the service. We do, however, see a change in some of the more complex calls and consultations received by the service. Increasingly women with multiple chronic diseases and/or exposures to drugs of abuse are the subjects of calls to the information service. Perhaps patient awareness of the potential for xenobiotics to affect fetal development has increased, and perhaps physicians and patients agree that women with certain chronic illnesses who may not even have considered pregnancy 10 or even 5 years ago are today living with their diseases and having children.

MANDATE The goal of Motherisk is threefold: 1.

2. 3.

To provide authoritative information and guidance to pregnant or breast-feeding patients and their health care providers regarding the fetal risks associated with drug, chemical, infection, disease, and/or radiation exposure during pregnancy or lactation To research unanswered questions on the safety of drugs, chemicals, infection, disease, and radiation during pregnancy and lactation To maintain a vital training and educational program in the area of reproductive and developmental toxicology at the undergraduate, graduate, and postgraduate levels

Over the last 10 to 15 years of its existence, the Motherisk program has grown into a service that today is able to provide this authoritative information based on much of its own research in the area of maternal-fetal medicine.

THE TEAM MEMBERS The Motherisk team consists of numerous individuals from various areas of the health care sciences. Although some team members affiliated with the program are based at other hospitals, most of them are based within the Division of Clinical Pharmacology and Toxicology at the Hospital for Sick Children. Table 1 describes the distribution of team members. The postdoctoral MD fellows training within the Division of Pharmacology and Toxicology are on call for Motherisk for at least 1 week every month. During their oncall rotation, they are available to patients or health care providers over the telephone for consults that require more expertise than is initially available at the first intake call from the information specialist. The fellows also participate weekly in clinic consultations and perform and supervise much of the research conducted within the program. The information specialists spend most of their time on the telephone consultations and also participate

Motherisk: The Toronto Model Table 1

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Full-time Director—pediatrician/clinical pharmacologist and toxicologists Senior scientists—pediatricians, neurologist, pharmacologist/toxicologist Assistant director—MSc. clinical pharmacology, information specialist Clinical fellows—MD subspecializing in clinical pharmacology/toxicology Coordinator—information specialist Medical secretary Information specialist—BSc Part-time/occasional Addiction specialists—physician, PhD Clinical pharmacologist—physicians Geneticists—physicians Genetics counselors—MSc Medical information specialist—clinical pharmacists Medical toxicologist physicians Pediatrician—Physician Psychologist—PhD Psychometrist—MSc Social workers—MSc Statisticians—PhD Students Graduate—pharmacology and toxicology, pharmacy, genetics Undergraduate—pharmacology, toxicology, medicine, pharmacy, midwifery

in the various research endeavors. Other team members serve as consultants for specific cases where unique expertise is required, and they may also participate in research projects. While the coordinator overseas the day-to-day operations and activities of the information specialists, the assistant director and director oversee the operations of the program as a whole.

THE TELEPHONE CONSULTATION The telephone consultation is available to both health professionals and the public at large. While calls from patients form the bulk of the consultations, health care providers, mainly physicians, represent 20% of the calls to the service daily. The telephone service operates between 9:00 a.m. and 5:00 p.m. Monday through Friday (EST) and closes only for Canadian statutory holidays. During these hours of operation, calls are received immediately by an information specialist. Because of the high volume of calls, calls are kept in sequence by a queuing system at some times in the day until an information specialist (counselor) is available. Initially, calls are documented and screened by the information specialist to obtain relevant details of the patient’s medical history and to determine whether the call can be satisfactorily answered over the telephone. While this is the case for greater than 95% of the calls to the service, some callers are referred for a clinic appointment or, when a patient is not able to travel to the clinic in Toronto, to the physician on call. Each week

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A. Figure 1 The telephone intake form. Front (page 1) of intake form used to document maternal characteristics, drug exposures, and advice given (A). Back (page 2) of intake form used to document exposure to chemicals, infectious disease, and infant details in the case of calls regarding breastfeeding (B).

approximately 10 to 15 callers are brought into the clinic and an additional 10 to 12 patients are referred to the on-call staff. Furthermore, physician callers who wish to discuss the risks with multiple or alternative drug protocols are generally referred to the team member on call. While the decision to refer a call to clinic is at the discretion of the information specialist, the following are criteria or guidelines used by the information specialists to determine which patients should be referred to clinic:

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1. Patient has a chronic illness (e.g., epilepsy, lupus, inflammatory bowel disease). 2. Patient reports substance abuse (e.g., alcohol, cocaine, heroin, hallucinogens, tranquilizers). 3. Patient has or may have exposure to known or suspected teratogen during pregnancy (e.g., anticonvulsants, antineoplastics, misoprostol, organic solvents, isotretinoin, benzodiazepines, systemic steroids). 4. Pregnancy is complicated by psychosocial problems. 5. Patient’s physician has made referral to clinic. 6. Patient has complicated multiple exposures. 7. Patient expresses desire to be seen in clinic despite not meeting any of the criteria above (e.g., high maternal anxiety, previous pregnancy with adverse outcome).

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Regardless of the exposure or magnitude of risk, all calls to the program are documented first on the telephone intake form displayed in Fig. 1. This telephone report form has undergone significant changes since the inception of the telephone service, a reflection of the changes in volume of calls, types of calls, and needs of the research protocols. It has become clear that the form is designed precisely for proper identification of potential risk factors in a particular patient. Patients are asked details of their obstetrical and medical histories and vitamin intake. The interview also includes ascertaining any exposure to drugs, which may include prescription, nonprescription, or illicit drugs. If the primary concern is an infectious disease, radiation, or chemical exposure, these parameters are also recorded (Fig. 1B). Beyond the identification of the particular exposure, determining the amount (or dose or level), timing, and duration of exposure are all particularly important. The timing relative to gestational age may alter the information presented to the patient. For example, lithium is known to be associated with cardiac anomalies. A patient may contact the service in her 16th week of pregnancy concerned that she may need to be started on lithium because of her difficulties in coping with day-to-day activities. Since cardiac formation is known to be complete by this point, the patient can be assured that commencing therapy will pose no harm to her fetus. At the same time, the patient will be informed that continuation of treatment throughout the remaining duration of pregnancy may be associated with neonatal lithium toxicity. As the infant clears the drug from its systemic circulation, these effects will disappear, something of which both mother and physician should be aware. Likewise, doses or levels of exposure are critical for risk assessment. Certain exposures (such as radiation or vitamin A) may present different outcomes, depending on the degree of maternal exposures. The obstetric and medical history are also critical in defining risk for a patient. Often, in ascertaining a medical history, it becomes apparent that a patient may have some underlying disease for which she takes medication but that may not have been the primary reason for contacting the service. Furthermore, the obstetrical history may highlight risks that the patient may not have been aware of or even have questioned. For example, a previous terminated pregnancy with a known neural tube defect warrants discussion, as the patient should be advised to take higher doses of folic acid when planning another pregnancy. Again, this would probably not be the primary reason for contacting the service. As with medication, determining exact gestational ages becomes critical with maternal infectious diseases. Varicella, rubella, and other infectious diseases may pose different risks, depending on the gestational age at the time of acute maternal infection, which many patients are unaware of before the call. Although the exact risks of chemical exposures in pregnancy remain to be elucidated, counselors obtain as many details of the type and duration of exposure, type of protection used, and presence of adverse events that may be indicative of excessive exposure. Ruling out all other risks, the callers are subsequently counseled on the effects of the substance constituting the primary reason for the call. All calls are completed with the explanation of the baseline risks for major malformations in the general population. It is critical that patients understand and be aware of this baseline risk; for most callers, their particular risk is not higher than this. There is often also a brief discussion of the availability of amniocentesis for patients who may have risks of chromosomal anomalies and of the benefits of folic acid supplementation for all patients planning a pregnancy.

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Each day, some 20% of the calls received by the program pertain to drug use in a lactating patient. As with exposures in pregnancy, a telephone intake form is filled out (Fig. 1) documenting medical history. Along with maternal data and demographics, the back (Fig. 1B) of the form contains an area to document brief details pertaining to the infant—namely, date of birth, gestational age, birth weight, and feeding habits. All of these parameters are critical in formulating a risk assessment. Counselors use the information in conjunction with milk-excretion data in several reference materials to determine whether the infant is likely to experience adverse events. Infant age, for example, is critical, because neonates and premature infants exhibit varied drug clearance rates such that they may be more susceptible to drugs through breast milk. On the other hand, older infants who receive most of their nutrition from solid foods and receive smaller volumes of breast milk throughout the day are less likely to experience adverse effects from drugs in breast milk since they will be exposed to less drug. While documentation is quite rigorous for each phone call, it has become apparent that this process is essential for both adequate counseling and accurate collection of information used in follow-up and for research purposes. Although some calls each day are prolonged, with experience, counselors reach a level of proficiency and thoroughness that allows them to complete between 30 and 40 calls each day. Patients can expect to spend 7 to 10 minutes, on average, with the counselor. Currently the Motherisk Program receives and responds to 3000 calls per month, a total of some 35,000 calls annually. This exhibits quite a contrast to the 300 calls we were receiving in the first year of the telephone service and even to the 1000 calls monthly, described in the last edition of this text published in 1994 (4). Since all calls to the program will be answered, we receive calls from across North America and very occasionally Europe—usually Canadians calling from abroad. Almost all of the calls, however, originate from Canada and the bulk of these from the greater Toronto area (area codes 416 and 905). Long-distance calls make up 35% of the daily total. Although the majority of calls are directly from patients or their partners, approximately 20% are from health care providers, two-thirds of these being physicians. The rest of the calls from health care providers are placed by pharmacists and public health nurses or prenatal educators. As discussed earlier, calls vary significantly in the type of question as well as the number of exposures. The average number of exposures questioned is 1.3 per call. When divided by exposure type, prescription medications are most often inquired about (45%), followed by over-the-counter products (31%) and illicit or recreational substances (5%) and by infectious diseases (5%), cosmetic agents (5%), and finally chemicals (4%).

NEW SPECIALIZED SERVICES While the general Motherisk service just described constitutes the bulk of our activities and continues to grow in volume each year, the program now offers several other specialized services to patients and health care providers. Although some of these services were originally research-oriented, it is anticipated that the clinical activities will continue beyond study completion. In addition, several of the services present unique opportunities to reach the nation as a whole by offering toll-free lines and bilingual services (English and French).

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Nausea and Vomiting in Pregnancy (NVP) Program The first of our specialized services created is that which we refer to as the NVP line. Instituted in early 1996, the NVP service was initiated to conduct a study on the behavior of women suffering from NVP in Canada and the United States with special focus on the termination of otherwise wanted pregnancies. The study documented current advice, NVP management practices, maternal morbidity (5), risk perceptions (6) and the effects of NVP on quality of life (7). After studying nearly 7000 patients who called the line, the service evolved to provide counseling to pregnant women and health care providers about nausea and vomiting during pregnancy and related sequelae (8). This counseling includes information about potential treatments for NVP, including both pharmacological (9) and nonpharmacological (10) therapies, and it provides support to patients who frequently have had nowhere else to turn. Patients in the Toronto area can now book an appointment for a clinic visit and be seen by a specialist. Moreover, the NVP program continues to study the effects of NVP and its treatment on the outcome of pregnancy and the health of the mother and fetus. The results of some of these studies have already been published (5– 7) and in October 1998 the program and the manufacturer of Diclectin (Duchesnay Inc.) sponsored the First International Conference on Nausea and Vomiting of Pregnancy, which brought together experts from around the world (11). This bilingual service operates from Monday to Friday, 9:00 a.m. to 5:00 p.m. EST. Patients calling during these hours will generally have immediate contact with an information specialist who will provide specific counseling about the management and treatment of NVP. Depending on suitability and patient consent, the caller may also be asked to participate in a particular research study.

Varicella and Pregnancy The ability of varicella (chickenpox) to induce malformations in fetuses is well known and was documented as far back as 1947 (12,13). Although the risks are generally quite low (14,15), the malformations induced by in utero varicella infection are severe. Varicella is typically a childhood disease; however, there are some women who may reach adulthood with no history of infection and remain nonimmune into their childbearing years. This is of particular relevance to the Toronto area, where women may be emigrating from countries where childhood varicella is not as common. Furthermore, many patients simply do not know of their immune status, which creates a situation of severe anxiety when exposure to active infection occurs during pregnancy. The varicella and pregnancy service is supported by Cangene Corporation, a Canadian manufacturer of VZIG (human varicella zoster immune globulin). The initial purpose of the service was to study the effects of VZIG in preventing or modifying the course of maternal infection (16). Patients calling the varicella and pregnancy line directly or the general Motherisk line who have unknown immune status and have exposure to active infection in pregnancy are invited in to the hospital for immune screening, which is performed in the pharmacology laboratory by the study coordinator in less than 1 hour. Patients were recruited into the study only if screening indicated they were nonimmune. Although this study is now in its data-analysis phase, at the Motherisk Program and the manufacturer continue to support screening in patients with exposure to varicella in pregnancy and with no known history of infection. Patients who are shown to be nonimmune will be offered VZIG in an open-label trial. The goal of the service will be to network with other health care facilities in order to expand these activities and clinical and trials across the country.

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HIV Healthline and Network Initial team meetings for the Motherisk HIV Healthline and Network began in the fall of 1997. The program was officially launched at a press conference on World AIDS Day, December 1, 1997 (17). Its objectives are as follows: To provide information and counseling on all issues involved in HIV and its care during pregnancy and lactation To establish a national network of health care providers interested in this area of maternal-fetal medicine To study the short- and long-term fetal risk/safety of antiretroviral therapy in pregnancy be creating a national registry of HIV-infected pregnancies There is an urgent need to provide information to pregnant women about these issues. In addition, this population of women with HIV represents a different group of patients with unique concerns, very different from those using the general Motherisk service. This service is an extension of Motherisk’s primary service and is also a significant collaboration with the pediatric HIV/AIDS Program and The Hospital for Sick Children (18,19). It allows patients to receive care from Motherisk information specialists, pediatric infectious disease physicians, nurses, social workers, and others in the community. Women, their families, and their health care providers can call this confidential toll-free service and obtain evidence-based information about HIV and its treatment in pregnancy from a counselor trained specifically in the medical and social issues of these patients. Along with counseling about fetal risks, patients are given referrals to health care providers in their own communities who care for pregnant women with HIV/AIDS. Patients can remain anonymous, although those interested in participating in the national registry provide contact details so that network members can obtain detailed medical information and conduct follow-up. Since physicians from across the country are already network members, patients continue to receive care through their own health care providers and still participate in the national registry. All children in the Toronto area born to mothers with HIV/AIDS in pregnancy are followed by the pediatric HIV program and The Hospital for Sick Children. Children are monitored for HIV status, and with this new Motherisk service, all will have long-term follow-up as well. Data collected from intake to followup are standardized and are similar to those collected by other Motherisk services, with modifications specific for maternal illness. Data-collection forms are provided to all network members so data can be documented at a site near the patient and consistently across the network. All data are then maintained by a centralized secure database in Toronto. As informed HIV testing of all pregnant women becomes a reality in Canada (20), the need for such a service becomes obvious. In the near future, many women will learn of their HIV status for the first time in pregnancy. Alcohol and Substance Use Helpline The newest of our specialized services is the Motherisk Alcohol and Substance Use Helpline (21). Established in late 1998, this toll-free service operates from 8:00 a.m. to 8:00 p.m. EST and is sponsored by the Brewer’s Association of Canada. Dedicated counselors provide information and counseling to pregnant women, health care providers, and adoptive parents about the risks of alcohol, smoking, and other substance use in pregnancy. The number of calls to the Alcohol and Substance Use Helpline have increased rapidly,

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Table 2 Referred Services for Patients Contacting the Alcohol and Substance Use Helpline Support groups Child care and/or special needs child care Prenatal services Medical/detoxification services Fetal alcohol syndrome/fetal alcohol–related abnormality assessments Foster parent/adoptive parent help General and addiction outpatient counseling Training and education for the general public Genetic resources Methadone maintenance clinics Crisis lines Aboriginal services Residential programs Referral/resource services Special needs adult services

with over 600 calls since November 1998. The service is currently averaging 7 to 10 calls daily. The efforts of this service will help us to continue researching the effects of these agents on the child exposed in utero. Once again, because of the unique characteristics of these callers, counselors provide information even when the caller wishes to remain anonymous. One of the key features of the service is an extensive database of resources available across Canada. If a need is identified by either the caller of the counselor, patients can be given information and referrals to agencies in their home community. This means that patient will have access to a variety of services (Table 2) that they might not readily have gained access to without the support of the counselors on the Helpline. The service is also a collaboration with specialists from within The Hospital for Sick Children as well as outside it.

THE CLINIC CONSULTATION Each week between 10 and 20 patients are referred to the clinic, which is held within The Hospital for Sick Children. Some patients self-refer while others are referred by their physicians. All patients are seen by one of the team physicians, who provide verbal consultation regarding the exposures in pregnancy as well as obtaining a more detailed patient history in order to determine the presence of other potential risk factors. The current form used to document this consultation is seen in Fig. 2. As is clear from the form, the contact description for the patient includes both home and work phone numbers as well as an address, name, and phone number of another stable contact and her physician’s name and addresses. All of these parameters become useful upon follow-up, described later in this chapter. Documentation also includes details about medical and obstetrical history, genetic history, exposures in pregnancy (including drugs, chemicals, infection, radiation, and alternative therapies), paternal exposures, and demographic/socioeconomic variables. Of utmost importance are details about the current pregnancy—that is, any information about exposures or maternal or paternal health not collected at the intake telephone call that may

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play a role in pregnancy outcome. This information is particularly useful to the consulting physician, who may become aware of other risk factors while interviewing the patient.

THE FOLLOW-UP INTERVIEW Pregnancy follow-up is an integral part of the program. Regular follow-ups are conducted daily, with the data being used to enrich the current status of knowledge on the safety of exposures in pregnancy. Follow-up usually occurs in the child’s first or second year of life, although—depending on the primary objective of the follow-up—it may occur earlier or later in the child’s life. Most follow-ups are conducted directly with the mother over the telephone. Since the number of daily consultations prohibits follow-up on all patients contacting the service, several groups of patients are identified as a priority for followup. These include: Patients meeting the criteria for inclusion into a particular research protocol All patients seen in the clinic Patients exposed to substances for which safety-in-pregnancy information is limited or nonexistent Patients exposed to drugs during lactation, for which outcome of the infant is desired During the telephone follow-up, details of the course and outcome of pregnancy are documented on the follow-up form (Fig. 3). Subsequent to this telephone interview, a letter is sent to the child’s physician confirming and adequately defining the child’s medical condition, health status, and/or malformations. In addition to standard follow-up, selected cohorts of patients undergo a more detailed follow-up in person. This more comprehensive interview may include examination by a pediatrician or geneticist or psychological testing, depending on the specific objectives.

INFORMATION RESOURCES Both the telephone and clinical consultation services use a variety of resources to provide information to patients and health care providers. The initial resource for all counselors and physicians is a collection of individual drug statements or agent reviews. This collection of reproductive risk monographs is updated with the help of all team members and maintained by the assistant director; it forms the basis for patient consultation. These materials are also included in consult letters to physicians when relevant. A number of other resources are used in formulating a risk assessment for a particular patient. These include standard reference texts in the area (4,22,23), as well as journal searches from Medline EMbase, current contents, and the Repro Tox Database. In addition, team members regularly participate in meta-analyses and systematic reviews of exposures in pregnancy. Particularly when the existing literature for a particular agent is inconsistent or controversial, these systematic reviews/analyses are an effective way to summarize the data to reach an overall conclusion about the fetal risks/safety. Examples of such reviews are summarized in Chapter 36. As new reports or studies concerning exposures in pregnancy or lactation are published, they are brought to weekly rounds attended by all team members, where they are critically appraised and reviewed. For new agents and periodically for older agents, the manufacturer is consulted regarding any unpublished reports concerning the drug. This

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(1) Figure 2 The clinic consult form (pages 1 and 2).

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includes both animal reproductive/teratology studies as well as postmarketing surveillance reports in humans. These may be in the form of a registry collated and updated by the manufacturer periodically or voluntary reports of inadvertent pregnancy exposure. Certain cases, exhausting all of these resources, require consultation with experts in a particular field and colleagues experienced in teratology information. Information collected throughout this process is then summarized and incorporated into the reproductive risk monographs for further use by all team members.

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(3) Figure 2 Continued (pages 3 and 4).

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TECHNICAL SUPPORT Operation within the Hospital for Sick Children allows the program and all team members to be connected to a network with access to the library for literature retrieval services. These in-office searching capabilities increase the efficiency of the counseling process and allow for more rapid identification of relevant reference material. The computerized and on-line Repro Tox Database is stored on site for use by team members when necessary and is updated quarterly by subscription. The University of Toronto also provides access

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(1) Figure 3 The follow-up form (pages 1 and 2).

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for faculty, graduate students, and postgraduate trainees to numerous other catalogs databases, and electronic journals directly via the Internet. For most patients, information obtained during initial consultation and subsequent follow-up are stored in the customized Motherisk database designed by a private firm specializing in database development; it runs in ACI’s 4TH Dimension (24). The program is a cross platform, allowing for use in both the Macintosh and PC working environments currently used at the hospital. An example entry screen is shown in Fig. 4. The database is also capable of intricate searches and composes detailed summaries and reports useful

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(3) Figure 3 Continued (pages 3 and 4).

for generating statistics, analyzing trends and assisting in formulating research questions. Passwords and various levels of security limit access to particular data or features of the database to individual users. Most data entry is conducted by the administrative support, although other team members may also participate. The overall data management for the program is the responsibility of the assistant director.

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EDUCATION Throughout the academic year including the summer session, undergraduate, graduate, and postgraduate trainees (research fellows) all participate in daily activities and research within the Motherisk Program. Undergraduate students from the University of Toronto— usually members of the departments of pharmacology, toxicology or pharmacy—conduct

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Example screen shot of the Motherisk Database running in 4th Dimension.

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their own research projects, alone or within a group, under the supervision of other team members. Prior to commencing research activities, however, new students undergo intensive training, which includes a series of formal lectures conducted by the assistant director and coordinator, reading assignments, and observation. Medical students also conduct research projects or may briefly attend the program as observers. Graduate students and postgraduate trainees often conduct several research projects of their own along with supervising undergraduate activities. Various annual meetings, such as the OTIS meeting, provide a forum for trainees to present their research results to peers and colleagues outside of the program. These educational activities of the program have proven to be an invaluable learning experience for students and faculty alike and provided ongoing opportunities for expanding our research endeavors.

FINANCIAL SUPPORT Each year the hospital allocates a portion of its funds from the Ontario Ministry of Health to the Motherisk Program. This funding supports the positions of three counselors and covers minimal administrative costs. Furthermore, some positions are filled as part of the educational curriculum of trainees. Since counseling and follow-up ultimately become part of research activities, funding for some counselors as well as secretarial and administrative support and computer costs can be covered by external research grants. Grants generally awarded to the director or to a trainee are obtained from a variety of funding agencies such as the Medical Research Council of Canada (MRC) and others. This may include industry or other specialized agencies, depending on the nature of the specific research protocols. Although physician telephone consultations are not billed, patient consultations conducted in the clinic setting are billed weekly through the Ontario Health Insurance Plan. Patients presenting a valid health card do not pay for the clinic consultation service.

SUMMARY Ensuring the well-being of all unborn children is impossible without appropriate resources and informed patients. Antiquated attitudes have propagated misinformation among medical professionals and lay persons alike. Our own experience has shown that this has often resulted in disastrous outcomes, such as termination of an otherwise wanted pregnancy or irrational fears and inadequate maternal treatment. Settings such as our own are ideal for promoting evidence-based risk assessments to large numbers of patients and health care providers while maintaining educational and research portfolios. The Motherisk Program has initiated and sustained an effective approach to counseling in the field of reproductive toxicology. Time and experience have proven invaluable as we have striven to accomplish our goals of providing authoritative information on infant or fetal risk after maternal exposure to drugs, chemicals, or infectious diseases. Moreover, our prospective method of data collection minimized recall bias and enables us to accurately and routinely accumulate patient details and pregnancy outcome data. These activities allow us to provide information in areas for which there are shortcomings in the current medical literature. We look forward to the changes and challenges the next decade brings.

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REFERENCES 1. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338(16):1128–1137. 2. Koren G, Klein N. Bias against negative studies in newspaper reports of medical research (see comments). JAMA 1991; 266(13):1824–1826. 3. Koren G, Feldman Y, Shear N. Motherisk–A new approach to drug/chemical teratogenicity. Vet Hum Toxicol 1986; 28:563–565. 4. Koren G. Maternal-Fetal Medicine: A Clinician’s Guide, 2nd ed. New York: Marcel Dekker, 1994. 5. Mazzota P, Magee L, Koren G. Therapeutic abortions due to severe morning sickness: unacceptable combination (see comments). Can Fam Physician 1997; 43:1055–1057. 6. Mazzotta P, Magee LA, Koren G. The perception of teratogenic risk by women with NVP. Clin Pharmacol Ther 1999; 65:200. 7. Mazzotta P, Magee LA, Taddio A, Koren G. Risk determinants for legal abortion among Canadian and American women suffering from nausea and vomiting of pregnancy. Clin Invest Med 1998; Suppl:S11. Abstr. 8. Anonymous. Motherisk Helpline for women suffering from nausea and vomiting during pregnancy (NVP). The Motherisk Newsletter 1998; Spring[8]:5. 9. Mazzotta P, Gupta A, Maltepe C, Koren G, Magee L. Pharmacologic treatment of nausea and vomiting during pregnancy. Can Fam Physician 1998; 44:1455–1457. 10. Leduc C. Treating morning sickness by non-pharmacological means. The Motherisk Newsletter 1998; Spring[8]:6–7. 11. Anonymous. Highlights from the first international conference on nausea and vomiting of pregnancy. The Motherisk Newsletter 1998; Fall[9]:1–8. 12. Laforet EG, Lynch CL Jr. Multiple congenital defects following maternal varicella: report of a case. N Engl J Med 1947; 236:534–537. 13. Brunell PA. Fetal and neonatal vericella-zoster infections. Semin Perinatol 1983; 7:47–56. 14. Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases (see comments). Lancet 1994; 343(8912):1548–1551. 15. Pastuszak AL, Levy M, Schick B, Zuber C, Feldkamp M, Gladstone J, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy (see comments). N Engl J Med 1994; 330(13): 901–905. 16. Inocencion G, Loebstein R, Lalkin A, Geist R, Petric M, Koren G. Managing exposure to chickenpox during pregnancy: new program. Can Fam Physician 1998; 44:745–747. 17. King S. A Motherisk HIV Healthline update. The Motherisk Newsletter 1998; Fall[9]: 3,8. 18. Ratnaplan S, King S, Koren G. Testing women for HIV. Can Fam Physician 1997; 43:1349– 1351. 19. Anonymous. The Motherisk HIV Healthline and Network. 1998; Spring[8]:5. 20. Bureau of HIV/AIDS SaT. Perinatal Transmission of HIV. HIV/AIDS Epi Update. Health Canada, Laboratory Centre for Disease Control, April 2000. URL:http://www.hc-sc.gc.ca/hpb/ lcdc/bah/epi/peri_e.html. 21. New toll-free helpline : alcohol and substance use in pregnancy. The Motherisk Newsletter 1998; Fall[9]:2. 22. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998. 23. Drugs and Human Lactation. 2nd ed. Amsterdam: Elsevier, 1996. 24. 4th Dimension. Win 9x. ACI SA, 1996.

39 The Way Women Perceive Teratogenic Risk The Decision to Terminate Pregnancy Tommy Ho, Adrienne Einarson, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

Clinical Case A pregnant patient demands an abortion of an otherwise wanted pregnancy, saying that she drank three drinks per night over 3 days while on vacation, at 2 weeks postconception. You explain that this exposure is not known to increase her teratogenic risk, but she is still upset and determined. How can you quantitate the data and provide effective counseling in this case?

INTRODUCTION The main goal of counseling women on their teratogenic risk is to present to them an accurate, up-to-date estimate of their specific risks. However, the same data may be received and interpreted very differently by different patients, leading them to individual conclusions and finally to the decision to continue or terminate pregnancy. Well-publicized figures from North America and Europe reveal that approximately one child is aborted for every child born (1,2), and while pregnancies are terminated for a variety of reasons, incorrect perception of a teratogenic risk may be an important factor. Most women who have been made aware of major malformations or chromosomal aberrations through ultrasound or amniocentesis choose to terminate pregnancy (3). As documented by the Greek experience after the Chernobyl disaster, even an unbased suggestion of adverse fetal outcome may prompt women to terminate pregnancy ‘‘to be on the safe side’’ (4). This phenomenon is clearly evident in regards to radiodiagnostic procedures performed during pregnancy. Many associate ‘‘radiation’’ with the effects of the atomic bomb and other nuclear disasters that have come about in world history. Usually, radiodiagnostic procedures involve fetal exposures to low doses of ionizing radiation in the realm of less than 5 rad. This level of exposure is not considered to be teratogenic (5). In spite of this, many pregnant women exposed to such radiation are rather concerned and consider 789

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termination of their pregnancy. Even after information is provided in regards to the safety of specific radiodiagnostic procedures, their perception of teratogenic risk remains well above the baseline population risk (6). Special attention and consideration should be given when counseling pregnant women exposed to low-dose ionizing radiation. During the first year of Motherisk, we were impressed by the number of cases of misperception and distorted information regarding the potential teratogenic risk of drugs and chemicals. In particular, we felt that many women tend to assign an unrealistically high risk to medications not known to be teratogenic. In some cases, this misperception has led to termination of pregnancy. In an attempt to objectively quantify women’s perception of their teratogenic risk, a 10-cm visual analog questionnaire was designed (Fig. 1). After collection of all patients’ data (see Chapter 28), and before delivering our view of the apparent risk, patients are asked to assign to their potential risk for major malformations a number between 0% and 100%. We also ask what, in their opinion, is the risk for major malformations in the general population, because their knowledge of baseline risk is crucial for their perception of their own risk. In addition, patients are asked to quantify from 0% to 100% their tendency to terminate or continue pregnancy. The completion of this questionnaire is followed by informing the patient of all known information about the exposure(s) in question. Subsequently, the questionnaire is repeated. Patients are urged to express their own views and not to answer the questionnaire in a way they might think would please the interviewer. Analysis of the first 80 cases on whom the visual analog scale (VAS) was used between September and December 1986 reveals the power of this tool in detecting misperception and misinformation (7). Before receiving up-to-date information about the specific exposure, women exposed to nonteratogens assigned a mean risk of 24 ⫾ 2.8% for major malformations. After the interview, however, the risk was perceived as lower (14.5 ⫾ 3%, p ⬍ 0.01). The risk for major malformations in the general population was estimated as 5.6 ⫾ 1.3%, which

Figure 1 Visual analog scale.

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is comparable to the real figure in the literature. The perceived risk before and after our intervention was significantly different from that estimated by the patients for the general population (Fig. 2). The tendency for continuation of pregnancy showed a significant change following the interview (from 7.9 ⫾ 0.3 to 8.7 ⫾ 0.3 in the analog scale, p ⬍ 0.01). Eleven patients were exposed to medications known to be teratogenic. Their perceived teratogenic risk was unchanged (36.2 ⫾ 11.7% before and 36.7 ⫾ 15.6% after the interview). Their tendency for termination/continuation of pregnancy did not change following the interview. Three of them did decide to terminate pregnancy within a few weeks of the consultation. Eleven of our patients were single mothers. Although they did not perceive their risk differently from married women, those who had been exposed to nonteratogens showed a significantly higher tendency to terminate pregnancy before the interview (4.7 ⫾ 1.2 on VAS units single mothers vs. 8.1 ⫾ 0.4 married, p ⬍ 0.05). Following the intervention, their perception significantly changed, being less likely to terminate their pregnancy (7.4 ⫾ 1.2, p ⬍ 0.05) but the VAS was still different from married women. No correlation was found between estimation of risk (or tendency to terminate/ continue pregnancy) and number of preparations consumed by the woman, age, parity, or socioeconomic status. No differences in perception of risk were detected between women referred by physicians and those who were self-referred. This analysis indicates that pregnant women exposed to nonteratogenic agents believe they have a risk of 1 in 4 of having a child with major malformations. This figure is very close to the known risk of thalidomide (8). Importantly, these women estimated the risk in the general population to be 5%, which is similar to the real figure of 4–5% (9). This means that the concept of teratogenic risk was well understood and that women

Figure 2 Patient-assigned risk of major malformation for parents not exposed to teratogens.

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were well informed about the risk in the general population. In addition, it lends clinical significance to the unrealistically high risk assigned by these women to their nonteratogenic exposures. This phenomenon was well described in a study by Mazzotto et al. (1997) where women with nausea and vomiting of pregnancy (NVP) in their first trimester were prospectively followed. Over three-quarters of the 260 women enrolled initially believed that pharmacologic treatment of NVP increased their teratogenic risk. After having been counseled in regard to the extensive literature on the safety of anti-emetics (other than thalidomide which is the only medication ever to have been positively proven to cause birth defects), these women were followed up at 20 weeks’ gestation. The risk perceived decreased significantly after counseling (10) Two basic reasons can be put forward to explain the unrealistically high teratogenic risk assigned by pregnant women: misinformation and misperception. Misinformation Advisories on potential teratogenic risk appear constantly in the lay media, usually to stress risks, and very rarely to address the safety of specific drugs. A recent analysis of 15 different popular magazines disclosed poor scientific standards and a clear tendency to be misleading or inaccurate (11). There was a tendency to alarm readers without justification. In addition, popular books dealing with pregnancy often tend to assign risk to drugs not proven to be risky. For example, the author of Will My Baby Be Normal? states, ‘‘Do not take any aspirin or medication that include aspirin if you think you might be pregnant. Midline body defects . . . have been attributed to this drug’’ (12). Such defects are not believed to be associated with salicylates in humans. In yet another instance, J. Elkington entitled his book on reproductive toxicology The Poisoned Womb, although most of the data discussed do not prove poisoning in humans (13). A possible source of misinformation is the Physicians’ Desk Reference, which includes warnings on exposures during pregnancy that are no longer correct. Reference books dealing with drug use in pregnancy have been published (9,14,15) and should be used by physicians caring for women in pregnancy. Another source of misinformation is physicians. We have dealt with more than a few cases in which physicians advised women to terminate pregnancy despite nonteratogenicity (Fig. 3). This may reflect a defensive approach in the current litigious atmosphere, or the possibility that physicians themselves are misinformed. Our data indicate that women referred by physicians did not have a more accurate perception of risk than self-referred patients. A prime example of physician misinformation is seen with the use of cocaine. To date, there has been really no evidence to suggest that cocaine increases teratogenic risk in any meaningful way above the population baseline. However, a survey administered by Koren et al. (16) revealed that the majority of participating physicians felt that malformations were associated with cocaine use. These same physicians would also wish to terminate a pregnancy where exposure to cocaine occurred during the first 8 weeks of gestation. This is alarming, as physicians’ erroneous perceptions may lead them to offer women unjustified terminations of pregnancy. Fortunately the same analysis showed that, in most cases, counseling pregnant women exposed to cocaine is successful in changing their tendencies towards termination.

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Figure 3 Letter of a Motherisk patient who had been advised by other physicians to terminate pregnancy.

Misperception Our results show that even after we had advised women that medications taken by them did not increase their risk of having a malformed child, their own perceived risk was significantly higher than their perception of risk in the general population. It is conceivable that during pregnancy there is an increased sensitivity to this issue, leading to a distorted perception of risk. Of special interest is the approach of single mothers: while assigning a teratogenic risk similar to married women before receiving our advice, they were much less ready to continue pregnancy with such a risk. Single mothers may have a variety of psychological, moral, and socioeconomic reasons to discontinue pregnancy. For them, a distorted perception of teratogenic risk may be the last straw in the decision to terminate pregnancy. Our intervention appears to have significantly changed the perception of women exposed to nonteratogenic agents in terms of estimating the risk as well as in the tendency to terminate/continue. This tendency was best documented in the subgroup of single mothers, in which some of the women who were already booked for dilatation and curettage decided to carry on the pregnancy. If postinterview assessment still revealed an unrealistically high perception of risk or tendency to terminate pregnancy, we would spend additional time to explain to the woman that her apparent risk, based on current knowledge, is lower than the one perceived by her. It may be argued that women contacting a consultative service such as Motherisk are a selected group of patients with a higher degree of concern, and therefore their perception does not accurately represent the total population of pregnant women. Yet, it is such individuals who are more likely to decide to terminate pregnancy based on wrong information. It is also possible that some women who are ambivalent about continuing their preg-

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nancy seek a legitimate medical reason for termination. In both cases, accurate information will help the woman and her family to make a knowledgeable decision.

THE IMPACT OF RISK PERCEPTION ON WOMEN’S DECISION TO CONTINUE PREGNANCY In an attempt to assess the relevance of the risk perception as measured by us in predicting women’s apparent decision about their pregnancy, we analyzed the 123 women who expressed a tendency of 50% or more to terminate their pregnancy between September 5, 1986 (the date the VAS was first introduced) and January 29, 1988 (Table 1). At the time of the consultation all 123 women verbally expressed serious consideration of terminating their pregnancy and documented this on the VAS. Of these, the following were excluded from further analysis: 5 came for prospective advice and did not become pregnant until the analysis of the data; 3 refused to participate in the telephone follow-up; 7 could not be reached at the contact telephone numbers; and 30 had not yet reached their expected date of confinement (EDC). Thus, our study group consisted of 61 women who decided to continue their pregnancy despite their initial tendency and 17 who chose to terminate their pregnancy. The two groups [continued pregnancy (CP), n ⫽ 61, and therapeutic abortion (TA), n ⫽ 17] did not differ statistically in their mean age, number of pregnancies, number of previous live births, therapeutic or spontaneous abortions, or number of exposures in the pregnancy of question, where ‘‘exposures’’ included every medical preparation, chemical, or radiation reported during the consultation. The tendency to terminate pregnancy before receiving the relevant medical information did not differ significantly between the CP and TA groups (34.3 ⫾ 2.5% vs. 24.8 ⫾ 5.4%, respectively, p ⬎ 0.05). Following the interview, however, there was a highly significant difference in the response of the two groups: women who eventually terminated their pregnancies had a nonsignificant increase in the tendency to continue pregnancy and in most cases did not pass the 50% point (24.8 ⫾ 5.4% to 45.1 ⫾ 9.8%) ( p ⬎ 0.1). Their tendency to terminate pregnancy after the counseling process was significantly different from the CP group ( p ⬍ 0.0001).

Table 1 Study Population Women who tended ⱖ50% to terminate their pregnancy prior to our information Women who tended ⱖ50% to continue their pregnancy Exclusions Prospective cases (not yet pregnant) Refusals of follow-up Lost for follow-up Had not reached EDC Study cohort (n ⫽ 78) Decided to continue pregnancy (CP) Decided to terminate (TA) a

Outcomes as follows: 57 normal infants and 4 miscarriages.

123 246 5 3 7 30 61 a 17

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Of 61 women in the CP group, 4 had a miscarriage between 8 and 12 weeks of gestation. The other 57 women had normal pregnancy outcomes, with no apparent major malformations or developmental delay up to 9 months of postnatal age. Table 2 presents the analysis of the 17 women who chose to terminate their pregnancy. In two cases, women were exposed to drugs known to have adverse fetal outcome (BCNU for mycosis fungoides and warfarin for prosthetic valve), and in a third case an amniocentesis done because of maternal age (⬎35 years) tested positive for Down’s syndrome. Of interest, one woman exposed to nonteratogens claimed in the follow-up interview that her decision to terminate pregnancy was based on the information she received during the Motherisk consultation; however, the summary letter sent to her physician clearly stated that she did not have an increased teratogenic risk. One woman attributed her decision to advanced age and poor gynecological history, and another had an increased genetic risk for major malformations. In two cases, the women claimed that their obstetricians encouraged them to terminate pregnancy owing to a high teratogenic risk (up to 80%) despite our advice of no such increased risk. Eight women who perceived their teratogenic risk as high despite our advice indicated that this was their main reason for termination; four of them were unmarried. Of the 78 evaluable pregnancy patients who intended to terminate their pregnancy prior to our consultation, it is probable that we reversed the tendency in 61 (57 normal healthy babies and 4 miscarriages). Although it is impossible to prove that all these pregnancies would have been terminated without our intervention, it is conceivable that this might have been the case, since most women who showed a greater than 50% tendency to terminate pregnancy after our intervention eventually did so. The two groups, TA and CP, did not differ in a large number of characteristics and had very similar rates of drug exposures. However, most of the 17 cases in the TA group expressed obvious explanations, unrelated to the exposures in question, as factors that led them to decide to terminate their pregnancy. Four of them were unmarried; in the analysis above we have shown that single mothers, despite estimating their teratogenic risk in a similar manner to married women, have a significantly higher tendency to terminate their pregnancy. Table 2

Analysis of Reasons for Therapeutic Abortion as Indicated by the Women

Reason Exposure to drug with a potential adverse fetal effect Down’s syndrome detected in amniocentesis Advanced age with poor gynecological history Higher genetic risk for major malformations Advised to terminate pregnancy by obstetricians despite exposure to nonteratogens Unmarried women Fears of higher teratogenic risk despite Motherisk advice Claimed termination was according to Motherisk advice (not confirmed by summary letter) a

Number of cases a 2 1 1 1 2 4 8 1

Total exceeds 17 (the number of women who chose to terminate their pregnancy) because some women had more than one reason for termination.

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After confirming the clinical relevance of the VAS, we now use the information collected not only for epidemiological endpoints, but also for individual cases. For example, if after the interview the woman has a tendency of termination higher than 50%, it is probably that she will not continue her pregnancy. If we are impressed that the teratogenic risk is the main reason for her tendency, and not other social, psychological, or personal reasons, we extend the interview to explain again the lack of risk associated with her exposure. The same insight is employed to counsel women exposed to teratogenic agents, if their perception does not reflect realization of an increased risk. Clinical Case Answer Using the visual analog scale, we have shown that if the woman, before leaving your office, has a 50% or more tendency to terminate pregnancy, she will almost always carry this plan into effect. If your patient has shown such a tendency, you may wish to take more time to discuss her risk and to explain that it does not exceed the baseline. This may be the last chance. REFERENCES 1. Macpherson AS. Health status report 1983. City of Toronto, Department of Public Health, April 1985, p 37. 2. Shairn RN. A cross-cultural history of abortion. Clin Obstet Gynecol 1986; 13:1–17. 3. Berbie AB, Elias S. Amniocentesis for antenatal diagnosis of genetic defects. Clin Obstet Gynecol 1980; 7:5–12. 4. Trichopoulos D, Zavitsanos X, Koutis C, Drogani P, Proukakis C, Petridous E. The victims of Chernobyl in Greece: Induced abortions after the addicent. Br Med J 1987; 295:1100. 5. Koren G. Maternal–Fetal Toxicology—A Clinician’s Guide. 2nd Edition, Revised and Expanded. New York: Marcel Dekker, Inc. 1994. 6. Bentur Y, Horlatsch N, Koren G. Exposure to Ionizing Radiation During Pregnancy: Perception of Teratogenic Risk and Outcome. Teratology 1991; 43:109–112. 7. Koren G, Bologa M, Long D, Feldman Y, Shear N. Perception of Teratogenic Risk by Pregnant Women Exposed to Drugs and Chemicals During the First Trimester. Am J Obstet Gynecol 1989; 160:1190–4. 8. Lenz W. Thalidomide embryopathy in Germany: 1959–1961. Prog Clin Biol Res 1985; 163c: 77–83. 9. Schardein JL. Chemically Induced Birth Defects. New York: Marcel Dekker, Inc. 1985. 10. Mazzotta P, Magee L, Maltepe C, Lifshitz A, Navioz Y, Koren G. The Perception of Teratogenic Risk By Women with Nausea and Vomiting of Pregnancy. Reprod Toxicol 1999; 13: 313–319. 11. Gunderson SA, Martinezx LP, Carey JC, Kochenon NK, Emergy MG. Critical review of articles regarding pregnancy exposures in popular magazines. Proceedings of the 26th Teratology Society Meeting, Boston, 1986; Abstract 88. 12. Scher J. Will My Baby Be Normal? How to Make Sure. New York: Dial Press, 1983, p 31. 13. Elkington J. The Poisoned Womb. London: Viking Press, 1985. 14. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, 2nd ed. Baltimore: Williams & Wilkins, 1986. 15. Shepard TH. Catalog of Teratogenic Agents, 5th ed. John Hopkins University Press, 1986. 16. Koren G, Gladstone D, Robeson C, Robieux I. The Perception of Teratogenic risk of Cocaine. Teratology 1992; 46:567–571.

40 Evaluating the Effects of Drugs in Pregnancy A Guide to Critical Assessment of the Literature Thomas R. Einarson The University of Toronto, Toronto, Ontario, Canada

INTRODUCTION Sir William Osler stated that ‘‘the desire to take medicine is perhaps the greatest feature which distinguishes man from the animals.’’ That desire has resulted in the production and consumption of vast quantities of pharmaceutical entities. In fact, the use of drugs in Western society has increased to the point that virtually every person has been exposed to them. Unfortunately, some of the drugs that are being consumed are not completely innocuous. In particular, the adverse effects of drugs in pregnancy have become the focus of considerable concern to the public subsequent to the thalidomide disaster that occurred during the 1950s. In prescribing medication, particularly for the pregnant patient, the benefits of drug therapy must be weighed against the costs. In addition to direct costs, adverse events and their sequelae as well as economic consequences must be considered. The prudent practitioner wishes to provide patients with optimal care while avoiding problems. To accomplish this goal, it is imperative that an appropriate level of current knowledge be maintained. Drug information is presently being provided by a host of sources that vary widely in quality, credibility, validity, and usefulness. Information on drugs in pregnancy is most often meager at best, and it is not unusual to find conflicting reports. Thus the individual practitioner must be able to read the literature critically and know how to assess the value of an article.

METHODS OF BECOMING INFORMED Methods for acquisition of drug-related knowledge include primary literature (medical journals), secondary literature (textbooks, drug compendia), professional meetings, colleagues, other health professionals, drug information centers, product monographs, and 797

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manufacturers’ sales representatives. Depending on the information required, these sources vary widely in their ability to provide the practitioner with adequate information with which to make informed decisions. Weston (1) reported that physicians most frequently utilized medical journals for drug information, followed closely by consultation with colleagues. Third was attendance at professional meetings. Stinson and Mueller (2) produced similar results in a survey of 402 physicians. Medical literature was the prime source of drug information, and 99% of the respondents claimed that they regularly consulted medical journals. Others have found differing results. Utilizing primary medical literature ranked fourth in a survey by Nickman and coworkers (3), and fifth by Covell et al. (4). Thus, original research reports are not being read by all practitioners.

WHY READ THE LITERATURE? Keeping Up Patient care is rapidly advancing as research provides newer and more efficacious agents. If these new agents are indeed better, then they should be used. In addition to learning about improvements in therapy, it is essential to read the literature to be knowledgeable about adverse events. To provide optimal patient care, reading the primary literature is essential. There are also less altruistic reasons for maintaining current knowledge. In cases of litigation, courts often decide on the basis of what is ‘‘normal’’ or ‘‘standard practice,’’ or what the ‘‘the prudent practitioner’’ would do. To know what is considered appropriate, one must constantly read.

The Issue of Bias Information supplied by manufacturers is provided in several forms: product monographs, advertising, and verbally through sales representatives. Monographs are prepared as leaflets, and also may appear in texts such as the Physician’s Desk Reference (PDR) (5) in the United States, or the Compendium of Pharmaceuticals and Specialties (CPS) (6) in Canada. Although the monographs must comply with federal regulations, they are not complete in their disclosure of information. Descriptions of adverse events are usually limited to a listing of possible or documented occurrences. Obviously, information on unauthorized uses of drugs is omitted. Manufacturers have a vested interest in promoting their products, which can be a source of bias. It is the function of sales representatives to generate revenue through increased sales of their own products. The profit incentive could encourage major bias in providing information. The PDR is published by the manufacturers of the pharmaceutical products it describes, and inclusion is voluntary. The CPS is published by the Canadian Pharmaceutical Association and may therefore be less prone to bias. However, the main purpose of these books is to present product monographs; PDR and CPS are not intended to be texts for therapeutics or pharmacology. Thus, despite widespread use, they do have some limitations. Books often take years to prepare and publish, and thus may contain information that is incomplete or outdated. Most often, books are not peer reviewed. As a result, they

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may contain flaws and may reflect personal opinions rather than generally accepted scientific knowledge. In addition to editorials and commentaries, journals present abstracts, articles, and reviews, which provide information that may be used in clinical decision making. Abstracts are often incomplete and final versions may never be published for a number of reasons. Reviews can sometimes be biased, with two reviewers arriving at opposite conclusions. Research articles are reports made by researchers who describe their work firsthand. Thus, research articles appear to be the best source of information for the practitioner. Because most of the primary literature is peer reviewed, it is less prone to bias and thus is to be preferred as a source of information concerning drugs and their effects. Peerreviewed articles are often given more credence than those that have not been peer reviewed. Therefore, clinical decision makers should be able to read and evaluate the primary literature and apply the information to their patients.

EVALUATING THE JOURNAL The journal in which an article is published may have a great influence on the article’s perceived value. A journal may be the official publication of a professional society; it may be owned by a large publisher, or even by drug manufacturers. Obviously, ownership could influence the content of the journal. Another factor not often considered is the source of revenue for the journal. Some are financed through subscriptions; others receive funding from the dues paid to the professional society that publishes them. Some are totally financed by drug companies; others are financed through the sale of advertising. It is best to determine the ownership and publication policy of the journal when considering an article. An article that is interspersed with commercial advertisements may not be as free from bias as one from a journal having no commercial ads, or having them confined to a separate section. Most journals receive unsolicited manuscripts from authors who receive no remuneration. These are considered to be highest in quality. Some journals pay authors to write papers for them; others require a fee to have the papers published. In such cases, there is a conflict of interest, and less credibility is often given to paid articles. This information is often contained in the ‘‘Requirements for Authors’’ section. Perhaps the gold standard in journals is the New England Journal of Medicine, which contains little commercial advertising, is peer reviewed, has a panel of experts available to critique most subjects, and is funded through subscriptions.

PROPERTIES OF GOOD STUDIES To evaluate the literature properly, the practitioner must understand the organization of an article as well as concepts of research design, statistical analysis, and logic. He or she must be able to identify strengths and weaknesses of different designs and to use judgment to determine the credibility or importance of the results. Studies may be classified as correlational or experimental. Correlational studies include surveys and simple observations. Experimental studies involve the manipulation of a variable while all else is held constant, thus proving that the intervention caused the result. Studies of the latter type are to be preferred because they eliminate competing

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explanations for the obtained results. Campbell and Stanley (7) present a thorough discussion of the advantages of experimental design. Scientific papers must be organized in a manner that allows the reader to be able to fully understand exactly what took place and to evaluate the results. Generally, articles are arranged as follows: introduction, methods, results, discussion, and conclusions. Introduction The introduction should be brief and to the point. Its purpose is to present the statement of purpose. The purpose must be stated explicitly; if not, it is impossible for the reader to determine whether the research achieved its goal. The introduction may contain background information to support the undertaking of the study. Such background should contain only pertinent references and factual information. Some writers will state not only the purpose of the study but also the hypotheses they tested. That practice is commendable and should be encouraged. At the heart of the research lies the purpose of the study (and the hypotheses, if stated). The remainder of the paper should be constructed to demonstrate how the research addressed the problem at hand and what resulted from it. In other words, all other parts must relate to the purpose. For that reason, it is crucial that the purpose of the paper be stated explicitly. Methods The methods section should be so explicit that the reader could duplicate the study. It is important to know exactly how the study was carried out. The methods section should include information about the sample collection and testing, instrument validation and use, procedures involved, data collection and analysis, and criteria for judging results. Sample Ideally, researchers would identify an entire population of interest and randomly select subjects for inclusion in their study. However, in reality, such a situation never occurs; convenience samples are always used. To be truly random, every member of the population of interest must have an equal chance of being selected. What is important is that the sample be representative of the population to which results will be extrapolated. In general, the larger the sample, the more representative it will be. The problems with large samples are the cost involved, the time needed for processing, and the logistics of analysis. Researchers thus try to use as small a sample as possible while obtaining significant results that may be generalized to other people. To minimize problems associated with sampling, several techniques are used. A sample may be selected and subjects then randomly assigned to treatment or control groups. Random assignment, although it does not totally correct for lack of random selection, serves to limit bias through minimizing differences between groups. Thus, differences in outcome may be attributed to the intervention with a greater degree of certainty. To help assure that groups being investigated are similar, it is preferable for researchers to compare groups with respect to all variables that could affect outcome. For example, age and socioeconomic status (SES) of the mother have been known to affect fetal outcomes. If adverse outcomes on the fetus were of interest, groups of subjects must be compared to detect any differences. If differences were found, they would have to be dealt

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with either through stratification (i.e., compare only offspring of mothers of a similar age or SES) or through statistical analysis (i.e., holding age as a covariate). It is important to note that statistical tests only detect differences that may exist; they do not guarantee sameness. Only when groups are significantly different do tests indicate a problem. To gauge the degree of difference, exact statistics should be presented (e.g., p ⫽ 0.067 rather than p ⬎ 0.05), as suggested by Bailar and Mosteller (8). Independent Variables An independent variable is one that is manipulated in an experimental study, such as the dose of a drug or the length of time of a treatment. Variables that cannot be manipulated, such as sex or race, are called moderator variables or grouping variables. These variables must be described explicitly in the methods section so that the reader knows exactly what has been done. The choice of independent variables must reflect the purpose of the study. Dependent Variables The dependent variables is that which is measured. It could be the presence of a teratogenic outcome after exposure to a drug, or the measure of systolic blood pressure after consumption of an antihypertensive medication. One needs to ask whether the dependent variable being measured is, in fact, a valid measure for the purpose of the study. Instrument The instrument, the device used for measuring the results, may be a survey questionnaire, a blood pressure cuff, or an expert who judges whether a child is normal or abnormal. It is critical that the validity of the instrument be verified for the purpose of the study. Validity may be equated with accuracy of measurement. In other words, it is the degree to which an instrument measures what it is intended to measure. As stated above, validity is assured for a specific purpose; if the instrument were used for more than one purpose, it would have to be validated for each. Most often, face validity is determined by having experts or knowledgeable persons read and evaluate a questionnaire. A pretest should be done to detect flaws and to improve questions. New laboratory test results are usually compared with those from standard procedures. If so, a correlation co-efficient may be reported. Validity is most important to determine; however, it is very often subjective and difficult to measure. As a result, reliability coefficients are often presented in an attempt to provide some indirect evidence that the instrument may be valid. Reliability coefficients measure consistency and, in contrast to popular misconception, are a property of the data, not of the instrument. If an instrument is valid, it will produce reliable data (i.e., r ⱖ 0.80); however, the reverse may not be true. For example, an instrument could reliably measure invalid data (i.e., by producing the same wrong answer time after time, it would show itself to be consistent but not accurate). Thus, high reliability is no guarantee of what is really desired, validity. However, if the reliability coefficient is low (i.e., ⬍ 0.4), then the instrument is most likely not valid and research results should be suspect. Raters When judgments are made by different individuals concerning a variable of interest (e.g., a diagnosis of an adverse drug reaction), it is preferable to have the individuals judge independently and then compare the judgments. Several statistical methods have been developed for determining the degree of agreement among judges. If the variable being judged is measured on a continuous scale (i.e., at interval level), Pearson’s r is often

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calculated. Rosenthal (9) presents a method for adjusting r among several judges. For ranked data, Kendall’s tau may be calculated between two judges, or Kendall’s W for three or more (10). For categorical data, such as diagnosis kappa (11,12) may be used. Tests of statistical significance should be presented for each coefficient. Statistical Tests The methods section should state the statistical test used for verifying each hypothesis. Authors should not simply list the tests without context; it should be made clear how each will be applied. The preferred format is to present the hypotheses to be tested, which are derived from the purpose of the study. Ideally, they would be stated in the same order as in the introduction. The error level that will be tolerated should be stated explicitly. Perhaps the most commonly selected alpha level is 0.05. However, there is nothing magic about that number; it is quite arbitrary. Many researchers would accept 0.10 as an acceptable level, especially with exploratory work such as in a pilot study. Parametric statistics, such as Student’s t-test and analysis of variance, are most commonly seen. However, their use is predicted on the assumption that the variable under study is normally distributed in the population being studied, that measurement is at least interval level, and that samples are randomly selected. Most researchers are willing to allow the first two assumptions, but the third is never achieved. As a result, nonparametric (also called distribution-free) statistics may be preferred, especially with small sample sizes. Statement of Limitations A good study will state its limitations as well as its delimitations. No study can look at all possible patients or types of patient, all types of adverse reaction, or all drugs. As a result, each study will have its limitations. If these are stated, the reader can better judge the importance of the study findings and to place them in their proper context. Results Results should be presented systematically in the same order as the stated objectives. Tables may be used to present data, but should not duplicate the text. Frequencies should be accompanied by percentages for the reader’s convenience. Statistical tests should state the test used, the value of the test, the degrees of freedom, and the significance value. For example, one should say that no difference between groups are detected with respect to SES [χ 2 ⫽ 1.22, degrees of freedom (df ) ⫽ 2, p ⫽ 0.543] rather than simply stating there was no difference. It is appropriate to describe the sample of subjects and to compare groups with respect to variables that could affect outcomes. Any pilot test results should then be presented, followed by a presentation of data from each hypothesis test. Any finding that was incidental may be mentioned, but conclusions may not be drawn if the researchers did not plan to investigate those findings. Discussion Often, the discussion section may be combined with results or conclusions, or both. The purpose is to elaborate on results to bring them to a conclusion. Reference should be made to other similar work, and justification presented for differing results.

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Conclusions The statements made from research should be of prime concern to the reader. It is the validity of these statements that is subject to threats as described by Campbell and Stanley (7). The reader should examine them carefully and determine whether the study design, sample selection, and methods support statements made. In addition, the generalizability of the statements is limited by the sample selected and by the nature of the experiment. The authors should state the limitations of the applicability of the findings. Only a randomly selected sample is truly representative of the population, and that is virtually impossible to achieve. Perhaps the most common misuse of research results is the conclusion that correlation demonstrates causation. If two events occur at the same time, or in sequence, it does not prove that one caused the other. The reader should beware of conclusions that overstep the data. To prove causation, one must use rigid experimental design, and even that has limitations. A good rule is to be skeptical. A common error is to take evidence from a cross-sectional study, such as a survey, and make longitudinal statements from it. For example, if one did a survey that compared opinions of young people with those of old people and found a difference, one could not conclude that as people age, their opinions change. Conclusions must be based on the research performed. To make a conclusion about changes associated with aging, one would have to conduct a longitudinal study on a group of people and measure their opinions at different ages.

PROBLEMS OF RESEARCH IN PREGNANCY Several difficulties arise in evaluating drugs for use in pregnant patients. Perhaps the greatest problem is that no drugs are tested in pregnant women. All pharmaceutical products approved for marketing must be tested on animal models, but such models are not always appropriate. In fact, thalidomide was tested on rats and mice but failed to produce teratogenic outcomes. As a result, information regarding the use of drugs in pregnancy must be generated by alternate methods. These methods include editorials, case reports, anecdotal letters to the editor, and epidemiological studies. However, such reports have shortcomings. They most often focus on possible adverse effects of a drug in pregnancy; rarely do they address the issue of safety in pregnancy. Such information would also be useful for clinical decision making.

Case Reports Case reports are submitted to journals by clinicians and researchers, usually on a volunteer basis. The quality of the reports varies with the authors and situations. Ideally, a patient would be rechallenged with the drug to determine whether the same reaction would be repeated. However, such a practice may be impractical, impossible, or unethical. A major benefit of case reports is the identification of rare events. These events include effects due to a rarely used drug, a rare disease, a rare combination of drugs, or a rare or unusual occurrence of an adverse effect. Examples: the identification of aplastic anemia following chloramphenicol administration to children and observations of the de-

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velopment of phocomelia after maternal thalidomide ingestion. These reports alerted authorities to major problems, of which we are all now aware. The disadvantage is that causation cannot be established from case reports. Consider the case of Bendectin (a combination of doxylamine succinate and pyridoxine hydrochloride), an antinauseant used in pregnancy. Case reports associated a supposed syndrome of birth defects and maternal consumption of Bendectin during pregnancy. Lawsuits followed, and researchers began to analyze mountains of data. As a result, the only drug indicated for nausea of pregnancy was removed from the market owing to adverse publicity. However, a recent meta-analysis (13) has demonstrated that the statistical combination of all published data on Bendectin shows it not to be associated with abnormal fetal outcomes. Thus, case reports should be evaluated with the fact in mind that they do not prove causation. Often, case reports will alert clinicians to new indications for drugs. For researchers, they suggest new areas of study and hypotheses to be tested. Another useful function is to verify the effectiveness of a treatment in groups that have not been clinically tested. For example, drug trials rarely include neonates or pregnant women. What are particularly lacking are case reports of drugs that have been safely used in pregnancy. Such information would be as valuable as reports of adverse events. Such reports are now being collected by the Motherisk team at the Hospital for Sick Children in Toronto and are shared with interested practitioners. Editorials An editorial is usually an opinion expressed by a learned author or a small group of experts. Most often, these opinions are supported by clinical data and experience (14). Editorials are most useful for describing the state of the art for a particular topic, for identifying clinical problem areas, or for describing what may be expected in ‘‘normal’’ therapeutics. Nonetheless, editorials are opinions, subject to personal biases. Letters Letters to the editor are unsolicited accounts that may contain case reports, brief experiments, or preliminary research data. They are usually not peer-reviewed and may contain opinion and personal bias. Some journals, such as the Lancet and the New England Journal of Medicine, publish many letters that are often given great credence. They have similar drawbacks to case reports and should be given similar consideration. Correlational Studies Since experimental studies are not commonly performed on pregnant women, researchers have developed correlational methods that may be applied to establish facts about drug use. Three main types that use correlational methods are surveys, case control studies, and cohort studies. Surveys are cross-sectional and provide important information. The nature of a survey, however, does not permit longitudinal conclusions. Surveys do identify areas that require further study. Readers should note that surveys cannot establish causation, as discussed above.

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When large bases of information are available, it is possible to perform epidemiological studies on the data (15). In such cases, huge sample sizes may be achieved. Therefore, results are more likely to converge on the truth. Epidemiological studies may be either prospective or retrospective. Prospective studies begin on a specified date and follow cases through time to note the occurrence of a specified outcome. Retrospective studies look back into records to detect evidence for exposure to a drug or for adverse reactions. The latter may be subject to bias from the researcher, who often must make judgments. As a result, prospective studies may be considered to be of higher quality than retrospective studies. However, the former require large numbers of subjects and tend to be very time-consuming and costly. Case-control studies begin with a particular outcome and search the records for evidence of exposure to a drug. A comparison group of nonaffected subjects is selected and records are searched to determine the rate of exposure in normals. Rates are compared to arrive at an odds ratio for a drug producing a specific adverse effect. A ratio of unity (i.e., 1) indicates no drug effect, but higher values may signify a relationship. Confidence intervals should be presented to indicate whether a relationship is statistically significant. If unity is within the interval, there is no association between the drug and an adverse effect. Conversely, if the interval excludes unity, there is a relationship. The presence of a relationship does not prove absolutely that the drug caused the event. One must weigh all the available evidence, including animal models, case reports, and theories of mechanisms behind the reaction. Cohort studies are opposite to case-control studies. They begin with a group of subjects exposed to a drug and a comparison group of nonexposed subjects and follow the subjects prospectively (or retrospectively in a chart review) to determine the frequency of adverse events. A risk ratio is calculated, which is very similar to the odds ratio of case-control studies. Prospective cohort studies are ideal in that they measure incidence of adverse events. However, a cohort study requires a very large number of subjects, especially if the adverse event under study is rare. Case-control studies can produce similar data with fewer subjects, hence they are more often employed.

META-ANALYSIS In reading the literature, one may be presented with a number of studies producing varied results. The problem is how to analyze the data to arrive at an overall conclusion concerning the relationship of a drug and a given outcome. In the past, reviews were done, but these were subject to much bias. A mathematical method has been developed to help overcome bias and arrive at a single overall value that describes the drug-outcome relationship; namely, meta-analysis. Glass (16) coined the term meta-analysis to refer to the statistical combination of research from independent studies. Since that time, meta-analysis has become increasingly popular as a method for summarizing the literature (17). The prefix meta is used in the sense of secondary, in that results of completed studies may be aggregated to arrive at an overall summary estimate of the true effect of a drug. For epidemiological studies, meta-analysis gives an overall odds ratio that describes the relationship between a drug and an outcome. Einarson et al. (13) have presented a

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method for meta-analysis of epidemiological studies. Other methods have been presented for clinical trials (18,19). Meta-analysis is to be preferred as a method for aggregation of results from individual studies because it is systematic, thorough, quantitative, and less prone to bias. Studies that vary in quality may be given more weight than those of lower quality throughout (20,21). Similarly, studies having larger sample sizes may be given more weight. Readers are encouraged to consult meta-analyses for reviews of specific drugs. Presently, the Motherisk team at the Hospital for Sick Children in Toronto is collecting meta-analyses of drugs in pregnancy. These analyses will be used to assist clinicians and pregnant patients in their decision-making process. REFERENCES 1. Weston K. Sources of drug and other biomedical information. Drug Inf J 1979; 13:11–14. 2. Stinson ER, Mueller DA. Survey of health professionals’ information habits and needs. JAMA 1980; 243:140–143. 3. Nickman NA, Hadsall RS, Wertheimer AI. Pharmacist not yet a drug advisor. Drug Intell Clin Pharm 1988; 22:174–175. 4. Covell DG, Uman GC, Manning PR. Information needs in office practice: are they being met? Ann Intern Med 1985; 103:596–599. 5. Physician’s Desk Reference, 47th ed. Oradell, NJ: Medical Economics Company, 1993. 6. Krogh CME, ed. Compendium of Pharmaceuticals and Specialties, 22nd ed. Canadian Pharmaceutical Association, Ottawa, Ontario, 1987. 7. Campbell DT, Stanley JC. Experimental and Quasi-Experimental Designs for Research. Boston: Houghton Mifflin, 1963. 8. Bailar JC, Mosteller F. Guidelines for statistical reporting in articles for medical journals. Ann Intern Med 1988; 108:266–273. 9. Rosenthal R. Meta-Analytic Procedures for Social Research. Beverly Hills, CA: Sage, 1984. 10. Siegel S. Nonparametric Statistics for the Behavioral Sciences. New York: McGraw-Hill, 1956. 11. Cohen J. A. coefficient of agreement for nominal scales. Educ Psychol Meas 1960; 20:37– 46. 12. Fleiss JL. Measuring nominal scale agreement among many raters. Psychol Bull 1971; 76: 378–382. 13. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiologic studies. Drug Intell Clin Pharm 1988; 22:813–824. 14. Leeder JS, Spielberg SP, MacLeod SM. Bendectin: the wrong way to regulate drug availability. Can Med Assoc J 1983; 129:1085–1087. 15. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research: Principles and Quantitative Methods. New York: Van Nostrand Reinhold, 1982. 16. Glass GV. Primary, secondary, and meta-analysis of research. Educ Res 1976; 5:3–8. 17. Wolf FM. Meta-analysis. N Engl J Med 1987; 317:576. 18. DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986; 7:177–188. 19. L’Abbe´ KA, Detsky AS, O’Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987; 107:224–233. 20. Chalmers TC, Smith H. Blackburn B. A method for assessing the quality of a randomized controlled trial. Contr Clin Trials 1981; 2:31–49. 21. Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analyses of randomized controlled trials. N Engl J Med 1987; 316:450–455.

41 Bendectin/Diclectin for Morning Sickness: A Canadian Follow-Up of an American Tragedy Melanie Ornstein, Adrienne Einarson, and Gideon Koren The Hospital for Sick Children, Toronto, Ontario, Canada

INTRODUCTION Nausea and vomiting affect approximately 50% of pregnant women. In the majority of cases, this is a self-limited problem during the first trimester, resulting in only minor discomfort. Severe nausea and vomiting extending into the second and third trimesters is experienced by approximately 10 to 17% of women, but only 0.35% develop true hyperemesis gravidarum, characterized by intractable vomiting with weight loss, dehydration, electrolyte, and acid-base disturbances (1–9). Studies have suggested that nausea and vomiting may actually be associated with a better fetal outcome presumably due to better implantation and placental function (6,9). However, other data have demonstrated that women who experience severe vomiting are at increased risk for preeclampsia, intrauterine growth retardation, and hospitalization, with its inherent risks and financial costs (1–9). The initial management of mild nausea and vomiting includes reassurance of the self-limiting nature of the problem, advice to avoid potentially nauseating situations and foods, and eating small, frequent meals and dry, bland foods. Drug therapy is typically only considered when conservative measures have been unsuccessful. Bendectin was introduced in the United States in 1956 by Merrell Dow Pharmaceuticals as a tri-ingredient product: doxylamine succinate, an antihistamine with antiemetic properties, dicyclomine hydrochloride, an antispasmodic agent, and pyridoxine hydrochloride (vitamin B6 ) to prevent possible deficits during pregnancy and to synergize the antinauseant activity (10). Dicyclomine hydrochloride was dropped from the formulation in 1976, based on results of randomized control trials comparing each component alone and in combination versus placebo (10). In 1978, the drug Diclectin (doxylamine and pyridoxine) was licensed for use in Canada by a company in Quebec, Duchesnay Incorporated. In 1969 the first allegations regarding possible teratogenic effects of Bendectin resulting in congenital limb deformities were filed (10). These were single-case studies with

From Reprod Toxicol 1995; 9(1):1–6.  1995 Elsevier Science Ltd. 807

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neither controls nor specification of patient’s past medical history and associated risk factors. In 1983, Merrell Dow ceased worldwide production of Bendectin due to negative media publicity and increasing legal costs and insurance premiums, despite winning their legal battles and despite numerous studies that have failed to demonstrate any causal relationship between Bendectin and congenital malformations (10–19). In a meta-analysis of 20 studies with over 200,000 patients, Bendectin use was documented not to be associated with increased teratogenic risks (13). The removal of Bendectin from the market resulted in a therapeutic gap in the treatment of severe nausea and vomiting in pregnancy, leaving physicians with limited alternatives (18–21). Subsequently, doctors either chose not to treat nausea and vomiting or used other antiemetics that have not been as adequately studied. For example, dimenhydrinate (Gravol) is not specifically indicated for use in pregnancy, and the manufacturer mentions pregnancy among the contraindications for using the drug, as teratogenicity data are limited. Thus, pregnant women in many countries have been denied an effective antiemetic to prevent what is, in some instances, a serious complication of pregnancy (18). In all pregnancies there is a baseline risk of 1 to 3% of having a baby with a major congenital abnormality (22–24). It has been estimated that more than 30 million infants were exposed to Bendectin by the time of its removal from the market (10–12). With a background malformation rate of 3%, chance alone would account for 900,000 infants born with major defects. As Brent (25) pointed out ‘‘the general consensus among teratologists is that Bendectin is one of the best-studied drugs of all time for use in pregnancy, and the great preponderance of evidence generally exonerates it from any harmful effects. Despite all this evidence, the controversy surrounding Bendectin continues today, and this one drug alone has received media and research attention with far-reaching implications with respect to the influence of public opinion on medical decision making, libel and medicine, and toxic tort cases.’’

THE RESPONSE IN CANADA Immediately after Merrell Dow ceased production of Bendectin, the Toronto Globe and Mail ran a story on June 10, 1983. A spokesman from a U.S. Public Citizen Health Research Group was quoted there as saying that pregnant women and their unborn babies would be spared the risk of exposure, and another thalidomide disaster would be averted (26). In 1987, families began to assemble legal cases and The CBC Morning Show aired a story about three families claiming Bendectin had caused congenital malformations in their children (27). A developmental biologist, Dr. Stewart Newman, was interviewed, and he claimed that Bendectin was responsible for a whole host of defects including limb malformations, heart problems, cleft palate, and brain damage (27). In 1989, the Toronto Star reported a series of articles on Bendectin/Diclectin, drawing a strong parallel to the thalidomide tragedy (28–30). The goal of the media is obviously to inform the public about disease, its possible causes, and specific treatments (31,32). However, much of the Canadian medical news was about individual cases, without always clearly communicating all the facts. The Canadian coverage did not discuss the concept of baseline risk of malformations, and in only one article was there mention of the body of literature showing no connection between Bendectin and birth defects. Although nearly every scientific study

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has provided reassuring evidence of the drug’s safety, headlines in the news media suggested otherwise. In response to the negative publicity and public pressure, the federal department of Health and Welfare responded by sponsoring a special advisory committee to advise the Minister on the safety of Diclectin. The committee included an expert panel of consultants in teratology from Canada and the United States, a representative from the Health Protection Branch, and representatives from the special advisory committee on reproductive physiology. Their review included examination of human epidemiologic studies, animal studies, and in vitro studies. In its review, the Committee evaluated all available animal and human studies on the use of the doxylamine-vitamin B6 combination. In August 11, 1989, a consensus statement was developed, which concluded that Bendectin/Diclectin presents no measurable reproductive risk. After considering the relevant data, the panel submitted the following recommendations in response to the Minister’s questions: Q1. Given available data, is there evidence that exposure to Bendectin/Diclectin during pregnancy increases the risk of congenital malformations in the offspring? A. No. Numerous studies in animals and in humans that have been reported in the scientific and medical literature demonstrate that Bendectin is not a teratogen. A compound that has no teratogenic effect can be expected, solely on the basis of chance, to be associated with congenital malformations if it is used widely by pregnant women. The types of congenital malformations reported will vary considerably, not following a consistent pattern of birth defects. The safety of Bendectin/Diclectin in the management of nausea and vomiting of pregnancy has been established by its use in many thousands of pregnant women. The types and numbers of abnormal offspring born to these women were in no way different from those that would be expected to occur in a similar group of women who did not take these drugs during pregnancy. The panel believe that the risk of Bendectin had been grossly misrepresented to the public. Q2. Does Bendectin/Diclectin serve a useful role in the management of nausea and vomiting of pregnancy? A. Yes. These drugs were the only ones for which sufficient evidence of safety and effectiveness in the management of nausea and vomiting of pregnancy was submitted to drug regulatory bodies in Canada and abroad, thereby allowing this claim to be made. No other drugs have been nearly so well investigated for this purpose. It must be emphasized that Bendectin was never banned from sale in any country. It was withdrawn from the market worldwide in 1983 by the manufacturer, who found the legal costs of defending its use (successfully in the majority of cases) to be prohibitive. There has been an unfortunate consequence in this withdrawal for pregnant women. For example, in the United States, the number of women being admitted to hospital suffering from severe nausea and vomiting of pregnancy has increased twofold. Q3. Does the benefit to risk assessment of Diclectin indicate that it should be removed from sale in Canada? A. No, for the reasons cited above. It would be a disservice to Canadian women to withdraw this drug from the market.

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Q4. If the answer to question three is no, what restrictions, if any, should be placed on the sale of Diclectin? Are any changes needed in the physician or patient labeling? A. There should be no restrictions placed on the availability of Diclectin in Canada. It should be indicated for the management of nausea and vomiting of pregnancy without the qualifications that exist at present. The panel believes that there is an overemphasis on cautionary statements in the current labeling for Diclectin that is not reflected in recent studies that have been reported in the medical and scientific literature. The labeling should be modified accordingly. The recommendations of the Committee were adopted by the Department of Health and Welfare, and the labeling of Diclectin was changed to recommend the drug for morning sickness as a first line treatment. The Postlabeling Period Despite the clear and unambiguous new label of Diclectin for use in pregnancy, continuous follow-up by the Motherisk Program in 1991 to 1993 has revealed that many physicians and pharmacists were still telling women that Diclectin was unsafe in pregnancy. At least one large distributer of pharmaceuticals refused to carry Diclectin to avoid liability. In order to examine the prescribing practices of physicians with respect to antiemetics in pregnancy, a questionnaire was devised that investigated how physicians managed nausea, vomiting, and hyperemesis gravidarum and whether or not they prescribed Diclectin and Gravol. Three groups of physicians were recruited: (1) hospital-based obstetricians (both residents and staff), (2) hospital-based general practitioners, and (3) communitybased physicians. A questionnaire was also designed for pregnant women who contacted Motherisk specifically about concerns related to the treatment of nausea and vomiting. This questionnaire elicited information regarding the severity of their nausea and vomiting and what treatments, if any, had been recommended and/or tried. Proportions among groups of participants were compared by chi-square analysis. Analysis of the physician’s questionnaire revealed a fairly consistent approach to the initial conservative management of nausea and vomiting, including dietary recommendations and reassurance of women regarding the time-limited nature of the problem. The use of Gravol and Diclectin to pharmacologically manage emesis is shown in Table 1. The vast majority of physicians (80 to 100%) preferred to use Gravol, which is not labeled in Canada specifically for use in pregnancy and for which pregnancy is listed as a contraindication. The use of Diclectin varied, with hospital-based obstetricians feeling fairly Table 1 Physician’s Questionnaire

Number of physicians Prescribe Gravol Gravol only as last resort Prescribe Diclectin Diclectin only as last resort a

I. Hospital-based obstetrician

II. Hospital-based general practitioners

III. Communitybased physicians

42 42 (100%) 5 (11.9%) 41 (97.6%)a 4/41 (9.8%)

43 40 (93%) 8/40 (20%) 29 (67.4%) 5/29 (17.2%)

40 32 (80%) 5/32 (15.6%) 23 (57.5%) 4/23 (17.4%)

p ⬍ 0.001 between group I and group II or III.

Bendectin/Diclectin for Morning Sickness Table 2

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Pregnant Women’s Questionnaire

Total number First trimester Cared for by general practitioner Cared for by obstetrician Rated nausea/vomiting as severe Hospitalized Drugs recommended by health care provider Diclectin Gravol No medication

27 23 16 9 23 5

(85.25%) (59.3%) (33.3%) (85.2%) (18.5%)

9 (33.3%) 10 (37%) 8 (29.6%)

comfortable prescribing this drug (97.6%), as compared to hospital-based family doctors and community physicians who used the drug with greater reluctance (67.4% and 57.5%, respectively; p ⬍ 0.001), and more often as a last resort (17%). In Canada, communitybased doctors and/or hospital general practitioners are very often the primary caregivers during the first trimester of pregnancy, before most women see an obstetrician. As most pregnant women experience nausea and vomiting during the first trimester, many of these women are not, therefore, likely to benefit from the use of an antiemetic recommended by its label. On the other hand, women requiring hospitalization due to the complications of severe nausea and vomiting are being prescribed Diclectin by hospital-based obstetricians, albeit probably later than was necessary and after complications already were present. The Motherisk Program receives approximately 7000 to 8000 telephone inquiries per year, and of these, approximately 240 (3%) are related to Gravol and 120 (1.5%) concern Diclectin. For 1 month (January 1994), all women calling Motherisk to inquire about the management of nausea and vomiting were interviewed. Although the number of women in the general population affected with severe nausea and vomiting is small, their proportion among women contacting Motherisk was 85%, and five women (18.5%) required hospitalization and intravenous rehydration. Thus, this small group represented women at highest risk for possible complications of emesis and those who would, therefore, benefit most from possible pharmacologic management with Diclectin. Table 2 documents that only one-third of this high-risk group were prescribed Diclectin to manage their severe nausea and vomiting, one-third were recommended Gravol, and another third were not treated pharmacologically at all, possibly supporting Brill-Edwards and Leeder’s (12) observation that many physicians avoid drug use entirely during pregnancy.

DISCUSSION The results of this survey indicate that Diclectin is being used by physicians in Canada for the treatment of emesis in pregnancy. However, it is used most frequently by hospitalbased obstetricians who routinely see pregnant women later in their pregnancy or once nausea and vomiting are so severe that intervention is necessary. Diclectin was used less frequently than Gravol, despite Diclectin being the drug of choice advocated by the Department of Health and Welfare task force and being the only drug to be labeled specifically for pregnancy. It appears from the comments written by physicians on the questionnaire

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that Diclectin continues to elicit fears of possible teratogenicity and subsequent legal action. However, Canada has not followed the lead of the United States in succumbing to negative media portrayals and threats of legal action. The American tragedy was that drug availability was determined by the media, the litigation process, and public response, rather than as a result of careful examination and scientific research (10,14,20). The implications of the Bendectin story are far reaching, indeed. Of major importance is that the adverse affects of severe nausea and vomiting, and any treatment to modify it, are not likely to be optimally studied (10). In other words, research into developing and marketing products of any type for pregnant women are likely to be curtailed due to a litigious environment (10,19,20,24). In the United States, Bendectin and the controversy surrounding it has resulted in an enormous debate on what constitutes scientific evidence and expert scientific testimony (18,34–36). Court cases dealing with toxicology have tended to rely on scientifically valid, peer-reviewed research (35–37). However, based on law suits involving Bendectin, the U.S. Supreme Court has advocated giving judges more latitude in deciding what is good science (18,34,35). As Marwick noted ‘‘. . . While it is true that speculation is an essential part of science and it is true that new ideas may have a hard time gaining acceptance, it does not follow that untested science belongs in the court . . .’’ (18). The legal quest for compensation for a baby with a birth defect is obviously very emotional (38). However, as Brent points out, the litigation process itself can have negative consequences for the family and may prolong the family’s anger and suffering and interfere with the ability to accept and reorganize (38). Brent and others, based on the experiences of the Bendectin litigation in the United States, advocate certain solutions for avoiding possibly unnecessary lawsuits (10,38). These include establishing authoritative sources of information to assist the courts in interpreting scientific literature, education of pregnant women, and the public in general, regarding the baseline incidence of congenital malformations, and making plaintiffs aware of the length of the litigation process and the disorganizing effect on the family (10,17,27,38). In both the United States and Canada, programs such as Motherisk strive to present the most up-to-date information on safety or risk(s) of any given compound in an unbiased manner so as to minimize the perception of risk where applicable and ensure any pregnancy-related decisions be taken by optimally informed patients (22,23). In August 1999, the FDA reaffirmed its view that Bendectin is an efficacious and safe drug for nausea in pregnancy. Lastly, the Bendectin saga has demonstrated how powerful and detrimental mass media can be in influencing public opinion and health policy (10,14,39,40). The media is seen as a channel of information from the expert community to the public. It, therefore, plays a role in health risk communication that is an important public health goal (41,42). However, how the information is portrayed influences how it is interpreted. The Canadian experience has shown us, however, that responding to negative media attention with an authoritative approach by the regulatory agency can result in a much more positive reaction. Yet, despite a clear message on the safety of Bendectin/Diclectin, it is taking years in Canada to change the negative trends produced by the American and Canadian media publicity. We have recently shown that American women suffering from morning sickness are substantially less likely to receive antiemetics in pregnancy than Canadian patients.

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This was associated with longer working hours lost, more weight loss, and more hospitalizations for morning sickness in the United States (43). We believe, however, that the role of protecting the rights of pregnant women for safe drugs and preventing the continuous trend of orphaning them from the benefits of new agents cannot lie only on governmental regulatory agencies and scientists. It is crucial that women’s groups, which have been shown to be vocal and effective in many other issues, should take a more central role in this battle for safe drugs for women and their fetuses. Otherwise, the battlefield will always be controlled by the quick-to-act media mob and not by carefully and responsibly responding science.

REFERENCES 1. Godsey RK, Newman RB. Hyperemesis gravidarum: a comparison of single and multiple admissions. J Reprod Med 1991; 36:287–290. 2. Zhang I, Cai W. Severe vomiting during pregnancy: antenatal correlates and fetal outcomes. Epidemiology 1991; 2:454–457. 3. Behrman CA, Heidger ML, Scholl TO, Arkangel CM. Nausea and vomiting during pregnancy: effects on birthweight. J Adoles-Health Care 1990; 11:4418–4422. 4. Gross S, Librach C, Cecutti A. Maternal weight loss associated with hyperemesis gravidarum: a predictor of fetal outcome. Am J Obstet Gynecol 1989; 160:906–909. 5. Chin RKH, Lao TT. Low birthweight and hyperemesis gravidarum. Eur J Obstet Gynaecol Reprod Biol 1988; 28:179–183. 6. Walters WAW. The management of nausea and vomiting during pregnancy. Med J Aust 1987; 147:290–291. 7. Ka¨lle´n B. Hyperemesis during pregnancy and delivery outcome: a registry study. Eur J Obstet Gynaecol Reprod Biol 1987; 26:291–302. 8. Depue RH, Bernstein L, Ross RK, Judd HL, Henderson BE. Hyperemesis gravidarumin relation to oestradiol levels, pregnancy outcome, and maternal factors: a seroepidemiologic study. Am J Obstet Gynecol 1987; 156:1137–1141. 9. Biringer A. Antinauseants in pregnancy: teratogens or not? Can Fam Physician 1984; 30: 2123–2125. 10. Leeder JS, Spielberg SP. Teratogenicity and litigation. In: Koren G, ed. Maternal—fetal toxicology: a clinicians’ guide. New York: Marcel Dekker, 1990; pp 415–425. 11. Pellegrini EM, Koren G. Motherisk I: a new model for counselling in reproductive toxicology. In: Koren G, ed. Maternal—fetal toxicology: a clinicians’ guide. New York: Marcel Dekker, 1990; pp 355–372. 12. Koren G, Feldman Y, MacLeod SM. Motherisk II: the first year of counselling on drug, chemical and radiation exposure in pregnancy. In: Koren G, ed. Maternal-fetal toxicology: a clinicians’ guide. New York: Marcel Dekker, 1990; pp 383–402. 13. Special Advisory Committee, Health Protection Branch. Report on the safety of Bendectin/ Diclectin for use in the management of nausea and vomiting of pregnancy. Canadian Health and Welfare Department; August 1989. 14. Brill-Edwards MM, Leeder JS. Bendectin: implications for the future. A report. Motherisk Program, Hospital for Sick Children, Toronto; 1990. 15. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiological studies. Drug Intell Clin Pharm 1988; 22:813–823. 16. Leeder JS, Spielberg SP, Macleod SM. Bendectin: The wrong way to regulate drug availability. Can Med Assoc J 1983; 129:1085–1087.

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17. Shiono PH, Klebanoff MA. Bendectin and human congenital malformations. Teratology 1989; 40:151–155. 18. Orme MLE. The Debendox saga. Br Med J 1985; 291:918–919. 19. Holmes LB. Teratogen update: Bendectin. Teratology 1983; 27:277–278. 20. Marwick C. Court ruling on ‘‘Junk Science’’ gives judges more say about what expert witness testimony to allow. JAMA 1993; 270:423. 21. Brannigan VM, Bier VM, Berg C. Risk statistical inference and the law of evidence: The use of epidemiological data in toxic tort cases. Risk Anal 1992; 12:343–351. 22. Skolnick A. Key witness against morning sickness drug faces scientific fraud charges. JAMA. 1990; 263:1468–1473. 23. Newman SA. Bendectin—birth defects controversy. In: Skolnick A, ed. In reply. JAMA. 1990; 264:569–570. 24. Saunders EJ, Saunders JA. Drug therapy in pregnancy: the lessons of diethylstibestrol, thalidomide and Bendectin. Health Care Women Int 1989; 11: 423–432. 25. Product Monograph. Diclectin: combination of doxylamine succinate with pyridoxine hydrochloride, antinauseant against nausea and vomiting of pregnancy. Laval, Quebec: Duchesnay Inc, 1990. 26. Brent R. The Bendectin saga: another American tragedy. Teratology 1983; 27:283–286. 27. The Globe and Mail, June 10, 1983, p. 2. 28. Lowry RB. Bendectin update: jury ignores scientific evidence. Bull Hered Dis Program Alberta 1987; 6:9–10. 29. Hurst L. Drug still on market feared another thalidomide. The Toronto Star, Feb. 25, 1989; A1, A4. 30. A pregnancy drug under suspicion. The Toronto Star, March 1, 1989, A26. 31. Hurst L. Canada alone in selling anti-morning sickness pill: battle lines form over pregnancy drug. The Toronto Star, March 4, 1989, D5. 32. Shaper AG. Epidemiology for every man: a population perspective. West Indies Med J 1989; 38:70–73. 33. Wiggs JW. Correspondence. South Dakota J Med 1990; 43:23–24. 34. Jick SS, Garrison JM. Discontinuation of Bendectin. Am J Public Health 1988; 78:322–323. 35. Marshall E. Supreme court to weigh science. Science 1993; 259:588–590. 36. Mervis J. Supreme court to judges: start thinking like scientists. Science 1993:261;22. 37. Gray C. The medico-legal society: libel and medicine. Medicolegal J 1991; 59:142–156. 38. Scialli AR. Bendectin, science, and the law. Reprod Toxicol 1989; 3:157–158. 39. Brent R. The law and congenital malformations: legal issues in teratology. Teratology 1986; 13:505–543. 40. Higginson J, Chu F. Ethical considerations and responsibilities in communicating health risk information. J Clin Epidemiol 1991; 44:51S–56S. 41. McCallum DB, Hammond SL, Corello VT. Communicating about environmental risks: how the public uses and perceives information sources. Health Educ Q 1991; 18:349–361. 42. Marcos LR. Media power and public mental health policy. Am J Psychiatry. 1989; 146:1185– 1189. 43. Mazzotto P, Maltese C, Novioz Y, Magee LA, Koren G. Attitudes, management and consequences of nausea and vomiting of pregnancy in the United States and Canada. Int J Gynecol Obstet. 2000; 70:359–365.

Index

Abnormalities congenital, 153, 158 Abortifacients, 232 Abortion, 157, 172, 337 Abruptio placenta, 6, 334, 335, 400 Absorption-drug, 1 Abstinence syndrome, 363 Acceptable daily intakes (ADIs), 23 Accutane, 167 Acebutolol, 193, 268, 468, 479, 480, 555, 674 Acetaminophen, 50, 119, 184, 268, 674 Acetaminophen overdose, 234 Acetate, 468 Acetazolamide, 202, 268, 674 Acetohexamide, 268 Acetylation, 6 Acetylcholinesterase (AChE), 658, 664 Acetylsalicylic acid, 196 Achenbach behavior checklist, 98 Activated charcoal, 233 Acyclovir, 185, 674 Addison’s disease, 160 Adoption, 445 β-Adrenergic blockers, 708 α 2-adrenergic supersensitivity, 346 Adverse drug reactions (ADR), 570 Adverse effect, 25 AFP, 654, 663 β 2-Agonists, 121 Aidsa, 698 Airborne concentrations, 509 Alanine glyoxalate aminotransferase deficiency, 662

Albumin, 4 Albuterol, 268, 674 Alcohol abuse, 469 Alcohol consumption-moderate, 495 Alcohol dehydrogenase, 468 Alcohol use, 448 Alcohol, 15, 41, 60, 321, 322, 339, 361, 371, 467, 775 Alcoholic drink, 496 Alcohol-related birth defects (ARBD), 472 Alcohol-related neurodevelopmental disorder (ARND), 472 Alfalfa, 571 Alfentanil, 268 Alkylating agents, 60 Allergic rhinitis, 50 Alloimmune antiplatelet antibodies, 662 Aloe vera, 571 Aloeaceae, 571 Alpha 1-acid glycoprotein, 4 Alphaprodine, 269 Alport’s syndrome, 657 Alprazolam, 199, 674 Aluminum acetate, 51 Aluminum hydroxide, 51 Alveolar uptake, 3 Amanita phalloides, 248 Amantadine, 674 Ambenonium, 269 American Conference of Governmental Industrial Hygienists, 509 Amiloride, 674 Amino acid transport, 481 815

816 5-Aminosalicylic acid, 204, 714 Aminoglutethimide, 269 Aminopterin syndrome, 61 Aminopterin, 39, 61, 674 Amiodarone, 14, 201, 269, 674 Amitriptyline, 191, 674 Ammonia, 126 Ammonium chloride, 269 Amniocentesis, 654, 657 Amniocentesis, early, 659 Amniotic fluid, 4, 657 Amobarbital, 674 Amoxicillin, 14, 185, 674 Amphetamine, 269, 336, 359, 325, 674 Ampicillin, 5, 10, 117, 185, 269, 674 Analgesics, 2 Androgenic drugs, 39 Anemia, 337 Anencephaly, 663 Anesthesia, 123 Anesthetic agents, 3 Anesthetic gases, 510 Aneuploidy, 654 Aneuploidy, segmental, 656 Angelica sinensis (Oliv.) Diels, 576 Angiotensin-converting enzyme, 708 Angiotensin-converting-enzyme inhibitors, 39, 44 Aniline, 558 Animal studies, 509 Ankylosing spondylitis, 159, 160 Anomalies, major, 158 Antacids, 51 Antiarrhythmic agents, 7 Antibiotics, 117 Anticardiolipin antibodies, 699 Anticholinergic drugs, 39 Anticonvulsants, 7, 67 Anti-D immunoglobulin, 660 Antidepressants, 85 Antidigoxin antibody fragments, 243 Antidotes, 233 Antiemetics, 2 Antifibrinolytic drugs, 51 Antihistamines, 269, 739 Antihypertensive agents, 13 Antimetabolic agents, 61 Antimicrobial agents, 2 Antineoplastic agents, 15, 211, 214 Antiphospholipid antibodies, 699 Antithyroid drugs, 15, 39 Anxiety, 105

Index Anxiolytic medications, 121 Aortic valve stenosis, 158, 161 Apiaceae, 576 Aplasia cutis, 39 Aprotonin, 270 Arctium lappa, 572 Arctostaphylos uva-ursi, 584 Area under the concentration-time curve, 10 Arsenic overdose, 246 Arthrogryposis, 663 Arthropathy, 159 5-ASA, 714 ASA, 158, 719 ASA/P trial, 152 Asparaginase, 270 Aspartame, 124 Aspirin, 50, 119, 152, 270, 675 Astemizole, 50, 51, 120 Asteraceae, 572, 573, 574, 575, 578 Asthma, 151, 154, 159, 160, 700 Ataxia telangiectasia, 656 Atenolol, 14, 15, 158, 162, 193, 270, 674, 675 Atropine, 233, 241, 675 Attachment, 483 198 Au, 627 Autoantibodies, 162 Autoimmune diseases, 162 Autoimmune thrombocytopenia, 152 Autosomal dominant conditions, 654 Autosomal recessive conditions, 654 Azatadine, 675 Azathioprine, 158, 270, 675, 714 Azauridine, 61 Azlocillin, 11 Bacteriuria, asymptomatic, 726 Barbiturate withdrawal, 362 Barbiturates, 39, 321, 327, 362, 371 Battery manufacturer, 507 Bayley Scales of Infant Development, 98, 357, 433 Beclomethasone, 675 Belladonna, 675 Bell’s palsy, 154 Benazepril, 675 Bendectin (doxylamine plus pyridoxine), 40 Bendectin, 38, 40, 121, 739, 807 Benzene, 557, 558 Benzodiazepines, 39, 42, 50, 61, 68, 105, 321, 327, 362, 363, 739 Benzoic acid, 374

Index Benzoyl peroxide, 50 Benzthiazide, 675 Benztropine, 271, 675 Benzyl-penicillin, 5, 10 Beta-adrenergic blockers, 13 Beta-adrenergic-receptor antagonists, 51 Beta-lactams, 10 Betamethasone, 160, 271, 675 Betaxolol, 675 Bias-publication, 798 Bilirubin glucuronyl transferase, 348 Binge alcohol consumption, 476 Biological markers, 455 Biotransformation, 4 Bipolar affective disorder, 51 Birth control, 171 Birth defect, 153, 158 Birth length, 387 Birth weight, 151, 157, 387, 446 Bisacodyl, 50 Bismuth subsalicylate, 51, 675 Bisoprolol, 675 Black cohosh, 572 Bleach, 125 Bleomycin, 271 Blood alcohol concentration (BAC), 476 Blood-brain barrier, 478 Bloom’s syndrome, 656 Brain development, 446 Brazelton Neonatal Behavioral Assessment Scale, 358 Breast-feeding, 13, 175 Breastmilk, 14, 177 Breech presentation, 337 Bretylium, 201, 675 Bromides, 271, 675 Bromocriptine, 14, 211 Brompheniramine, 120 Bulking agents, 122 Bumetanide, 675 Burdock, 572 Busulfan, 271, 675 Butalbital, 362 Butoconazole, 675 Butorphanol, 271 Butriptyline, 676 14

C, 627 Ca, 627 Ca-125, 703 Cadmium, 510, 558 Caffeine, 4, 271, 676 47

817 Calamine lotion, 51 Calcitonin, 271 Calcium carbonate, 51 Calcium channel blockers, 13, 708 Calcium, 50 Calendula officinalis, 573 Camphor 374, 272 Camphor overdose, 243 Cancer, 46 Cannabaceae, 580 Cannabinoids, 321, 326, 340, 435 Capsicum annum, 573 Captopril, 193, 272, 676 Carbamates, 127 Carbamazepine, 8, 14, 39, 44, 61, 75, 77, 158, 162, 188, 272, 676 Carbamazepine-10,11 trans-diol, 8 Carbamazepine-10,11-epoxide, 8, 77 Carbamyl phosphate synthetase deficiency, 662 Carbenicillin, 676 Carbimazole, 272, 286, 676 Carbon 14 (14 C), 621 Carbon disulfide, 555 Carbon monoxide (CO), 61, 127, 456, 511, 676 Carbon monoxide poisoning, 255 β-carotene, 480 Carboxyhemoglobin, 260, 340, 456 Carcinogenesis, 38 Carcinogenicity, 15 Cardiac dysrhythmias, 342 Cardiac output, 3 Carey Temperament Scale, 98 Carisoprodol, 676 Carteolol, 676 Casanthranol, 676 Case report, 293 Case-control studies, 43, 153, 159, 160, 162, 163, 502 Catalog of teratogenic agents, 23 Cefaclor, 676 Cefadroxil, 185, 676 Cefalexin, 12 Cefalothin, 12 Cefazolin, 12 Cefotaxime, 14 Ceftriaxone, 12, 676 Celiprolol, 676 Cell-cell adhesion, 481 Center for Epidemiologic Studies Depressed Mood Scale, 99

818 Cephalexin, 185, 676 Cephalosporins, 11, 12 Cephalosporins first-generation, 12 Cephalosporins, second-generation, 12 Cephradine, 676 Cerebral palsy, 158 Cervical polyps, 659 Cetirizine, 120 Chamomile, German, 574 Chaste tree, 574 Chemical industries, 555 Chernobyl accident, 633 Child neurodevelopment, 447 Children’s Aid Society, 321 Chi-square test of homogeneity, 154 Chlorambucil, 60, 272, 676 Chloramphenicol, 185, 272 Chlordane, 516 Chlordiazepoxide, 273, 363, 676 Chloroform, 558 Chloroprene, 513 Chloroquine, 119, 204, 273, 676, 719 Chlorothiazide, 202, 273, 677 Chlorpheniramine, 677 Chlorpromazine, 51, 198, 273, 361, 372, 677 Chlorpropamide, 273, 677 Chlortetracycline, 677 Chlorthalidone, 203 Chlorzoxazone, 677 Cholestatic effect, 4 Cholestyramine, 274, 677 Cholinesterase inhibitors, 511 Cholinesterases, 359 Chondrodysplasia punctata, 43 Chorioamnionitis, 660 Chorion frondosum, 659 Chorion laeve, 659 Chorionic villus sampling (CVS), 653, 654, 659 Chromosomal rearrangment, 656 Chromosome abnormalities, 653 Chromosome breakage, 656 Cigarette smoking, 455, 456 Cigarette use, 448 Cigarettes, 447 Ciguatera, overdose, 248 Cilastatin, 11 Cimetidine, 122, 203, 274, 677 Cimicifuga racemosa, 572 Ciprofloxacin, 117, 185, 677 Cisapride, 203, 741 Cisplatin, 274

Index 13-cis-retinoic acid, 169 Clarithromycin, 677 Clavulanate, potassium, 677 Clearance rate, 7, 76 Cleft palate, 151, 152, 154, 158, 159, 161, 163 Clemastine, 677 Clindamycin, 50, 185, 677 Clofazimine, 274 Clomiphene, 677 Clomipramine, 191, 363 Clomocycline, 677 Clonazepam, 199, 274, 677 Clonidine, 193, 346, 372, 677 Clorazepate, 678 Clotrimazole, 118, 678 Cloxacillin, 186, 678 Clusiaceae, 584 C max , 7 CNS hyperexcitability, 361 57 Co, 627 58 Co, 627 60 Co, 627 CO 2 , 468 Cocaine use, 456 Cocaine, 7, 42, 44, 61, 69, 325, 335, 383, 445, 455, 678, 739 Cocaine-dependent women, 432 Cochrane Review, 154 Codeine, 50, 120, 184, 274, 345, 371, 678 Cohort studies, 43, 153, 159, 161, 163 Colostrum, 177 Combined immune deficiency disorders, 662 Compendium of Pharmaceuticals and Specialties, 798 Complementary and alternative medicine (CAM), 569 Compliance, 76 Congenital abnormality, 653 Congenital toxoplasmosis, 158 Congenital varicella syndrome, 727 Constipation, 50 Contraception, 170, 171 Controlled-release formulation, 8 Cordocentesis, 661 Corticosteroids, 62, 121, 151, 153, 154, 157, 159, 160, 162, 163, 714, 719 Corticotropin, 160, 678 Cortisol, 177 Cortisone, 151, 152, 160, 162, 678 Cosmetic products for hair care, 124 Cotrimoxazole, 158 Cough, 50

Index Coumarin derivatives, 274, 678 57 Covitamin B12, 630 60 Covitamin B12, 630 51 Cr, 627 51 Cr-albumin, 630 Cranberry, 575 51 Cr-chromate red blood cells, 630 Creatinine clearance, 4 Critical window of development, 162 Crohn’s disease, 154, 160, 700 Cromolyn sodium, 50, 678 Crown-rump length, 662 137 Cs, 627 129 Cs-chloride, 631 Cumulative odd ratio, 154, 162 Cupressaceae, 580 Current Contents, 153, 737 CVS, 658 Cyanide overdose, 247 Cyclacillin, 678 CyclicAMP, 480 Cyclizine, 51 Cyclophosphamide, 14, 39, 60, 274, 678 Cyclosporin, 14, 275, 678 Cyclothiazide, 679 Cyproheptadine, 679 Cystic fibrosis, 657 Cytarabine, 61, 275, 679 Cytotoxic drugs, 656 Dactinomycine, 275 Danazol, 39, 275, 679 Dandelion, 575 Dandy-Walker syndrome, 39 Danish registry of lithium babies, 85 Dapsone, 119, 275 Data extraction, 154 Daughters of radium-226, 621 Daunorubicin, 275, 679 DDT, 517 Deafness-congenital, 161 Decongestants, 50 Deferoxamine, 240, 275 Dehydration, 12 Dehydroepiandrosterone sulfate (DHEAS), 665 Dehydrogenation, 6 Dehydropeptidase, 11 Demeclocycline, 679 Dental amalgams, 127 Depomedroxyprogesterone, 172 Depression, 50, 99

819 Desipramine, 191 Deterministic effects, 605 Developmental delay, 15 Developmental milestones, 437 Devil’s claw, 576 Dexamethasone, 160, 275, 679 Dextroamphetamine, 679 Dextromethorphan, 50, 120 Diabetes mellitus, 46, 663 Diabetes, 50 Diathermy, 636 Diatrizoate, 276 Diazepam, 5, 14, 40, 199, 276, 351, 372, 375, 679 Diazoxide, 276 Dibenzepin, 679 Dibromochloropropane, 512 Dibromomethane, 512 Dichloromethane, 558 Diclectin, 39, 40, 51, 807 Diclofenac, 197, 679 Dicloxacillin, 11 Dicumarol, 679 Dicyclomine, 679 Dieldrin, 516 Dienestrol, 679 Diethylstilbestrol (DES), 39, 42, 62, 276, 679 Diflunisal, 679 Digitalis overdose, 242 Digitalis, 276 Digoxin, 4, 7, 12, 14, 201, 708 Dihydrocodeine bitartrate, 276 Diltiazem, 194, 679 Dimenhydrinate, 50, 51, 121, 277, 680 Dimercaptosuccinic acid, 246 Dioscorea villosa, 585 Dioscoreaceae, 585 Dioxins, 518 Diphenadione, 680 Diphenhydramine, 50, 51, 120, 364, 680 Diphenoxylate, 680 Disopyramide, 202 Disruptive parenting, 448 Distribution drug, 1 Disulfiram, 680 DNA, 75 DNA analysis, 654 Docusate sodium, 50, 122, 277 Domperidone, 203 Dong Quai, 576 Dosage regimens, 159

820 Dose-response curves, 455 Dose-response relationship, 24 Dothiepin, 680 Double-outlet right ventricle, 158, 161 Down syndrome, 655, 663 Doxepin, 191, 277, 680 Doxorubicin, 14, 680 Doxycycline, 117, 680 Doxylamine, 38, 680 D-penicillamine, 245 Droperidol, 680 Drug absorption, 2 Drug compliance, 5 Drug distribution, 3 Drug elimination, 4 Drug formulation, 2 Drugs of abuse, 215 Ductus arteriosus, 39 Dyes, 124 Dyphylline, 680 Dysplastic kidneys, 158, 161 Ebstein’s anomaly, 39, 45, 63, 88 Echinacea, 577 Echoplanar Imaging (EPI), 662 Eczema, 160 EDTA, 245 Electromagnetic rays, 605 Elimination, 1 EMBASE, 153, 737 Embryonic palate, 161 Embryoscopy, 653 Employment, 448 Enalapril, 194, 277, 680 Encephalopathy, 340 Endocarditis, 338 Endosulfan, 516 Enflurane, 510 Enoxacin, 680 Environmental pesticides, 126 Environmental Protection Agency (EPA), 23, 24 Ephedra sinica Stapf., 582 Ephedraceae, 582 Ephedrine, 277, 680 Epichlorhydrin, 512 Epidemiological studies, 42, 154 Epidermolysis bullosa dystrophica, 662 Epidermolysis bullosa lethalis, 662 Epidermolytic hyperkeratosis, 662 Epilepsy, 46, 73, 105 Epinephrine, 277, 680 Epoetin alfa, 277, 680

Index Erb’s palsy, 158 Ergot alkaloids, 214 Ergotamine, 14, 211, 277, 681 Ericaceae, 575, 584 Erythroblast, 666 Erythromycin, 50, 117, 186, 681, 704 Erythroxylon coca, 445 Esmolol, 278, 681, Estradiol, 4, 681 Estrogen, 4, 176 Estrogens conjugated, 681 Ethacrynic acid, 278 Ethambutol, 725 Ethanol, 15, 44, 467, 681 Ethchlorvynol, 363 Ethinyl estradiol, 681 Ethisterone, 681 Ethoheptazine, 681 Ethosuximide, 15, 189, 278, 681 Ethotoin, 681 Ethyl biscoumacetate, 681 Ethylene dibromide, 512 Ethylene oxide, 512 Ethynodiol, 681 Etodolac, 681 Etoposide, 278, 681 Etretinate, 39, 65, 167, 279, 681 Evening primrose, 578 Evidence-based Risk Assessment, 161 Exposure assessment (EA), 556 Exposure index, 182

Fabaceae, 571, 581 FAE, 482 Famotidine, 203, 682 Fanconi’s anemia, 656 Fansidar, 119 59 Fe, 627 59 Fe-citrate Felbamate, 78 Fenfluramine, 682 Fentanyl, 279, 700 Feritin, 340 Fertility, 606 Fertility-male, 510 Fetal alcohol syndrome, 44, 60, 322, 339, 467 Fetal alcohol syndrome-diagnosis, 474 Fetal alcohol syndrome-epidemiology, 470 Fetal alcohol syndrome-mechanisms, 478 Fetal alcohol syndrome-prevention, 484 Fetal alcohol syndrome-risk factors, 476

Index Fetal alcohol syndrome-secondary disabilities, 482 Fetal alcohol-related abnormalities (FARA), 467 Fetal circulation, 6 Fetal death, 157 Fetal growth, 151 Fetal hair, 461 Fetal hydantoin syndrome, 8, 45, 64, 67, 75 Fetal imaging, 658 Fetal loss, 658 Fetal loss recurrent, 152, 161, 162 Fetal malformations, 495 Fetal Minamata disease, 45 Fetal reduction, 664 Fetal solvent (or gasoline) syndrome, 535 Fetal trimethadione syndrome, 65 Fetal warfarin syndrome, 45 Fetoplacental unit, 5 α-fetoprotein (AFP), 654, 658, 703 Fetus, 4 Feverfew, 578 (FISH), 654 Flecainide, 202, 279 Fluconazole, 186, 682, 741 Flucytosine, 118, 682 Flunitrazepam, 682 Fluorescent in situ hybridization, 654 Fluorouracil, 279, 682 Fluoxetine, 50, 90, 192, 682, 739, 741 Fluphenazine, 279, 364, 682 Flurazepam, 682 Flurbiprofen, 197, 682 Fluvoxamin, 192 FM, 636 Folate supplementation, 76 Folate, 137, 340 Folic acid deficiency, 682 Folic acid, 73, 141 Follicle stimulating hormone, 177 Follow-up, 153, 154 Food and Drug Administration, 24, 38, 49, 168 Formaldehyde, 513 Fosinopril, 682 Free-radical damage, 479 Frequency factor rating score (FFRS), 556 5-FU, 61 Fuel gas, 127 Furosemide, 203, 682 67 Ga, 627 Gabapentin, 7, 10, 78, 279, 682

821 Gamma rays, 605 Gangliosides, 479 Gastric acid secretions, 3 Gastric emptying time, 2 Gastric pH, 3 Gastrointestinal absorption, 2 Gemfibrozil, 682 Genital herpes, 659 Gentamicin, 11 Gestational age, 157 Gestational sac, 659 GFR, 7 Ginkgo biloba, 579 Ginkgoaceae, 579 Global assessment scale, 99 Glomerular filtration rate (GFR), 1, 4, 77 Glucocorticoids, 38, 50, 51, 151, 161 Glucose-6-phosphatase deficiency, 662 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 117 Glucuronidation, 6 Glutaraldehyde, 513 Glutethimide, 363 Glyburide, 280, 682 Glycerin, 50, 374 Glycyrrhiza glabra, 581 Goiter-fetal and neonatal goiter, 39 Gold salts, 719 Gold sodium thiomalate, 682 Gold, 211, 215 Goldenseal, 579 Graves, 712 Gray, 604 Gray-scale ultrasonography, 662 Griseofulvin, 118, 682 Growth deficiency, 472 Growth hormone, 177 Growth retardation, 615 Guaifenesin, 683 Gucocorticosteroid, 153 Gy, 604 3

H, 627 Habituation, 446 Hair, 457 Hair analysis (cocaine), 458 Hair analysis (nicotine), 459 Hallucinogens, 326 Halogenated hydrocarbon solvents, 513 Haloperidol, 51, 198, 683 Halothane, 3, 123, 510 Harlequin ichthyosis, 662 Harpagophytum procumbens DC, 576

822 Hay fever, 160 Hazard Identification, 24 hCG, 654, 703 Head circumference, 400 Headache, 50 Health determinants, 447 Hematuria, 335 Hemodialysis, 233 Hemoglobinopathies, 662 Hemolytic anemia, 335 Hemophilia, 657, 662 Heparin, 51, 683, 708, 728 Hepatic biotransformation, 1 Hepatic drug elimination, 4 Hepatic drug metabolism, 1 Hepatic microsomal enzyme, 4 Hepatic rupture, 335 Hepatic tumor, 664 Hepatitis B, 322 Hepatitis, 337 Herbal medicine, 569 Herbal remedies, 232 Heroin, 324, 338, 371, 683 Hexachlorophene, 683 Hexamethonium, 280, 683 197 Hg, 627 203 Hg, 627 Hirschprung’s disease, 158, 161, 162 HIV infections, 322, 335, 338, 775 Home environment, 448 Human chorionic gonadotropin (hCG), 664 Human teratogenesis, 38 Humulus lupulus, 580 Hydralazine, 51, 194, 280 Hydrastis canadensis, 579 Hydrochlorothiazide, 203, 683 Hydrocodone, 683 Hydrocortisone, 160 Hydroflumethiazide, 683 Hydronephrosis, 727 Hydroxychloroquine, 119, 204, 683 Hydroxyprogesterone, 280, 683 Hydroxyzine, 51, 363, 683 Hyperalgesia, 346 Hyperbaric oxygen, 261 Hyperbilirubinemia, 348 Hyperelastosis, 64 Hyperemesis gravidarum, 12 Hypericum perforatum, 584 Hyperreflexia, 346 Hypertension, 46, 51, 446 Hyperthyroidism, 51

Index Hypnosedatives, 327 Hypoalbuminaemia, 1, 4 Hypoglycemic drugs, 39 Hypokalemia, 340 Hypospadias, 158, 161 Hypothyroidism, 39, 158 Hypoxemia-fetal, 446, 481 123

I, 627 I, 627 131 I, 627 192 I, 627 131 I-fibrinogen, 631 Ibuprofen, 197, 281, 683 Idarubicin, 281 IDLH, 509 125 I-human serum albumin, 631 Illicit substances, 322 Imipenem, 11, Imipramine, 192, 683 111 In, 627 113m In, 627 111 In-DTPA, 631 In vitro fertilization (IVF), 657 Incidence rate, 161 Inclusion criteria, 159 Index of parental attitudes, 99 Indigo carmine, 683 Indomethacin, 197, 281, 683 Infant development, 431 Inflammatory bowel disease, 159, 160 Inhaled steroids, 154 Inhibin, 654, 665 Insecticides, 126 Insomnia, 105 Insulin (human), 50, 177, 282 Insulin dependent diabetes mellitus, 665 Interrater agreement, 154 Intestinal motility, 2 Intragenic probes, 656 Intrauterine growth retardation, 46, 293, 447, 477, 661, 664 Intrauterine infections, 662, 664 123 I-iodide, 631 Iodides, 282 Iodinated glycerol, 683 Iodine, 15, 216, 683 Iodine-containing substances, 211 123 I-iodohippurate, 631 131 I-iodohippurate, 631 131 I-oleic acid, 631 Ion trapping, 6 125

Index

823

Ionizing radiation, 605 Ionizing radiation-biological effect, 606 Ipecac-induced emesis, 233 Ipratropium, 684 Iprindole, 684 IQ, 471 Iron overdose, 239 Iron, 480, 699 123 I-rose bengal, 632 131 I-rose bengal, 631 123 I-sodium iodide (15% uptake), 632 Isoflurane, 3 Isoniazid, 186, 282, 684, 725 Isoproterenol, 282, 684 Isotretinoin, 39, 41, 44, 65, 167, 684 Isoxsuprine, 283 Itraconazole, 684 131 I-triolein, 631

Lisinopril, 284, 684 Lithium carbonate, 14, 63 Lithium, 5, 12, 14, 39, 45, 50, 51, 85, 198, 211, 284, 685, 741 Local anesthetics, 51 Locus ceruleus, 346 Lomefloxacin, 685 Loperamide, 203, 685 Loratadine, 193, 685 Lorazepam, 200, 284, 685 Lovastatin, 685 Low birth weight, 151, 347, 386 Lowest observed adverse effect level (LOAEL), 30 Lupus anticoagulant, 162, 664, 699 Lupus, 154, 160 Luteotropic hormone, 177 Lysergic acid diethylamide, 685

Juniper, 580 Juniperus communis, 580

Ma Huang, 582 Magnesium hydroxide, 51 Magnesium sulfate, 285 Magnetic resonance imaging (MRI), 622, 653 Malathion, 127 Malformation, 38, 383 Malformations Major, 386 Malnutrition, 337 Maloprim, 119 Mammary tissue, 176 Mammography, 701 Manganese, 480 Mania, 51 Mantel-Haenszel Summary (OR), 154, 159 Maprotiline, 685 Marfan’s syndrome, 657 Margin of exposure (MOE), 33 Marijuana, 340, 685 Mass-media, 812 Material safety data sheets (MSDS), 530 Maternal addiction, 448 Maternal age, 156, 448 Maternal compliance, 448 Maternal diseases, 653 Maternal infection, 448 Maternal IQ, 433 Maternal race, 448 Maternal serum α-fetoprotein, 654 Maternal serum screening, 654 Maternal STD, 448 Maternal-Fetal Drug Equilibration, 6 Maternal-placental-fetal unit, 1

40

K, 627 K, 627 Kanamycin, 283 Karyotype, 654 Kava, 581 Ketamine, 283 Ketoconazole, 186, 684 Ketoprofen, 684 Ketorolac, 197, 684 42

Labetalol, 13, 51, 194, 283, 684 Laminaceae, 583 Lamotrigine, 10, 684 Lanugo, 461 Laser, 639 Laxatives, 122 LDH, 703 Lead overdose, 244 Lead, 62, 515, 531, 536 Left ventricular atresia, 161 Levofloxacin, 684 Levonorgestrel implants, 41 Levothyroxine, 684 L-hyoscyamine, 684 Licorice, 581 Lidocaine, 4, 123, 284, 684 Limb reduction defects, 661 Lindane, 117, 516, 684 Liotrix, 684 Lipophilic drugs, 6

824 Matricaria recutita, 574 Maximum concentration limits (MCLs), 23 Maximum permissible exposure, 620 McCarthy Scales of Children’s Abilities, 98, 450 Mebendazole, 685 Mechlorethamine, 60, 685 Meclizine, 51, 685 Meclofenamate, 685 Meconium, 457, 460 Meconium staining, 359 Medicago sativa, 571 Medline, 153, 737 Medroxyprogesterone, 41, 285, 685 Mefenamic acid, 197, 685 Melaleuca alternifolia Cheel, 584 Melphalan, 285, 685 Menadione, 285 Mental health, 483 Mental retardation, 483, 610 Mentha x piperita, 583 Meperidine, 13, 184, 285, 685, 700 Mephenytoin, 685 Mepindolol, 685 Mepivacaine, 285 Meprobamate, 686 6-Mercaptopurine, 285, 686, 714 Mercuric sulfide, 63 Mercury, 515, 558 Merrell Dow, 808 Mestranol, 686 Meta-analyses, 43, 105, Meta-analysis, 151, 152, 153, 159, 160, 161, 162, 163, 383, 495, 547, 738, 805 Metaproterenol, 686 Methacycline, 686 Methadone maintenance substitution, 321 Methadone maintenance, 324 Methadone, 286, 371 Methamphetamine, 686 Methazolamide, 686 Methenamine, 686 Methicillin, 11 Methimazole, 15, 39, 51, 199, 686 Methocarbamol, 686 Methotrexate, 14, 39, 61, 286, 686 Methotrimeprazine, 686 Methoxyflurane, 3 Methyclothiazide, 686 Methyl mercury, 45, 63, 686 Methyldopa, 51, 194, 286, 686 Methylene blue, 286, 687

Index Methylene chloride, 511 Methylergometrine, 204 Methylphenidate, 687 Methylprednisolone, 160 Methysticum, 581 Metoclopramide, 51, 203, 687 Metocurine, 4 Metolazone, 687 Metoprolol, 195, 687 Metronidazole, 118, 186, 687, 739 Mexiletine, 202 Miconazole, 118, 687 Microcephaly, 610 Microglossia, 161 Micronutrients, 480 Microphthalmia, 473 Microwaves, 636 Midazolam, 200, 286 Mifepristone, 687 Migraine, 50 Milk-to-plasma (M: P) ratio, 1, 14, 178, 179 Minamata disease, 127 Mindoxidil, 687 Minocycline, 687 Minoxidil, 195, 287 Miscarriage, 157, 655 Misinformation, 792 Misoprostol, 39, 42, 63, 69, 287, 687 Misperception, 793 Moebius sequence, 39, 63 Morning sickness, 807 Morphine, 184. 287, 700 Mosaicism, 661 Mosaicism-placental, 661 Motion sickness, 51 6-MP, 61 MRI, 702 MSAFP, 654, 664 Mucopolysac-charidosis, 657 Multiples of the median (MoMs), 664 Mutation analysis, 656 Myasthenia gravis, 663 Myelosuppression, 15 Myometrium, 4 Myotonic dystrophy, 657 Myrtaceae, 584 22

Na, 627 Na, 627 Nabumetaone, 687 Nadolol, 195, 287, 687 Nalbuphine, 287 24

Index Nalidixic acid, 187, 687 Naloxone, 287 Naphazoline, 50 Naphthalene overdose, 248 Naproxen, 197, 287 Narcotic opioids, 319 Narcotic withdrawal, 349 Narcotics, 321, 324 National Institute for Occupational Safety and Health, 509 Natural gas, 127 Nausea and vomiting of pregnancy, 3, 40, 51, 774 Nematocide, 512 Neonatal abstinence syndrome, 371, 373 Neonatal bleeding, 73 Neonatal death, 157 Neonatal hemorrhage, 79 Neonatal hypoglycemia, 39 Neonatal withdrawal, 371 Nephrosis, congenital, 664 Neural tube defects (NTDs), 8, 39, 45, 73, 61, 137, 663 Neurobehavioral development, 43 Neurodevelopment, 97 Neurodevelopmental risks, 445 Neuronal circuitry, 477 Neuronal loss, 477 Niacin, 480 Nicotinamide adenine dinucleotide, 468 Nicotine, 6 Nicoumalone, 687 Nifedipine, 13, 158, 162, 195, 687 Nitrazepam, 200 Nitrendipine, 195 Nitrofurantoin, 187 Nitroglycerin, 287 Nitroprusside, 287 Nitrous oxide, 123, 510 Nizatidine, 203 No observable adverse effect level (NOAEL), 30, 510 Nonoxynol-9, 687 Nonsteroidal ani-inflammatory drugs, 39, 50 Nonstochastic effect, 605 Norethindrone, 287, 687 Norfloxacin, 117, 688 Norgestrel, 688 Norplant, 172 Nortriptyline, 192, 287, 688 Nuchal translucency, 655, 665

825 Nutmeg overdose, 247 Nutritive sucking behavior, 378 Nutt, 572 Nystatin, 118 Obidoxime, 241 Occupational exposures, 507, 529 Occupational Safety and Health Administration (OSHA), 508 Odds ratio, 497 OEL, 556 Oenothera biennis, 578 Ofloxacin, 187, 688 Oligohydramnios, 657 Olsalazine, 688 Omeprazole, 688, 741 Onagraceae, 578 Oncogenesis, 615 Opiate withdrawal, 347 Opioids, 39, 337, 345, 372 Opipramol, 688 Opium 374 Optic nerve hypoplasia, 473 Oral clefts, 108, 152, 159, 163 Oral contraceptives, 40, 122, 170, 211, 216, 287, 688 Organic solvents, 63, 125, 339, 514, 516, 531, 532, 547 Organochlorine insecticides, 516 Organogenesis, 152 Organophosphate pesticide poisoning, 233, 241 Organophosphates, 126 Ornithine carbamyl transferase deficiency, 662 Orogastric lavage, 233 Ovarian cysts, 664 Oxazepam, 200, 688 Oxcarbazepine, 78 Oxidation, 6 Oxprenolol, 195, 688 Oxycodone, 184 Oxymetazoline, 50, 288 Oxyphenbutazone, 688 Oxytetracycline, 688 Oxytocin, 176 Oxytotic drugs, 6 32

P, 627 P-450, 480 Paints, 125 Palate development, 152

826 Para-amino salicylic acid, 688 Paraldehyde alone, 351 Paramethadione, 39, 688 Paraquat overdose, 247 Paregoric, 351, 372, 375 Parity, 156, 448 Paroxetine, 688 Passiflora incarnata, 582 Passifloraceae, 582 Passion flower, 582 Passive diffusion, 1 Pedaliaceae, 576 Pedigree risk, 656 PEL, 508 Penbutolol, 688 Penicillamine, 64, 689 Penicillin, 4, 14, 117, 187, 722 Penicillin G, 10 Penicillin V, 11, 187, 689 Pentamidine, 689 Pentazocine, 288, 345, 689 Pentoxifylline, 689 Peppermint, 583 Peptic ulcer disease, 51 Perchloroethylene, 560 Percutaneous fetal blood sampling, 661 Percutaneous umbilical blood sampling (PUBS), 653, 661 Percutaneous umbilical cord sampling, 654 Permanent wave solutions, 125 Permissible emission levels (PELs), 23 Permissible exposure limit, 508 Perphenazine, 198, 689 Pethidine, 13 PGE 2 , 700 PGF 2a , 700 Pharmacogenetic variability, 25 Phenacetin, 689 Phenazocine, 288 Phenazopyridine, 689 Phencyclidine, 326, 340 Phendimetrazine, 689 Phenindione, 689 Pheniramine, 689 Phenobarbital, 8, 15, 78, 189, 211, 288, 351, 361, 372, 375, 689 Phenol, 517 Phenolphthalein, 50 Phenothiazines, 363 Phenoxymethylpenicillin, 11 Phenprocoumon, 689 Phenylbutazone, 689

Index Phenylephrine, 50, 120, 689 Phenytoin, 4, 7, 8, 14, 39, 41, 45, 64, 67, 74, 77, 189, 288, 689 Phocomelia, 65 Physician’s Desk Reference (PDR), 37, 733, 798 Phytonadione, 689 Pindolol, 288, 689 Piperaceae, 581 Piperacillin, 11 Piperazine, 118, 689 Piperonyl butoxide, 118 Piperoxane, 346 Piroxicam, 197, 690 PIVKA, 79 Placenta praevia, 337 Placenta, 4, 231 Placental barrier, 6 Placental blood flow, 5 Placental hormones, 4 Placental position, 657 Placental sampling, 653 Plasma volume, 3, 76 Platelets, 662 Pneumothorax, 337 Podophyllum, 289, 690 Polyacrylamide gel electrophoresis (PAGE), 664 Polybrominated biphenyls (PBBs), 517 Polychlorinated biphenyls (PCBs), 63, 69, 517, 531, 690 Polycystic kidneys, 664 Polydactyly, 158 Polydrug use, 478 Polymerase chain reaction (PCR), 655 Polythiazide, 690 Positive predictive value, 161 Postcoital contraceptives, 42 Potassium 40 (40 K), 621 Potassium iodide, 690 Poverty, 448 Povidone-iodine, 690 Prazosin, 51 Precipitous delivery, 359 Preconceptional counseling, 79 Prednisolone, 160, 162, 205, 289, 690 Prednisone, 151, 152, 155, 158, 160, 161, 162, 289, 723 Pre-eclampsia, 13, 712 Pregnancy outcome, 157 Pregnancy prevention program, 167 Pregnancy-induced hypertension, 6

Index Pregnancy-specific b 1 -glycoprotein, 665 Preimplantation blastomere biopsy, 654 Preimplantation diagnosis, 653, 657 Premature labor, 337, 726 Premature rupture of membranes (PROM), 337, 400 Prematurity, 155, 157, 387, 447, 448, 664 Prenatal care, 448 Prenatal diagnosis, 653 Preterm delivery, 334 Primaquine, 119 Primidone, 15, 190, 289, 690 Probenecid, 690 Procainamide, 202 Procarbazine, 690 Prochlorperazine, 690 Progesterone, 2, 4, 122, 158, 176, 690 Prolactin, 176 Promazine, 289 Promethazine, 289, 690 Propafenone, 202 Propofol, 290 Propoxyphene, 345, 690 Propranolol, 4, 14, 195, 290, 690 Propylthiouracil (PTU), 15, 39, 51, 199, 290, 690 Prospective controlled cohort study, 151 Prospective study, 152, 154, 158, 161 Prostaglandins, 69, 480 Prostitution, 334 Protein binding, 1, 4, 7, 76 Proteinuria, 335 Prozac, 90 Pruritus, 51 Pseudocholinesterase, 664 Pseudoephedrine, 120, 205, 691 32 P-sodium phosphate, 630 Psoriatic arthropathy, 160 Psychiatric comorbidity, 448 Psychoactive drugs, 39 Psychopathology, 483 Puerperium, 12 Pulmonary absorption, 1, 3 Pulmonary stenosis, 158, 161 Pyelonephritis, 726 Pyloric stenosis, 158, 161 Pyrantel pamoate, 118 Pyrethrins, 118 Pyribenzamine, 338 Pyridoxine, 38, 291, 691, 725 Pyrimethamine, 119 Pyrvinium pamoate, 118

827 Quality assessment score, 154 Quality assessment, 153, 154 Quality of the studies, 159 Quazepam, 691 Quinacrine, 691 Quinapril, 691 Quinethazone, 691 Quinidine, 202, 291 Quinine, 119, 232, 249, 291, 691 Quinolones, 741 224

Ra, 627 Ra, 627 Rad, 604 Radar, 636 Radiation, 128, 519, 603 Radiation-ionizing, 603 Radiation-nonionizing, 603 Radio waves, 636 Radiodiagnosis, 617 Radiodiagnostic procedures, 623 Radioiodine, 282 Radionuclides, 626 Radiopharmaceuticals, 211, 214 Radiotherapy, 701 Radon, 633 Ramipril, 691 Ranitidine, 51, 122, 203, 691 Ranunculaceae, 572, 579 Rating factor (RF), 556 Raven’s Standard Progressive Matrices, 433 RBE, 604 RCT, 152 Real-time imaging, 662 Recall bias, 46 Recommended exposure limit, 509 Recreational cocaine, 431 Reduction, 6 Reference dose (RfD), 29 REL, 509 Relative biological effectiveness, 604 Relative risk (RR), 153 Rem, 604 Renal blood flow, 4 Renal excretion, 1 Renal insufficiency, 335 Renal plasma flow, 7 Renal tubular acidosis, 340 Reproductive toxins, 507 Reserpine, 291, 691 Restricted growth, 38 Retinoic acid, 68, 691 226

828 Retinoid embryopathy, 44 Retinoid, 39, 65, 167, 455 Reynell language test, 450 Rhabdomyolosis, 340 Rhesus disease, 662 Rheumatoid arthritis, 154, 159, 160 Rh-ve-sensitized women, 660 Riboflavin, 480 Rifampicin, 4, 291 Rifampin, 691, 725 Ritodrine, 291 RNA, 75 Robert’s syndrome, 656 Roentgen, 604 Roentgen-equivalent man, 604 RR, 158, 162 Rubella, 662 Rupture of membranes, 660 35 S, 627 Saccharin, 124 Sacral agenesis, 663 Safety sheets, 508 Salbutamol, 120 Salicylates overdose, 237 Salicylates, 5, 38, 40, 42 Sample size, 159 Sarcoidosis, 154, 160 Scavenging enzymes, 75 Schultz-Bip, 578 Scopolamine, 291 75 Se, 627 Secobarbital, 362, 691 Seizure control, 73 Seizures, 337, 361 Selenium, 480 75 Se-selenomethionine, 630 Sensitivity analysis, 154, 498 Sertraline, 192, 691 Sex hormones, 739 Sex-linked conditions, 654 Sexual activity, 477 Sexually transmitted diseases, 334 Short-term exposure limit, 509 SIDS, 351, 360 Sievert, 604 Silver nitrate, 707 Simethicone, 691 Simvastatin, 691 Single motherhood, 448 Single-gene disorders, 653, 656 Slippery elm, 583

Index Small for gestational age, 293 Snake bites, 249 Cocaine users, social, 431 Social drugs, 215 Socioeconomic index, 143 Socioeconomic status, 433, 448, 476 Sodium iodide, 691 Sodium salicylate, 6 Sodium transporter, 12 Solanaceae, 573 Solvents, 326 Sotalol, 15, 195, 292, 691 Sparfloxacin, 691 Spearman’s rho, 159 Spermatogenesis, 606 Spermicides, 38, 40, 691, 739 Spina bifida, 65, 161, 655 Spiramycin, 724 Spironolactone, 203, 692 Spontaneous abortion, 535, 551, 656 Spreng, 584 85 Sr, 627 90 Sr, 627 SSRIs, 741 St. John’s Wort, 584 Stabilization, 233 Statistical tests, 802 Steady-state drug concentrations, 4 STEL, 509 Sterility, 606 Sterilization, 172 Stillbirth, 151, 157, 446 Stimulants, 321, 358 Stochastic effect, 605 Strabismus, 473 Streptokinase, 51 Streptomycin, 292 Styrene, 518, 559 Subfertility, 160 Substance P, 346 Substance use, 775 Substance withdrawal syndrome, 373 Sucralfate, 51, 692 Sugar substitutes, 124 Suicidal gestures, 232 Sulfadoxine, 119 Sulfamethoxazole, 187 Sulfasalazine, 160, 692, 714 Sulfisoxazole, 187 Sulfonamides, 117, 292, 692 Sulfur, 118 Sulindac, 292, 692

Index Sulphasalazine, 205 Sumatriptan, 205, 692, 741 Summary OR, 163 Supportive care, 233 Syphilis, 337 Systemic lupus erythematosus, 159, 663 TA: therapeutic abortion, 156 Tachycardia, 446 Talipes equinovarus, 659 Tamoxifen, 292, 692 Tanacetum parthenium, 578 TAR syndrome, 662 Taraxacum officinale G.H., 575 Tay-Sachs, 657 99m Tc, 627 99m Tc-diphosphonate, 630 99m Tc-DTPA, 630 99m Tc-human albumin microspheres, 630 99m Tc-human serum albumin, 632 99m Tc-lung aggregate, 632 99m Tc-macoaggregated albumin, 630 99m Tc-pertechnetate, 630 99m Tc-polyphosphate, 632 99m Tc-sodium pertechnetate, 632 99m Tc-stannous glucoheptonate, 632 99m Tc-sulfur colloid, 631 99m Tc-sulfur colloid, 632 Tea tree oil, 584 Tegison, 167 Temazepam, 201, 692 Teratogen Information Services, 43, 733, 747 Teratogenic risk, 47, 789 Terbutaline, 292 Terconazole, 692 Terfenadine, 193, 692 Terpin hydrate, 692 Testicular hypoplasia, 606 Testosterone, 469 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 518 Tetrachloroethylene, 514, 559, 560, 561 Tetracycline, 39, 65, 117, 187, 292, 692 Thalidomide, 38, 39, 41, 45, 65, 167, 172, 455 Thalidomide b, 692 Theophylline, 4, 14, 121, 206 Therapeutic abortion, 232 Therapeutic irradiation, 654 Thermoluminescent dosimeters (TLD), 622 Thioguanine, 692

829 Thiopental, 510 Thiopropazate, 693 Thiothixene, 693 Threshold limit value, 509 Threshold limit value-time-weighted average (TLV-TWA), 530 Thrombocytopenia, 335 Thrombophlebitis, deep vein thrombosis, 51 Thyroid, 693 Thyroid-parathyroid hormone, 177 201 Tl, 627 204 Tl, 627 201 Tl-chloride, 631 Tidal volume, 3 Time-weighted average, 509 Timolol, 195, 693 Tipolidine, 193 TLV, 509 TLV-TWA, 555 Tobacco, 328, 693 Tolazamide, 693 Tolbutamide, 693 Tolmetin, 693 Toluene, 339, 559, 562 Topiramate, 78 Total body water, 1 Toxemia, 12, 337 Toxoplasmosis, 662 Tranquilizers, 2 Transfusions, 721 Transitional milk, 177 Transplantation, 151, 154 Trazodone, 192 Tretinoin, 50, 693 Triamcinolone, 160, 693 Triazolam, 693 Trichlormethiazide, 693 Tricyclic antidepressants, 50, 90, 363 Trifluoperazine, 693 Trimethadione, 39, 65, 693 Trimethoprim, 117, 187, 693 Tripelennamine, 50 Triprolidine, 693 Trisomy, 18, 665 Tryptophan, 480 ‘‘Ts and blues’’, 338 TSH, 712 TWA, 509 uE3, 654 Ulcerative colitis, 154, 160

830

Index

Ulmaceae, 583 Ulmus rubra Muhl., 583 Ultrasound, 637, 657 Umbilical vein, 6 Unbound (‘‘free’’) drug, 4 Uncertainty factor (UF), 30 Undescended testicles, 158, 161 Uniparental disomy, 661 Ureidopenicillins, 11 Uterine abnormalities, 659 Uterine blood flow, 4 Uterine irritability, 338 Uterine vascular resistance, 446 Urticaria, 160 Uva-ursi, 584

Visual impairment, 473 Vitamin A acid, 50, 694, 741 Vitamin B 12 deficiency, 700 Vitamin E, 480 Vitamin K, 73, 79, 725 Vitex agnus-castus, 574 Volume of distribution, 3, 469

Vaccines, 123 Vaccinium macrocarpon Ait, 575 Vaginal bleeding, 660 Valproic acid, 6, 7, 8, 39, 45, 65, 78, 190, 694 Vancomycin, 187 Varicella, 774 Vascular disruption, 661 VD, 3 VDRL, 723 Verapamil, 196 Verbenaceae, 574 Video display terminals, 128, 531, 532, 634 Vigabatrin, 7, 10, 78 Vinblastine, 694 Vincristine, 694 Vineland Adaptive Behavior Scales, 433

127

Warfarin, 14, 39, 41, 42, 45, 62, 206, 694, 708, 728 Weber ex Wiggers, 575 Wechsler adult intelligence scale-revised, 98 Whole-bowel irrigation, 233 Wild yam, 585 Withdrawal syndrome, 325, 345 Xe, 627 Xe gas, 631 133 Xe, 627 Xeroderma pigmentosum, 656 X-linked disorders, 654 X-rays, 128, 605 Xylometazoline, 50 127

169 90

Yb-DTPA, 631 Y, 627

Zidovudine, 694, 698 Zinc oxide, 51 Zona pellucida, 654 Zopiclone, 192 Zuclopenthixol, 694 Zygosity, 657

About the Editor

Gideon Koren is Director of the Motherisk Program at the Hospital for Sick Children, Toronto, Ontario, Canada, and Professor of Pediatrics, Pharmacology, Pharmacy, Medicine, and Medical Genetics at the University of Toronto, Canada. The author of over 800 peer-reviewed articles, abstracts, and books, including Nausea and Vomiting of Pregnancy: State of the Art 2000 (The Motherisk Program), he is a Diplomat of the American College of Medical Toxicology and the Royal College of Physicians and Surgeons of Canada, as well as a Senior Scientist of the Canadian Institutes of Health Research. A member of the American Society of Clinical Pharmacology and Therapeutics, the American Academy of Toxicology, the Israeli Medical Association, and the Canadian Society of Clinical Investigation, Dr. Koren received the M.D. degree (1973) from the Sackler School of Medicine, Tel Aviv, Israel.

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