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 Foreword

Many years ago, the great scientific books were written by individual authors. In our field of develop-
mental biology and teratology, many of us still keep these books on our shelves because they are
‘‘classics,’’ even though portions of these texts may be outdated. Books that come to mind are Paul
Weiss’s text on embryonic development (1939), Warkany’s classic on congenital malformations
published after a life of research and clinical involvement in teratology (1971), Wilson’s book on
environmental causes of birth defects (1973), and Kalter’s excellent text dealing with the teratology
of the central nervous system (1968). Scientists sometimes forget that these books are authored by
one colleague. In ‘‘modern times,’’ one writes a book by corresponding with twenty, thirty, or
more colleagues, and then includes the book among the references listed in one’s curriculum vitae.
Multiauthored books can be excellent resources, but they rarely become classics.
This foreword is written as an introduction to the third edition of James Schardein’s classic
on chemical teratogenesis. It is truly a life’s work, necessitating hours of literature review and, of
course, the collection of these references. The immensity and completeness of the bibliography and
the extensiveness of the index makes the book a necessity for teratologists who wish to become
familiar with many aspects of environmental reproductive risks. Besides presenting exhaustive re-
views of the literature dealing with the reproductive effects of chemicals and drugs, Schardein has
prepared numerous tables that summarize these reproductive effects clearly and succinctly.
If you fail to read Chapter 1, you will miss an enormous amount of teratology common sense.
In fact, the first chapter could be a book all by itself. Schardein’s views on the utilization of in vivo
animal testing and in vitro tests for determining teratogenic risks in humans represent a scholarly
tutorial on these subjects.
There seem to be so many books that deal with the subjects covered by Schardein (Scialli et
al., 1995; Friedman and Polifka, 1994; Shepard, 1998; Briggs et al., 1998; and Gilstrap and Little,
1998). Do we need all these books? I cannot answer that question, except to say you can never
have too many good books, and each of these books has a different perspective. It is important that
many respected scholars share their expertise in books and peer-reviewed articles, because a unanim-
ity of opinion about subjects that could be controversial can be cited by authors expressing similar
viewpoints. In some respects, teratology opinions and speculations can be inflammatory, especially
when expressed by individuals with little experience in the field. Therefore, it can be comforting
to know that erroneous and unscholarly pronouncements can be rebutted easily because of the litera-
ture that is available. Teratologists may wonder why there is not a unanimity of opinion about many
aspects of teratology. But most scientific and medical fields have some areas of controversy.
Teratology is unique because the subject matter deals with such a high proportion of rather
emotional medical problems. Dr. Warkany reviewed some aspects of this subject in Congenital
Malformations (1971). He pointed out that mothers who delivered babies with congenital malforma-
tions were punished in ancient times. The implication was that the mother must have done something
dishonorable to be punished with the birth of a malformed child. Even to this day there are certain
diseases that are thought of as punishments or afflictions. The diseases of affliction—cancer, mental
retardation, genetic diseases, abortion, and congenital malformations—are the ones that engender
an inordinate amount of guilt and anger; these also represent a larger share of negligence litigation
malpractice suits and long term burdens for the families (Brent, 1999). You will note that four of

iii
iv FOREWORD

the five diseases of affliction are diseases related to reproduction. So it is not surprising that reproduc-
tive failure can be a burdensome problem to the family that is affected.
We look forward to many more editions of James Schardein’s Chemically Induced Birth De-
fects.
Robert L. Brent, M.D., Ph.D., D.Sc.
Distinguished Professor
Louis and Bess Stein Professor of Pediatrics
Professor of Radiology, Pathology, Anatomy and Cell Biology
Jefferson Medical College
Head, Laboratory of Clinical and Environmental Teratology
Alfred I. duPont Hospital for Children
Wilmington, Delaware

REFERENCES
Brent, R. L. (1999). Utilization of developmental basic science principles in the evaluation of reproductive
risks from pre- and postconception environmental radiation exposures. Teratology 59: 182–204.
Briggs, G. G., Freeman, R. K., and Yaffe, S. J. (1998). Drugs in Pregnancy and Lactation: A Reference
Guide to Fetal and Neonatal Risk. 5th Ed., William & Wilkins, Baltimore.
Friedman, J. M. and Polifka, J. E. (1994). Teratogenic Effects of Drugs: A Resource for Clinicians (TERIS).
Johns Hopkins University Press, Baltimore.
Gilstrap, L. C. and Little, B. B. (1998). Drugs and Pregnancy, 2nd Ed., Chapman & Hall, New York.
Kalter, H. (1968). Teratology of the Central Nervous System, University of Chicago Press, Chicago.
Scialli, A. R., Lione, A., and Padgett, G. K. B. (1995). Reproductive Effects of Chemical, Physical, and
Biologic Agents Reprotox. Johns Hopkins University Press, Baltimore.
Shepard, T. H. (1998). Catalog of Teratogenic Agents. 9th Ed. Johns Hopkins University Press, Baltimore.
Warkany, J. (1971). Congenital Malformations: Notes and Comments. Year Book Medical Publishers,
Chicago.
Weiss, P. (1939). Principles of Development: A Text in Experimental Embryology. Henry Holt, New York.
Wilson, J. G. (1973). Environmental and Birth Defects. Academic Press, New York.
 Preface

Suspicions are justified, perspicacity is necessary; but it is not wise to present suspicions and
beliefs as facts, lest we create modern superstitions. We find now that modern unproven beliefs
reach millions of people by popular magazines, radio, and TV. There is a danger that we may
become the most superstitious population of all times. Let us be specific about dangers and
not condemn all drugs and chemicals as fetotoxic, let us not confuse suspicions with facts, or
we do great harm to our fellow man.
J. Warkany, 1972
According to estimates, of about 3 million infants born in the United States each year, some 250,000
will have birth defects (Dwivedi and Iannacocone, 1998). In other words, of about 10,684 babies
born in the United States on an average day, 781 have low birth weight, 411 are born with a birth
defect, 81 die before their first birthday, and 18 die as a result of a birth defect (March of Dimes,
1998). In addition, countless lives are claimed each year through spontaneous abortion, stillbirth,
and miscarriage due to defective fetal development.
Congenital anomalies rank about sixth among all causes of death in the United States, according
to published data.* Some 10 times as many children die of malformations as from contagious dis-
eases, and they account for 20% of all postnatal deaths (Mofenson et al., 1974). Furthermore, almost
one-half of the children confined in hospitals are there because of prenatally acquired birth defects
(Shepard, 1989). The social burden can be more fully appreciated when one considers that birth
defects affect the daily lives in some way or another of 15 million persons in the United States
alone, and the cost of caring for individuals with major disorders is staggering (almost $13 billion
annually over 20 years ago) (Wallace, 1976). With estimates that as many as 75,000 chemicals may
be in use at present and new ones added each year, the concerns over chemical and drug causation
of birth defects have reached immense proportions, and show no signs of abating.
Anxieties generated by these gloomy statistics have led in recent years to implications of envi-
ronmental agents as a potential source of reproductive failures and induction of congenital malforma-
tion. Witness the real or imagined claims in contemporary history of hazardous events associated
with methyl mercury, alcohol, cigarette smoking, PBBs and PCBs, red dye #2, OCs, spray adhesives,
DES, anesthetic gases, caffeine, 2,4,5-T, dioxin and Agent Orange, lead, Bendectin, cocaine, and,
of course, the notorious thalidomide.
The frequency of some types of reproductive impairment has changed in time at a rate much
too rapid to be explained by genetic changes or changes in other intrinsic factors (Nisbet and Karch,
1983). Drugs and other chemicals are part of the broad spectrum of environmental factors that are
known or suspected to impair reproductive success in humans, and there is at present only limited
evidence that can be used to estimate their overall importance. While there are data to indicate that
drugs and chemicals have substantial adverse effects on reproduction in highly exposed groups,
such as smokers and drinkers, evidence that they may have such effects in the general population
is scant and inconclusive. This is because it is extremely difficult, if not impossible, to investigate

* National Center for Health Statistics, 1978.

v
vi PREFACE

possible effects of widespread, low-level exposure in the environment. Thus, while it has been
estimated that only a fraction of the total spectrum of defects observed in humans is due to drugs
and environmental chemicals, it is highly important that all potential chemical teratogens be identi-
fied and measures taken to control use or exposure to them by pregnant women and their unborn
children.
Over twenty years ago, I cited the fact that more than 1900 chemicals had been tested for
teratogenicity in animals, of which about one-third were teratogenic (Schardein, 1976). My current
estimate, substantiated by studies reported in this volume, is that more than 4100 chemicals have
been tested to date, and again about one-third (34%) are teratogenic, as shown in the table.

Number Chemicals Tested for Teratogenicity

Teratogenic
Tested Clearlya Probablyb Possiblyc Not teratogenicd
4153 291 730 372 2760
a
In two or more species.
b
Based on limited testing or positive in majority of species tested.
c
Equivocal or variable reaction, and/or less than obvious response.
d
At least by testing regimens employed.

It is the purpose of the present volume to catalog the available data on drugs and chemicals
with respect to their potential teratogenicity in animals and in humans. Each year, as the list of
drugs available to the consumer grows and the number of environmental chemicals and pollutants
increases, it becomes increasingly important to establish criteria by which agents can be accurately
determined for possible hazard before public use, if birth defects are ever to be prevented. A number
of other reference works have appeared on drug or chemical usage since the preparation of the
second edition of this work, but no volume is available that correlates the laboratory and clinical
teratogenic properties of environmental chemicals in the same manner as this book. It is hoped that
the present work will serve as a useful source of reference to scientists and clinicians now and in
years to come.
Justification for revising this work lies in the continuing need for identifying chemical exposures
that present potential toxicity to the developing human conceptus. And while it is true that no major
epidemics of birth defects have surfaced since intensive animal testing was implemented more than
30 years ago, there are hazards to be concerned about: witness the devastating effects on offspring
of mothers using cocaine. Furthermore, the laboratory and clinical data this volume contains provide
needed updated information on potential hazards to individuals involved in providing information
and counseling to the public sector (e.g., physicians and health counselors). The addition of well
over 1000 new entries to this revised edition is a clear indication of how much the information
database on teratogens is growing and underscores the difficulties in accessing it in a timely fashion.
The chemicals discussed in the text include those in current use, some still considered experi-
mental, and others now obsolete or withdrawn from use. They include chemicals to which we are
exposed, either intentionally or not. This work does not include nonchemical potential sources of
teratogenesis (i.e., radiation, infectious disease, and physical factors).
Sources for the information given in this volume are many. It will be most appreciated by
teratologists that the task of keeping contemporaneous in the field is an extremely difficult, if not
completely impossible, task. It has been estimated, for instance, that the number of new publications
in the field of teratology is about 2500 per year (Wassom, 1985). Nonetheless, several sources of
information in addition to the usual journal and book references are indispensable, and were of
special value to me in this endeavor. The most useful of these to me currently is Tech Track
(published by NERAC, Inc.), which provides timely listings of the contents of more than 50 scien-
tific journals that contain material relating to the subject of developmental toxicology (teratology).
PREFACE vii

The data obtained from this and other sources are added to my personal computerized database to
facilitate information retrieval.
Virtually all chemicals included are listed by generic names as an aid in identification and for
consistency. For agents to which generic names have not been assigned, chemical names are used;
in a few cases, specific trade names are used when this name is most commonly used. Sources for
agent identity and information included in this volume are the current editions of the American
Drug Index (Lippincott); USAN and the USP Dictionary of Drug Names (U.S. Pharmacopeial Con-
vention, Inc.); The Merck Index: An Encyclopedia of Chemicals and Drugs (Merck & Co.); Martin-
dale, The Extra Pharmacopoeia (The Pharmaceutical Press); Hawley’s Condensed Chemical Dic-
tionary (Van Nostrand Reinhold); Drug Reference Guide to Brand Names and Active Ingredients
(C. V. Mosby); Physician’s Desk Reference (Medical Economics Co.); Drug Facts and Comparisons
(Lippincott); Pesticide Index (Unwin Bros., Ltd.); Dictionary of Chemical Names and Synonyms
(Lewis); and Dictionary of Drugs, Chemical Data, Structures and Bibliographies (Chapman and
Hall).
The basic layout of this work is simple and straightforward. All agents used therapeutically as
medicinals or drugs are discussed under their respective area of therapeutic use (e.g., anticonvulsants,
cancer chemotherapeutic drugs) in Chapters 3 through 24; the remainder of the agents, those having
strictly chemical or industrial uses, are discussed in Chapters 26 through 33. The single exception
is Chapter 29, which includes a few agents used therapeutically but are more logically placed in
Part II because of the larger group to which they belong. The two parts are preceded by a general
chapter on drug use in pregnancy (Chapter 2) and chemical exposure in pregnancy (Chapter 25),
respectively. This format permits direct comparisons of agents within a given group. The first chapter
of this work outlines the principles of teratogenesis as they apply to pregnancy exposure.
Teratogenic reactions tabulated in the tables in the various laboratory species are indicated ⫹,
teratogenic; ⫾ equivocally teratogenic; and ⫺, not teratogenic. Such designations are not meant to
be interpreted as the final arbiters of teratogenicity. They indicate in simple form the reaction under
the specific experimental condition in the species described in the published reports. In defense of
this binary designation, let me state in the strongest possible terms, that I am well aware that under
the right conditions, all chemicals will elicit some measure of toxicity, be it teratogenesis or any
of the other three classes of developmental toxicity. Indeed, this very aspect is emphasized through-
out this work. However, the intent here is to present to the reader seeking teratologic data on a
given chemical, in the simplest terms, what the published studies have demonstrated. The reactions
thus represent a teratogenic effect, or equivocal one, or none at all, under the conditions or regimen
employed in the cited study. Nothing more or less is intended. The reader must, of course, read the
cited publications to obtain additional details beyond those provided here in the text.
The published reports obviously vary in quality, and, since I have made subjective judgments
in considering the specific experimental evidence offered, there is no certainty as to whether the
assessments made are reflective of overall teratogenic potential under all conditions of use or expo-
sure. Both old and new studies were considered for inclusion. Given the choice of a recent Good
Laboratory Practices–conducted study that is scientifically sound and one that is neither, I chose
the former. It should be mentioned with regard to quality of teratogenic studies that one group of
investigators found that only 10% of published studies they examined of teratogenic evaluation of
specific agents were conducted adequately.* This is a sad commentary, but unfortunately true, and
it is this unevenness in quality of data to be evaluated that makes interpretation difficult in many
instances, and even more tenuous in extrapolating to likely human hazard.
Data in this volume represent results evolving only from experimental studies in animals with
treatment given in the organogenesis period, i.e., the regimen that might be expected to induce

* Holson, J. F., Kimmel, C., Hogue, C., and Carlo, G. Data presented at the 1981 Toxicology Forum
Annual Meeting, Arlington, Virginia.
viii PREFACE

terata and other developmental toxicity under appropriate conditions. Obviously, there is a wealth
of published data relating to other aspects of reproduction, for instance, in fertility and reproduction
studies, perinatal and postnatal studies, and multigeneration studies. While many of these might
interest the reader because they too are in the province of reproductive toxicology, the major objec-
tive of this volume is correlation of data related to the induction of malformations. Absence of
certain chemicals from the presentation then, does not necessarily mean that the chemical has not
been studied experimentally; it only indicates that data concerning the chemical have not been pub-
lished in the context of teratogenesis. The emphasis on data from humans too has been placed on
reports in which exposure to drugs or chemicals was primarily in the first trimester of pregnancy,
again, the period when congenital malformations would be expected to occur were they causally
associated with administration. Where pertinent to the overall presentation, I have taken license to
discuss other developmental toxicity.
Data from studies in which unusual or unique methods of administration or assessment and
that vary from traditional methods are not considered except when such methods impart a special
meaning to the data. This is because such methods do not permit metabolism of the chemical nor
do they allow placental movement. These include direct fetal injections, intra-amniotic injections,
and in vitro cultures.
Discussion of experimental teratology has been limited to mammals. Three species—the mouse,
the rat, and the rabbit—have been emphasized, because of their almost universal use by experimental
teratologists, but less widely used species are also included. These data are correlated with the
clinical human data as the major focus. For the sake of conserving space, I have included only
literature citations of initial reports and those I considered most pertinent to the overall characteriza-
tion of a given chemical’s teratogenic potential. This treatise is not meant to be an intensive critical
review of all published literature in the field of teratogenesis; it is hoped however that the work is
as comprehensive in scope as any such effort could expect to be based on one experienced investiga-
tor’s review of the vast body of literature representing the field of this science.
Some effort has been made in this edition to place effects in animals as much in perspective
to human exposures as feasible. For example, the concern expressed for an agent with potential
developmental hazards for a population of 100,000 individuals is much greater than for the same
chemical to which only 100 individuals are exposed. This is done for drugs by providing information
on prescription or nonprescription sales of the drug where appropriate, and direct comparisons be-
tween doses producing developmental effects in animals compared to doses taken by humans. For
chemicals, production and exposure data are used in this context.
Finally, I would greatly appreciate any reader calling to my attention any outright error or
inaccuracy in reporting any study cited in the interest of correct representation in future volumes.

James L. Schardein

REFERENCES
Dwivedi, R. S. and Iannacocone, P. M. (1998). Effects of environmental chemicals on early development.
In: Reproductive and Developmental Toxicology. K. S. Korach, ed., Marcel Dekker, New York, pp.
11–46.
March of Dimes (1998). Miracles brochure 5(3).
Mofenson, H. C., Greensher, J., and Horowitz, R. (1974). Hazards of maternally administered drugs. Clin.
Toxicol. 7: 59–68.
Nisbet, I. C. T. and Karch, N. J. (1983). Chemical Hazards to Human Reproduction. Noyes Data Corp.,
Park Ridge, New Jersey.
Schardein, J. L. (1976). Drugs As Teratogens. CRC Press, Cleveland.
Shepard, T. H., Catalog of Teratogenic Agents, 6th Ed., Johns Hopkins University Press, Baltimore, 1989.
Wallace, H. M. (1976). Economic costs of fetal and perinatal casualties. In: Prevention of Embryonic,
PREFACE ix

Fetal, and Perinatal Disease. R. L. Brent and M. I. Harris, eds., U.S. Government Printing Office,
Washington, D.C., pp. 19–25.
Warkany J. (1972). Introduction. In: Klingberg, M. A., Abramovici, A., and Chemke, J., eds. Drugs and
Fetal Development. New York: Plenum Press.
Wassom, J. S. (1985). Use of selected toxicology information resources in assessing relationships between
chemical structure and biological activity. Environ. Health Perspect. 61: 287–294.
 Acknowledgments

Special acknowledgment is due several individuals who aided me greatly in the preparation of this
volume.
Dr. Bern Schwetz, as usual, was a constant source of encouragement for me to undertake this
project, and I am grateful for his wise counsel and friendship. A number of my colleagues inspired
me to create a new edition, based on their extensive use of previous editions.
I owe a debt of gratitude to several individuals at WIL Research. First, to Dr. Joseph Holson,
President and Director, who provided me, first, with his enthusiasm to work on a new edition, and
second, with the means to do so. To Ms. Carmen Walthour, who so unselfishly prepared the entire
manuscript as her regular position of Office Supervisor would allow, and in her personal off-hours
when this was not possible, I owe a debt of gratitude. Her skills are truly enviable. I am sure my
colleagues in the laboratory also sacrificed my counsel so I could complete the task.
I would like to personally thank my Production Editor at Marcel Dekker, Inc., Ms. Theresa
Dominick, for her patience and diligence in assuring that my many alterations to the manuscript
over the course of its production would be included in this printing. Every author should be so
fortunate to have such an understanding editor to work with.
I again thank my wife, Mary, for understanding my need to pursue this project once again and
who provided, as always, the proper environment to fulfill my wishes. It would not have been
possible without her.
Finally, the responsibility for the content of this book rests entirely with me. The format is my
creation, designed solely with ease of readability in mind. Scientific decisions and interpretations
of data also lie with me, and I assume credit or disfavor for all judgments made. I only hope the
volume serves, as it apparently has in the past, the purpose intended to all individuals who deal
with teratology issues on a daily basis.

xi
 Contents

Foreword Robert L. Brent iii

Preface v
Acknowledgments xi

1 Principles of Teratogenesis Applicable to Drug and Chemical Exposure 1

PART I. DRUGS

2 Drug Usage in Pregnancy 67

3 Thalidomide: The Prototype Teratogen 89

4 Drugs Affecting Blood 121

5 Agents Used for Pain 139

6 Anesthetics 167

7 Anticonvulsants 179

8 Psychotropic Drugs 237

9 Hormones and Hormonal Antagonists 281

10 Drugs Used in Respiratory and Allergic Disorders 359

11 Antimicrobial Agents 379

12 Antiparasitical Drugs 435

13 Insulin and Oral Hypoglycemic Agents 453

14 Thyroid-Acting Agents 463

15 Drugs Affecting Muscular Action 475

16 Gastrointestinal Drugs 489

17 Cardiovascular-Renal Drugs 517

xiii
xiv CONTENTS

18 Cancer Chemotherapeutic Agents 559

19 Immunological Agents 613

20 Chemical Antagonists 631

21 Foods, Nutrients, and Dietary Factors 653

22 Food Additives 693

23 Personal and Social Drugs 715

24 Miscellaneous Drugs 763

PART II: CHEMICALS

25 Chemical Exposure in Pregnancy 797

26 Pesticides 819

27 Metals 875

28 Industrial Solvents 909

29 Diagnostic Agents, Radiochemicals, and Dyes 941

30 Plastics 953

31 Toxins 969

32 Air, Water, and Soil Pollutants 997

33 Miscellaneous Chemicals 1019

Index 1055
 About the Author

JAMES L. SCHARDEIN is Senior Vice President and Director of Research at WIL Research Labo-
ratories, Inc., Ashland, Ohio. The author of two books and more than 140 abstracts, manuscripts,
and book chapters, he is a former section editor of Fundamental and Applied Toxicology. He is a
certified Fellow of the Academy of Toxicological Sciences, a former council member of the Teratol-
ogy Society, and a former president of the Developmental and Reproductive Toxicology section of
the Society of Toxicology and of the Midwest Teratology Association. Mr. Schardein received the
B.A. degree (1956) and the M.S. degree (1958) from the University of Iowa, Iowa City.
 1
Principles of Teratogenesis Applicable to
Drug and Chemical Exposure

I. Introduction 1
II. Basic Principles of Teratogenesis 3
A. Susceptible species 3
B. Susceptible stage of development 5
C. Dose dependency 7
III. Manifestations of Deviant Development 12
A. Malformations 12
B. Growth retardation 17
C. Embryolethality 18
D. Functional impairment 19
IV. Other Factors in Assessing Developmental Effects 20
A. Male-mediated effects 20
B. Developmental variations 21
C. The modifying influence of maternal toxicity and designation of ‘‘teratogen’’ 23
D. Pharmacokinetic considerations 25
E. Structure–activity relations 26
V. Use of Animal Models to Assess Human Risk 27
VI. Recent History of Teratology and Evolution of Methods of Testing for Evaluating Devel-
opment 29
A. Alternative testing methods 35
VII. Uses of Teratological Data by Governmental Agencies 37
VIII. Evaluation of Human Risk 39
References 45

I. INTRODUCTION
Congenital malformations or birth defects are a major public health concern. In this country, birth
defects occur in a frequency of 20 : 1000 to 30 : 1000 livebirths, and an additional 60 : 1000 to 70 :
1000 are observed in the interval between birth and 1 year of age (Hook, 1981). In 1995, this
translated into 411 babies with birth defects of almost 11,000 born every day; 18 of these die every
day as a result of a birth defect.* Minor anomalies represent another 140 : 1000 (Hook, 1981), and
minor to severe mental retardation accounts for 0.7–0.8% incidence (Rosenberg, 1984). Congenital
malformations account for approximately 14% of all infant deaths (Warkany, 1957). Birth defects

* National Center for Health Statistics, 1995.