Teratology in the Twentieth Century: Congenital Malformations in Humans and How their Environmental Causes were Established

By H. Kalter

This book is an an up-to-date survey and summary of present knowledge and future expectations regarding the environmental causes of congenital malformations in human beings, beginning with the earliest discoveries of the 20th century up to the latest ideas and problems at its end, presents views and comments on the progress made over the century in understanding human prenatal maldevelopment.

• Language: English
• Publisher: Elsevier Science
• Release date: Jun 6, 2003
• ISBN: 9780080542355

Book preview

Teratology in the Twentieth Century

Congenital Malformations in Humans and how their Environmental Causes were Established

Harold Kalter

University of Cincinnati, OH, USA

Table of Contents

Cover image

Title page

Copyright

Dedication

PREFACE

Chapter 1: Teratology in the 20th century Environmental causes of congenital malformations in humans and how they were established

1 Introductory matters

2 Definitions

3 Classification

4 Frequency

5 Early human studies

6 Pioneering works

7 Early experiments

8 New challenges

9 Thalidomide

10 Testing for teratogenicity

11 Teratological detours

12 Surveillance of congenital malformations

13 Epidemiology of congenital malformations

14 Human disease as teratogen

15 Environmental hazards and disasters

16 Disease medication and teratogenesis

17 Folic acid and human malformations

18 Alcohol consumption during pregnancy

19 The accomplishment and the expectation

Subject Index

Copyright

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First edition 2003

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Dedication

To my wife – Bella Briansky Kalter and our sons Eliot, Henry, John

PREFACE

Teratology is at once among the oldest and youngest of human preoccupations. Coincident with man’s first observations of the stars were his recordings of human and animal deformities, and from the earliest recordings of this fascination with the form and meaning of abnormality, a continuous line extends to modem struggles to understand and control these manifestations. After long occupying an honorable but peripheral place in the halls of philosophical and scientific pursuits, teratology has come to take a position at the hub of a complex crossroads of human concerns.

This shift in its fortune has taken several forms. Fetal maldevelopment has become the concern of environmentalists, activists of various persuasions, industrial organizations, governmental agencies, ethicists, parents, etc.—that is, individuals and groups whose actions are impelled by apprehension. Such motives are of course not without basis; the trauma of thalidomide left a scar yet raw. For still others—clinicians, academics, experimentalists—the upsurge in the interest in fetal maldevelopment is at a different level, and their pursuits are broad, taking external agents as but one of the causes of defective development.

Puzzlement over abnormal development has many strands; it cannot be confined to the bounds of a single discipline, and that is why its varied threads interweave with an amazing multitude of pursuits; why among its practitioners are many disparate and unrelated subjects—from anatomy to zoology, from embryology to epidemiology, these and many other areas of knowledge and study have given teratology a richness of content and an ever-unfolding newness and challenge that comprise its strength.

This book is about the dangers that often beset the most marvelous of all mysteries. Most marvelous is not the origin of the universe, the formation of the earth, the emergence of the amoebae—none so marvelous as the conception and development of a baby, but none so tragic as the death or deformity of such miraculous beings.

In nature, the innumerable obstacles to procreation are counterbalanced only by fecundity. Everywhere there is extravagant abundance and profligacy: a plenitude of pollen, seeds, sperm, and embryos, and in contrast a modicum of progeny. This superfluity is nature’s way of dealing with its hit-or-miss, trial-and-error course of action. To produce a quota of births, an excess of zygotes must be provided in anticipation of the great number that will be lost as they develop.

Is it all part of a plan that the great majority of human products of fertilization should perish during the course of pregnancy? Those that fail to reach birth—teleologically interpreted as being mercifully sifted out—comprise a large proportion of the accidents of nature that result in defective conceptuses. Forty to sixty percent of spontaneous abortions are chromosomally abnormal, while only 0.6% of livebom infants have such abnormalities, leading to the calculation that 90% of embryos with such abnormalities are spontaneously lost. Similarly, noting that 40-50% of SABs are morphologically abnormal, it is calculated that by birth, 80% of defective conceptions are eliminated and a mere(l) 3% of newborns are congenitally malformed.

Decade by decade, over the course of the 20th and into the present century, the rate of death of children in the first year of life decreased in many parts of the world. This was largely due to the conquest of serious infectious diseases of infancy and to improvement in nutrition and hygiene. As these problems abated, other causes of early death of children became increasingly prominent, congenital malformations most conspicuous among them, the most unyielding of all the reasons infants still die and are seriously ill.

To prevent malformations, not just by the expedient of aborting malformed fetuses, it is necessary to know what the causes of congenital malformations are. In the aggregate, they are now the cause of about one-fifth of deaths under 1 year and one-third of the deaths of infants less than 1 month old, up 50% in the last several decades. Present-day knowledge of their causes is still most imperfect. To one extent or another, the cause of less than half of all congenital malformations is known.

So little is known, perhaps is knowable, that it often seems we are desperate to find answers to long-sought questions and are precipitate in promulgating them. They pour out and are given prominence in the science sections of our weekly magazines and daily newspapers. How can one be protected against the onslaughts of discovery made today and unmade tomorrow as the speed of travel and communication is exceeded only by the velocity of new revelation? Will the man in the street become as inured to the buffetings of factual contradiction as the modem youngster is to the raucous sounds he calls music?

The public knows about congenital malformations, or birth defects, as they have been led to be called by popularizing organizations that do not trust the public to be able to pronounce long words—they know about amniocentesis, fetal ultrasound scanning, chorionic villus sampling, and genetic and teratology counseling services, because everyone knows or knows about a family in which these abnormalities have happened, and fear it will happen in theirs.

Where have the answers to the ultimate questions—what are the causes of and how to prevent CM—come from? Experimental teratology was never intended to supply them. Its raison d’être has been to illuminate, to delineate relations, to point the way. Where then has this knowledge, such as it is, come from? From bits and pieces from here and there outside the laboratory, a slowly emerging miscellany of fragments. In all, the implicated or suspected external agents have amounted to a handful of infectious, metabolic, endocrinological, environmental, and pharmaceutical culprits, sometimes prematurely incriminated and later absolved.

The inner world as well has yielded recognition of its involvement only by accretion of innumerable diverse lines of evidence. Systematic attempts to sum up the knowledge of what is known and what is left to know about the causation of congenital malformations have all pretty much come to the same ‘bottom line.’ No further evaluation with any originality has been made for some years now, so it appears we have come to a standstill in this matter. These judgments reckoned that, all told, the causes of perhaps onethird of all serious congenital malformations are now identified. This leaves two-thirds or more unaccounted for, the great majority, which seems not to have either a simple genetic or clear environmental basis, as these are now defined. They are not metaphysical, I suppose, but perhaps close to it. Can many be unique, like the untold ‘ew’ syndromes reported in almost every issue of certain medical genetics journals, never to be repeated, having apparent resemblance to those foregoing only because of limited maldevelopmental pathways? Accident is repugnant to the modem scientific mind, implying as it does unpredictability and unpreventability. But, let’s face it, accidents do happen, as many bumper stickers these days explicitly announce, and the more complicated the system, the more often and the more ways it can go wrong. Murphy’s law with a biological twist. Should this possibility make us pessimists—no, only realists, and realists think of ways to approach new situations. So, let us think.

What is known, hopefully, is the portal to the future. This article summarizes the past and the latest findings and opinions about the environmentalmthat is, nonhereditary—teratological forces that malform the unborn creature between the moment of conception and birth. Let us then turn to this book, asserting, with Antonio that

In nature there’s no blemish but the mind;

None can be call’d deform’d but the unkind.

Teratology in the 20th century Environmental causes of congenital malformations in humans and how they were established

Harold Kalter *,     Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Children’s Hospital Research Foundation, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA

Keyword

Teratology

Enviromnental causes

Congenital malformations

PREFACE

1 INTRODUCTORY MATTERS

Coincidental discoveries

Early genetic studies

2 DEFINITIONS

Introduction: styles

A small parenthesis

Congenital means present at birth

Malformations: abnormalities of structure

Recognition of malformations

Major and minor malformations

Minor malformations and variants

3 CLASSIFICATION

Introduction: why classify

Classification by cause

Classification by type

Classification by pathogenesis

Nomenclature

Taxonomic innovations

The developmental field concept

4 FREQUENCY

Introduction: early findings

Difficulties of establishing frequency

A matter of names

How often do malformations happen?

A definite definition

An aside

Why investigate malformation frequency

Ascertainment

Underestimating frequency

Overestimating frequency

Biological factors

Miscellaneous factors

5 EARLY HUMAN STUDIES

Introduction: the principal objective

X-irradiation

Introduction: animal studies

Human pelvic irradiation

Introduction: early radiation use

An irradiation-caused abnormality

Eye abnormalities

Dose, time, and effects

Dose matters

Murphy’s contribution

Atomic radiation

The Hiroshima and Nagasaki bombs

What these studies found

Microcephaly and mental retardation

Other radiation sources

Rubella

Introduction: new perception

The discovery

The German measles epidemic

Teratological principles

Timing and malformation pattern

The 1964 epidemic

Time versus agent: the ‘critical’ period

The debate

Gestational age and frequency

An old disease

A teratogen disappears

Other infectious diseases

Influenza

Cytomegalovirus

Toxoplasmosis

Varicella-zoster virus

Problems regarding intrauterine infection

Intrauterine infection in animals

6 PIONEERING WORKS

Irradiation studies not appreciated

Vitamin deficiency

Hale and deficiency of vitamin A

Discovery greeted skeptically

Warkany and deficiency of riboflavin

Searching for the cause

The all-important details

Cautions and critics

7 EARLY EXPERIMENTS

Introduction: new needs and ideas

Principles of teratology

Vitamin A and diaphragmatic hernia

Power of genetics

Basis of diaphragmatic hernia

Early investigators

Trypan blue

Trypan blue’s teratogenic ‘mechanism’

Hypoxia

A little break: Down syndrome

Cortisone studies and by-products

Relevance to humans

Induced and spontaneous malformations

Genetics and individual responses

The multifactorial/threshold concept

A new concept of embryotoxicity

A variety of experiments

Vitamin antimetabolites

Folic acid

Folic acid antimetabolite human use

8 NEW CHALLENGES

Infant mortality and malformations

Teratology conferences

The Teratology Society

9 THALIDOMIDE

The event

The thalidomide syndrome

The revelation

Thalidomide: safety and sales

Toxicity in adults

Thalidomide in the USA

Thalidomide’s teratogenic mechanism

Dose– and time–response relations

Animal studies with thalidomide

Postscript: was anyone to blame?

The future?

10 TESTING FOR TERATOGENICITY

Proposals for drug testing

The procedure

The consequence

The dose–response curve

Teratogens and mutagens

11 TERATOLOGICAL DETOURS

Bendectin

The product

Alleged teratogenicity

Legal action

Blighted potatoes

Search for the cause of NTD

Were potatoes the answer?

Animal studies

Avoidance trials

Female sex hormones

Genital defects

Nongenital defects

Defect nonspecificity

Diethylstilbestrol

Introduction: fetal wastage

DES usage

The revelation

Dosage and timing

The Registry

The Project

Critique

Congenital abnormalities

Summary and conclusion

12 SURVEILLANCE OF CONGENITAL MALFORMATIONS

Introduction: fears and demands

Surveillance and monitoring

Monitoring’s limited abilities

13 EPIDEMIOLOGY OF CONGENITAL MALFORMATIONS

The classical method

Epidemiology of malformation communities

Familial studies

Pyloric stenosis

Clefts of the lip and palate

Neural tube defects

14 HUMAN DISEASE AS TERATOGEN

Phenylketonuria

Introduction: discovery and basis

Pregnancy outcome

Congenital malformations

Mental retardation in balance

Intrauterine growth retardation, microcephaly, and mental retardation

Dose and time matters

PKU varieties

Maternal PKU therapy

PKU frequency

Population malformation load

PKU in animals

Antagonist administration studies

PKU mutants

Embryo culture studies

Histidinemia

Final word

Insulin-dependent diabetes mellitus An old disease

Pregnancy outcome

Perinatal mortality

Spontaneous abortion

Later studies: glycosylated hemoglobin

Congenital macrosomia

Gestational diabetes

Gestational diabetic outcomes

Preconceptional diabetes and malformations

Minor malformations in diabetic pregnancy

Specific malformations

Caudal dysplasia

CNS malformations

Cardiovascular malformations

Principles of teratology: applied to diabetes

Does diabetes obey teratological principles?

Concluding remarks

Hyperthermia

15 ENVIRONMENTAL HAZARDS AND DISASTERS

Introduction: widespread dangers

Iodine deficiency

The story of iodine

Not an ordinary teratogen

Endemic goiter

Organic mercury

The Minamata epidemic

Congenital Minamata disease

Source of the methylmercury

The Iraq epidemic

Matters of environment and dose

Studies elsewhere

Agent Orange

Wartime use

Male exposure toxicity

Exposure of Vietnamese nationals

Exposure of US military

Ranch handers and reproduction

Exposure of Australian military

Agricultural and occupational herbicide exposure

Herbicide exposure and the sex ratio

The sex ratio phenomenon

Human tampering and the sex ratio

The political dimension

The aftermath

Seveso

Sellafield

Chernobyl

Polychlorinated biphenyls

Cola-colored babies

PCB-exposed American children

Love Canal: a study in political teratology

A chronology

The mounting hysteria

Love Canal and chromosomes

The last word

16 DISEASE MEDICATION AND TERATOGENESIS

Introduction

Retinoids

Vitamin A teratology

Teratoepidemiology of vitamin A

Risk assessment

Synthetic retinoids

Introduction: vitamin A toxicity

Isotretinoin

The population at risk

The retinoic acid embryopathy

Species dosage differences

Further teratologic threat: etretinate

Acitretin

Dose–response relations

Topical tretinoin use

Anticonvulsant drugs

Introduction: the ‘falling sickness’

Therapy of epilepsy: fetal consequences

Fetal hydantoin syndrome

Recognizing minor defects

Is epilepsy itself teratogenic?

Epilepsy and spontaneous abortion

Major congenital malformations

Carbamazepine

Valproic acid

Altered anticonvulsant use

Anticonvulsants and neurodevelopment

Critique

Summary

Animal studies

Lithium Its discovery

Its teratogenicity

Ebstein’s anomaly

The retraction

The finale

17 FOLIC ACID AND HUMAN MALFORMATIONS

Folic acid deficiency: long-debated effects

Maternal folic acid status and NTD

Later folate concentration studies

The connection develops

NTD definition

Maternal vitamin usage and NTD

Folic acid and NTD recurrence

Folic acid and NTD occurrence

Atlanta study

NIH study

Boston study

The debate

Two widely separated studies

Other recent studies

Boston case-control study

California study

NTD: emigration and acculturation

China study

Has folic acid prevented NTD?

Folic acid food fortification

NTD secular decline

Terathanasia

Prenatal diagnosis

Has the secular decline continued?

Addendum

Genes and NTD risk

18 ALCOHOL CONSUMPTION DURING PREGNANCY

Introduction: blessing and curse

Early Seattle study

Fetal alcohol syndrome

FAS expanded

FAS specificity

Diagnosing the FAS

Fetal alcohol effects

The epidemiological process

Prospective studies

Moderate drinking

The NIH study

Chronological overview

A palpebral fissure parenthesis

Major malformations

Minor malformations

Long-term effects on growth

Retrospective studies

Orofacial defects

Limb defects Other conditions in older children

Critique

Alcohol and neurodevelopment

Longitudinal studies

Alcohol and spontaneous abortion

Summary and critique

Prevalence of the FAS

The fundamental problem

Animal abortion studies

Finale

B. Franklin on wine

19 THE ACCOMPLISHMENT AND THE EXPECTATION

20 BIBLIOGRAPHY

21 INDEX

To my wife—Bella Briansky Kalter and our sons Eliot, Henry, John

1 Introductory matters

The 20th century saw the flowering of the science of teratology, and with its closing, its successes and shortcomings in those years merit relating. Teratology, the study of physical abnormalities of the newbom—congenital malformations—is an old human concernment, not surprisingly, since such conditions have afflicted human beings since the dawning of the species; an antiquity attested by prehistoric anthropological evidence and by written records from as early as nearly 5000 years ago. Thus, as the century, and indeed the era known as the second millennium, has drawn to a close, it is fitting to retrospect upon its contributions to the understanding of these phenomena, sources of horror and bewilderment, that have long preoccupied human thought and imagination.

Always it has been asked, what do these aberrant, often monstrous, apparitions mean, and more recently, how do they happen. Attempts to delve into these matters, traced from ancient times, yield a record of human folly, fear, and fancy, old subjects that have been abundantly recounted (e.g., Martin, 1880; Barrow, 1971), so need nothing more said about them here. Objectivity regarding such phenomena, meagerly evidenced before, truly arrived with the 19th century, when anatomists, embryologists, and pathologists with observational prowess not yet surpassed, meticulously described, classified, and categorized congenitally malformed humans and animals ( Saint-Hilaire, 1832–7; Taruffi, 1881–94; Ballantyne, 1904; Schwalbe, 1906–37), and the threshold of modernity was approached later in that century, when experimentalists, tentatively exploring the how, produced abnormalities in birds and amphibians ( Dareste, 1877) and set the scene for advancements in the new and now recently closed epoch.

1.1 Coincidental discoveries

Two entirely disconnected events occurring at the outset of the 20th century define the initiating moment for modern teratology: the ‘rediscovery’ early in 1900 of Mendel’s laws of inheritance (related by Dunn, 1965), and the use of the then recently discovered Roentgen rays to induce malformations in laboratory animals ( Hippel, 1907). These strands, destined to become intimately entwined, epitomize the dichotomy—heredity and environment—in the foremost quest in modern teratology, the search for the causes of human prenatal maldevelopment.

From early on, these polarities drove the twofold search for causation. Between them at first there seemed to be an unbridgeable gap; an example of which was clearly reflected in the views of two eminent reproductive pathologists—ironically even studying the same material, early human fertilized ova—when one wrote that careful study of my [pathological] specimens… establishes beyond doubt… that all of them… are due to external influences ( Mall, 1908), while the other believed that defective ova arose from intrinsic defects ( Hertig et al., 1959). It may be remarked parenthetically that what is perhaps strangest about these two pronouncements is that the former was made at a time when abnormal prenatal development was thought to be predominantly, if not wholly, of genetic origin ( Baur et al., 1921, 1931), and the latter, per contra, when environmental influences on embryonic development, as shall be seen, had by then been well established.

However, in the beginning, and for many years, the anachronistic former view yielded to the latter, and the main purpose of studying human and animal congenital abnormality was to establish and classify patterns of inheritance (e.g., Pearson, 1912; Wright and Eaton, 1923; Dobrovol-skaïa-Zavadskaïa, 1927). Human abnormalities that particularly lent themselves to this pursuit obviously were those of incontestably hereditary origin, specific though individually often rare skeletal abnormalities like brachdactyly and chondrodystrophy, purposes readily addressed when such conditions did not skip generations or sometimes occur in overlooked form. Brachydactyly, consisting of abnormally short fingers and toes, eminently fitting this prescription, was in fact the first human structural abnormality shown to be inherited in a manner conforming to the rules delineated by Mendel ( Farabee, 1905).

1.2 Early genetic studies

In the early decades of the century, vast pedigrees were gathered of families containing members with such abnor-malities, e.g., in addition to those mentioned, symphalan-gism, polydactylism, harelip (as cleft lip was long known), cleft palate, etc., some of the most extensive of them published beginning in 1912 by the Galton Laboratory in London in its Treasury of Human Inheritance, edited overall by Karl Pearson. While some of these aberrations were discovered to be inherited in simple fashion ( Bell, 1951), others had a more complicated pattern of descent. The latter class, in fact, have been the more intellectually challenging, and much study was later to be devoted to the problems they entailed ( Carter, 1977).

Incidentally, it must not be forgotten in dwelling on these olden years that keen discernment in even more olden times had already recognized that various human characteristics were hereditary and had diligently traced their passage from generation to generation, but without grasping the patterns of transmission embedded in them ( Stern, 1965).

2 Definitions

2.1 Introduction: styles

Before discussing any branch of knowledge, especially complex ones, the subject and the terms used in its practice must be defined, i.e., limits fixed, as the foundation for a common understanding of its purposes and for charting progress in its study. Teratology, the subject of this history, is the science of congenital malformations in all its aspects, and as that term is the keystone of the subject, we begin with an attempt to convey its meaning.

The designation ‘congenital malformation’ has been defined in various ways, and as an introduction to the problems that have been encountered in coming to some understanding and agreement about its meaning, it is useful to note examples of the many pronouncements that have been made regarding it. The task can be appreciated even from the following short selection, most from an earlier time when basic questions were still to be worked out, which though often variations of one another differ in some important respects, and in so doing, some commonality will emerge from them. To wit:

Congenital malformations are structural defects present at birth. They may be gross or microscopic, on the surface of the body or within it, familial or sporadic, hereditary or nonhereditary, single or multiple ( Warkany, 1947).

… congenital malformations [are] gross structural abnormalities present at birth…observed at the supracellular level ( Fraser, 1959).

… a malformation is…a macroscopic abnormality of structure attributable to faulty development and present at birth ( McKeown and Record, 1960).

Congenital malformations [are] abnormalities of structure present at birth and attributable to faulty development ( Carter, 1963).

… a major anomaly is one which has an adverse effect on either the function or the social acceptability of the individual; a minor defect [on the other hand] is one which is neither of medical nor cosmetic consequence to the patient ( Marden et al., 1964).

A malformation is an abnormality in size, shape, location, or structure of any part caused by antenatal disturbances in development ( Potter, 1964).

… a defect of structure or form present at birth and noted at routine inspection within the first ten days of life…( Nelson and Forfar, 1969).

Even the slightest abnormality… ( Endl and Schaller, 1973).

… a gross physical or anatomic developmental anomaly…present at birth or… detected during the first year of life ( Myrianthopoulos and Chung, 1974).

… conditions thought to be of prenatal origin whether or not they were manifest at birth [including] structural defects, functional abnormalities, inborn errors of metabolism, and chromosomal aberrations ( Christianson et al., 1981).

… malformations are all-or-none traits, that is, they are not graded…and at their mild end do not shade into normality ( Opitz and Gilbert, 1982); thus, they are qualitative [author’s emphasis] defects of embryogenesis ( Opitz, 2000).

A major congenital anomaly [is] one that is incompatible with survival, is life-threatening, or seriously compromises an individual’s capacity to function normally in society ( Otake et al., 1990).

Several disagreements are present even in these few attempts to characterize this sometimes vague phrase. In two of them, the conditions referred to are said to be ‘supracellular’ or ‘macroscopic,’ but in a third they can also be ‘microscopic.’ In others, instead of macroscopic, the more homey word ‘ gross’ is used, which as a dictionary says is taken to mean visible to the naked eye, but another says the conditions can also be within the body. Almost all accept that they are present at birth, even if not expressed till later. Most consider that the term refers to severe degrees of faultiness of structure, causing death or serious medical consequences, while functional abnormalities are excluded, but not always.

Another writer, however, distinguishes between severe and less severe malformations, but being ‘all-or-none,’ they differ somehow from minor deviations. Others are even more accepting and include even the slightest abnormality as well as chromosomal aberrations and biochemical errors, ostensibly even when not accompanied by or resulting in physical abnormalities. However, the danger of such inclusiveness, as it has been put, is that it may become so all embracing as to lose significance ( Potter, 1964).

Only once was a most fundamental matter alluded to: that malformations may be hereditary or nonhereditary; a basic distinction to be looked into below.

Although these quotations reflected various perspectives and were open to debate, there was one thing with respect to the abnormalities themselves that was universally acknowledged: that major malformations cause death or serious medical consequences, whereas the so-called minor ones have as their hallmark that they are of neither ‘medical nor cosmetic concern.’ The latter defects have posed their own sets of problems of definition and recognition (e.g., see Pinsky, 1985; Merlob, 1994); they will be discussed below.

2.2 A small parenthesis

Here it may be useful to note that various locutions have often been used interchangeably for such conditions (e.g., Taffel, 1978), congenital abnormality, congenital defect, congenital anomaly, and birth defect, as well as congenital malformation. Since there is no reason for this multiplicity except elegant variation, only the last one will be used here, except when another will suit a particular purpose. As for ‘birth defect,’ it should be considered a misnomer, leading to misunderstanding and confusion, since it carries the implication of damage originating at and even caused by birth; but that is not the term’s only potential abuse. Its provenance will be recapitulated below.

Malformations are abnormalities that can occur at any time in the life of an individual, e.g., in childhood or later, as a result of trauma or infection. Our concern is with a specific type, congenital malformation, and it is this use that must be explained, one word at a time.

2.3 Congenital means present at birth

In medicine, it was once customary to divide disease into two opposing classes, congenital and acquired, the former meaning inborn or innate, i.e., hereditary, and the latter not inherited. For teratology, however, these two terms need not be contrasting at all, but also they have come to have specialized signification.

The word congenital has a complex history. The Shorter Oxford English Dictionary on Historical Principles ( Onions, 1956, p. 369) states that congenital, which first made its appearance in English in 1796, means existing from birth or born with. This is equivocal since one part excludes presence before birth, while the other does not seem to do so. Funk and Wagnalls Standard College Dictionary ( Anon., 1963, p. 285) makes the latter sense explicit when it gives as its meaning existing prior to or at birth…, but then adds, as does The American Heritage Dictionary of the English Language ( Morris, 1969, p. 280), but not hereditary, thereby resurrecting a usage that had almost expired.

Cutting through these ambiguities, the modern-day scientific meaning of congenital, which has been adopted by teratology, is simply ‘present at birth,’ with no connotation as to etiology—a topic which for the moment shall be deferred.

However, differing from the distinction given above, things congenital may also be acquired. The crucial question is, when does the acquiring take place? While ‘present at birth’ implies origin or presence before birth, it ignores the practical matter of time of this origination and of its recognition. Thus, it becomes necessary to draw a further distinction or classification: endogenous origin, from germ cells, and exogenous origin, from environment. In this work, the primary focus is given to the latter.

2.4 Malformations: abnormalities of structure

Defining ‘malformation’ is the still greater challenge. Broad definitions, e.g., abnormalities attributable to faulty development ( McKeown and Record, 1960) or structural defects present at birth ( Warkany, 1971), leave their key parts unsettled. Strictly speaking, abnormalities of structure can be said to include aberrations ranging from the submicroscopic to the glaringly gross. In practice, however, such semantic quibbles make for no difficulty, because the malformations dealt with in clinical, epidemiological, and experimental teratology are almost exclusively those seen by the naked eye or detected by standard clinical instruments and usual investigational procedures. Thus debarred are not only nonqualifying ‘structural’ abnormalities, such as molecular and cellular ones, but also those in the categories of isolated metabolic, endocrinologic, functional, and so on, which like everything on earth have a physical basis, but nevertheless do not come into the purview of this work.

The term ‘faulty development’ can also be reasonably dealt with by limiting malformations to irreversible events arising from disturbances of development of primary embryonic structures and organogenesis, which occur in the earliest months in human pregnancy and equivalent times in other mammalian species and thus exclude conditions such as tumors, nevi, angiomata, etc.

Also excluded, therefore, are conditions arising almost exclusively in the postembryonic, i.e., fetal period, such as those associated with maternal administration of coumarins (Van Driel et al., 2002) and the prenatal growth-retarding effect of tobacco smoking occurring by itself ( Simpson, 1957).

2.5 Recognition af malformations

Just as definition is necessary for joint agreement of usage, so are uniform criteria of the time of recognition vital for comparability of observation. Not surprisingly, major malformations are predominantly first detected in the neonatal period, at the time when in most parts of the world, infants are present in hospital and can be most conveniently examined. Thus, the vast record concerning most malformations, not only the conspicuous and medically more demanding ones, rests on observations made during this period. Early examination as well allows the recording of neonatally lethal conditions which will not yet have been lost. Thus, with the exception of a relatively few malformations, especially of certain types, which may be overlooked at this time and not discovered till some months afterward, the great majority of records and reports of congenital malformations have pertained to discoveries in the neonatal period, in babies while still in hospital.

Major malformations in experimental teratology, to be discussed in detail below, are defined as gross abnormalities detectable by external observation or special procedure at or preceding birth.

2.6 Major and minor malformations

Many sorts of aberrant physical characteristics have a prenatal origin, but not all of them are of equivalent medical import. Thus, while all may be considered ‘abnormal’ (the complexities into which this epithet can entangle one will be explored below) they differ in their consequences for viability, health, and well-being. The conventional distinction is that between major or serious congenital malformations (i.e., grave in character) and minor defects and trivial physical variants (parenthetically, Leck (1969) used ‘sub-stantial’ as a synonym for ‘serious,’ but ambiguity mars its usefulness. Opitz (2000) said that since malformations are severe or mild, there is no such thing as a minor malformation, employing his customary terminological precision to distinguish the latter from minor ‘anomalies’).

There are pragmatic reasons for this primary distinction. Major congenital malformations are those of such drastic departures from the norm that they cause or are associated with prenatal or perinatal death, require surgical or medical care soon after birth, or are gravely physically handicapping, and, some would add, impose an extreme cosmetic burden, while minor defects and others to be mentioned have no or little medical importance.

Understandably, the major abnormalities have been a focus of the medical and investigational world, as well as of the lay public (growing since about mid-20th century, as other causes of neonatal urgency abated and they thus increased in conspicuousness), and because of this, they have been long and widely chronicled and thus form a body of record against which comparison and analysis are made ( Warkany and Kalter, 1961; Kalter and Warkany, 1983).

Ironically, many of these conditions are the most frequently occurring abnormalities of development, frequent in this context meaning of the order of 1–2 per thousand births. They include, among them, numerous sorts of malformations of every organ and system of the body—central nervous, cardiovascular, orofacial, gastrointestinal, urogenital, skeletal. Incidentally, considering that many of these malformations were usually lethal or impaired reproduction in the days of premodern medicine and often still ordain the same fate, what this means as far as evolutionary dynamics is concerned would make for an interesting, but far-diverting, topic of discussion.

2.7 Minor malformations and variants

Relatively trivial physical divergences from the typical, commonly known as minor congenital malformations or anomalies, come in many forms, but are usually of little or no medical or cosmetic consequence. Depending on what is considered a minor malformation (since there is little consensus here) and the assiduity of the search for them, the number an individual may be discovered to possess can vary from few to many, and the frequency of the newborn population so affected can likewise vary greatly.

An early foray into this then-uncharted field found that 14.7% of unselected newborn infants had at least 1 of 26 different minor anomalies, mostly of the external ear and hand, and in addition, 14.3% had 1 or more of 14 normal phenotypic variants, again mostly of the ear and face (e.g., folding over of the upper helix and hemangiomas) ( Marden et al., 1964). In an expanded search, 42.9% of children not exposed prenatally to certain drugs had 1 or more of 104 unnamed physical features, designated minor malformations ( Holmes et al., 1985). Other studies have similarly found that some large fraction of infants have such minor physical features, in the absence of associated major congenital malformations ( Méhes, 1983, 1988; Merlob et al., 1985; Leppig et al., 1987).

This apparent abundance made it necessary to give such features some objective evaluation of importance. A trendsetting attempt was made by arbitrarily dividing them into those occurring in more or less than a certain proportion of infants (the suggested one being 4%) and calling only the less common ones defects ( Smith, 1971). However, because there has been no agreement about which particular minor defects are meaningful for etiological or developmental investigation, interest in such categorization and, in fact, in them as isolated (i.e., not accompanying major malformations) phenomena may have had its day.

Many of these traits are physical or morphometric variants with not the least medical importance (and for which the designation ‘abnormal’ is wholly inappropriate). As for the more frequent isolated ‘nonvariants,’ in the absence of agreement of which are to be accepted as defects and which not, progress will be impeded in determining their heuristic value ( Pinsky, 1985; Leppig et al., 1987; Merlob, 1994). The crucial word here is ‘isolated,’ since minor defects when appearing together with medically significant malformations may take on a relevance they otherwise lack, e.g., as supposed teratogenic ‘danger signals.’

3 Classification

3.1 Introduction

Almost as important as the necessity of defining entities is that of putting them into an orderly arrangement, i.e., of classifying them. In biology and medicine, classification is precisely ordered, in effect is itself a science, with various names. In the former, it is called taxonomy and comprises rules for grouping organisms into categories based on shared characteristics or traits, and in the latter, nosology, the classification of diseases, a system of categories to which morbid entities are assigned according to some established criteria ( Onions, 1956; Morris, 1969; Anon., 1977). In teratology, matters are not that simple. Some years ago, Neel (1958) wrote no entirely satisfactory classification of congenital abnormalities has yet been devised, and many would say that is still true today.

Teratology, being a branch of medicine, schemes for applying classification to it, like those for diseases, fall mostly into the categories of etiology, pathogenesis, and outcome, with aims different from one another. Systems of classification founded on causation, the etiology of congenital malformations—in distinction to those based on pathogenesis and outcome, which are directed as much toward theoretical considerations—are expressly oriented toward their ultimate prevention.

It is as well to confess immediately that knowledge of the causes of congenital malformations is still sparse ( Kalter and Warkany, 1983), and while applauding the breakthrough discoveries in the last century, noted below, that have permitted major environmental teratogens (i.e., malformation-causing entities) such as ionizing radiation, the rubella virus, aminopterin, and thalidomide to be avoided or rendered harmless, much still remains to be learned, especially about endogenous causes of maldevelopment and their prevention.

3.2 Classification by cause

The difficulties of discovering the causes of abnormal fetal development did not impede, perhaps stimulated, efforts to devise systems of etiological classification, which indeed began years ago. A sweeping formulation, analogous to Galton’s (1889) division into nature and nurture, was the classic partition into genetic and nongenetic and its elaboration by Gruenwald (1947). In covering all contingencies, in the former, he included spontaneous, induced, and somatic mutations, and—bewilderingly—overripeness of the egg, and in the latter, explicitly defined as agents affecting the phenotype without effect on the genotype, were included all imaginable types of environmental agents—mechanical actinic, chemical (excessive, inadequate), temperature (high, low), and infectious—almost all known through early experiments with embryos of rodents, birds, amphibians, and other laboratory creatures, a list hardly enlarged upon even today.

An addition to this overall scheme was offered by Penrose (1951) with a theoretically important, though still conjectural, consideration: interactions between mother and foetus of both hereditary and environmental origin, such as antigenic incompatibility and biomaternal factors. Among the standard influences in the maternal environment of toxic, nutritional, and other factors, he included psychological traumata, but not with any great confidence in their reality. With the addition to the genetic category of abnormalities associated with chromosomal aberrations, discovered since Gruenwald and Penrose wrote, these outlines remained essentially unadvanced when a comprehensive summary of the subject appeared later in the century ( Kalter and Warkany, 1983), and it seems have largely continued so till today.

An important contribution to the fabric of these outlines made by this summary was the calculation of the quantitative role of each of the etiological categories (it should first be noted that earlier it was well documented, as will be discussed below, that the total frequency of major malformations in newborn children is about 3%). The calculation estimated that single mutant genes are the cause of about 7.5% of all congenital malformations, that about 6% of all serious malformations is associated with chromosomal abnormalities, and that all known, still not overcome, discrete major extraneous causes—infectious and noninfectious maternal illnesses, environmental substances, pharmaceutical drugs, etc.—are responsible for or associated with possibly another 5%. To these may be added as much perhaps as 20% or so of all malformations due to the combined action of environmental and genetic components, i.e., multifactorial situations (incidentally, one sees these exact percentages repeatedly cited, but with attribution often missing). Summing these, one sees that the etiology of fewer than half, perhaps far fewer than half, of all congenital malformations had been identified to one extent or another at that time, but it is safe to say the partitions are not substantially different at the time of this writing.

It is this large terra incognita that it must again be confessed for which no answer is as yet in hand. How much of this residue has, as its basis, still-to-be-discovered environmental teratogens and the multitude of single genes that are daily revealed to be responsible for prenatal mishaps is for the future to unveil.

A possible reason for this poverty of etiological understanding is the relatively limited final forms that are attained by the majority of isolated individual malformations and the limited number of pathogenetic pathways that are traversed to do so, which with few exceptions obscures and often gives little clue to their possibly diverse causation. By default, therefore, the main unambiguous classificatory scheme existing at present is by abnormality type.

3.3 Classification by type

A system of putting arrays of malformations into an order based on morphological appearance has various advantages and purposes, e.g., storage and retrieval of diagnostic data and coding of entries on fetal death and birth records. However, by far, its predominant use has been in facilitating recognition and comparison. This is the practical and universal basis of classification that necessity has forced on students of human congenital malformations. The entities, however, that can be included in such schemes are numerous, and discussions about what, according to varying needs, they should contain have been arduous (see, e.g., Davison, 1963; Potter, 1964).

Among the most comprehensive of descriptive classifications of congenital abnormalities, which it owes of course to the fact that it primarily serves the requirement of indexing hospital and other records for data storage and retrieval, is that contained in the International Classification of Diseases (ICD) ( WHO, 1992). Aside from the new name given in a recent revision to the chapter devoted to congenital abnormalities, congenital malformations, deformations and chromosomal abnormalities, and the expansion of some subentries, there is little fundamentally different from previous revisions. It is arranged by system, part, and organ and includes virtually every deviation from normal originating prenatally present at birth or attributable to conditions present at birth, regardless of medical importance or etiological status.

An early version of the ICD scheme was applied to a birth certificate survey by the National Center for Health Statistics of congenital anomalies in live births in the US ( Taffel, 1978). Some of its criticized features were that various items were scattered throughout the ICD under different headings and consequently were identified with difficulty and had to be omitted, and that the system did not accommodate multiple or combined occurrences of malformations.

It is these deficiencies, but particularly the undiscriminating equal weight it gives entities of very different prognosis, giving no guidance to the recording of more or less meaningful abnormalities, that not only diminish its usefulness to the clinician, public health worker, and epidemiologist, but moreover relinquish an important pedagogic function.

Other extensive formulations have attempted, more or less clumsily, to deal with another of the ICD’s shortcomings, i.e., the categorizational and coding difficulties presented by the fact that malformations frequently occur in multiples involving several bodily systems (e.g., Neel, 1958;