Prevention of congenital malformations

Prevention of congenital malformations

is Professor Emeritus of Research Pediatrics at the University of Cincinnati and Attending Pediatrician at the Cincinnati General Hospital. He is also...

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is Professor Emeritus of Research Pediatrics at the University of Cincinnati and Attending Pediatrician at the Cincinnati General Hospital. He is also Director of Mental Retardation Research, Institute for Developmental Research at the Children’s Hospital Research Foundation in Cincinnati. Dr. Warkany was born and educated in Vienna, Austria, where he graduated from the University of Vienna Medical School. Some of the societies that Dr. Warkany is a member of are The American Pediatric Society, The Society for Pediatric Research, and The Teratology Society. Dr. Warkany has received many prestigious awards, among them are the Award for Distinguished Achievement, Modern Medicine, 1964; the American Association on Mental Deficiency Research Award, 1976; Humanitarian Award, V.J. Sarte National Hydrocephalus Foundation, 1977.


INTEREST in congenital malformations has varied through the centuries of recorded medical activities. Historically there have been great variations in the explanations of birth defects, and preventive attempts have followed prevailing beliefs of the culture. A few examples from the history of teratology illustrate this point. Some of the oldest teratologic descriptions are seen in sculptures and images from antiquity, with no explanation and no expression of the artist’s attitude toward the anomaly. One of the oldest documentation of a congenital malformation is a figurine with two heads found in a shrine in southern Turkey which is thought to be over 8,000 years old. To archeologists this figure is a double-headed goddess, but to physicians it is a dicephalic conjoined twin, gne of many presentations of this monstrosity. We cannot say why such a sculpture was placed in a shrine together with other gods and goddesses. Was it to prevent recurrence of this or other malformations? Dicephalic sculptures, carvings, and drawings have been found in many parts of the world; they are a striking subject of primitive art, but they 3

do not tell us what the observers thought of such miraculous births. In medieval Europe, pictures of birth defects were fabricated, printed, and sold at county fairs for the entertainment of the populace. In the 15th and 16th centuries many illustrations of deformed children and adults were disseminated, some supplemented by texts that suggest the attitude of the people toward these vagaries of nature. Some deformities were interpreted as warnings from a God who disapproved of the sins of the times and promised better offspring in return for a pious life. Thus, good behavior was recommended for prevention of the horrible monstrosities. These medieval images and their accompanying printed texts may also be applied to the numerous presentations of malformations in antiquity.l Other written texts on malformations indicate different attitudes. There are Babylonian records of birth defects which were collected for other reasons. Clay tablets found near the Tigris river in the 19th century are replete with references to congenital malformations. These teratologic observations were collected by Babylonian priests for the purpose of divination. Ancient astronomers studied celestial events as well as unusual terrestrial events because they believed in causal connections between their observations and future happenings. Births of defective children, together with the positions of the stars, sun, and moon, served as omens for the land, the king, and the household into which the children were born. An elaborate system of divination was developed which was so respected that the Babylonian beliefs spread far beyond their homeland throughout Asia and Europe, and even to America. Many Greek and Roman philosphers were firm believers in prognostication and with it they stoically accepted man’s fate as predetermined and unalterable. In Rome, augurs interpreting omens as part of the religious life were so influential that Cicero (106-43 B.C.) devoted an entire book, “De Divinatione,” to this subject, although he himself was skeptical. Another skeptic was the enlightened essayist of the 16th century, Michel Eyquem de Montaigne (1533-1592), who, though familiar with the general belief in the prognostic value of malformed children, wrote: “It is better to let it alone for in things already past there needs no divination.” Those who followed the Babylonian concept and believed in the predetermination of terrestrial events were fatalists. Since the births of malformed children were connected with and dependent on celestial situations, they were accepted as unavoidable, and prevention seemed impossible.2 Many philosophers of antiquity speculated about the fact of reproduction. A most original concept was contributed by the Greek philosopher Empedocles in the fifth century B.C., who was so impressed by the existence of human monstrosities that he considered them primary formations and the forerunners of 4

man. He developed a theory of evolution somewhat related to the modern one. It assumed an accidental appearance of single organs that got together in a variety of combinations, with survival of the fittest. Empedocles wrote that at first “many heads sprung up without necks and arms wandered bare and bereft of shoulders. . . . Eyes strayed up and down in want of foreheads. . . . Solitary limbs wandered, seeking for union. . . . Many creatures with faces and breasts looking in different directions were born. . . . These things joined together as each might chance. . . .” The monstrous specimens that came into being by fortuitous unions of these parts soon became extinct but the fit formations survived as animals and men. Thus, Empedocles considered monstrosities to be forerunners of normal beings and natural selection to be a screening process. This concept of survival of the fittest antedated Darwin by 2,300 years. Aristotle (384-322 B.C.) had good knowledge of teratologic facts. He knew of redundance and reduction of hands, feet, fingers, and toes; he mentioned imperforate anus, noted absence of the gallbladder, spleen, or kidney, and described hermaphroditism or pseudohermaphroditism in appropriate terms. But I am not aware that he considered prevention. There were many other speculations about malformations in subsequent centuries which need not be described here. Instead, we can turn to Ambroise Pare (1510-1590 A.D.), a celebrated surgeon of the Renaissance and a reformer of wound treatment, who found time during his long life to write a treatise on “Monsters and Marvels” (1573 and subsequently) which was translated and reedited by Janis L. Pallister in 1982.3 Pare’s treatise reflects the superstitions of his time and the times before him, but he also mentions some sound principles of embryology that are still valid today. In the 16th century it was fashionable to write about monsters and prodigies, but Pare’s work is outstanding because, unlike some of his contemporaries, he dealt with causes rather than with ends (purposes) of malformations. At the outset he enumerates 13 causes. The first is the glory of God, the second His wrath. The latter is aroused by men and women’s sins, which theoretically can be avoided. Monstrous and marvelous creatures can be attributed to errors the parents make in copulation like brutish beasts and to conceiving during menstruation, which makes it likely that sick or deformed children will be born. A monster was born with a horn on its head, two wings, a single foot, an eye on his knee, and hermaphroditism following an unjustifiable battle between a pope and a king. Such marvels were sent by God to warn us of threatening misfortunes. This idea is the same as that expressed in many of the printed and illustrated medieval pamphlets mentioned earlier. Too great a quantity of seed or too little of it is given as third and fourth causes of monsters. To document this, Pare offers a remarkable illustrated catalogue 5

of conjoined twins and persons with supernumerary organs. For those who do not believe these stories, the parents’ names, their residences, and the years of birth of these marvels are cited. Too much seed also explained why some women could carry several children in one pregnancy (from two to six and more); hermaphrodites could also result from a “superabundance of matter,” which could be contributed by the father or mother. Causes 10 and 11 describe qualitative changes of the seed, “rotten or improperly mixed.” Although these causes brought about miraculous creatures, there is no suggestion of how seminal irregularities could be prevented. The fifth cause cited was manageable to a certain extent. It was an important rule that malformed persons who survived and became adults should not live “among us” because they could spoil the fruit of the pregnant women by the apprehension and by ideas they arouse. But these were only exceptional cases, since the expectant woman would also be influenced by looking at pictures or at frogs. The danger of deformation of the embryo was thought to exist only during the first 5-6 weeks of pregnancy, because thereafter the unborn was completely formed. This thought predates the modern concept of sensitive periods during gestation, a concept still used and abused in medical circles. Protection of the mother from adverse visual impressions during early pregnancy was therefore an important preventive measure. Causes 6, 7, and 8 can be summarized as mechanical. They were accepted long before and after Pare and will be discussed later. Cause g-hereditary or accidental illnesses of a parent, particularly the mother-was a rather modern concept. Body size and weight, deformities of the spine and hip, and flat noses are transmitted from parents to children. The same is true for functional defects such as speech anomalies or epilepsy. If the father and the mother are fools, the children are rarely if ever intelligent. Nonetheless, one must not make a definite rule out of this, for we see parents who have any one of these disorders and yet the children don’t have them “because the formative power has corrected this defect.” Thus there is an innate corrective force but no means by which we can influence such hereditary tendencies. It is rather suprising to find as the 12th cause of malformations deformities faked by beggars and imposters. Evidently, Pare was quite involved in unmasking malingerers who tried to obtain monetary advantage by appealing to the compassion of their fellow men. More important is cause 13, which deals with monsters produced by demons, devils, and witches. The belief in such supernatural forces was so strong in Pare’s time that their existence was not doubted by learned doctors, including Pare, who dealt at length with magic and the possessed. He did not describe their role in the origin of monsters, but we know from other sources that when children were born with malformations resembling the image of the devil 6

or of animals, there were dire consequences for the child or the mother. Pare summarized the beliefs on teratology before his time; his work, translated into English, is easily available to readers interested in the history of congenital malformations.3 PREMODERN ERA In subsequent centuries similar works on monstrosities were published by Fortunio Licetus (16161, Aldrovandus (16421, and others, who combined descriptions of realistic and fantastic malformations with theories of their causation without contributing to preventive measures. An outstanding medical scientist, William Harvey, known as the discoverer of the circulation of the blood, also wrote a treatise on the reproduction of animals (“De Generatione Animalium,” 1651 and 1653). Following his sovereign King Charles, who was an enthusiastic hunter, he had daily opportunities to dissect bucks and does. In addition, he observed for many years the reproduction of fowl and various domestic animals, which resulted in a number of fundamental conclusions. He stated, for instance, that almost all animals, even those which bring forth their young alive, including man, are produced from eggs: Omne viuum ex ouo which was a rather risky guess, made 175 years before von Baer discovered the true mammalian ovum. At a time when many scientists believed that all embryonic parts were formed simultaneously and were preformed in the spermatozoon, merely growing during development (preformation theory), Harvey’s observations showed that embryonic organs developed in succession (epigenesis). This implied that malfo~ations could arise after conception during embryogenesis. Harvey also introduced the concept of arrested development as an explanation for congenital malformations. Harelip was attributed to persistence of the oral aperture, which stretched from ear to ear in fetuses: “In the development of the human foetus, the upper lip only coalesces in the midline at a very late period.“4 A long list of writers could be cited who in the 17th and 18th centuries contributed to teratology, the science of congenital malfo~ations, but it was in the 19th century that this branch of medicine reached an acme. By that time physicians had an admirable knowledge of the morphology, embryology, and taxonomy of abnormal human and animal development. In a classic work, J.W. Ballantyne summarized the history and teratologic info~ation accumulated before the 20th century.’ He was an obstetrician and gynedologist who regarded congenital malformations as the result of antenatal pathology, with emphasis on placental, uterine, and amniotic factors, both mechanical and infectious. Consequently he considered antenatal hygiene as a preventive approach: antenatal treatment was primarily maternal. 7

One could influence the unborn infant by altering its environment or by transmitting medicinal substances through the mother. Prematernity and pregnancy clinics and hospitals were recommended, diet and occupational exercise in pregnancy were discussed. Medication for fetal syphilis, treatment of placental disease, and antenatal treatment of hemophilia were subjects of antenatal hygiene. Maternal diseases and disorders could interrupt the chain of normal heredity, but there was a chance of recovery from the parental illnesses, infections, or noxious drugs (narcotic or alcoholic). Marriages of consanguinity and postponement of matrimony till late in life were to be avoided. Ballantyne’s recommendations apply chiefly to prevention of diseases in late fetal life, but there was little information on how to prevent congenital malformations. Ballantyne considered heredity and germinal pathology as predisposing factors to malformations, but he did not emphasize them or explain them. However, E. Schwalbe in his early volumes, Morphologic der Missbildungen,5 wrote extensively on the role of heredity, germ plasma, germ cells, chromosomes, and mutations in causing congenital malformations; according to him, endogenous as well as exogenous factors must be considered, although they sometimes cooperated and their respective contributions were not always discernible. These publications appeared four decades after Mendel’s discovery of the principles of heredity in 1866, but those laws had not yet been applied to human malformations. At the end of the 19th century interest in teratology declined sharply. Bacteriology, nutrition, and surgery were the focus of medical interest, and pediatrics made great strides in the reduction of infant mortality with the help of these scientific advances. The small percentage of children born with malformations was not of great interest at that time. It was known at the turn of the century that some malformations were passed on from parents to children while others were not. Some malformations, particularly minor ones, were used to illustrate that mendelian laws did apply to human inheritance. Early medical geneticists recorded selected pedigrees as examples of dominant or recessive traits. But many common malformations such as neural tube defects, facial clefts, or clubfoot, although showing a tendency to heredity, failed to follow the rules of genetic transmission. Modification of these rules by including reduced penetrance, variable expressivity, and new mutations made it possible to “explain” all human malformations by heredity, including some which are now known to be due to viruses and drugs. So many pedigrees of inherited malformations became available that enthusiastic medical geneticists about 1930 declared that all symmetric congenital malformations were hereditary. They were not influenced by experimental teratology which flourished during the 19th and 20th century and demonstrated that many 8

malformations and monstrosities could be produced in eggs of birds, reptiles, and amphibia by environmental agents. Geneticists asserted at that time that mammalian embryos were protected from such interferences by the maternal body. It was only from 1940 on that mammalian experimental teratology demonstrated that many types of congenital malformations-single, multiple, symmetric and familial-could be produced in rats, mice, rabbits, and pigs by exogenous agents such as chemicals, drugs, and nutritional deficiencies. At about the same time, some observations in children showed that viruses and other infectious organisms could induce congenital defects that were sometimes indistinguishable from hereditary malformations. MODERN ERA New teratogenic factors were recognized beginning in 1959, when chromosomal abnormalities were established as causes of physical and mental defects in children. Although this extended the realm of genetic causation, the transmission of the defects did not appear to follow mendelian rules. Curiously, in the same year an epidemic of congenital malformations was attributed to a drug, thalidomide, taken by expectant mothers to combat nausea of pregnancy and sleeplessness. These teratologic discoveries coincided with renewed interest among pediatricians in congenital malformations. The preventive measures of early pediatrics were paying off. Infant mortality decreased steadily as contagious diseases and nutritional disorders such as scurvy and deficiency rickets disappeared. Public health statistics showed shifts in the percentages of causes of children’s deaths. In 1910, for instance, about 30% of infant deaths were ascribed to diarrhea and enteritis and only 5% to congenital malformations; 30 years later, in 1940, deaths from enteritis had decreased to 10% and deaths from malformations had increased to 10%. These trends in infant mortality continued in subsequent decades so that now congenital malformations have become of great relative importance. Also, disorders of prenatal origin assumed an increasing role in every day pediatric practice. This was due to improved diagnostic methods, particularly x-rays, which showed that many pneumonias and gastroenteric and urologic disorders formerly attributed to infections were basically due to predisposing malformations.6 All this demonstrated that congenital malformations, once considered negligible curiosities, were actually a public health problem that deserved the full attention of the medical profession. It is hoped now that malformations present at birth will become preventable, like other children’s disorders which were so successfully combatted by pediatrics in the past. At present, congenital malformations are regarded as genetic, chromosomal, or environmental in origin. Prevention is directed 9

at recognition and elimination of these factors. The genetic and chromosomal problems differ fundamentally from those attacked by early pediatricians. Rethinking and retooling become necessary for teratologic research. Before these causal determinants are discussed, it should be pointed out that prevention of human diseases and disorders has not always been achieved by direct removal of well-defined causes but also by indirect methods which lead to prevention without knowledge of specific noxious agents. Many contagious diseases were eliminated decades before their primary causes were known and open to attack. Some of the worst scourges of mankind, leprosy and tuberculosis, were significantly reduced in frequency by such diverse measures as isolation, cleanliness, improved nutrition, and better housing long before the injurious bacilli were discovered and treated. Similarly, some epidemics of acute infectious diseases were stopped by simple procedures when the chain of events which led to the disaster was interrupted. To give one classic example, in 1854 there occurred in London a cholera epidemic that was particularly severe in the Broad Street area, where deaths were over 20 times more frequent than in other districts. A Cholera Inquiry Committee examined this phenomenon and a Dr. John Snow found that nearly all of the deaths had occurred within a short distance of a water pump on Broad Street from which the affected population got their water. Some persons who worked in industries within the district and some prisoners who were in a workhouse located in the same area remained well. Snow explained this by the fact that these establishments had their own wells, so that their populations did not drink water from the Broad Street pump, which later was found to be connected with a cesspool that drained its contaminated contents into the infected well. At Snow’s recommendation, the handle of the suspected pump was removed and the well was closed; this ended the epidemic. This was a remarkable result, achieved 29 years before Robert Koch’s discovery of the cholera vibrio. In discussing prevention of congenital malformations direct as well as indirect preventive measures must be considered.6 DIRECT PREVENTION

The oldest rational theories of the origin of congenital malformations are mechanistic, dating back to Hippocrates and Aristotle. Hippocrates assumed that crowding in the womb caused prenatal deformities and so anticipated 19th century teratologic beliefs. Aristotle believed that increased pressure on the unborn caused deformities. Maternal trauma, uterine narrowness, and fusion of germs were other explanations offered by the ancients for monstrous births. Pare cited examples of monsters created by narrowness or smallness of the womb and by maternal habits 10

such as sitting too long, sitting with legs crossed, or strapping their bellies too tightly. As a result of crowding, children were born bent, hunchbacked, or with hands and feet twisted. As an example of the last-mentioned effect of maternal constriction, a person is depicted with arthrogryposis (curved joints), antedating the modern description of this disorder by about 350 years.3 Mechanistic theories .about malformations continued through the centuries, although some teratologists, among them J.F. Meckel (18121, denied the teratogenic efficacy of mechanical causes because they gave no explanations for inherited structural anomalies. Ballantyne4 analyzed the pressure theories and differentiated between external and internal pressures, each type having several subgroups of causes that could be deforming by mechanical interference. These theories are being rediscovered by contemporary physicians who treat certain deformities in accordance with their presumed origin. It is understandable that some orthopedic surgeons tend to attribute certain malformations of bones or joints to prenatal malpositions. Some pediatricians point to the “position of comfort” assumed by some newborn babies and explain it as remnants of intrauterine crowding. Recently, much has been made of differences between “malformations” and “deformations,” the latter considered as secondary effects by uterine constraint on originally normal fetuses. Deformations are said to be more benign, with a good prognosis, in contrast to malformations arising in early embryonic life. It is also asserted that the recurrence risk for deformations is low unless the cause of the deformity is a persisting one, like bicornate uterus. Thanks to prenatal diagnostic methods such as sonography and fetoscopy, intrauterine malpositions may become recognizable and correctable in prenatal life. Although it is unlikely that numerically many congenital malformations can be prevented in this way, in certain cases prenatal diagnosis and repair can be very important. One of the most feared neural tube defects, congenital hydrocephalus, which threatens the life of mother and infant, has been treated by cesarean section or craniotomy with sacrificing of the child. Now attempts are made to shunt the head’s intraventricular fluid into the amniotic fluid. In utero treatment aims at prevention of distocia and prenatal brain damage. Other congenital malformations such as diaphragmatic hernia, hydronephrosis, and other malformations of the urinary tract have also been attacked by in utero surgery. Much experimental work is under way along these lines aimed at surgical prevention of prenatal damage. Another rational appyoach to teratogenesis was based in the past on the theory that diseases of the mother or fetus could cause monstrosities. The Italian anatomist and pathologist Giovanni Battista Morgagni, in “Seats and Causes of Disease” (17611, included monstrosities in his observations. He believed 11

that anencephaly and spina bifida resulted from the pressure of fluid within a hydrocephalus that becomes overextended by the impelling force of the water, which “draws asunder” the tender surrounding fetal tissues. The idea that inadequate escape of cerebrospinal fluid at various stages of embryonal and fetal development leads to such dysraphic disorders as meningocele, myelocele, syringomyelia, diastematomyelia, hydrocephaly, hydranencephaly, exencephaly, and anencephaly is still being defended.7 This theory actually deals only with the pathogenesis of the neural tube defects and does not explain the increased pressure within the neural tube. Some more concrete diseases that interfere with normal spinal fluid circulation have been identified but account for only a few neural tube defects. INFECTIOUS TERATOGENS Many infections have been considered as causes of congenital malformations, but it was not until 1942, when N.M. Gregg described congenital cataract following German measles in the mother, that an infectious teratogen was established.’ In fact, congenital heart disease, deafness, and mental retardation were included in the embryopathy of infants exposed to the rubella virus in early pregnancy. This fundamental disclosure was made by an astute clinician who had to defend his conclusions because it was difficult to understand that the relationship of a common contagious disease to a striking embryopathy had been missed by physicians all these years. He thought this was so because the rubella epidemic in Australia at that time was unusually severe causing swelling of the glands of the neck, sore throat, involvement of the wrist and ankle joints, and severe general disturbances. This explanation was not correct. It was an experiment of nature that occurred in Australia during World War II which made it possible to recognize the rubella epidemic and its teratologic sequelae. Many women moved to cities from the country for war work, and many were affected by rubella. Under normal conditions rubella epidemics in cities chiefly affected children, while adults remained well because they had been naturally immunized by the disease during childhood. In Australia, however, many women had grown up on isolated farms in the country and were not exposed to rubella until they moved to the city, which made possible a rare phenomenon: an adult rubella epidemic. Subsequently it was found that in other countries nonepidemic and mild rubella occurring during pregnancy could have similar effects on the embryo. This discovery immediately raised hopes that such malformations produced by this and other viruses could be prevented if immunity could be conferred on all women of reproductive age. Various attempts were made to 12

achieve this for rubella but it took about 35 years to develop a vaccine capable of protecting such women and of reducing rubella and the rubella embryopathy to a minimum in the United States and in other developed countries.g Western equine encephalitis is transmitted by mosquitoes. In rare cases it can be transmitted to the fetus and cause permanent neurologic damage. No vaccines are available for humans yet. Prevention is best accomplished by elimination of breeding places for mosquit0es.l’ Venezuelan equine encephalitis can affect human beings infected by mosquitoes. Maternal infection can result in abortion or congenital malformations in the child. After early infection microencephaly, hydrocephaly, and hypoplasia of the medulla and the cerebellum have been observed. For prevention, infected hosts (horses and small mammals) and breeding places for mosquitoes must be eliminated.” Toxoplasmosis is due to a sporozoan, Toxoplasma gondii. It has been known for 60 years that this agent can cause congenital hydrocephaly, microphthalmia, and chorioretinitis. It is estimated that in the United States the incidence of maternal toxoplasmosis is 0.5%. Only women who become acutely infected during pregnancy may have a child with congenital toxoplasmosis. If they acquire the disease in the first trimester, it is transmitted less often than in later stages of pregnancy, but manifestations of congenital toxoplasmosis are more severe following earlier invasion. More than 90% of fetal infections acquired in the third trimester are asymptomatic. In the United States congenital toxoplasmosis can be reduced by having susceptible women avoid eating uncooked meat and avoiding close contact with infected cats and their feces. Women with acute syphilis during pregnancy can have children with congenital syphilis manifested by maculopapular rashes, mucous patches, rhinitis, hepatosplenomegaly, jaundice, chorioretinitis, pseudoparalysis, etc. In preantibiotic eras late congenital syphilis was known to cause Hutchinson triad-nerve deafness, interstitial keratitis, and notching of the upper central incisor teeth. But many other signs and symptoms occurred, including microcephaly and mental retardation. Prevention is effected by treating infected women and suspected newborns with penicillin.

Fetal x-irradiation can lead to congenital malformations in man and animals. By 1929 it was known that intrauterine growth retardation, microcephaly, skull defects, spina bifida, microphthalmia, and limb malformations could occur in children whose mothers had been treated during pregnancy with large 13

(“therapeutic”) doses of roentgen rays. As this danger became widely publicized,” therapeutic pelvic irradiation largely ceased during pregnancy and in women of reproductive ages, and this particular source of congenital malformations has become extremely rare. Very seldom irradiation for cancer of a woman not known to be pregnant may still cause a radiation embryopathy. Following the atomic bombs explosions in Hiroshima and Nagasaki in 1946, children born to Japanese women pregnant at the time and exposed to radiation showed a relatively high incidence of microcephaly and mental retardation. There was a relationship between the incidence of microcephaly and distance from the hypocenter as well as gestational age of the fetuses at the time of exposure.i’ Prevention of adverse radiation effects have been thoroughly analyzed and discussed.13 TERATOGENIC DRUGS

Much attention is given to chemical teratogenesis. Aminopterin, a folic acid antagonist, widely used as an abortifacient some 30 years ago, proved to be teratogenic, as demonstrated in fetuses and infants. When abortion failed to occur and the fetuses were removed surgically, hydrocephaly, anencephaly, encephalomyelocele, or facial clefts were observed. In one well-documented case the mother attempted abortion with aminopterin in the second month of pregnancy and developed signs of folic acid deficiency, which was successfully treated while the pregnancy continued. The child, born 2 weeks after term, showed marked intrauterine growth retardation, megalencephaly, posterior palate cleft, webbed neck, and clubhands and clubfeet. The cranial bones were incompletely ossified, as in osteogenesis imperfecta. The child died 1 day after birth. A few subsequent infants with similar anomalies survived and developed a syndrome of retarded growth and ossification, slow mental development, hypertelorism, posterior palate cleft, and micrognathia. When the teratogenic effects of aminopterin became known the drug was no longer used as an abortifacient. A methyl derivative of aminopterin, methotrexate, taken as treatment for psoriasis by pregnant women, also resulted in the birth of infants with congenital defects. These rare cases of drug-induced congenital malformations were soon overshadowed by the epidemic of congenital reduction malformations of the limbs (amputations or phocomelias) which occurred between 1958 and 1961 in Germany and in other countries where thalidomide was available to pregnant women. This drug was taken as a soporific and particularly for nausea and vomiting in early gestation. It has been estimated that in West Germany more than 5,000 children were malformed by thalidomide. Of these, one third died soon after birth. The malforma14

tions were not limited to the skeleton of the extremities but also involved the external and inner ears and the cardiac, intestinal, and urogenital systems. The CNS usually escaped severe malformations, but pareses of the facial and abducens nerves and convulsions were sometimes observed. The teratogenic effect of thalidomide was most pronounced when the drug was taken between the 35th and 45th days after the last menstrual period. McBride in Australia and Lenz in Germany recognized the causal connection between thalidomide and the epidemic of malformations almost intuitively. Lenz was guided by the suspicion of a physician’s wife who had taken the drug for many months before and during pregnancy. She developed severe polyneuritis and gave birth to a severely malformed child. Alerted by this woman, Lenz collected other cases and in November 1961 he made the following statement before a pediatric audience: “From a scientific point of view it seems premature to discuss it. But as a human being and as a citizen, I cannot remain silent about my observations.” This dilemma between a suspicion and scientific proof will often be faced by observing practicing physicians. To make this situation more poignant it should be mentioned that at the same time, another German pediatrician initiated a search for the new teratogen by distributing to parents questionnaires which considered numerous causative possibilities such as detergents, preservatives, insecticides, and varnishes; thalidomide emerged in the eighth place of suspected culprits. Some parents suggested atomic bomb tests and television. After the case against thalidomide had become very strong, the drug was withdrawn from the market and the phocomelia epidemic stopped within a year. This reads like a simple story of causation and prevention, but the interested reader should study retrospectively the difficulties encountered by the investigators in the search for this chemical teratogen. One of the confusing factors was that pregnant women usually took a large number of drugs, some of which became suspect by association. Thus meclizine, an antihistamine and antinauseant, which was widely used at the time of the thalidomide epidemic, together with the guilty drug was taken by 25% of the mothers who had children with typical skeletal malformations, but meclizine was also taken by 26% of the mothers of normal children. Avoidance of masculinizing progesterones has reduced the incidence of genital anomalies caused by treatments with such agents. Unfortunately, discovering that drugs have specific teratogenie features may not lead to the prevention of congenital malformations produced by them because their discontinuation may not be advisable or possible. Although anticonvulsant drugs taken during pregnancy increase the incidence of congenital malformations to a certain extent, withholding such drugs from 15

all epileptic women of reproductive age to avoid injury to fetuses cannot be recommended. In 1979 the Committee on Drugs of the American Academy of Pediatrics confirmed that there is an increased risk of congenital heart disease and cleft palate among the offsping of women with epilepsy, most of whom are on anticonvulsants. Part of this increase may be caused by phenytoin. The risk of all abnormalities in the infants may be about 4%5%, which is approximately double the rate of malformations in the general population. The Committee recommended that no woman should receive anticonvulsant medication unnecessarily. When a woman who has epilepsy and requires medication asks about pregnancy she should be advised that she has a 90% chance of having a normal child and should not be routinely urged to consider abortion.14 Discontinuation of medication in a woman whose epilepsy is controlled by medication may cause seizures, and prolonged seizures could cause serious sequelae to her and the fetus. During the last few years special attention has been paid to valproic acid (Depakene), which has been widely used to control epilepsy in Europe. Epidemiologists reviewing incidences of birth defects have concluded that it is very likely that valproic acid causes spina bifida in about 1% of fetuses exposed to it in early pregnancy. This risk is high and similar to the risk of having a baby with spina bifida after previously having had a baby with a neural tube defect. Anticoagulants such as warfarin also present dangers to unborn children, but without such drugs women with a tendency to thromboembolic complications are in danger of serious accidents. Of several hundred reported pregnancies in which coumarin derivatives were used, one sixth resulted in abnormal live-born children, one sixth in abortion or stillbirth, and two thirds in normal infants. At first it was thought that this danger could be circumvented by using heparin, but heparin also resulted in difficulties in one third of the conceptuses.15 Anesthetics have been considered as teratogens, and exposure of operating room nurses to anesthetic gases has been thought responsible for increased abortion rates. One could avoid some such difficulties by keeping women of reproductive age out of operating rooms, but if it is true, as has been asserted, that men exposed to noxious fumes emanating from anesthetics can cause reproductive failure of their wives, protection of their offspring would probably limit modern surgery to a minimum.6 . Alcohol has long been suspected as a danger to normal pregnancy, but despite millenia of warning, it is still in great demand by men and women. Alcohol use is denounced in the Bible, forbidden by Muslim law, and has been fought over for centuries in Western countries. In old case reports on congenital malformations one often finds alcoholism of the parents mentioned, and Ballantyne discussed the subject thoroughly.4 He pointed to 16

the fact that passage of alcohol to the fetus has been proved. Already in the 19th century the literature was replete with reports on reproductive failure due to maternal alcoholism. Ballantyne stated, “For the female habitual drunkard it is apparently the best thing to be committed for a term of imprisonment early in her pregnancy; the prison baby may be the best.” Thus we encounter jail as a preventive factor! Epilepsy, idiocy, and congenital malformations were blamed on drunken parents. But there was controversy on the subject until in 1968 and subsequently a “fetal alcohol syndrome” emerged, giving credence to the idea of damage to the fetus by this toxin. Since the components of this syndrome are not specific the estimates of its frequency vary considerably. The danger of maternal chronic alcoholism to the unborn cannot be denied and alcohol ingestion before and during pregnancy should be discouraged, but the chance of complete preventability of prenatal alcohol exposure is small, since history has shown that no threat of adverse consequences has succeeded in eliminating this dangerous chemical from human consumption.6 There is much speculation about chemical compounds in the external environment as causes of birth defects. The best known chemicals that can contaminate the environment and reach the fetus through the mother are organic mercury compounds, particularly methylmercury. In Japan several hundred children suffered brain damage before birth by exposure to mercury which the mothers had ingested with fish and shellfish taken from Minamata Bay. For many years a factory that used mercuric salts as catalysts in the production of acetaldehyde and vinyl chloride discharged its waste into Minamata Bay. Methylmercury formed in the process was taken up by fish and shellfish, which were part of the food of the fisherman and their wives. Some of these developed a neurologic disease that consisted of ataxia, tremor, impairment of speech, constriction of visual fields, defective hearing, and sensory disturbances. The course of the disease (Minamata disease) varied in intensity and duration. Women who became pregnant passed their organic mercury through the placenta to their fetuses, damaging their brain. Congenital Minamata disease was characterized by delay of neck control, sitting, standing, walking and failure of visual, social, and mental development. As the children grew older they showed growth retardation, undernutrition, moderate microcephaly, exaggerated deep reflexes, hypertonia, and contractions. Most were incapable of learning and had an IQ of 75 or less. Removal of the organic mercury compounds from the area ended the epidemic of Minamata disease, including its congenital form.16 Similar epidemics occurred in other parts of Japan as well as in Iraq. In Iraq the source of methylmercury was imported grain that had been treated with a mercurial fungicide. 17


Among maternal diseases diabetes mellitus can be a cause of congenital malformations. Before the introduction of insulin in the treatment of this disease, births of term children to diabetic women were so rare that an association of birth defects and maternal diabetes could not be established. After insulin treatment of young diabetics became possible (1923) it was noticed that infants of diabetic mothers had various peculiar features. It was asserted in the 1940s that congenital malformations were included among the pecularities of these infants and that some characteristics of infants of diabetic mothers were even present in children born to these mothers before they became diabetic. These findings were not generally accepted until 15 years ago, when a large Danish study showed that congenital malformations were about three times more frequent in infants of diabetic mothers than in controls and that the increase in malformations was particularly pronounced in infants of mothers with vascular complications. These findings were a challenge to diabetologists, and after some trials it was demonstrated that the excess of malformations in infants of diabetic mothers could be prevented if strict metabolic control was begun in prospective mothers before conception and continued during the first critical weeks of pregnancy. ” But there remains the problem of prevention in latent prediabetes. Great efforts have been made to find environmental teratogens by clinical observations and by monitoring birth defects on a large scale, but there are difficulties in such studies, and not many new discoveries have been obtained by these efforts. Recently valproic acid (Depakene), used in patients with epilepsy and first suspected to be teratogenic in single case reports, has been shown by the Institut Europeen des Genomutations in Lyon and by other surveillance servicesl’ to be a cause of spina bifida when taken in early pregnancy. THE PHYSICIAN’S ROLE IN DISCOVERY OF ENVIRONMENTAL TERATOGENS

Practicing physicians have aided in the discovery of teratogens by observing maternal habits or diseases and relating them to anomalies of their children. Some of these conclusions have been relevant, others not. What should a physician do who suspects a teratogenic etiology of an infant’s malformation? In successful cases a letter to the editor of a medical journal with the request for reports of similar observations has initiated larger epidemiologic studies that confirmed or failed to confirm the suspected relationship. This sequence of events has occurred in several cases without doing any harm. If, however, a suspicion is 18

prematurely communicated to a daily newspaper and is reported as a fact to lay persons, much harm can be done to mothers, physicians, nurses, and pharmaceutical houses by uncritical headlines, which may create modern superstitions. GENETIC VERSUS MAN-MADE


Genetic factors are probably most important numerically as causes of congenital malformations, and during the last two decades chromosome anomalies also have been recognized as the basis of many malformations. In regard to these causes, direct prevention means prevention of mutations, point mutations as well as chromosome mutations. Mutations can result in sterility, embryonic death, malformations, or genetic diseases. Although one speaks of induced and spontaneous mutations there are no sharp lines between these since some agents such as x-rays and certain chemicals are present in many environments so that some mutations which seem spontaneous to us may actually be induced without being recognized by us. As long as we are ignorant of the causes of spontaneous mutations we cannot practice direct prevention in man, but as spontaneous mutations in bacteria, fungi, and plants are now elucidated, such mutations may become explainable in man also. At present, attention must be given to man-made mutations and their prevention. It has long been known that mutations can be induced by ionizing radiation, and x-ray mutagenesis has been studied in many fields of biology. That x-rays are teratogenic in animals and in man was recognized soon after their introduction into medicine. There were also early warnings to avoid irradiation of women during pregnancy, and it has long been recommended to avoid exposure to adverse radiations of men, women, and fetuses in order to prevent both mutagenic and teratogenic injuries. Embryonic cells are susceptible to mutagenic effects of radiation throughout gestation, and there is evidence that cytogenetic abnormalities persist after intrauterine irradiation.13 X-ray irradiation of male mice resulted in changes manifested in subsequent generations. Litters sired during a short fertile period were small, and about one third of the young again had small litters. This semisterility was transmitted to later generations by reciprocal chromosomal translocation. The small litters were due to the death in utero of some of the offspring. Some of the embryos found in the uteri of females mated to semisterile males showed severe exenceEhalies. In this way it was demonstrated that x-irradiation of male mammals could produce hereditary malformations.ig The x-ray doses used in these observations and experiments were large (several hundred rad). There is controversy about the permanent cytogenetic effects of low doses of x-irradiation (< 10 19

rad). One must remember that there exist some sources of radiation, such as background radiation, that cannot be eliminated. There is great anxiety about man-made radiation from nuclear power reactors and from consumer products. Protection from such radiation is at the center of popular attention, and one can assume that no safety measures will be overlooked to exclude these sources of possible mutation. Irradiation as a medical procedure is well evaluated and controlled. There exist guidelines for its use, and unnecessary exposures should be avoided in all patients. When diagnostic or therapeutic irradiation is indicated because of health problems, questions arise about the danger of mutation to an embryo carried by a woman. Such cases must be dealt with individually according to the guidelines of the National Council of Radiation Protection and Measurements.i3 Thanks to recognition and the attention given to man-made radiation, mutations and congenital malformations due to this source can now be reduced to a minimum. The threat of mutations by environmental chemicals is difficult to evaluate. Mutagenicity by many substances used in medicine, industry, agriculture, food preservation, cosmetics, and other sources had been long considered but was not proved until mustard gas was shown to be mutagenic in the 194Os, with effects similar to those of x-rays. It is probable that the effect of these chemicals is a far greater hazard than that posed by ionizing radiation. Great efforts are being made to assess genetic hazards derived from dangerous chemicals and to induce government, industry, and medicine to prevent their spread in order to avoid damage to human offspring. Their ascertainment, however, is difficult because chemicals show marked specificity for different organisms, and substances mutagenic in test systems are not necessarily mutagenic in man. We are exposed to thousands of potentially mutagenic chemicals. Only a few hundred have been tested, and those under suspicion must be observed through many generations. In addition to the removal of injurious mutagens, genetic engineering and manipulation have been considered as a direct approach to the prevention of hereditary malformations. Although such methods are still far from realization, there is already strong opposition to them by religious group~.~~ INDIRECT


As long as our knowledge of “primary” causes of congenital malformations is still quite limited and most such malformations are not manageable, we must look for accessory causes, which are sometimes more obvious and easier avoided. As mentioned earlier the 1854 cholera epidemic in London was stopped by removal of a pumphandle. Other infections have been suc20

cessfully halted by unspecific methods before the responsible microorganisms were known. For example, childbed fever occurred in alarming epidemics in leading European teaching hospitals staffed by outstanding obstetricians of the 18th and 19th centuries. Progress in obstetric knowledge and crowding of the population brought women into large hospitals which were, however, swept by epidemics ofchildbed fever. In Vienna as many as 10% of women admitted to hospitals for delivery died of childbed fever. There were many theories about these disasters, but it was not until 1847 that a Hungarian physician, Ignaz Philipp Semmelweis, found an answer and prevention for this puzzling disease. He was confronted with an unexplained situation which helped him in the near-elimination of childbed fever. There were then in the Vienna General Hospital two obstetric clinics. In the one used for teaching medical students the mortality from childbed fever was about 12%, whereas in the other, where midwives were taught, the mortality was only 3%. This difference persisted for many years. Semmelweis noted that the medical students who worked in the dissecting room before examining women at delivery carried on their hands some evil-smelling cadaverous material that was not removed by simple washing with water and soap. Only washing with chlorine water or chlorinated lime removed the “cardaveric odor” and with it the noxious cadaveric putrefaction. When the students were forced to wash their hands in bowls containing chlorine solutions before entering the obstetric wards, the mortality in the clinic where they were taught fell from 12% to 2% within a few months. This was a great success for that time. By such an indirect method as washing of hands, which removed the evil odor brought from the dissecting room, childbed fever was successfully attacked more than 30 years before streptococci were recognized as the causative organisms and 88 years before chemotherapy was possible.6 Similarly, malaria was eradicated in many places by drying up marshes in the neighborhood of infested cities. Tuberculosis was reduced by better nutrition and housing. Infant mortality, a subject more closely related to congenital malformations, also was fought without knowledge of specific causes and remedies. Figures available from England indicate that during the 18th century about 400 of 1,000 liveborn babies died in infancy! Such unbelievable losses were accepted because it was thought that infant death was a normal biologic process. The deaths, of course, were due to general poverty of the parents, crowding, and filth, which resulted in diarrhea and spreading of other infectious diseases. At the beginning of the 19th century in England as well as in New York City the infant mortality was still 250 per 1,000 liveborn babies. This horror slowly but steadily subsided. By 1918 infant mortality in the United 21

States was about 100 per 1,000 live births; in 1982, it was 12. Attention to and reduction of poverty and of overcrowding, improvement of sanitation, replacement of outhouses by indoor facilities, installing of window screens, teaching of infant care in neonatal clinics, breast feeding, and purification of cow’s milkall these mundane measures contributed to the reduction of infant mortality, illustrated by a steadily declining curve. This curve was not greatly influenced when antibiotics became available in 1935. Much was achieved without attention to the microbial causes of enteritis and other specific destroyers of infants’ lives6 Indirect and nonspecific prevention was not limited to infectious diseases. In many regions of the world there existed since antiquity a form of physical and mental subnormality called endemic cretinism. In some places it was so prevalent that whole valleys or villages were kept in poverty by the existence of so many defective persons. This disorder was associated with endemic goiter, which was essentially due to iodine deficiency within the affected areas. It is now known that the best method to wipe out endemic goiter and cretinism is general distribution of iodized salt. However, these disorders were also reduced in regions where, for various reasons, iodized salt was not given or was not available. Expanding commerce, building of roads and railroads, and importing foods, drinks, and fertilizers imperceptibly brought iodine to iodine-starved areas, which reduced goiter incidences and wiped out endemic cretinism. These are a few examples that illustrate the diversity of accessory factors which can prove preventive in certain situations because they interrupt the morbific process.6 SOME PREVENTIVE METHODS Interrupting

the Mechanism

Studies of mechanisms that lead to congenital malformations are actually studies of the long chains of prenatal events which result in malformations present at birth. Aside from their theoretical interest to teratologists, such studies may lead to preventive measures by locating weak links in the chains, which can then be removed. But mechanism research is an endless enterprise, since every old or new morphological, chemical, or physical method can be applied, yielding results that, though appreciated by the investigator and his colleagues, are seldom useful in preventing malformations. Many examples can be cited to illustrate this point. Experiments on cleft palate formation or spina bifida pathogenesis have been possible for decades, but the results have not yet led to prevention of these malformations. Such experiments will go on and should go on, but they are not the only way to find preventive measures. Sometimes clinical 22

observations of experiments of nature have delivered the key to prevention. It is important to emphasize this because it tells the practicing physician that his observations are important and that he may be facing an experiment of nature of great significance. His observations are always interesting but drawing conclusions may need expert help and advice, since chance aggregations can mislead. the person who generalizes his or her findings too early. Genetic Counseling

and Prenatal


Prevention of genetically determined malformations is achieved by indirect methods such as counseling or prenatal diagnosis, which, in case of abnormality, gives the parents an option of abortion to prevent the birth of a malformed child. Although this type of prevention has been hailed by some scientists, it is admitted that these methods prevent only a minority of malformations. Usually advice is sought only by parents who have already had an abnormal child or who have an affected close relative. Not all eligible parents seek counseling, and not all counseled families stop having children. If parents accept the counselor’s risk prediction and practice birth control, their decision prevents not only the births of abnormal children but also, in most cases, the birth of normal children as well, since the risks are usually less than 100%. Many parents, when informed of the possibility of abortion, refuse this option for religious or other reasons. Prospective genetic counseling by mass screening and prenatal diagnosis applies only to a few birth defects. Open neural tube defects can be diagnosed by measurement of amniotic fluid cy-fetoprotein (AFP) between 13 and 24 weeks of pregnancy. Such tests can be very important for parents who have already had a child with a neural tube defect, but most children with such anomalies are born to mothers who did not have a previous warning by an abnormal birth; the testing of women known to be at risk can reduce the incidence of neural tube defects by only 10% or less. However, estimation of AFP in maternal serum could be made a routine procedure, particularly in regions and populations at high risk for neural tube defects, and therefore can predict these malformations in some expectant mothers, giving the parents a choice of continuing or discontinuing the pregnancy. Amniocentesis is also useful in the early diagnosis of fetuses with chromosomal disorders and some metabolic diseases. Ultrasound, amnioscopy, apd radiography are other procedures that can aid in the recognition of malformed fetuses and in the reduction of abnormal births by early abortion if the parents opt for this procedure. There is also a positive side to prenatal diagnosis: in high-risk marriages, normal findings may be of benefit to anxious parents and result in continuation of pregnancy 23

and the birth of children that would not have been born without prenatal assurance and proof of normalcy. Unfortunately, some of the prenatal tests recommended are still subject to errors, and different observers and laboratories are not always in agreement. This sometimes leads to awkard situations because the time for selective abortion is limited. Refinement and standardization of tests and examinations will be of great value to parents who know that their offspring are at risk. At present, physicians should keep informed about the status of prenatal diagnosis and communicate to future parents the possibilities of testing. Whatever the attitude of the physician or counselor, he or she is obligated to tell the parents about the existence of prenatal tests and let them decide what to do. It must be realized that induced abortion for eugenic purposes is considered a reasonable procedure by some but infanticide by others.6 Natural


Can births of abnormal fetuses be reduced without induced abortions? There exist effective natural mechanisms which reduce congenital malformations by spontaneous abortions, but these preventive mechanisms are not completely effective; they need support and perfection. It has been estimated that about 15% of recognized human pregnancies end in spontaneous abortions and that about 60-70% of aborted human conceptuses (less than 9 weeks in developmental age) have structural abnormalities. By examining surgically removed uteri and tubes it was noted that 38% of ova found showed anomalies. In Japan, where for some time curettage was performed for social reasons, large numbers of embryos became available for analysis; the prevalence of external malformations in more than 3,000 embryos (310 weeks’ gestational age) was surprisingly high. The incidence of spina bifida, cyclopia, and polydactyly was 10 times higher in embryos than in neonates, indicating that about 90% of some externally malformed embryos are spontaneously eliminated before birth.21 Similarly, prenatal spontaneous screening has been demonstrated by comparison of chromosomal anomalies in early embryos with those occurring in neonates. In first-trimester spontaneous abortuses, chromosomal anomalies are found in 60%, whereas they are found in only 0.6% in newborn children. All these observations point to very effective, natural prenatal screening processes that help in reducing malformations in fetuses reaching the end of gestation. It has been estimated that without spontaneous abortions there would be a 12% incidence of congenitally malformed babies instead of the 2%-3% incidence one observes now. Natural elimination of abnormal ova and embryos-a process called terathanasia-is apparently the most effective preventive mechanism in the area of congenital 24

malformations. The 2%-3% of abnormal babies born can be considered failures of these natural screening processes. It is logical to ask whether this process could be supported by medical measures that would further reduce the incidence of congenitally malformed children. There is no answer to this question at the present time and very little thought has been given to this problem so far. How does. the maternal organisms distinguish between normal and abnormal conceptuses? Studies should be made in women and in animals of the abilities of pregnant mammals to “recognize” abnormal fetuses and to expel them while maintaining the gestation of normal fetuses. This concept seems fantastic, but no progress will be made unless physicians and other scientists direct their attention to this problem. Thirty years ago it seemed a hopeless task to find poliomyelitis strains that infected the organism and produced immunity without causing paralysis. Yet after the problem was well defined and after a systematic search was carried out, such strains were found and used as live polio vaccines. No selective procedures of terathanasia will be discovered unless one looks for them. There exists a mouse strain in which cleft lip occurs spontaneously in about 20% of the offspring. After treatment of mothers with thyroxin during pregnancy, cleft lip frequency of young at term decreases to zero, owing to increased mortality of cleft lip embryos. This illustrates that a simple treatment of the mother can result in deaths of abnormal embryos with preservation of the norma1.23 Similar metabolic differences in women may decide whether a mother carries an abnormal baby to term or aborts the embryo spontaneously. It may be possible to confer the ability of spontaneous abortion of the abnormal by simple treatments of women at risk.6S 22 EFFICACY OF PREVENTIVE MEASURES

In general, congenital malformations are among the disorders whose preventability has not greatly improved within the last decades. There have been successes in preventing certain congenital malformations, and methods have been devised to remove fetuses with such defects before they are born. But the overall incidence of malformations in stillborn and newborn children has not been appreciably reduced by preventive methods that have been so successful in reducing contagious and nutritional diseases in man. It is obvious that the specific preventive methods so far applied have not been very effective. The ideal means of prevention is the removal of primary etiologic factors. If they can be ascertained and found manageable, every effort should be made to counteract them. In addition, secondary accessory factors deserve attention because they may be more 25

suitable to manipulation than primary causes. As a lead in this direction, the natural history of spontaneous abortion and prenatal screening processes should be studied in order to search for new ways for prevention of developmental errors, which still contribute greatly to human mortality and morbidity. REFERENCES 1. Hollaender E.: Wunder, Wundergeburt und Wundergestult. Stuttgart, Ferdinant Enke, 1922. 2. Warkany J.: Congenital Malformations: Notes and Comments. Chicago, Year Book Medical Publishers, 1971. 3. Pare A.: On Monsters aid Marvels (transl. J.L. Pallister). Chicago, University of Chicago Press, 1982. 4. Ballantyne J.W.: Antenatal Pathology and Hygiene: The Embryo. Chicago, Chicago Medical Book Co., 1904. 5. Schwalbe E.: Die Morphologie der Missbildungen des Menschen. Jena, 1906. 6. Warkany J.: Prevention of congenital malformations. Teratology 23:175189,198l. 7. Gardner W.J.: The Dysruphic States. Amsterdam, Excerpta Medica, 1973. N.M.: Congenital cataract following German measles in the mother. 8. Gregg Trans. Ophthalmol Sot. Aust. 3~35-45, 1942 S.: Present status of measles and rubella immunization in the 9. Krugman United States. J. Pediatr. 90:1-12, 1977. 10. Sever J.L., Larsen J.W., Grossman J.H.: Handbook of Perinatul Infection. Boston, Little, Brown & Co., 1979. 11. Murphy D.B.: Outcome of 625 pregnancies in women subjected to pelvic radium or roentgen irradiation. Am.J. Obstet. Gynecol. 18:i79-187, -1929. 12. Miller R.W.: Small head size after atomic irradiation. TeratoZopY -” 14:355358, 1976. 13. Brent R.L.: Environmental factors: Radiation, in Brent R.L., Harris M.I. (eds.): Prevention of Embryonic, Fetal, and Perinatal Disease. Bethesda, Md., John E. Fogarty International Center for Advanced Study in the Health Sciences, DHEW Publication No. (NIH) 76-853, 1976. 14. American Academy of Pediatrics Committee on Drugs: Anticonvulsants and pregnancy. Pediatrics 63:331-333, 1979. 15. Hall J.G., Pauli R.M., Wilson K.M.: Maternal and fetal sequelae of anticoagulation during pregnancy. Am. J. Med. 68:122-140, 1980: 16. Tsubaki T.. Irukavama K. (edsl: Minamatu Disease. Amsterdam, Elsevier Scientific Publishing Corp., 1977. K., Reiher H., Semmler K., et al.: Prevention of congenital mal17. Fuhrmann formations in infants of insulin-dependent diabetic mothers. Diabetes Cure 6:219-233, 1983. 18. Robert E., Guibaud P.: Maternal valproic acid and congenital neural tube defects. Lancet 2:937, 1982. by X-rays of hereditary changes in mice. Ge19. Snell G.D.: The introduction netics 20:545-567, 1935. 20. Vogel F., Motulskv A.G.: Human Genetics: Problems and Approaches. Ber__ lin;Springer-Verlag, 1979. 21. Nishimura H.K.. Takano K.. Tanimura T.. et al.: Hieh incidence of several malformations in the early human embryos as compired with infants. Biol. Neonate 10:93-107, 1966. 22. Warkany J.: Terathanasia. Teratology 17:187-192, 1978. D.M.: Thyroxin-induced differential mortality of mouse embryos 23. Juriloff with cleft lip. Dev. Pharmacol. Ther. 2:17-31, 1981.