Teratology requires a multiple disciplinary approach, including epidemiology, pediatrics, genetics, obstetrics, toxicology, ophthalmology, cardiology, dentistry, biochemistry, and many others. Politicians, lawyers, unions, and the lay public also have become interested in congenital malformations.

Teratology is the study of “teras.” The word teras is derived from ancient Greek mythology and means a prodigy, a wonder, something that is beyond normal. A teras could be a divinely beautiful creature or an ugly monster. There are many teras in ancient mythology--the sphinx, the mermaid, and Minotaur-all of which combine animal and human characteristics. Frankenstein, King Kong, Superman, and imagined creatures from other planets are the teras of today. Throughout history, malformations of the eyes have been especially fascinating to people. In Babylonian clay tablets from as early as 4,000 years ago, monsters with one eye on the forehead or with eyes on the neck, back, and anus were portrayed. The cyclops is another example of the fascination with eye malformations. Homer tells about Ulysses, who came to the island of the cyclops and had to fight the evil single-eyed giant, who was trying to kill and eat his men.

Since ancient time, it was believed that the mammalian fetus developed in the shielded environment of the maternal uterus and that external factors could not significantly influence development. There existed, however, some concern that various agents could be hazardous to the child. The adverse effects on the offspring due to maternal abuse of alcohol during pregnancy have been known for thousands of years. The Bible (Judges 13:7) warns the pregnant woman against eating “unclean things” and drinking “strong drink” to produce a perfect offspring. In the middle of the 18th century, the famous painter William Hogarth described the disadvantage of drinking excessive amounts of gin in his painting entitled Gin Lane (Fig. 1). Approximately 1 century later, Charles Dickens made the following comments in his Pick-wick Papers: “Betsy Martin, widow, one child, and one eye. Goes out chafing and washing, by the day; never had more than one eye, but knows her mother drank bottled stout, and shouldn't wonder if that caused it .… Thinks it not impossible that if she had always abstained from spirits, she might have had two eyes by this time.”³ A wide and amusing exposé on teratology of the past was given by Warkany.⁴

Modern genetics in the early 20th century promoted the study of congenital malformations to provide simple explanations of the etiology of human malformations previously considered untreatable and unpreventable. Modern teratology did not take shape until the middle of the 20th century. Although the adverse effects of radiation on the fetus had been recognized earlier, an ophthalmologist, Norman Gregg, discovered in 1941 that a high proportion of women infected with rubella virus during the first trimester of pregnancy gave birth to infants with defects.⁵ With the thalidomide tragedy in the 1960s, the field of teratology expanded quickly. Progress in medicine in the last 30 years has resulted in improved prevention and treatment of congenital malformations, although knowledge about the cause and prevention of these malformations remains extremely limited.

Approximately 3% of all newborns have a congenital anomaly requiring medical attention, and approximately one third of these conditions can be regarded as life-threatening. With increasing age and detection of certain functional changes, the rate of congenital defects doubles.⁶ Mental retardation, which occurs in approximately 3% of school-age children, is often congenital. Preterm and stillborn infants have significantly higher rates of congenital malformations. Among spontaneously aborted embryos and fetuses, the rate of structural abnormality varies from 7% to 24%. Based on data from several teratologic researchers, it has been estimated that the causes of congenital defects are specific teratogenic agents in 8% to 10%, monogenic in 15% to 25%, chromosomal in 15% to 28%, and unknown (including multifactorial) in 40% to 65% (Fig. 2).⁷

Many teratogens affect the eyes. Ophthalmologists can be very helpful in recognizing teratogenic lesions, because we are able to observe small anomalies produced during a specific short period of development. These lesions produce symptoms that can be measured by simple, fairly exact clinical methods that are neither painful nor dangerous to the child. A comparison of available detailed data on embryonic eye development in humans and animals and experimental animal research provides information regarding the periods during which the malformations were produced and the etiologic causes of the defects.

In 1977 Wilson and Fraser⁸ described and discussed the general principles of teratology and its consequences in a way that is stilt relevant for the science. Examples of these principles include the following:

1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors.
   It is well known that not all children exposed to a toxic agent are adversely affected. The genotype; the absorption, metabolism, and detoxification of the agent; and the rate of placental transfer vary in mothers and their fetuses. Great differences exist between different species of animals (e.g., most rabbit and mouse strains are resistant to thalidomide, while humans and higher mammals are highly sensitive to this drug).^9,10 Even homogeneous strains of animals show “intrastrain” differences, so all members of the same litter (equivalent to twins and triplets in the human species) do not react similarly to exposure to teratogenic agents. An agent applied during the susceptible period may cause some embryos to die, others to be stillborn, others to survive with varying degrees of malformations, and others to develop normally. Probably a majority of spontaneously occurring malformations are the result of a combination of many complex genetic and environmental factors.
   
2. Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.
   During some periods of development, the embryo or fetus is more sensitive to teratogenic agents. Damage during the preimplantation period generally produces little altered morphogenesis because the ovum usually dies; during organogenesis, however, the embryo is highly sensitive, and exposure may produce major morphologic changes. The greatest danger is associated with a relatively short period of critical embryogenesis between germ layer differentiation (gastrulation) and completion of major organ formation. As organogenesis advances during the latter part of the embryonic period, both teratogenicity and lethality steadily decline. During the subsequent fetal period, the fetus undergoes rapid growth, differentiation, and functional maturation of tissues and organs and is less sensitive to morphologic alterations.
   The concept of susceptibility is based largely on work with experimental animals in which it is possible to control and study the effect of teratogenic agents at different times. Specific timetables for animals and humans have been identified for a number of chemical teratogens. The critical period of many known human teratogens, including rubella^5,11 and thalidomide,^12,13 is during the first 60 days. Thalidomide has a short sensitive period--days 20 to 36 after fertilization (Fig. 3). As soon as organogenesis begins, the embryo becomes highly susceptible to most teratogenic agents, but this does not mean that overt developmental events can be exactly correlated with the time that the agent is active. Anomalies can be induced before the earliest primordium appears in the embryo.
   
3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).
   Causative agents may act in different ways, and conversely, different etiologic agents may cause changes by the same mechanism. The early changes in a developing system often are not readily apparent because they occur at subcellular or molecular levels. To become manifest, the mechanisms must lead to more demonstrable cellular and tissue alterations. It is difficult to gain insight into the initial event in humans for most agents because of experimental design problems. Animal research is frequently used. Developing cells may be altered in a variety of ways, such as mutation, chromosomal breaks, mitotic interference, altered nucleic acid integrity or function, lack of normal precursors or substrates, altered energy sources, changed membrane characteristics, osmolar imbalance, or enzyme inhibition. The consequences may be reduced cell death, changed cell interactions, reduced biosynthesis, impeded morphogenetic movement, or mechanical disruption of tissues.
   
4. The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.
   The reaction of an early embryo prior to its differentiation to a toxic agent is death. During the embryonic period the embryo reacts by malformation and during the fetal period, by growth retardation and functional disorder.
   

TABLE ONE. Sequence of Human Ocular Development

TABLE TWO. Sequence of Mouse Ocular Development

HUMAN EMBRYOLOGY

Pregnancy is roughly calculated to be 266 days (38 weeks) after fertilization or 280 days (40 weeks) from the onset of the last menstrual period (gestational age). Following conception the fertilized egg is implanted in the uterus during the second week (days 7 through 12 to 14 after fertilization). During the third week gastrulation occurs, the primitive streak and the embryonic ectoderm begin to form, the neural ectoderm with the neural tube and the neural crest is visible, and the heart, blood vessels, and primordia of the eyes and ears begin to develop. The fourth to eighth weeks (days 18 to 20 through 55 to 60) constitute the embryonic period and are the most important 5 weeks of human development, because the development of all major external and internal structures begins during this period. The three germ layers differentiate into various tissues and organs. By the end of the embryonic period, the beginnings of all major organ systems have been established, and the embryo begins to look like a human with the formation of the brain, heart, liver, somites, limbs, ears, nose, and eyes.

The fetal period (weeks 9 through 38) is primarily characterized by body growth and differentiation of organ systems. The rate of body growth during the fetal period is rapid, especially between the 9th and 20th weeks, and weight gain is extremely rapid during the terminal weeks. At the same time, head growth is slowing compared with that of the rest of the body. Until this time the fetus is incapable of extrauterine existence, mainly because of immaturity of the respiratory system. Detailed data on human development can be found in reference literature, such as Moore's The Developing Human.¹⁴

Development of the Human Eye

A broad, up-to-date presentation of data on the development of the eyes is given elsewhere in these volumes. The shortened sequence of human ocular development is shown in Table 1 and in a review on ocular teratology.¹⁵

ANIMAL EXPERIMENTS

In modern society we are exposed to an overwhelming number of chemicals, drugs, pesticides, food additives, and other entities that require safety evaluations. Our population is significantly exposed to approximately 5 million chemicals.¹⁶ Shepard's catalog of teratogenic agents lists more than 2000 agents, approximately 1200 of which can produce congenital anomalies in experimental animals.⁶ Only approximately 30 of these agents, of which 18 are chemicals or drugs, are known to cause defects in humans (Table 3). This discrepancy is partly explained by the ease of performing animal experiments compared with the investigation of humans. Considerably more animals from several generations can be acquired in a short time and at a low cost, and controls can be found more easily among animals compared with humans. Conclusions drawn from animal experiments to humans must he applied with great caution. An agent that is toxic to animals may not have the same influence on humans, and the toxic doses may not be the same. Some drugs produce malformations in animals when administered at many times the usual therapeutic drug dose given in humans. Almost any agent can be shown to be teratogenic in animals if enough of it is given at the right time; even sodium chloride and sucrose have been shown to produce teratogenicity in animals when given in excess amounts.

TABLE THREE. Human Teratogens

Teratogenic Agents in Human Beings
  Radiation

  Atomic weapons; radioiodine; therapeutic

  Cytomegalovirus; herpesvirus hominis ? I and II; parvovirus B-19 (erythema infectiosum); rubella virus; syphilis; toxoplasmosis; Venezuelan equine encephalitis virus

  Alcoholism; cretinism (endemic); diabetes; folic acid deficiency (following gastric bypass surgery); hyperthermia; phenylketonuria; rheumatic disease and congenital heart block; virilizing tumors

  Aminopterin and methylaminopterin; androgenic hormones; busulfan; chlorobiphenyls; coumarin anticoagulants; cyclophosphamide; diethylstilbestrol
  Diphenylhydantoin and trimethadione
  Etretinate; lithium; mercury (organic); methimazole and scalp defects; peniciliamine; 13-cis-retinoic acid (Accutane and isotretinoin); tetracyclines; thalidomide; tri-methadione; valproic acid

Possible and Unlikely Teratogens
  Possible

  Binge drinking; carbamazepine; cigarette smoking; cocaine; disulfiram; folic acid deficiency; high vitamin A intake; lead; primidone; streptomycin; toluene abuse; varicella virus; zinc deficiency

  Agent Orange; anesthetics; aspartame; aspirin (but aspirin in the second half of pregnancy may increase cerebral hemorrhage during delivery); Bendectin (antinauseant); birth control pills; illicit drugs (marijuana, LSD); Metronidazole; oral contraceptives; rubella vaccine; spermicides; video display screens

In the investigation of basic mechanisms in teratogenesis, a tool equally important as in vivo experiments is in vitro testing with tissue culture, ova, organ, or whole embryo cultures. A wide range of such tests have been developed and are used to understand mechanisms of action and as routine screening procedures.

Ideally, the teratogenicity of a compound is recognized when adverse effects found in humans correlate to similar findings in animal experiments and in vitro studies, as has been shown for isotretinoin.^17–21 The opposite was found for thalidomide, a drug that produced pronounced and frequent malformations in humans but failed to do so in laboratory rodents.⁹

Studies using acute exposure regimens have been of particular value in identifying critical periods during embryogenesis for the induction of ocular abnormalities. Many different species of animals are used to screen agents for teratogenic properties. Differences in drug metabolism, developmental rate, and placental function require careful interpretation of animal studies for extrapolation to humans. Strains that exhibit a spontaneous incidence of a particular malformation will most likely exhibit that malformation at an increased incidence following exposure to an appropriate teratogen during the critical developmental period.²²

Potential teratogens are commonly administered for an extended period during gestation to maximize the probability of inducing malformations, while the period of organogenesis is considered to be the most vulnerable period for teratogenesis. The period during and after gastrulation has been demonstrated to be particularly sensitive for the development of the central nervous system and the eyes.^23,24

Various eye malformations have been produced in animal models, most commonly anophthalmia, microphthalmia, cataracts, and retinal dysplasia.²⁵ Many environmental and pharmaceutical agents have been used, including vitamin A,²⁶ 6-amino-nicotinamide,²⁷ sodium arsenate,²⁸ cadmium chloride,^29,30 cyclophosphamide,^31,32 vincristine,³³ and triparanol.³⁴ Many of the craniofacial abnormalities characteristic of human fetal alcohol syndrome have been reproduced in animal models, including pig tailed macaque monkeys^35,36 and mice.³⁷ Optic nerve hypoplasia, another typical sign of fetal alcohol syndrome, has been reproduced in rats,³⁸ and microphthalmia and retinal ganglion cell loss were found in pig tailed macaque monkeys.³⁹

Sequential observations of mouse embryos following acute exposure to ethanol or retinoic acid during gastrulation have demonstrated forebrain deficiency leading to microphthalmia and Peters' anomaly,^40,41 and retinoic acid treatment of hamsters has produced the same effects.^19,42 Reduction in the size of the optic vesicle combined with an abnormal orientation relative to the maxillary prominence results in induction of a small lens vesicle, which often remains attached to the surface ectoderm. More mildly affected embryos exhibit delayed lens vesicle detachment. Delay or failure of separation of the lens vesicle from the surface ectoderm results in mechanical interference with the axial migration of neural crest cells destined to form the anterior segment connective tissue structures. A variable degree of anterior segment dysgenesis characterized by axial corneal opacity and irido-corneo-lenticular attachments is the adult manifestation of this condition. Similar syndromes of anterior segment dysgenesis in mice have been observed following simultaneous exposure to x-rays and ultrasound or to ochratoxin A^43–45 during the same period of gestation, further emphasizing this critical gestational period for development of the eye.

CLINICAL CASE STUDIES

The detection of a new teratogen often has begun with the observations by alert clinicians of unusual signs in a few children, as occurred in the recognition of the fetal alcohol syndrome and rubella embryopathy. The ophthalmologist can contribute through expert clinical examination of the child, focusing on ocular findings.

The case history may provide useful information about etiology and should be carefully examined. Was there an infection, a fever, bleeding, or severe nausea in early pregnancy, or were there infertility problems? Could a disease have been transmitted from cats, dogs, or pet birds? Did the mother take any drugs, prescribed or not prescribed? Did she abuse alcohol or narcotic drugs or have poor nutrition?

Many syndromes produce a typical facial appearance that provides clues to the diagnosis, such as fetal alcohol syndrome and warfarin embryopathy. Midfacial hypoplasia, asymmetry or anomalies of the face or head, short eyelids, telecanthus, epicanthus, and motility disturbances, such as comitant and incomitant strabismus, are anomalies found in some teratogenic syndromes. The globes may be abnormally small or large and should be measured by ultrasonography. Corneal opacities, lipodermoids, Peters' anomaly, and other lesions of the anterior segments, colobomas of the iris, uvea, optic nerve head, and persistent hyaloid primary vitreous can be produced by the adverse action of teratogens. The optic nerve is frequently affected and shows unilateral or bilateral optic nerve hypoplasia, optic atrophy, and other anomalies, including pits and morning glory syndrome. Retinal pigmentation suggests an intrauterine infection affecting the eyes.

EPIDEMIOLOGIC METHODS

Epidemiology is of fundamental value for the identification of human teratogens. The majority of cases with birth defects are thought to be caused by an interaction between complex genetic and environmental factors. Such environmental factors have a low teratogenic potential and are therefore extremely difficult to identify by clinical observation alone; well-designed epidemiologic studies are the best way to identify them.⁴⁶

The steps a clinician should take to identify a new teratogen are usually the following: Unusual signs in a few children with a suspected etiologic cause lead to the collection of more cases. A retrospective study of children with similar findings is performed and when appropriate a prospective study.

The two main types of epidemiologic studies used are the forward-looking, prospective cohort study and the backward-looking, retrospective case-control study; these studies also may be combined.

The cohort study usually begins with the assembly of a sample of people who are exposed to a suspected toxin and a sample of those who are not. The groups are then followed up. The main disadvantage of the cohort study is the high expense and the long time required for its completion. Many developmental disturbances are rare, so one must follow up a large number of subjects to ascertain even a few cases. If, for example, a particular congenital malformation occurs at the rate of one in every 1000 births, several thousand pregnancies must be studied to ascertain more than a handful of cases. If interest centers on developmental defects that are detectable at birth, time considerations are of little consequence. If the study is focusing on defects that are detectable only later in life (e.g., mental retardation and poor vision), the time element becomes an important consideration.

In case-control studies a group of cases and a comparison (control) group are assembled, and their histories of exposure to the suspected toxic agent are contrasted. The case-control study directly addresses the presence of a history of increased exposure among those with the condition. A major problem of case-control studies involves biases in determining exposures, such as a reliable history of prior exposure.

The surveillance and monitoring of congenital malformations are widely practiced. A surveillance system is used to detect sudden or gradual changes in the incidence of specific types of malformations.

MATERNAL DISORDERS

Intrauterine Infections

RUBELLA. In 1941 an unusual number of cases of congenital cataracts appeared in Sydney and other parts of Australia. A closer investigation was initiated by ophthalmologist Norman Gregg.⁵ With his own 13 cases of cataracts and those from colleagues, 78 cases were identified. Gregg calculated that the early period of pregnancy in these children corresponded with the period of maximum intensity of the widespread and severe epidemic of German measles in 1940. It was found that in each case the mother had suffered from German measles early in her pregnancy, most frequently in the first or second month.^5,47 Gregg's original reports involved a constellation of defects with a combination of congenital heart, eye, and ear abnormalities. Congenital rubella was later recognized as an infection associated with a wide range of possible pathologic injuries. The infection may kill the fetus in utero, causing abortion or stillbirth. It may have no apparent effect on the delivery of a nor-mal-appearing liveborn infant or, at the other extreme, may result in severe multiple birth defects. A further complication to the clinical diagnosis is that maternal infection often is subclinical but may still result in a wide range of fetal damage.

Twenty years after Gregg's report, the rubella virus was isolated in tissue culture, and techniques for serodiagnosis of this infection were developed.^48,49 Gregg's report still stands as a hallmark of a teratologic investigation. The observation of a few of his own cases with similar pathology, the collection of additional cases from colleagues, the questioning of the mothers, and the conclusion that one common factor was present during one short and defined period in pregnancy provided an accurate and detailed description of the clinical manifestations of congenital rubella.

The eye lesions in rubella embryopathy consist of cataracts (80% bilateral), microphthalmos, pigmentary retinopathy, cloudy cornea, glaucoma, hypoplasia of the iris, and diminished reaction to atropine. Additional systemic manifestations include intrauterine growth retardation, cardiovascular lesions, central nervous system anomalies, and hearing and speech deficiency. Cataracts and heart disease may result from maternal rubella during the first 8 weeks of gestation and deafness from infection during the first 16 weeks of gestation. For cataracts the time of maternal rubella infection was estimated to be from 26 to 57 days of gestation, defined as the number of days from the onset of the last menstrual period until the onset of the characteristic rash (12 to 43 days postfertilization). Retinopathy is produced in the period from 16 to 131 days of gestation and coloboma and exotropia during days 32 to 50 of gestation.¹¹ Miller and co-workers⁵⁰ prospectively followed up more than 1000 women with confirmed rubella infection at different stages of pregnancy. Rubella defects occurred in all infants infected before the 11th week (principally congenital heart disease and deafness) and in 35% of those infected at 13 to 16 weeks (deafness only). No defects attributable to rubella were found in children infected after 16 weeks. The frequency of congenital infection is very high (91%) when symptomatic rubella occurs during the first trimester.⁵¹ During the second trimester, the rate of infection declines rapidly, possibly because the structure of the placenta is fully developed at this stage.

RUBELLA RETINITIS. Rubella retinitis has been recognized as one of the most frequent ocular abnormalities in children with congenital rubella.^52–54 Gregg⁵⁵ provided a colorful description of rubella retinitis: “It was like a piece of coarse Scotch tweed used for a sports coat over which pepper had been thrown.” A typical finding is widespread pigment deposits, usually of greatest density in the macula. Sometimes the pigment has a spiculelike form similar to that found in retinitis pigmentosa from which disease it has to be distinguished. Pigmentary retinopathy also is a common sign of many congenital infections, such as cytomegalovirus, toxoplasmosis, and herpes.

In 1969 Cooper and coworkers⁵⁶ studied the rubella epidemic that swept across the United States in 1964. A total of 376 children were affected, and results showed that eye symptoms were most common.

Gregg had the foresight to stress prophylaxis as the only treatment of choice. Rubella has become a rare disease in most countries because of the vaccination against rubella of prefertile girls.⁵⁷ However, today young black and Hispanic primiparous women in the United States are at an increased risk of delivering an infant with congenital rubella syndrome.⁵⁸

TOXOPLASMOSIS, CYTOMEGALOVIRUS, HERPES, VARICELLA-ZOSTER INFECTION. Toxoplasmosis. Toxoplasmosis is an infection caused by Toxoplasma gondii, a parasite with a complicated life cycle in which the cat appears to be the definitive host. Toxoplasmosis may appear as a congenital or an acquired infection. Maternal infection with toxoplasmosis early in pregnancy results in fetal death, and in midpregnancy it produces a widespread disease in the fetus, resulting in miscarriage or in severe damage. Maternal toxoplasmosis infection late in pregnancy produces acute signs of toxoplasmosis in the infant: encephalomyelitis, chorioretinitis, or visual involvement. The pregnant mother may have mild symptoms or may be asymptomatic, but severe birth defects may still occur in her fetus. The majority of infants are asymptomatic at birth, but sequelae of the congenital infection are recognized or develop later in life.

The main clinical manifestations of the symptomatic form of toxoplasmosis are microcephaly or hydrocephaly, cerebral palsy, epilepsy, mental retardation, cerebral calcification, and chorioretinitis.^59–61 The most important signs in the diagnosis of congenital toxoplasmosis are the three Cs: convulsions, calcification (intracranial), and chorioretinitis. Chorioretinitis is present in 80% of children with congenital toxoplasmosis and is most often bilateral; toxoplasmosis is considered one of the most common causes of chorioretinitis. The posterior pole and macula are predisposed to damage. Secondary changes occurring in other parts of the eye, such as iridocyclitis and cataracts, are considered to be complications of the chorioretinitis; microphthalmia, microcornea, cataracts, anisometropia, strabismus, nystagmus, and leukocoria also have been reported.^61,62 The optic nerve may be affected, either primarily or secondarily due to papilledema.

The distinguishing features of the intraocular lesions of congenital toxoplasmosis in infants are consistency of bilateral involvement of the macular region, the presence of an essentially normal retina and vasculature surrounding the lesions in all stages of the infection, rapid development of sequential optic nerve atrophy, and frequent clarity of the media in the presence of severe chorioretinitis.

In addition to other infectious congenital lesions, the differential diagnosis of eye lesions includes congenital anomalies, such as coloboma. The association of ocular, systemic, and serologic changes in toxoplasmosis, however, generally rules out a congenital malformation. The prognosis for new pregnancies in patients with toxoplasmic retinochoroiditis is difficult to establish. The most important factor in advising pregnant women with toxoplasmic chorioretinitis is whether or not the antibody titer increases during pregnancy rather than the clinical picture or the absolute values of antibody titer.⁶³ Periodic titration of the antitoxoplasma antibody during pregnancy is recommended as a preventive measure against congenital toxoplasmosis. The pregnancy may be continued if the antibody liter does not increase during pregnancy.

Cytomegalovirus Infection. Cytomegalic inclusion disease is characterized by the formation of large inclusion-containing cells that may appear in all visceral organs and the cerebrum. The causative factor is a large DNA virus that is closely related to the herpes simplex, varicella-zoster, and Epstein-Barr viruses. It infects many organs, including the eyes, lungs, kidneys, gastrointestinal tract, and reticuloendothelial system. Active cytomegalovirus infection is found in patients with acquired immunodeficiency syndrome (AIDS), bone marrow and solid organ transplant recipients, and neonates, making it a congenital or an acquired disease.

Intrauterine infection with cytomegalovirus is the most common of all intrauterine infections and occurs in approximately 0.5% to 2% of all newborn infants in the United States and other industrialized countries.^64,65

Chorioretinitis is the most typical ocular manifestation in congenital cytomegalovirus infection and is a cause of severe visual impairment. Other ocular manifestations include optic atrophy, anophthalmia, microphthalmia, optic nerve hypoplasia and coloboma, cataracts, retinal necrosis, and severe myopia.^64,66–75 Frenkel and coworkers⁷⁶ described seven children with congenital cytomegalovirus infection who demonstrated a higher than expected incidence of “rare” ophthalmologic abnormalities, including anophthalmia and Peters' anomaly. Cytomegalovirus chorioretinitis cannot be differentiated from the lesions produced by other intrauterine infections on the basis of location or appearance. Toxoplasmosis would present the greatest difficulty of differential diagnosis because the syndrome of chorioretinitis with cerebral calcification, hepatosplenomegaly, and anemia are typical of toxoplasmosis and cytomegalovirus.

Herpes. Herpes simplex viruses belong to a large group of DNA viruses that possess common morphologic features. This group is composed of at least three other viruses that occur in humans: cytomegalovirus, varicella-zoster, and Epstein-Barr virus. These viruses have several common properties, including their ability to persist throughout the life of the infected host and the induction of intranuclear inclusions in infected cells.

The many common clinical and pathologic features associated with herpesvirus infections of dogs, cats, pigs, cows, and horses are particularly relevant to fetal and neonatal human disease.⁷⁷ Ocular involvement in neonates with herpes simplex infection include keratoconjunctivitis, chorioretinitis, microphthalmia, and retinal dysplasia.⁷⁸ Secondary complications of keratoconjunctivitis are chorioretinitis and cataracts, recurrent herpetic keratitis, and residual corneal ulcer.

Varicella-zoster. The characteristics of fetal varicella syndrome are skin lesions occurring as cicatricial areas that correspond to dermatome distribution, atrophic limbs, cerebral atrophy, seizures, low birth weight for gestational age, and skeletal, gastrointestinal, and genitourinary anomalies.⁷⁹ A variety of ocular anomalies also have been reported, including chorioretinitis (the most common), anisocoria, nystagmus, microphthalmia, cataracts, corneal opacity, atrophy and hypoplasia of the optic discs, heterochromia, and Horner's syndrome.^80–88

SYPHILIS. For centuries syphilis has been a well-known potent human teratogen. Today, detection and treatment in the majority of cases make clinical congenital syphilis uncommon in the Western world. Unfortunately, congenital syphilis has increased recently in children born to mothers who are young, unmarried, from lower socioeconomic backgrounds, and receive little prenatal care.⁸⁹ In a 1990 study by Burkett and associates, syphilis was present in 15% of the patients whose mothers had abused cocaine during pregnancy.⁹⁰ In 1986 congenital syphilis was found in one of every 10,000 liveborn children in the United States⁹¹ ; in 1988, 18.4 cases per 10,000 births were found in Miami, a threefold increase from 1986.⁹²

The damage caused by fetal infection with Treponema pallidum that is untreated during pregnancy ranges from fulminant neonatal sepsis and death to asymptomatic infection persisting in childhood and culminating in tertiary syphilis occurring in early adolescence.

By convention, clinicians classify congenital syphilis as “early” and “late.” This terminology specifically refers to the time in the child's life when the diagnosis is made. Early congenital syphilis is an infectious, life-threatening disease apparent in children younger than 2 years of age.

Late congenital syphilis appears in children older than 2 years of age and is asymptomatic in two thirds of all cases. Serology is invariably positive. Those with clinical findings have more classic stigmas of congenital syphilis, including the Hutchinson's triad, which consists of interstitial keratitis, notched incisors, and VIII nerve deafness. Additional signs are dental and bony deformities (mulberry molars, saber shins, saddle nose, frontal bossing, palatal perforation, and Clutton's joints), cutaneous lesions (rhagades and gummas) and rarely neurologic and cardiovascular defects. Dissemination of syphilis to the fetus is possible at all stages of maternal infection, including the late latent stage, when asymptomatic patients remain persistently seropositive.

The most important ocular involvement is interstitial keratitis, which is characterized by photophobia, pain, excessive lacrimation, and blurred vision. On physical examination, conjunctival hyperemia, miosis, edema, clouding, and vascularization of the cornea are present.⁹³ Ocular manifestations, such as chorioretinitis, salt and pepper fundus, glaucoma, uveitis, and chancres of the eyelid, have been described in early congenital syphilis.^94,95

Because chorioretinitis occurs in infants who have been affected with a variety of infectious agents, including rubella, cytomegalovirus, T. gondii, and herpes simplex virus, these are included in the differential diagnosis for chorioretinitis.

Parenteral penicillin G remains the drug of choice to treat the pregnant syphilitic mother, just as it is for nonpregnant adults and for those with congenital syphilis.⁹⁶

Diabetes

The incidence of major congenital malformations among infants of diabetic mothers is two to three times higher than for the nondiabetic population.^97–100 The risk is limited to patients whose diabetes antedates pregnancy and is not found among patients with gestational diabetes. There is an increased frequency of spontaneous abortions and congenital malformations in the infants of mothers with vascular complications of diabetes, and they tend to increase with the severity of the complications and in cases of poorly controlled diabetes in the first trimester.^97,101–105

Congenital anomalies among infants of diabetic mothers include neural tube anomalies, anencephaly, and cardiac, skeletal, renal, gastrointestinal, and pulmonary anomalies.^106–108 Caudal regression syndrome, although very rare, causes what has been regarded as the most typical associated lesion in maternal diabetes.¹⁰⁹ However, there seems to be no clear-cut phenotype for diabetic embryopathy; several etiologic factors and mechanisms are probably involved. All of these malformations arise from a disturbed development early in pregnancy.

Regarding eye anomalies, Peterson and Walton described a constellation characterized by segmental optic nerve hypoplasia, altitudinal or sector visual field defects, and normal visual acuity in 17 children of diabetic mothers.¹¹⁰ Kim and coworkers described 10 patients with superior segmental optic nerve hypoplasia, all of whom were the children of diabetic mothers.¹¹¹ Seventeen of 20 eyes had signs of superior, segmental optic nerve hypoplasia. Kim and coworkers concluded that the presence of superior segmental optic nerve hypoplasia strongly suggests maternal diabetes. Septo-optic dysplasia was found at autopsy in an infant of a diabetic mother.¹¹² Ptosis and eyelid coloboma also have been noted among children born to diabetic mothers.

Alcohol

FETAL ALCOHOL SYNDROME. At the end of the 1960s, reports from France^114,115 claimed that maternal alcohol abuse during pregnancy produced children with a similar pattern of growth retardation, mental deficiency, and congenital anomalies. In the United States, Smith and Jones made the same observations and called world attention to what they termed the fetal alcohol syndrome (FAS).^116–118 Since then FAS has been recognized in most industrial countries, Today, it is probably the most common teratogenic syndrome.

Because there are no laboratory tests to provide a definite diagnosis, the diagnosis of FAS is based on clinical findings alone. An attempt to identify criteria for FAS was made by Sokol and Clarren.¹¹⁹ In addition to a history of maternal drinking, the children must exhibit signs from each of three categories: (1) prenatal or postnatal growth retardation (weight, length, or height below the tenth percentlie when corrected for gestational age); (2) central nervous system involvement (including neurologic abnormality, developmental delay, behavioral dysfunction or deficit, intellectual impairment, or structural abnormalities, such as microcephaly [head circumference below the third percentlie] or brain malformations found on imaging studies or autopsy); (3)a characteristic face, currently qualitatively described as including short palpebral fissures, an elongated midface, a long and flattened philtrum, thin upper lip, and flattened maxilla (Figs. 4 AND 5). Children with only some of these features and a history of gestational exposure to alcohol are diagnosed as having fetal alcohol effects.

Many different organs, such as the heart, skeleton, neural tube, and kidneys, can be affected by the teratogenic effects of alcohol. 120,121 In addition to retarded mental and motor development, affected children have developmental perceptual and behavioral characteristics, a pattern that is not altered with time.^118,122,123

Ophthalmic Manifestations of FAS. Short horizontal palpebral fissures are the most common findings observed in the outer eye region in FAS.^124–127 Telecanthus (marked increase in the intercanthal distances between the medial canthi) and epicanthus also are frequently seen. Unilateral or bilateral, generally mild, ptosis also is common, and strabismus, most often esotropia, occurs in up to half of the cases.^124–126 Microphthalmia may occur, but unless unilateral or pronounced, it is difficult to identify without biometric measurements. A high frequency of errors of refraction also is found,^125,126 ranging from severe myopia to moderate hyperopia. Visual impairment is a frequent finding.^125–127 A wide range of abnormalities of the anterior segments and media have been recognized among children with FAS. Microcornea and corneal opacities; anterior chamber angle abnormalities; iris defects; combinations of these malformations, such as Peters' (Fig. 6) and Axenfelds anomaly; glaucoma; cataracts; and persistent hyaloid also may be observed.^124,128 A steep corneal curvature seems to be a constant sign of FAS.¹²⁹

A wide spectrum of abnormalities of the fundus also is often observed.^126–128 Optic nerve anomalies are common, mostly consisting of unilateral or bilateral hypoplastic optic nerves that occur in up to half of affected children (Fig. 7).¹²⁶ Nystagmus and severe visual impairment are present in the most pronounced cases of optic nerve hypoplasia. The retinal vessels, mostly arteries, often are tortuous and exhibit an abnormal width and course over the retinal surface (Fig. 8).^125,127

In summary, typical children with FAS are small, mildly mentally retarded, and hyperactive. They have microcephalus and a characteristic face with short palpebral fissures, a broad flat bridge of the nose, a small upturned nose, and a long upper lip with a flat philtrum. The most common ocular findings are esotropia, impaired vision, optic nerve hypoplasia, and tortuous retinal arteries.¹³⁰

Mental retardation is a cardinal feature of FAS, and FAS is now considered to be the leading cause of mental retardation in the Western world.¹³¹ Typical ocular anomalies in FAS may be found in at least 10% of children with mental retardation.¹³²

FAS was originally described in France, a country with a high alcohol consumption, and has since been recognized in many countries, such as Chile,¹³³ Hungary,^134,135 Germany,^136–138 and Ireland.^127,139 The incidence in France is about one in 700 newborns,¹⁴⁰ similar to that in Sweden where one in 300 live births may show some alcohol-related defects, and approximately one in 600 have complete manifestations of the syndrome.¹⁴¹ In the United States the incidence is between one in 322¹⁴² and one in 750.¹⁴³ The highest incidence has been noted among American Indians. May and colleagues¹⁴⁴ reported rates ranging from one in 100 to one in 750 live births among various Indian tribes in the southwestern United States. The prevalence of alcohol fetopathy among children in an Indian community in British Columbia was estimated to be 190 in 1000 children up to 18 years of age; 64% of the children were mentally retarded.¹⁴⁵

FAS is characterized by physical and behavioral disabilities. Mothers may not be “alcoholics” in the stereotypical sense but have abused alcohol during at least part of the pregnancy, Recent reports also have shown cognitive and behavioral deficits in children born to “social drinkers.”¹⁴⁶ Approximately one third of the children born to alcoholic mothers have the full FAS.^118,137 The nature and extent of damage to the fetus depends on many factors, including the time periods during pregnancy when the woman drank, the amount of alcohol intake, and biologic and genetic features of the fetus and mother. The sooner a woman stops drinking, the better her baby's outcome will be. A mother with one affected child will have children without FAS if she does not drink during subsequent pregnancies. Many women drink alcohol and smoke, a combination that may affect their children adversely.¹⁴⁷ The role of malnutrition also is difficult to sort out, as is the use of drugs. Comparative studies involving animals and humans indicate that there is a risk for defects of ocular structures from as early as the third week after fertilization until development is completed.

Drugs

THALIDOMIDE. Thalidomide was independently synthesized in Germany, Great Britain, and Japan in the mid 1950s. It was marketed as effective therapy for insomnia, anxiety neurosis, and nausea during pregnancy without acute toxic effects even in high doses. As a result, consumption rose rapidly. Complications, such as neurologic symptoms, were soon observed, which prevented its introduction in the United States. In 1960 an unusual kind of severe limb deformities occurred in epidemic proportions. Children were born with amelia and various degrees of phocomelia affecting the upper and lower extremities. Some of the children also had congenital heart disease; ocular, intestinal, and renal anomalies; and deformities of the external ears.^148–152 The German pediatrician Lenz became suspicious that thalidomide was the cause of the anomalies. In November 1961 he warned, “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.”^152a The drug was withdrawn from the market in late 1961 but remained on the market in Japan until September 1962. Lenz compared the frequency of affected births and the amounts of thalidomide sold each quarter in West Germany and showed that frequency was correlated very closely with thalidomide sales 9 months earlier (Fig. 9). Approximately 5000 children were affected in Germany and 700 each in Japan and Great Britain. Another 26 countries reported cases of thalidomide embryopathy.¹⁵³ It was estimated that approximately one third of the children died in early infancy because of major defects of vital organs. A detailed analysis of the Japanese cases was published in 1987.¹⁵⁴

Based on careful interviews with the mothers about the ingestion of thalidomide, the sensitive period for the teratogenicity of thalidomide was determined^12,13 to be from approximately days 20 to 36 after conception (days 35 to 50 after the first day of the last menstrual period) (see Fig. 3).

Ocular malformations, such as microphthalmos, coloboma of the iris and uvea, lens attachment to the cornea, optic disc anomalies, paralysis of the sixth and seventh cranial nerves, strabismus, and nystagmus, also were reported.^155–161 Recently, a study of Swedes with thalidomide embryopathy revealed that half of the patients had ocular motility disturbances, most often consisting of incomitant strabismus; Duane's syndrome also occurred frequently (Fig. 10A and B ).^162,163 Facial palsy (Fig. 11) and abnormal lacrimation were associated with the ocular motility disturbances. A few cases of microphthalmia and coloboma also were noted. Many of the affected patients had shorter or longer than normal axial length, high refractive errors, and corneal astigmatism.¹⁶⁴

ANTICONVULSANTS. Epilepsy is the most common neurologic disorder in pregnant women. The occurrence of epilepsy during pregnancy produces a conflict between the interests of the health of the mother and that of her child. Current neurologic practice demands control of the epilepsy. On the other hand it is well known that some anticonvulsants increase the risk of fetal malformation. Epilepsy and possible genetic factors associated with epilepsy also may play a role in the production of birth defects.

The association between maternal epilepsy, anticonvulsants, and an increased incidence of congenital abnormalities has been recognized for at least 25 years.^165,166 Among the various anticonvulsants, phenytoin (hydantoin), trimethadione, and valproic acid are now widely considered to be human teratogens.

Evidence suggests a twofold increase of congenital malformations in children born to epileptic mothers who took anticonvulsants during pregnancy compared with children of epileptic mothers who did not use such drugs.^166–170 The risk that an infant exposed to hydantoin in utero will have the clinical phenotype of the complete hydantoin syndrome is approximately 5% to 10%, whereas the risk of expression of some signs of the syndrome is roughly one in three.^171,172 The frequency with which the mother has seizures may relate to the frequency of defects in the offspring, as was found in a Japanese study¹⁷³ in which the incidence of fetal malformation in mothers who took anticonvulsants during pregnancy was found to be five times higher than that in mothers who did not. The incidence of fetal malformation was highest (12.7%) in the medicated patients who had epileptic seizures during pregnancy. When combinations of anticonvulsants are administered during pregnancy, the risk of an adverse outcome is likely to be more severe or more frequent than that associated with therapy with a single anticonvulsant.^172,174

Hydantoin. A specific fetal hydantoin (phenytoin) syndrome is by far the best characterized of the malformation complexes induced by anticonvulsants.

The classic features include craniofacial anomalies, prenatal and postnatal growth deficiencies, mental retardation, and limb defects.^171,175 There is midfacial hypoplasia, a short nose with anteverted nostrils, and a long upper lip. Fingernail hypoplasia also is a typical finding. Less frequently observed abnormalities include microcephaly, ocular defects, cardiovascular anomalies, genitourinary defects, and cleft lip and palate.^{166,171,172,175}

Affected children may exhibit eye signs, such as strabismus, ptosis, ocular hypertelorism, and epicanthal folds. Microphthalmos, iris and choroidal colobomas, persistent hyperplastic primary vitreous, congenital glaucoma, optic nerve abnormalities (such as optic nerve hypoplasia), bilateral retinoschisis with maculopathy, and persistent hyperplastic primary vitreous also have been reported.^176–180

Trimethadione, Paramethadione. Trimethadione and its close congener paramethadione are mainly used to treat petit real seizures. Epileptic women taking these drugs may give birth to children who have an increased frequency of congenital malformations¹⁸¹ and in whom a recognizable syndrome may occur--the fetal trimethadione syndrome.¹⁸² This syndrome includes intrauterine growth retardation, facial dysmorphia, cardiac anomalies, and occasionally urogenital malformations, skeletal abnormalities, and delayed mental development. The characteristic face has a broad nasal bridge, a V-shaped “mephistophelian” configuration of the eyebrow line, low-set ears with an anteriorly folded helix, and palatal anomaly.

Ocular signs, such as epicanthal folds, strabismus, poor vision, and myopia, have been described in children with the trimethadione syndrome.^181,182

Children exposed to trimethadione or paramethadione during pregnancy have a more severe outcome compared with those exposed to other anticonvulsants, resulting in fetal death or congenital malformations in up to 87% of pregnancies.

Valproic Acid. Valproic acid differs from the other teratogenic anticonvulsants in that it produces phenotypic effects, such as spina bifida and anencephaly.¹⁸⁴ Developmental delay or neurologic abnormalities and craniofacial anomalies of the type that can be seen with exposure to other anticonvulsants are found, as are urogenital and limb anomalies and heart defects.^185–187 Exposed children may have midfacial hypoplasia with a flat nasal bridge, hypertelorism, epicanthus, short nose, long upper lips, and small upper vermilion border. Strabismus, nystagmus, congenital glaucoma, and shallow orbits giving the impression of protruding eyes are among the reported ocular signs.^{185,186,188,189}

RETINOIC ACID. IsOtretinOin (13-cis-retinoic acid; Accutane) is an orally active congener and metabolite of the naturally occurring form of vitamin A. It has been used since 1982 in the treatment of severe cystic acne and psoriasis. An increased number of stillbirths and children with serious malformations were soon noted to be associated with the use of Accutane. The teratogenicity of isotretinoin is now well established, and its use is contraindicated during pregnancy. A pregnancy test is recommended before isotretinoin is taken.

Infants damaged by retinoic acid therapy during pregnancy demonstrate a pattern of malformations involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations include microtia/anotia, micrognathia, cleft palate, cardiovascular abnormalities, thymic defects, retinal or optic nerve abnormalities, and central nervous system malformations.^190–197 In addition to the reported cases of retinoic acid embryopathy, some exposures have a normal outcome but later have shown an impairment of the central nervous system, hearing, or vision.¹⁹⁷ Ophthalmic anomalies, such as microphthalmia, facial paralysis, and retinal or optic nerve abnormalities, are most commonly reported (Fig. 12).^{190,191,193,196}

Because isotretinoin is a recently recognized teratogen, not all aspects of the syndrome have yet been studied. Despite the scarce information available on ocular involvement in retinoic acid embryopathy, ophthalmologists should be alert to identify these children.

Recently, suspicion about teratogenicity of etretinate,^198,199 another retinoid, has been raised. Unlike isotretinoin, etretinate is stored in adipose tissue and is released into the circulation for a long time after treatment has ceased, raising concern about its use before conception.

ANTICOAGULANTS. Warfarin is a coumarin derivative widely used for its anticoagulant properties to treat thromboembolitic disease and patients with artificial heart valves. Warfarin crosses the placenta and has several effects on the developing fetus, depending on the time and length of exposure during gestation. A specific warfarin embryopathy due to exposure in the first trimester is characterized by severe nasal hypoplasia, bone stippling, ophthalmologic abnormalities, intrauterine growth retardation, and developmental de lay.^200–202 Ocular malformations include bilateral optic atrophy, microphthalmia, lens opacity, hypertelorism, and prominent eyes with small eyelids.^{200,203–206} Many children are partially or totally blind. Children with nasal hypoplasia may have distended lacrimal sacs because of the malformation of the nose.²⁰⁷

There seems to be a critical time of embryologic exposure between the sixth and ninth weeks of gestation.²⁰⁸ Kaplan described a liveborn male infant with Dandy-Walker malformation, agenesis of the corpus callosum, and Peters' anomaly of the right eye who was exposed to warfarin between weeks 8 and 12 of gestation and who had none of the stigmas of the warfarin embryopathy.²⁰⁹ The coincident occurrence of these birth defects would be consistent with malformation of the brain occurring by at least week 12 of gestation.

The incidence of human fetal warfarin embryopathy resulting in death or an anomaly has been estimated to be approximately 30%.²⁰⁸ Heparin has been suggested as an alternative therapy in pregnant women²¹⁰ because its larger-sized molecules do not pass through the placenta, but it is not a safe alternative according to other authors.^208,211

DIRECT TERATOGENS--RADIATION

During the 1920s and early 1930s, ionizing radiation was widely used to treat several diseases. Occasionally, the pelvic region was heavily irradiated in women in whom pregnancy was not suspected. It was soon learned that irradiation leads to severe damage of the fetus and that most, although not all, surviving children show marked abnormalities and malformations. The most common sequelae are microcephaly, mental retardation, microphthalmia, and cataracts.^212–217

Dekaban reviewed the reports on radiation damage during prenatal life and concluded that the most frequent abnormalities in children who were irradiated in utero were small size at birth and markedly stunted growth, microcephaly, mental retardation, microphthalmos, pigmentary degeneration of the retina, genital and skeletal malformations, and cataracts.²¹⁸ He also stated that a moderately large dose of ionizing radiation (more than 2.5 Gy, but the upper limit could not be stated) before 2 to 3 weeks of gestation is not likely to produce severe abnormalities in most children. Irradiation of the fetus with therapeutic doses between 4 and 11 weeks of gestation would lead to severe abnormalities of many organs in most or all exposed children. Irradiation in a similar dose range between 11 and 16 weeks of gestation may produce little or no eye (late cataracts not considered), skeletal, and genital organ abnormalities but frequently produces stunted growth, microcephaly, and mental retardation. Irradiation later in pregnancy may lead only to mild degrees of microcephaly, mental retardation, and stunting of growth.

Data from studies involving children born to survivors of the atomic bombing of Hiroshima and Nagasaki in 1945 clearly show that damage to the fetus depends on the dosage, stage of pregnancy, and the mother's distance from the explosion. Microcephaly with mental retardation was observed in children born to mothers exposed within 1200 m but not in any of those exposed at a greater distance,²¹⁹ provided there was no effective shielding, such as concrete, to protect the fetus from direct irradiation. Individuals with in utero exposure to A-bomb radiation and their mental retardation were reassessed,^220,221 and the investigators found that there was no risk at 0 to 8 weeks after conception. The highest risk of forebrain damage occurred at 8 to 15 weeks after fertilization, the time of the most rapid proliferation of neuronal elements. A mild impairment of growth is the only recorded abnormality in bomb survivors irradiated at 4 to 9 weeks of pregnancy (2 to 7 weeks of gestation).

Recently, data collected in Hiroshima and Nagasaki during the last 40 years from children of survivors of the atomic bombings were presented.²²² It was concluded that humans are less sensitive to the genetic effects of radiation than was assumed based on past extrapolations from experiments with mice.

Only a few publications report systematic analyses of morphologic ocular abnormalities following radiation. Microphthalmia, lens opacity, optic atrophy, chorioretinitis, strabismus, nystagmus, and abnormal retinal pigmentation have been observed, as has blindness in some cases.^{212,213,215–218,223}

FACTORS WITH UNCERTAIN OR UNLIKELY OCULAR TERATOGENICITY

HYPERTHERMIA. High fever at 4 to 6 weeks after fertilization might produce a similar clinical phenotype in infants. This consists of neural tube defects, hypotonia, microphthalmia, midface hypoplasia, and mild impairment of distal limb development.^224,225 No apparent effect on morphogenesis seems to occur if the mother has a fever during the latter half of gestation, and microphthalmia is the disorder most significantly related to a maternal febrile condition.^226,227

Animal experiments support the findings of major ocular structure defects following hyperthermia. A study by Webster and co-workers showed that when hyperthermia was induced during the gastrulation process in rats, microphthalmia was the most common malformation at all teratogenic temperatures and was frequently the only malformation seen with the shortest time exposure for a particular temperature.²³

In Finland almost every pregnant mother visits the sauna regularly, yet the incidence of central nervous system defects in Finland is among the lowest ever reported. The relatively mild hyperthermia during a short time in the sauna is not considered to be hazardous to the developing embryo.²²⁸

CYTOTOXIC DRUGS. Cytotoxic drugs are used to treat neoplasms and rheumatic diseases and were formerly used in attempted abortion. Since the first report that cytotoxic drugs given during the first trimester of pregnancy may be associated with fetal deaths and central nervous system malformations,²²⁹ long-term follow-up of children exposed in utero to various antineoplastic agents has demonstrated only rare abnormalities with no obvious pattern.^230–233 Cyclophosphamide therapy during the first trimester may be associated with malformations, including multiple eye abnormalities.²³⁴

PSYCHOPHARMACEUTICAL AND ANTICONVULSANT

DRUGS. Carbamazepine (Tegretol) has been suggested by many as the drug of choice for pregnant epileptic women because of serious concern about the effects of phenytoin, valproic acid, and trimethadione on the fetus. Birth defects associated with the use of carbamazepine, such as spina bifida, fingernail hypoplasia, craniofacial defects, developmental delay, and fetal head growth retardation,^235–237 recently have been reported. Schroer and Elhassani found opaque corneas, among other defects, following medication with carbamazepine.²³⁸

Phenobarbital has been used for more than 60 years to treat epilepsy. Although it is not a recognized teratogen, it may have similar effects on the child as phenytoin. Another agent, primidone, has been reported to have occasional associated ocular defects (hypertelorism, epicanthus, ptosis, and strabismus).^239,240 Upper lid coloboma, bilateral temporal lipodermoids, one slightly smaller eye, antimongoloid slant, mild ocular hypertelorism, and preauricular skin tags (Goldenhar-Gorlin's syndrome) were reported in an infant following exposure to primidone in utero.²⁴¹

Benzodiazepines have been widely prescribed to treat mental disease, anxiety states, restlessness, and insomnia, as well as epilepsy. The suspicion has been raised that these drugs may have hazardous effects on the embryo and fetus. In utero exposure to diazepam increases the risk of cleft lip and palate according to some authors.^242,243 Hypotonia with poor sucking reflexes, intrauterine and postnatal growth retardation, dysmorphic features, microcephaly, and neurologic abnormalities, especially focal involvement of cranial nerves, have been suggested to be related to maternal ingestion of different types of benzodiazepines during pregnancy.²⁴⁴ Many of these symptoms are found in other syndromes, the most important being FAS. Craniofacial abnormalities with a sullen and expressionless face and defects of cranial nerves, however, are not typical of FAS.

Ocular abnormalities, such as coloboma of the uvea and optic nerve, optic nerve hypoplasia, and Möbius' syndrome, were found in the eyes of children born to mothers who had used flunitrazepam and oxazepam during pregnancy,²⁴⁵ and an increased occurrence of strabismus was seen in children exposed to diazepam in utero.²⁴⁶

AIDS. Data regarding children born to mothers with AIDS are scarce. In 1986 Marion and coworkers described 20 infants and children who were born with similar dysmorphic features and whose serologic tests were human T-cell leukemia virus type III (HTLV-III) antibody positive, clearly suggesting a fetal HTLV-III infection.²⁴⁷ All were born to women who abused intravenous drugs. Characteristic signs were noted, including growth failure, microcephaly, and craniofacial dysmorphia, consisting of hypertelorism, a prominent boxlike forehead, a flat nasal bridge, long palpebral fissures with blue sclerae, mild upward or downward obliquity of the eyes, a short nose with flattened columella, a prominent philtrum, and patulous lips. The more severe stigmas occurred in patients in whom recurrent infections had developed within the first 6 months of life. Autopsy material from children with AIDS showed that the primary lesions were located in the lymphoreticular system (thymus and lymph nodes) and in the brain.²⁴⁸ Static or progressive encephalopathy due to human immunodeficiency virus infection of the central nervous system was found in 90% of children with congenital AIDS.²⁴⁹

Further information is needed for evaluation if AIDS is to be regarded as a teratogenic agent.

COCAINE. The teratogenicity of cocaine is not well known and is still controversial. A variety of major and minor congenital abnormalities without a typical syndrome pattern was noted in 17% of a group of children exposed to cocaine during pregnancy.⁹⁰ Congenital limb reduction defects or intestinal atresia or infarction were found in another study.²⁵⁰ A recent investigation of nine infants exposed to cocaine who were selected because of brain and ocular abnormalities²⁵¹ showed that strabismus was a consistent finding in all infants in whom adequate visual fixation had developed, either as exotropia or esotropia. Two children had nystagmus, one child had a unilateral third nerve palsy, two children were apparently blind, and three infants had abnormal optic discs (hypoplastic optic discs or disc atrophy). Good and associates described 13 children with documented intrauterine cocaine exposure, five of whom had optic nerve defects (atrophy and hypoplasia) and one child with microphthalmia and optic nerve colobomas.²⁵² All children had central nervous system abnormalities. Seven children had delayed visual maturation. Four children had massive and prolonged eyelid edema and signs of midfacial hypoplasia. The edema required treatment to prevent occlusion amblyopia.

LYSERGIC ACID DIETHYLAMIDE. Ocular malformations, such as anophthalmia, microphthalmia, corneal opacity, iris coloboma, cataracts, optic atrophy, and optic nerve hypoplasia, may be caused by maternal abuse of lysergic acid diethylamide (LSD) during pregnancy.^253–256

METHYL MERCURY POISONING. Methyl mercury is a cheap and effective fungicide. In the past it was frequently used to treat seed for sowing. In the Japanese cities of Minamata and Niigata, industrial discharges of mercury into local waterways produced a high concentration of methyl mercury in fish, resulting in poisoning of local fish-eating families with an epidemic of cerebral palsy with microcephaly. Ocular manifestations were not a focus. A chorioretinal membrane was reported in one case, and strabismus was reported in an additional 13 patients.^257,258

Methyl mercury poisoning can be prevented only by ensuring that the contaminant does not enter the food supplies. This requires that it no longer be used as a fungicide and that industrial discharges of mercury into the environment be halted. Methyl mercury has a long half-life (50 to 140 days), and women should avoid fish from contaminated areas when planning and during pregnancy.

OPHTHALMIC MEDICATIONS. A pregnant woman may have to use ophthalmic medications. The scarce available literature does not indicate that topical ophthalmic medications are teratogenic in humans.²⁵⁹ Kooner and Zimmerman^260,261 failed to recognize any ophthalmic defects regarding antiglaucoma therapy, and Frishman and Chesner²⁶² suggested that the use of beta-blockers is relatively safe during pregnancy. However, until data from definitive studies are available, they advise that pregnant women avoid, when possible, the use of beta-blockers during the first trimester, to use the lowest possible dose, and to discontinue beta-blocker therapy at least 2 to 3 days prior to delivery to limit the effects on uterine contractility and to prevent possible neonatal complications secondary to beta-blockade. The use of beta-blockers with beta₁ -selectivity, intrinsic sympathetic activity, or alpha-blocking activity is recommended. No reports about the use of timolol during pregnancy are available. Topical timolol administration in a breast-feeding woman has been shown to produce a timolol level in breast milk that is much higher than that in plasma, but the adverse effects of the high milk-plasma ratio of timolol could not be evaluated, although the risk of bradycardia in the infant must be considered.²⁶³

There is no evidence that carbonic anhydrase inhibitors are hazardous to the embryo and fetus when given to the mother during pregnancy. A sacrococcygeal teratoma associated with maternal use of acetazolamide from conception to the 19th week of pregnancy was reported in a neonate; the woman also received other medications.²⁶⁴ Animal studies have shown that a number of carbonic anhydrase inhibitors are teratogenic to laboratory animals, causing defects of the forelimbs in rats²⁶⁵ and hamsters.²⁶⁶

There is little evidence that pilocarpine is teratogenic. A pregnant woman who was near term was given pilocarpine and gave birth to a child suffering from signs mimicking neonatal meningitis.²⁶⁷

Few data are available about the adverse effects on the fetus of mydriatics, such as atropine, epinephrine, homatropine, or phenylephrine. Intrauterine exposure to epinephrine may produce cataracts in rats.²⁶⁸ Inguinal hernia and clubfoot have been described in association with sympathomimetics, and minor fetal malformations have been associated with parasympatholytics.²⁶⁹ Intravenous administration of scopolamine to women in labor may affect the fetal heart rate.^270,271 Samples and Meyer recommend that mydriatics be used during pregnancy only when clearly needed and that epinephrine and phenylephrine be contraindicated.²⁵⁹

The ability of corticosteroids to induce cleft palate²⁷² in mice has raised the possibility that these drugs may be teratogenic in humans. According to available data, specific malformations induced by systemically or topically administered hormones do not seem to occur. Bilateral congenital cataracts were reported in a child whose mother had received systemic corticosteroids during her pregnancy.²⁷³ Glucocorticoids applied ocularly in mice have produced a significant increase in the incidence of cleft palate and sex organ anomalies.²⁷⁴

Thimerosal, a mercury-containing substance, is used as an ophthalmic preservative. No teratogenic effects were found in rabbits when thimerosal was applied topically to the eye in doses equivalent to those used clinically.²⁷⁵

ANTIBIOTICS. The majority of teratogenic studies involving antibiotics in animals have yielded negative findings. Human studies, mostly consisting of case reports, are not convincing regarding the teratogenicity of antibiotics.²⁷⁶

Streptomycin used to treat tuberculosis has been associated with congenital nerve deaf- Hess.^277–279 Microcornea, microphthalmia with coloboma of the iris, and choroid in one eye and anophthalmos in the other have been reported in a child from India exposed to antituberculous treatment with ethambutol, rifampicin, and isoniazide in the first trimester.²⁸⁰

Systemic administration of chloramphenicol during late pregnancy can produce gray syndrome in neonates but is not regarded as being teratogenic in humans.²⁸¹ We could find no data on topical ophthalmic administration of chloramphenicol and birth defects.

Antiviral drugs, such as idoxuridine, administered topically to the eyes of pregnant rabbits produced fetal malformations, including exophthalmos and clubbing of the forelegs.²⁸² There are no available data regarding human teratogenicity of these drugs.

SMOKING. In 1957 Simpson first reported an association between maternal cigarette smoking and decreased birth weight.²⁸³ Cleft lip and palate have been found in significantly more women who smoked during pregnancy than in control women,²⁸⁴ and smoking is considered a risk for spontaneous abortion.²⁸⁵ There are still conflicting results with regard to whether an association between maternal smoking and the occurrence of congenital malformations exists, making it difficult to conclude whether smoking really is a terato gen.²⁸⁶ Strabismus is the only reported ophthalmic sign in infants born to mothers who smoked cigarettes during pregnancy.²⁸⁷

CAFFEINE. Caffeine is widely consumed by pregnant women. So far, it has not been associated with an increased frequency of congenital malformations in the offspring.²⁸⁸

FOLIC ACID. When given as a supplement around the time of conception, folic acid (a B vitamin) may prevent neural tube defects (anencephaly, spina bifida, and encephalocele). A recent study²⁸⁹ concluded that folic acid supplementation starting before pregnancy can now be recommended as preventive therapy in all women who have had a previous pregnancy with neural tube defects. Ocular defects were not mentioned among the congenital defects caused by folic acid deficiency, although such anomalies frequently are associated with neural tube defects.

VITAMIN A. There is no evidence that vitamin A (retinol) deficiency plays a significant role in human congenital abnormalities, although animal experiments have demonstrated a high frequency of associated ocular defects^290,291 ; there also is one case report of associated anophthalmia.²⁹² Although suspicious birth defects have been observed following excessive vitamin A ingestion, confirmation of human teratogenicity requires further investigation.^293,294 With respect to the findings in laboratory studies and human experience with other vitamin A analogs (isotretinoin and etretinate), there is a reason to caution against long-term exposures of 25,000 U/d or more in women who may become pregnant.

ENVIRONMENTAL AND OCCUPATIONAL FACTORS.

Humans are exposed to a wide range of environmental and occupational factors that may be hazardous to the embryo and fetus. This may cause anxiety in the pregnant mother, often raised by alarming reports in the media. It is difficult to prove the suggested etiologic causes of malformations that require carefully designed studies. Among the factors that have been studied are lead poisoning, exposure to ionizing radiation in pregnant female radiologists, hospital work in operating rooms, and the use of short-wave and microwave equipment or video screens.^295–298 None has been shown to be toxic to the fetus.

Almost half of the children in hospital wards are there because of some type of prenatally acquired malformation.⁶ Many of these children require neonatal intensive care because of prenatal and postnatal growth retardation and surgical repair and subsequent treatment for specific organ disorders. Apart from the suffering of the affected child and their families, patients with congenital malformations consume a great deal of medical expertise and cost--strong reasons to make great efforts to prevent as many birth defects as possible.

The aim of teratology is to remove or reduce a pregnant woman's contact with the teratogenic agent. This is done in a variety of ways, depending on the teratogen. Environmental factors, once proved to be teratogenic, often can be decreased or removed (e.g., methyl mercury poisoning). A vaccine may be developed against diseases (e.g., rubella). With anticoagulants and anticonvulsants, the use of these drugs during pregnancy should be limited, when possible, and the drug with the lowest teratogenic potential should be chosen. For diabetic women, careful control of their diabetes during pregnancy is emphasized.

The prevention of prenatal lesions caused by alcohol consumption provides the greatest challenge to society. It is a life-style problem that requires continuous professional education to detect and treat the at-risk groups--the alcohol abusers. There is no limit below which it is safe for the pregnant woman to drink alcohol. The full blown fetal alcohol syndrome, with its most devastating symptom--mental retardation, is the product of chronic maternal alcoholism but is just the tip of the iceberg. Lesions can occur at levels of alcoholic exposure significantly below that needed to produce dysmorphology. The real issue, then, is how little alcohol exposure is needed to produce any damage. The use of illicit drugs among women of childbearing age is a rapidly increasing problem in the Western world. Intense attention from medical and social authorities is required to make women understand that they are responsible for the future well-being of their unborn child and therefore have to refrain completely from the use of such drugs during pregnancy.

Duke-Elder S (ed): System of Ophthalmology, Vol IX. London, Henry Kimpton, 1977

Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck. New York, Oxford University Press, 1990

Jones KL: Smith's Recognizable Patterns of Human Malformations. Philadelphia, WB Saunders, 1988

McKusick VA: Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. Baltimore, Johns Hopkins University Press, 1988 Mann I: Developmental Abnormalities of the Eye. London, BMA, 1957

Mann I: Development of the Human Eye. New York, Grune & Stratton, 1964

Moore KL: The Developing Human. Philadelphia, WB Saunders, 1988

Schardein JL: Chemically Induced Birth Defects. New York, Marcel Dekker, 1985

Shepard TH: Catalog of Teratogenic Agents. Baltimore, Johns Hopkins University Press, 1989

Warkany J: Congenital Malformations: Notes and Comments. Chicago, Year Book Medical Publishers, 1971

Wilson JG: Environment and Birth Defects. New York, Academic Press, 1973

Wilson JG, Fraser FC (eds):Handbook of Teratology 1–4. New York, Plenum Press, 1977

1. Wilson JG: Environment and Birth Defects. New York, Academic Press, 1973

2. Shepard TH: Teratogenicity of therapeutic agents. Curr Probl Pediatr 10:5, 1979

3. Dickens C: The Posthumous Papers of the Pickwick Club, p 459. London, Oxford University Press, 1949

4. Warkany J: Congenital Malformations. Notes and Comments, p 6–19. Chicago, Year Book Medical Publishers, 1971

5. Gregg NM: Congenital cataract following German measles in the mother. Trans Ophthalmol Soc Aust 3:35, 1941

6. Shepard TH: Catalog of Teratogenic Agents. Baltimore, Johns Hopkins University Press, 1989

7. Shepard TH: Human teratogenicity. Adv Pediatr 33:225, 1986

8. Wilson JG, Fraser FC (eds): Handbook of Teratology 1, p 49–62. New York, Plenum Press, 1977

9. Cahen RL: Experimental and clinical chemoteratogenesis. Adv Pharmacol 4:263, 1966

10. Axelrod LR: Drugs and nonhuman primate teratogenesis. In Wollam DHM (ed): Advances in Teratology, pp 217–230. New York, Academic Press, 1970

11. Ueda K, Nishida Y, Oshima K, Shepard TH: Congenital rubella syndrome: Correlation of gestational age at time of maternal rubella with type of defect. J Pediatr 94:763, 1979

12. Lenz K, Knapp K: Die Thalidomid-Embryopathie. Dtsch Med Wochenschr 87: 1232, 1962

13. Nowack E: Die sensible Phase bei der Thalidomid-Embryopathie. Humangenetik 1:516, 1965

14. Moore KL: The Developing Human. Philadelphia, WB Saunders, 1988

15. Strömland K, Miller M, Cook C: Ocular teratology. Surv Ophthalmol 35:429, 1991

16. Shepard TH: Human teratogens: How can we sort them out? Ann NY Acad Sci 447:105, 1986

17. Lammer EJ, Chen DT, Hoar RM et al: Retinoic acid embryopathy. N Engl J Med 313:837, 1985

18. Webster WS, Johnston MC, Lammer EJ, Sulik KK: Isotretinoin embryopathy and the cranial neural crest: An in vivo and in vitro study. J Craniofac Genet Dev Biol 6:211, 1986

19. Willhite CC, Hill RM, Irving DW: Isotretinoin-induced craniofacial malformations in humans and hamsters. J Craniofacial Genet Dev Biol 2(suppl): 193, 1986

20. Dencker L, d'Argy R, Danielsson BRG et al: Saturable accumulation of retinoic acid in neural and neural crest derived cells in early embryonic development. Dev Pharmacol Ther 10:212, 1987

21. Pratt RM, Abbott BD, Watanabe T, Goulding EH: Craniofacial malformations induced by retinoids in mouse embryo culture. In McLachlan JA, Pratt RM, Markert CL (eds): Banbury Report 26: Developmental toxicology: Mechanisms and Risk, pp 227–242. New York, Cold Spring Laboratory, 1987

22. Cook CS, Sulik KK: Sequential scanning electron microscopic analyses of normal and spontaneously occurring abnormal ocular development in C57BI/6J mice. Scanning Electron Microscopy III: 1215, 1986

23. Webster WS, Germain MA, Edwards MJ: The induction of microphthalmia, encephalocele and other head defects following hyperthermia during the gastrulation process in the rat. Teratology 31:73, 1985

24. Germain M-A, Webster W, Edwards MJ: Hyperthermia as a teratogen: Parameters determining hyperthermia-induced head defects in the rat. Teratology 31:265, 1985

25. Spaeth GL, Nelson LB, Beaudoin AR: Ocular teratology. In Jakobiec FA (ed): Ocular Anatomy, Embryology and Teratology, p 975. Philadelphia, Harper and Row, 1982

26. Hale F: Relation of maternal vitamin A deficiency to microphthalmia in pigs. TX State J Med 33:228, 1937

27. Chamberlain JG, Nelson MM: Congenital abnormalities in the rat resulting from single injections of a 6-aminonic-otinamide during pregnancy. J Exp Zool 153:285, 1963

28. Beaudoin AR: Teratogenicity of sodium arsenate in rats. Teratology 10: 153, 1974

29. Barr M: The teratogenicity of cadmium chloride in two stocks of Wistar rats. Teratology 7:237, 1973

30. Tassinari MS, Long SY: Normal and abnormal midfacial development in the cadmium-treated hamster. Teratology 25: 101, 1982

31. Clavert A: Etudes des malformations oculaires déterminées chez l'embryon de Lapin par le cyclophosphamide. Arch Anat Histol Embryol 53:209, 1970

32. Singh S, Sanyal AK: Eye anomalies induced by cyclophosphamide in rat fetuses. Acta Anat (Basel) 94:490, 1976

33. DeMyer W: Cleft lip and jaw induced in fetal rats by vincristine. Arch Anat Histol Embryol 48: 180, 1965

34. Roux C: Action teratogene du triparanol chez l'animal. Arch Fr Pediatr 21:451, 1964

35. Clarren S, Bowden D: Fetal alcohol syndrome: A new primate model for binge drinking and its relevance to human ethanol teratogenesis. J Pediatr 101:819, 1982

36. Sheller B, Clarren SK, Astley SJ, Sampson PD: Morphometric analysis of Macaca nemestrina exposed to ethanol during gestation. Teratology 38:411, 1988

37. Sulik K, Johnston M: Sequence of developmental alterations following acute ethanol exposure in mice: Craniofacial feature of the fetal alcohol syndrome. Am J Anat 166:257, 1983

38. Pinazo-Duran MD: Efecto de la exposicion pre- y postnatal al alcohol sobre el desarrollo del nervio optico en la rata. Tesis doctoral, Universidad de Valencia, 1991

39. Clarren SK, Astley S J, Bowden DM et al: Neuroanatomic and neurochemical abnormalities in non-human primate infants exposed to weekly doses of ethanol during gestation. Alcohol Clin Exp Res 14:674, 1990

40. Cook CS, Nowotny AZ, Sulik KK: Fetal alcohol syndrome: Eye malformations in a mouse model. Arch Ophthalmol 105: 1576, 1987

41. Cook CS, Sulik KK: Keratolenticular dysgenesis (Peters' anomaly) as a result of acute embryonic insult during gastrulation. J Pediatr Ophthalmol Strabismus 25:60, 1988

42. Wiley MJ, Cauwenbergs P, Taylor IM: Effects of retinoic acid on the development of the facial skeleton in hamsters: Early changes involving cranial neural crest cells. Acta Anat 116:180, 1983

43. Shirai S: Eye abnormalities in mouse fetuses caused by simultaneous irradiation of x-rays and ultrasound: II. Developmental abnormalities of the eye. Cong Anom 18:269, 1978

44. Shirai S, Ohshika S, Yuguchi S, Majima A: Ochratoxin A: I. Developmental eye abnormalities in mouse fetuses induced by ochratoxin A. Acta Soc Ophthalmol Jpn 88:627, 1984

45. Shirai S, Ohshika S, Yuguchi S, Majima A: Ochratoxin A: III. Developmental abnormalities of the anterior segment of the eye induced in mice by ochratoxin A. Acta Soc Ophthalmol Jpn 89:753, 1985

46. Källén B: Search for teratogenic risks with the aid of malformation registries. Teratology 35:47, 1987

47. Alford CA, Griffiths PD: Rubella, In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, pp 69–103. Philadelphia, WB Saunders, 1983

48. Parkman PD, Buescher EL, Artenstein MS: Recovery of rubella virus from army recruits. Proc Soc Exp Biol Med 111:225, 1962

49. Weller TH, Neva FA: Propagation in tissue culture of cytopathic agents from patients with rubella-like illness. Proc Soc Exp Biol Med 111:215, 1962

50. Miller E, Cradock-Watson JE, Pollack TM: Consequences of confined rubella at successive stages of pregnancy. Lancet 2:781, 1982

51. Thompson KM, Tobin JO: Isolation of rubella virus from abortion material. Br Med J 2:264, 1970

52. Marks EO: Pigmentary abnormality in children congenitally deaf following maternal German measles. Br J Ophthalmol 31:119, 1947

53. Krill AE: The retinal disease of rubella. Arch Ophthalmol 77:445, 1967

54. Kresky B, Nauheim JS: Rubella retinitis. Am J Dis Child 113:305, 1967

55. Gregg NM, Marks EO: Pigmentary abnormality in children congenitally deaf following maternal German measles. Trans Ophthal Soc Aust 6: 122, 1946

56. Cooper LZ, Ziring PR, Ockerse AB et al: Rubella. Clinical manifestations and management. Am J Dis Child 118:18, 1969

57. Herrman KL: Rubella in the United States: Toward a strategy for disease control and elimination. Epidemiol Infect 107:55, 1991

58. Kaplan KM, Cochi SL, Edmonds LD et al: A profile of mothers giving birth to infants with congenital rubella syndrome. Am J Dis Child 144:118, 1990

59. Koch FLP, Wolf A, Cowen D, Paige BH: Toxoplasmic encephalomyelitis. Arch Ophthalmol 29: 1, 1943

60. Remington JS: Toxoplasmosis and congenital infection. In Bergsma D (ed): Intrauterine Infections. Birth Defects, Original Article Series 4, pp 47–56. New York, The National Foundations-March of Dimes, 1968

61. Remington JS, Desmonts G: Toxoplasmosis. In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, pp 143–263. Philadelphia, WB Saunders, 1983

62. Pettapiece MC, Hiles DA, Johnson BL: Massive congenital ocular toxoplasmosis. J Pediatr Ophthalmol 13:259, 1976

63. Oniki S: Prognosis of pregnancy in patients with toxoplasmic retinochoroiditis. Jpn J Ophthalmol 27: 166, 1983

64. Kinney JS, Onorato IM, Stewart JA et al: Cytomegaloviral infection and disease. J Infect Dis 151:772, 1985

65. Alford CA, Stagno S, Pass RE, Britt WJ: Congenital and perinatal cytomegalovirus infections. Rev Infect Dis 12:745, 1990

66. Burns RP: Cytomegalic inclusion disease uveitis. Arch Ophthalmol 61:376, 1959

67. Weller TH, Hanshaw JB: Virological and clinical observation on cytomegalic inclusion disease. N Engl J Med 266:1233, 1962

68. McCarthy RW, Frenkel LD, Kollarits CR, Keys MP: Clinical anophthalmia associated with congenital cytomegalovirus infection. Am J Ophthalmol 90:558, 1980

69. Tarkkanen A, Merenmies L, Holmstrom T: Ocular involvement in congenital cytomegalic inclusion disease, J Pediatr Ophthalmol 9:82, 1972

70. Miklos G, Orban T: Ophthalmic lesions due to cytomegalic inclusion disease. Ophthalmologica 148:98, 1964

71. Hittner HM, Desmond MM, Montgomery JR: Optic nerve manifestations of human congenital cytomegalovirus infection. Am J Ophthalmol 81:661, 1976

72. Christensen L, Beeman HW, Allen A: Cytomegalic inclusion disease. Arch Ophthalmol 57:90, 1957

73. Dvorak-Theobald G: Cytomegalic inclusion disease. Am J Ophthalmol 47:52, 1959

74. Hennis HL, Scott AA, Apple DJ: Cytomegalovirus retinitis. Surv Ophthalmol 34: 193, 1989

75. Alford CH: Chronic congenital infections of man. Yale J Biol Med 55:187, 1982

76. Frenkel LD, Keys MP, Hefferen SJ et al: Unusual eye abnormalities associated with congenital cytomegalovirus infection. Pediatrics 66:763, 1980

77. Nahmias AJ, Keyserling HL, Kerrick GM: Herpes Simplex. In Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, pp 636–678. Philadelphia, WB Saunders, 1983

78. Nahmias AJ, Visintine AM, Caldwell DR, Wilson LA: Eye infections with herpes simplex viruses in neonates. Surv Ophthalmol 21:100, 1976

79. Laforet EG, Lynch CL: Multiple congenital defects following maternal varicella. Report of a case. N Engl J Med 236:534, 1947

80. Srabstein JC, Morris N, Larke RPB et al: Is there a congenital varicella syndrome? J Pediatr 84:239, 1974

81. Charles NC, Bennett TW, Margolis S: Ocular pathology of the congenital varicella syndrome. Arch Ophthalmol 95:2034, 1977

82. Borzyskowski M, Harris RF, Jones RWA: The congenital varicella syndrome. Eur J Pediatr 137:335, 1981

83. Cotlier E: Congenital varicella cataract. Am J Ophthalmol 86:627, 1978

84. Brice JE: Congenital varicella resulting from infection during second trimester of pregnancy. Arch Dis Child 51:474, 1976

85. Frey HM, Bialkin G, Gershon AA: Congenital varicella: Case report of a serologically proved long-term survivor. Pediatrics 59:110, 1977

86. Webster MH, Smith CS: Congenital abnormalities and maternal herpes zoster. Br Med J 2:1193, 1977

87. Savage MO, Moosa A, Gordon RR: Maternal varicella infection as a cause of fetal malformations. Lancet 1:352, 1973

88. Lambert SR, Taylor D, Kriss A et al: Ocular manifestations of the congenital varicella syndrome. Arch Ophthalmol 107:52, 1989

89. Mascola L, Pelosi R, Blount JH et al: Congenital syphilis. Why is it still occurring? JAMA 252:1719, 1984

90. Burkett G, Yasin S, Palow D: Perinatal implications of cocaine exposure. J Reprod Med 35:35, 1990

91. Wendel GD: Gestational and congenital syphilis. Clin Perinatol 15:287, 1988

92. Ricci JM, Fojaco RM, O'Sullivan MJ: Congenital syphilis: The University of Miami/Jackson Memorial Medical Center Experience, 1986-1988. Obstet Gynecol 74:687, 1989

93. Duke-Elder S (ed): System of Ophthalmology, Vol 9, pp 306–321. London, Henry Kimpton, 1977

94. Nabarro D: Congenital Syphilis. London, E Arnold, 1954

95. Hill RM, Knox JM: Syphilis. In Kelly VC (ed): Brenneman's practice of pediatrics, Vol 2. Hagerstown, Harper and Row, 1972

96. Idsoe O, Guthe T, Willcox RR: Penicillin in the treatment of syphilis: The experience of three decades. Bull WHO 47(suppl), 1972

97. Pedersen LM, Tygstrup IN, Pedersen J: Congenital malformations in newborn infants of diabetic women. Correlation with maternal diabetic vascular complications. Lancet 1: 1124, 1964

98. Karlsson K, Kjellmer I: The outcome of diabetic pregnancies in relation to the mother's blood sugar level. Am J Obstet Gynecol 112:213, 1972

99. Diamond MP, Salyer SL, Boehm FH, Vaughn WK: Congenital anomalies in offspring of insulin-dependent diabetic mothers. Diabetes Educator 12:272, 1987

100. Reece EA, Hobbins JC: Diabetic embryopathy: Pathogenesis, prenatal diagnosis and prevention. Obstet Gynecol Surv 41:325, 1986

101. Kitzmiller JL, Gavin LA, Gin GD et al: Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 265:731, 1991

102. Greene MF, Hare JW, Cloherty JP et al: First-trimester hemoglobin A1, and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39:225, 1989

103. Mills JL, Knopp RH, Simpson JL et al: Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis. N Engl J Med 318:671, 1988

104. Mills JL, Simpson JL, Driscoll SG et al: Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 319:1617, 1988

105. Hanson U, Persson B, Thunell S: Relationship between haemoglobin A_1c in early Type 1 (insulin-dependent) diabetic pregnancy and occurrence of spontaneous abortion and fetal malformation in Sweden. Diabetologia 33: 100, 1990

106. Milunsky A, Alpert E, Kitzmiller JL et al: Prenatal diagnosis of neural tube defects. VIII. The importance of serum alpha-fetoprotein screening in diabetic pregnant women. Am J Obstet Gynecol 142:1030, 1982

107. Soler NG, Walsh CH, Malins JM: Congenital malformations in infants of diabetic mothers. Q J Meal 45:303, 1976

108. Cousins LA: Congenital anomalies among infants of diabetic mothers. Etiology, prevention, prenatal diagnosis. Am J Obstet Gynecol 147:333, 1983

109. Kucera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:61, 1971

110. Petersen RA, Walton DS: Optic nerve hypoplasia with good visual acuity and visual field defects. A study of children of diabetic mothers. Arch Ophthalmol 95:254, 1977

111. Kim RY, Hoyt WF, Lessell S, Narahara MH: Superior segmental optic hypoplasia. A sign of maternal diabetes. Arch Ophthalmol 107:1312, 1989

112. Donat JFG: Septo-optic dysplasia in an infant of a diabetic mother. Arch Neurol 38:590, 1981

113. Khoury MJ, Becerra JE, Cordero JF, Erickson JD: Clinical-epidemiologic assessment of patterns of birth defects associated with human teratogens: Application to diabetic embryopathy. Pediatrics 84:658, 1989

114. Lamache MA: Communications: Réflexions sur la descendance des alcooliques. Bull Acad Nat Médecine 151:517, 1967

115. Lemoine P, Harousseau H, Borteyru JP, Menuet JC: Les enfants de parents alcooliques. Anomalies observées. A propos de 127 cas. Ouest-Medical 21:476, 1968

116. Jones KL, Smith DW, Ulleland CN, Streissguth AP: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1: 1267, 1973

117. Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999, 1973

118. Jones KL, Smith DW, Streissguth AP, Myrianthopoulos NC: Outcome in offspring of chronic alcoholic women. Lancet 1: 1076, 1974

119. Sokol RJ, Clarren SK: Guidelines for use of terminology describing the impact of prenatal alcohol on the offspring. Alcoholism Clin Exp Res 13:597, 1989

120. Smith DF, Sandor GG, MacLeod PM et al: Intrinsic defects in the fetal alcohol syndrome: Studies on 76 cases from British Columbia and the Yukon territory. Neurobeh Toxicol Teratology 3: 145, 1981

121. Goldstein G, Arulanantham K: Neural tube defect and renal anomalies in a child with fetal alcohol syndrome. J Pediatr 93:636, 1978

122. Aronson M, Kyllerman M, Sabel K-G et al: Children of alcoholic mothers. Developmental, perceptual and behavioural characteristics as compared to matched controls. Acta Paediatr Scand 74:27, 1985

123. Streissguth AP, Aase JM, Clarren SK et al: Fetal alcohol syndrome in adoloscents and adults. JAMA 265:1961, 1991

124. Altman B: Fetal alcohol syndrome. J Pediatr Ophthalmol 13:255, 1976

125. Miller M, Israel J, Cuttone J: Fetal alcohol syndrome, J Pediatr Ophthalmol Strabismus 18:6, 1981

126. Strömland K: Ocular abnormalities in the fetal alcohol syndrome. Acta Ophthalmol 63(suppl 171 ), 1985

127. Chan T, Bowell R, O'Keefe M, Lanigan B: Ocular manifestations in fetal alcohol syndrome. Br J Ophthalmol 75:524, 1991

128. Miller M, Epstein R, Sugar J et al: Anterior segment anomalies associated with the fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 21:8, 1984

129. Garber JM: Steep corneal curvature: A fetal alcohol syndrome landmark. J Am Optom Assoc 55:595, 1984

130. Strömland K: Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol 31:277, 1987

131. Abel EL, Sokol RJ: Fetal alcohol syndrome is now leading cause of mental retardation. Lancet 2:1222, 1986

132. Strömland K: Contribution of ocular examination to the diagnosis of foetal alcohol syndrome in mentally retarded children. J Ment Defic Res 34:429, 1990

133. Mena M, Nazal R, Fernandez E et al: Prevalence of fetal alcohol syndrome at foster homes of the Servicio nacional de Menores VIII region, Chile. Rev Méd Chil 115:1218, 1987

134. Véghelyi PV, Osztovics M, Kardos G et al: The fetal alcohol syndrome: symptoms and pathogenesis. Acta Paediatr Acad Sci Hung 19:171, 1978

135. Vitéz M, Korányi G, Gönczy E et al: A semiquantitative score system for epidemiologic studies of fetal alcohol syndrome. Am J Epidemiol 119:301, 1984

136. Kirchner M: Das embryonale Alkoholsyndrom. Kinderärztliche Praxis 41:574, 1979

137. Majewski F, Majewski B: Alcohol embryopathy: Symptoms, auxological data, frequency among the offspring and pathogenesis. In Kuriyama K, Takada A, Ishii H (eds): Biomedical and Social Aspects of Alcohol and Alcoholism, pp 837–844. Amsterdam, Elsevier Science Publishers BV, 1988

138. Sokolowski F, Sokolowski A, Majewski F: Risiken für die Nachkommen alkoholkranker Frauen. Pädiat Prax 38:373, 1989

139. Halliday HL, Reid MM, McClure G: Results of heavy drinking in pregnancy. Br J Obstet Gynecol 89:892, 1982

140. Dehaene P, Crepin G, Delahousse G et al: Aspects épidémiologiques du syndrome d'alcoolisme faetal. Nouv Presse Med 10:2639, 1981

141. Olegård R, Sabel KG, Aronsson M: Effects on the child of alcohol abuse during pregnancy: Retrospective and prospective studies. Acta Paediatr Scand 275(suppl): 112, 1979

142. Quellete EM, Rosett HL, Rosman NP, Weiner L: Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Engl J Med 297:528, 1977

143. Hanson JW, Streissguth AP, Smith DW: The effects of moderate alcohol consumption during pregnancy on fetal growth and morphogenesis. J Pediatr 92:457, 1978

144. May PA, Hymbaugh KJ, Aase JM, Samet JM: Epidemiology of fetal alcohol syndrome among American Indians of the southwest. Soc Biol 30:374, 1983

145. Robinson GC, Conry JL, Conry RF: Clinical profile and prevalence of fetal alcohol syndrome in an isolated community in British Columbia. Can Med Assoc J 137:203, 1987

146. Streissguth AP, Barr HM, Sampson PD: Moderate prenatal alcohol exposure: Effects on child IQ and learning problems at age 7 years. Alcoholism Clin Exp Res 14:662, 1990

147. Plant ML, Plant MA: Maternal use of alcohol and other drugs during pregnancy and birth abnormalities: Further results from a prospective study. Alcohol Alcohol 23:229, 1988

148. Wiedeman HR: Hinweis auf eine derzeitige Häufung hypo- und aplastischer Fehlbildungen der Gliedmassen. Med Welt 37:1863, 1961

149. Kosenow W, Pfeiffer RA: Micromelia, haemangioma und duodenal stenosis. Monatsschr Kinderheilkd 109:227, 1961

150. McBride WG: Thalidomide and congenital abnormalities. Lancet 2:1358, 1961

151. Lenz W: Fragen aus der Praxis. Kindliche Missbildungen nach Medikament v Einnahme während der Gravidität? Dtsch Med Wochenschr 86:2555, 1961

152. Smithells RW: Thalidomide and malformations in Liverpool. Lancet 1:1270, 1962

152a. Warkany J: Congenital malformations: Notes and Comments, p 84. Chicago, Year Book Medical Publishers, 1971

153. Kajii T: Thalidomide experience in Japan. Ann Pediatr 205:341, 1965

154. Kida M (ed): Thalidomide embryopathy in Japan. Tokyo, Kodansha, 1987

155. Schott K: Conterganschaden und Augenmissbildung. Klin Monatsbl Augenheilkd 143:599, 1963

156. Gilkes MJ, Strode M: Ocular anomalies in association with developmental limb abnormalities of drug origin. Lancet 1:1026, 1963

157. Papst W: Thalidomid und kongenitale Anomalien der Augen. Ber Dtsch Ophthalmol Ges 65:209, 1964

158. Schmidt JGH: Augenmuskelparesen bei Thalidomid-Embryopatie. Ber Dtsch Ophthalmol Ges 65:215, 1964

159. Cullen JF: Ocular defects in Thalidomide babies. Br J Ophthalmol 48: 151, 1964

160. d'Avignon M, Barr B: Ear abnormalities and cranial nerve palsies in thalidomide children. Arch Otolaryngol 80:136, 1964

161. Zetterstr6m B: Ocular malformations caused by thalidomide. Acta Ophthalmol 44:391, 1966

162. Miller M, Strömland K: Ocular motility in thalidomide embryopathy. J Pediatr Ophthalmol Strabismus 28:47, 1991

163. Strömland K, Miller M: Thalidomide embryopathy clarifies developmental anomalies of the ocular system. Teratology 44: 17A, 1991

164. Strömland K, Miller M: Refractive evaluation of thalidomide embryopathy. Graefes Arch Clin Exp Ophthalmol 230: 140, 1992

165. Meadow SR: Anticonvulsant drugs and congenital abnormalities. Lancet 2:1296, 1968

166. Speidel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2:839, 1972

167. Fedrick J: Epilepsy and pregnancy: A report from the Oxford record linkage study. Br Med J 2:442, 1973

168. Lowe CR: Congenital malformations among infants born to epileptic women. Lancet 1:9, 1973

169. Bertollini R, Källén B, Mastroiacovo P, Robert E: Anticonvulsant drugs in monotherapy. Effect on the fetus. Eur J Epidemiol 3:164, 1987

170. Martinez-Frias ML: Clinical manifestation of prenatal exposure to valproic acid using case reports and epidemiologic information, Am J Med Genet 37:277, 1990

171. Hanson JW, Myrianthopoulos NC, Harvey MAS, Smith DW: Risks to the offspring of women treated with hydantoin anticonvulsants with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976

172. Hanson JW: Teratogen update: Fetal hydantoin effects, Teratology 33:349, 1986

173. Nakane Y, Okuma T, Takahashi R et al: Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: A report of a collaborative study group in Japan. Epilepsia 21:663, 1980

174. Holmes LB: The effects of exposure to phenytoin in utero. Proc Greenwood Genet Center 4:92, 1985

175. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285, 1975

176. Hampton GR, Krepostman JI: Ocular manifestations of the fetal hydantoin syndrome. Clin Pediatr 20:475, 1981

177. Wallar PH, Genstler DE, George CC: Multiple systemic and periocular malformations associated with the fetal hydantoin syndrome. Ann Ophthalmol 10: 1568, 1978

178. Wilson RS, Smead W, Char F: Diphenylhydantoin teratogenicity: Ocular manifestations and related deformities. J Pediatr Ophthalmol Strabismus 15: 137, 1978

179. Hoyt CS, Billson FA: Maternal anticonvulsants and optic nerve hypoplasia. Br J Ophthalmol 62:3, 1978

180. Bartoshesky LE, Bhan I, Nagpaul K, Pashayan H: Severe cardiac and ophthalmologic malformations in an infant exposed to diphenylhydantoin in utero. Pediatrics 69:202, 1982

181. German J, Kowal A, Ehlers KH: Trimethadione and human teratogenesis. Teratology 3:349, 1970

182. Zackai EH, Mellman WJ, Neiderer B, Hanson JW: The fetal trimethadione syndrome. J Pediatr 87:280, 1975

183. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome. Am J Dis Child 131:1389, 1977

184. Robert E, Guibaud P: Maternal valproic acid and congenital neural tube defects. Lancet 2:937, 1982

185. DiLiberti JH, Farndon PA, Dennis NR, Curry CJR: The fetal valproate syndrome. Am J Med Genet 19:473, 1984

186. Ardinger HH, Atkin JF, Blackston RD et al: Verification of the fetal valproate syndrome phenotype. Am J Med Genet 29:171, 1988

187. Verloes A, Frikiche A, Gremillet C et al: Proximal phocomelia and radial ray aplasia in fetal valproic syndrome. Eur J Pediatr 149:266, 1990

188. Tunnessen WW, Lowenstein EH: Glaucoma associated with the fetal hydantoin syndrome. J Pediatr 89: 154, 1976

189. Jäger-Roman E, Deichl A, Jakob S et al: Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr 108:997, 1986

190. Rosa FW: Teratogenicity of isotretinoin. Lancet 2:513, 1983

191. Benke PJ: The isotretinoin teratogen syndrome. JAMA 251:3267, 1984

192. Braun JT, Franciosi RA, Mastri AR et al: Isotretinoin dysmorphic syndrome. Lancet 1:506, 1984

193. de la Cruz E, Sun S, Vangvanichyakorn K, Desposito F: Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 74:428, 1984

194. Hill RM: Isotretinoin teratogenicity. Lancet 1:1465, 1984

195. Lammer EJ, Chen DT, Hoar R et al: Retinoic acid embryopathy. N Engl J Med 313:837, 1985

196. Hansen LA, Pearl GS: Isotretinoin teratogenicity. Acta Neuropathol 65:335, 1985

197. Rosa FW: Retinoic acid embryopathy. N Engl J Med 314:262, 1986

198. Happle R, Traupe H, Bounameaux Y, Fisch T: Teratogene Wirkung von Etretinat beim Menschen. Dtsch Med Wochenschr 109:1476, 1984

199. Lammer EJ: Embryopathy in infant conceived one year after termination of maternal etretinate. Lancet 2:1080, 1988

200. DiSaia PJ: Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis. Report of a case. Obstet Gynecol 28:469, 1966

201. Pettifor JM, Benson R: Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J Pediatr 86:459, 1975

202. Shaul WL, Hall JG: Multiple congenital anomalies associated with oral anticoagulants. Am J Obstet Gynecol 127:191, 1977

203. Holmes B, Moser HW, Halldorsson S et al: Mental Retardation: An Atlas of Diseases with Associated Physical Abnormalities, pp 136–137. New York, Macmillan Company, 1972

204. Becker MH, Genieser NB, Finegold M et al: Chondrodysplasia punctata. Am J Dis Child 129:356, 1975

205. Warkany J: Warfarin embryopathy. Teratology 14:205, 1976

206. Kleinebrecht J: Zur Teratogenität von Cumarin-Derivaten. Dtsch Med Wochenschr 107: 1929, 1982

207. Baillie M, Allen ED, Elkington AR: The congenital warfarin syndrome: A case report. Br J Ophthalmol 64:633, 1980

208. Hall JG, Pauli RM, Wilson KM: Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122, 1980

209. Kaplan LC: Congenital Dandy Walker malformation associated with first trimester warfarin: A case report and literature review. Teratology 32:333, 1985

210. Iturbe-Alessio I, Fonseca MC, Mutchinik O et al: Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 315:1390, 1986

211. Schardein JL: Chemically Induced Birth Defects. New York, Marcel Dekker, 1985

212. Stettner E: Ein weiterer Fall einer Schädigung einer menschlichen Frucht durch Röntgenbestrahlung. Jahrb Kinderh 95:43, 1921

213. Zappert J: Uber Roentgenogene fetale Microcephalie. Mschr Kinderheilkd 34:490, 1926

214. Murphy DP: The outcome of 625 pregnancies in women subjected to pelvic radium or roentgen irradiation. Am J Obstet Gynecol 18:179, 1929

215. Goldstein L, Murphy DP: Microcephalic idiocy following radium therapy for uterine cancer during pregnancy. Am J Obstet Gynecol 18:189,281, 1929

216. Goldstein L, Murphy DP: Etiology of ill health in children born after maternal pelvic irradiation. II. Defective children born after postconceptional maternal irradiation. AJR 22:322, 1929

217. Goldstein L: Radiogenic microcephaly. Arch Neurol Psychiatr 24:102, 1930

218. Dekaban AS: Abnormalities in children exposed to X-radiation during various stages of gestation: tentative timetable of radiation injury to the human fetus, part I. J Nucl Med 9:471, 1968

219. Plummer G: Anomalies occurring in children exposed in utero to the atomic bomb in Hiroshima. Pediatrics 10:687, 1952

220. Otake M, Schull WJ: In utero exposure to A-bomb radiation and mental retardation: A reassessment. Br J Radiol 57:409, 1984

221. Mole RH: Consequences of pre-natal radiation exposure for post-natal development. A review. Int J Radiat Biol 42: 1, 1982

222. Neel JV, Schull WJ, Awa AA et al: The children of parents exposed to atomic bombs: estimates of the genetic doubling dose of radiation for humans. Am J Hum Genet 46:1053, 1990

223. Nefzger MD, Miller R J, Fujino T: Eye findings in atomic bomb survivors of Hiroshima and Nagasaki: 1963-1964. Am J Epidemiol 89:129, 1968

224. Smith DW, Clarren SK, Harvey MAS: Hyperthermia as a possible teratogenic agent. J Pediatr 92:878, 1978

225. Layde PM, Edmonds LD, Erickson JD: Maternal fever and neural tube defects. Teratology 21: 105, 1980

226. Fraser FC, Skelton J: Possible teratogenicity of maternal fever. Lancet 2:634, 1978

227. Spraggett K, Fraser FC: Teratogenicity of maternal fever in (wo)man-a retrospective study. Teratology 25:78A, 1982

228. Saxén L, Holmberg PC, Nurminen M, Kuosma E: Sauna and congenital defects. Teratology 25:309, 1982

229. Nicholson HO: Cytotoxic drugs in pregnancy. J Obstet Gynaecol Br Commonw 75:307, 1968

230. Garber JE: Long-term follow-up of children exposed in utero to antineoplastic agents. Semin Oncol 16:437, 1989

231. Catanzarite VA, Ferguson JE: Acute leukemia and pregnancy: A review of management and outcome, 1972-1982. Obstet Gynecol Surv 39:663, 1984

232. Avilés A, Niz J: Long-term follow-up of children born to mothers with acute leukemia during pregnancy. Med Pediatr Oncol 16:3, 1988

233. Reynoso EE, Shepherd FA, Messner HA et al: Acute leukemia during pregnancy: The Toronto leukemia study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098, 1987

234. Kirshon B, Wasserstrum N, Willis R et al: Teratogenic effects of first trimester cyclophosphamide therapy. Obstet Gynecol 72:462, 1988

235. Hiilesmaa VK, Teramo K, Granström M-L: Fetal head growth retardation associated with maternal antiepileptic drugs. Lancet 2:165, 1981

236. Jones KL, Lacro RV, Johnson KA, Adams J: Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Engl J Med 320:1661, 1989

237. Rosa FW: Spina bifida in infants of women treated with carbamazepine during pregnancy, N Engl J Med 324:674, 1991

238. Schroer RJ, Elhassani S: Multiple congenital anomalies with prenatal carbamazepine exposure. Proc Greenwood Genet Center 8:31, 1989

239. Seip M: Growth retardation, dysmorphic facies and minor malformations following massive exposure to phenobarbitone in utero. Acta Paediatr Scand 65:617, 1976

240. Rating D, Nau H, Jäger-Roman E et al: Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women. Acta Paediatr Scand 71:301, 1982

241. Gustavson EE, Chen H: Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure. Teratology 32: 13, 1985

242. Safra MJ, Oakley GP Jr: Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 2:478, 1975

243. Saxén I: Associations between oral clefts and drugs taken during pregnancy. Int J Epidemiol 4:37, 1975

244. Laegreid L, Olegård R, Walström J, Conradi N: Teratogenie effects of benzodiazepine use during pregnancy. J Pediatr 114: 126, 1989

245. Strömland K: Ocular malformations in children exposed to drugs during gestation. Clin Pediatr 27:257, 1988

246. Nelson LB, Ehrlich S, Calhoun JH et al: Occurrence of strabismus in infants born to drug-dependent women. Am J Dis Child 141:175, 1987

247. Marion RW, Wiznia AA, Hutcheon RG, Rubinstein A: Human T-cell lymphotropic virus type III (HTLV-III) embryopathy. Am J Dis Child 140:638, 1986

248. Joshi VV, Oleske JM, Connor EM: Morphologic findings in children with acquired immune deficiency syndrome: Pathogenesis and clinical implications. Pediatr Pathol 10: 155, 1990

249. Curless RG: Congenital AIDS: Review of neurologic problems. Childs Nerv Syst 5:9, 1989

250. Hoyme HE, Jones KL, Dixon SD et al: Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85:743, 1990

251. Dominguez R, Vila-Coro AA, Slopis JM, Bohan TP: Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 145:688, 1991

252. Good WV, Ferreiro DM, Golabi M, Kabori JA: Abnormalities of the visual system in infants exposed to cocaine. Ophthalmol 99:341, 1992

253. Margolis S, Martin L: Anophthalmia in an infant of parents using LSD. Ann Ophthalmol 12: 1378, 1980

254. Apple DJ, Bennett TO: Multiple systemic and ocular malformations associated with maternal LSD usage. Arch Ophthalmol 92:301, 1974

255. Bogdanoff B, Rorke LB, Yanoff M, Warren WS: Brain and eye abnormalities. Am J Dis Child 123: 145, 1972

256. Hoyt CS: Optic disc anomalies and maternal ingestion of LSD. J Pediatr Ophthalmol 15:286, 1978

257. Matsumoto H, Koya G, Takeuchi T: Fetal Minamata disease. A neuropathological study of two cases of intrauterine intoxication by a methyl mercury compound. J Neuropathol Exp Neurol 24:563, 1965

258. Murakami U: The effect of organic mercury on intrauterine life. Adv Exp Biol Med 27:301, 1972

259. Samples JR, Meyer SM: Use of ophthalmic medications in pregnant and nursing women. Am J Ophthalmol 106:616, 1988

260. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy-Part I. Ann Ophthalmol 20: 166, 1988

261. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy-Part II. Ann Ophthalmol 20:208, 1988

262. Frishman WH, Chesner M: Beta-adrenergic blockers in pregnancy. Am Heart J 115:147, 1988

263. Lustgarten JS, Podos SM: Topical timolol and the nursing mother. Arch Ophthalmol 101:1381, 1983

264. Worsham GF, Beckman EN, Mitchell EH: Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 240:251, 1978

265. Layton WM, Hallesy DW: Deformity of forelimb in rats: Association with high doses of acetazolamide. Science 149:306, 1965

266. Layton WM: Teratogenic action of acetazolamide in golden hamsters. Teratology 4:95, 1971

267. Altman B: Ocular effects in the newborn from maternal drugs. In Leopold IH, Burns RP (eds): Symposium on ocular therapy, Vol 11, pp 97–98. New York, John Wiley & Sons, 1979

268. Pitel M, Lerman S: Studies on the fetal rat lens. Effects of intrauterine Adrenalin and noradrenalin. Invest Ophthalmol 1:406, 1962

269. Heinonen OP, Slone D, Shapiro S: Birth defects and drugs in pregnancy. Littleton, MA, Publishing Sciences Group, 1977

270. Boehm FH, Growdon JH: The effect of scopolamine on fetal heart rate baseline variability. Am J Obstet Gynecol 120: 1099, 1974

271. Shenker L: Clinical experiences with fetal heart rate monitoring of one thousand patients in labor. Am J Obstet Gynecol 115:1111, 1973

272. Lahti A, Antila E, Saxén L: The effect of hydrocortisone on the closure of the palatal shelves in two inbred strains of mice in vivo and in vitro. Teratology 6:37, 1972

273. Kraus AM: Congenital cataract and maternal steroid ingestion. J Pediatr Ophthalmol 12: 107, 1975

274. Ballard PD, Hearney EF, Smith MB: Comparative teratogenicity of selected glucocorticoids applied ocularly in mice. Teratology 16: 175, 1977

275. Gasset AR, Itoi M, Ishii Y, Ramer RM: Teratogenicities of ophthalmic drugs. II. Teratogenicities and tissue accumulation of thimerosal. Arch Ophthalmol 93:52, 1975

276. Schardein JL: Chemically induced birth defects. New York, Marcel Dekker, 1985

277. Leroux ML: Existe-t-il une surdite congenitale acquise due a la streptomycine? Ann Otolaryngol 67: 194, 1950

278. Robinson GC, Cambon KG: Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy. N Engl J Med 271:949, 1964

279. Warkany J: Antituberculous drugs. Teratology 20:133, 1979

280. Roy AS: Ocular malformation following ethambutol, rifampicin, isoniazide in the first trimester of pregnancy. Indian J Pediatr 57:730, 1990

281. Oberheuser F: Praktische Erfahrungen mit Medikamenten in der Schwangerschaft. Therapiewoche 31:2198, 197 l

282. Itoi M, Gefter JW, Kaneko N et al: Teratogenicities of ophthalmic drugs. I. Antiviral ophthalmic drugs. Arch Ophthalmol 93:46, 1975

283. Simpson WJ, Calif LL: A preliminary report on cigarette smoking and the incidence of prematurity. Am J Obstet Gynecol 73:808, 1957

284. Ericson A, Källén B, Westerholm P: Cigarette smoking as an etiologic factor in cleft lip and palate. Am J Obstet Gynecol 135:348, 1979

285. Kline J, Stein ZA, Susser M, Warburton D: Smoking: A risk factor for spontaneous abortion. N Engl J Med 297:793, 1977

286. Werler MM, Pober BR, Holmes LB: Smoking and pregnancy. Teratology 32:473, 1985

287. Christianson RE: The relationship between maternal smoking and the incidence of congenital anomalies. Am J Epidemiol 112:684, 1980

288. Barr HM, Streissguth AP: Caffeine use during pregnancy and child outcome: A 7-year prospective study. Neurotoxicology and Teratology 13:441, 1991

289. MRC Vitamin Study Research Group: Prevention of neural tube defects: results of the medical research council vitamin study. Lancet 338:131, 1991

290. Hale F: Pigs born without eye balls. J Hered 24:105, 1933

291. Wilson JG, Roth CB, Warkany J: An analysis of the syndrome of malformations induced by vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92: 189, 1953

292. Giroud A, Tuchmann-Duplessis H: Malformations congenitales. Role des facteurs exogenes. Pathol Biol 10:119, 1962

293. Geelen JA: Hypervitaminosis: an induced teratogenesis. Crit Rev Toxicol 6:351, 1979

294. Rosa FW, Wilk AL, Kelsey FO: Vitamin A congeners. In Sever JL, Brent RL (eds): Teratogen Update: Environ-mentally Induced Birth Defect Risks. New York, Alan R. Liss, 1986

295. Wagner LK, Hayman LA: Pregnancy and women radiologists. Radiology 145:559, 1982

296. Ericson HA, Källén AJ: Hospitalization for miscarriage and delivery outcome among Swedish nurses working in operating rooms 1973-1978. Anesth Analg 64:981, 1985

297. Källén B, Malmquist G, Mortiz U: Delivery outcome among physiotherapists: Is non-ionizing radiation a fetal hazard? Arch Environ Health 37:81, 1982

298. Ericson A, Källén B: An epidemiological study of work with video screen and pregnancy outcome. Am J Indust Med 9:447, 1986

299. Spaeth GL, Nelson LB, Beaudoin AR: Ocular teratology. In Jakobiec FA (ed): Ocular Anatomy, Embryology and Teratology, p 963. Philadelphia, Harper and Row, 1982