Chapter 39 Ocular Teratology KERSTIN STRÖMLAND and MARILYN MILLER Table Of Contents |
DEFINITION, PRINCIPLES, AND HISTORY EXPERIMENTAL APPROACH CLINICAL METHODS IN INVESTIGATION OF OPHTHALMIC TERATOLOGY HUMAN OCULAR TERATOGENS THERAPY?PREVENTION! REFERENCES |
DEFINITION, PRINCIPLES, AND HISTORY | ||
Teratology is the science that deals with causes, mechanisms, and manifestations
of structural or functional developmental deviations.1 A teratogenic agent is a drug, chemical, virus, physical agent, or deficiency
of which activation during the embryonic or fetal period alters
morphology or subsequent function in the postnatal period.2 It also can be defined by its ability to produce a congenital defect. 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:
|
EXPERIMENTAL APPROACH | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Comparative studies in animal and human embryology are of basic importance
in the detection of teratogens affecting humans. Developmental timetables
are getting more sophisticated (Tables 1 and 2) and indicate early interference by toxic agents (often so early that
many women may not yet be aware of their pregnancy).
TABLE ONE. Sequence of Human Ocular Development
TABLE TWO. Sequence of Mouse Ocular Development
* Note that the early postnatal period in species born with fused eyelids corresponds to the third trimester in the human.
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.
Atomic weapons; radioiodine; therapeutic Infections Cytomegalovirus; herpesvirus hominis ? I and II; parvovirus B-19 (erythema
infectiosum); rubella virus; syphilis; toxoplasmosis; Venezuelan equine
encephalitis virus Maternal metabolic imbalance Alcoholism; cretinism (endemic); diabetes; folic acid deficiency (following
gastric bypass surgery); hyperthermia; phenylketonuria; rheumatic
disease and congenital heart block; virilizing tumors Drugs and environmental chemicals Aminopterin and methylaminopterin; androgenic hormones; busulfan; chlorobiphenyls; coumarin
anticoagulants; cyclophosphamide; diethylstilbestrol
Binge drinking; carbamazepine; cigarette smoking; cocaine; disulfiram; folic
acid deficiency; high vitamin A intake; lead; primidone; streptomycin; toluene
abuse; varicella virus; zinc deficiency Unlikely 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 (Shepard TH: Catalog of Teratogenic Agents, 6th ed. Baltimore, Johns Hopkins University Press, 1989)
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 monkeys35,36 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 A43–45 during the same period of gestation, further emphasizing this critical gestational period for development of the eye. |
CLINICAL METHODS IN INVESTIGATION OF OPHTHALMIC TERATOLOGY |
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. |
HUMAN OCULAR TERATOGENS | |||||||
Several factors in the extrauterine and intrauterine environments of the
embryo and fetus influence the unborn child. In this section we focus
on teratogens with certified effects on the eyes. Most reports of a
single exposure or a few similar exposures have been omitted. Most recognized
human teratogens, such as intrauterine infections and drugs, act
indirectly through the mother's placenta, while a few, such as
radiation, act directly on the embryo and fetus (see Table 3). 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 France114,115 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 determined12,13 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 Zimmerman260,261 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 defects290,291 ; 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. |
THERAPY?PREVENTION! |
The best therapy against congenital malformations is prevention. Spaeth
and co-workers gave some useful advice to women considering pregnancy: “Avoid
all medications, drugs (including cigarettes and alcohol), and
radiation; be immunized against rubella prior to pregnancy; maintain
good general health; avoid vitamin deficiencies or excesses; pick
a mate carefully, being certain to avoid relatives; and become pregnant
between the ages of 20 and 28.”299 Gregg, in his initial report of children with rubella embryopathy in 1941,5 discussed the prognosis and stressed that the only sure treatment available
is that of prophylaxis. He suggested that “in all prenatal
clinics and maternity hospitals very careful histories should be taken
and recorded of exposure of the mother to infection of any kind during
the entire period of pregnancy.” 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. |