Teratology: Principles and Practice

Medical Problems in Pregnancy

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Teratology: Principles and Practice

Jeffrey M. Dicke, MD*

Teratology is the study of abnormal fetal development. As a science, teratology dates from the mid-twentieth century with the recognition that environmental factors can cause congenital malformations. Initially, it remained an isolated discipline because there was little relevance of teratological study to clinical medicine. Furthermore, the inability to diagnose and treat congenital malformations and the proportionately greater morbidity and mortality from infectious diseases combined to discourage a broad interest in teratology. The advent of the thalidomide tragedy in the early 1960s stimulated an intense search for the etiology, prevention, and treatment of congenital malformations, fueled largely by the concern of regulatory agencies, lawyers, and the public. Traditionally limited to gross structural malformations, current concepts of teratology have been expanded to include more subtle developmental anomalies such as intrauterine growth retardation, behavioral aberrations, demise, and other functional deficiencies. As such, teratology today is a discipline of special relevance to those involved in the care of the gravid female. The term "teratogen" derives from the Greek terata meaning monster. 41 In light of the expanded definition of teratology, a teratogen is any substance, organism, physical agent, or deficiency state present during embryonic or fetal life capable of inducing abnormal postnatal structure or function. The relevance of teratology derives from the fact that in the United States congenital malformations, low birth weight, and sudden infant death syndrome-in that order-are the leading causes of infant mortality, accounting for over one half of infant deaths as well as reduced life-expectancy in survivors. 71 Two to 4 per cent of live born infants have major structural abnormalities of which one third to one half will require medical and/or surgical therapy.27 If follow-up over a number of years is included, as many as 10 per cent of all children are felt to demonstrate stigmata of abnormal development. 71 In addition to the personal trauma of such aberrations, there

*Assistant Professor,

Department of Obstetrics and Gynecology, Washington University School of Medicine, JeWish Hospital, St. Louis, Missouri

Medical Clinics of North America-Vo!' 73, No. 3, May 1989

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is a substantial societal cost in the form of special education, facilities, and reduced productivity. Despite their significance, the etiology of congenital malformations is unknown in an estimated 65 to 70 per cent of all cases. Of the remaining, hereditable disorders, including those transmitted in Mendelian fashion, account for 15 to 20 per cent while chromosome disorders contribute an additional 5 per cent. The perception of the public notwithstanding, environmental factors, such as drug exposures, congenital infections, and maternal systemic disorders, are presumed to be responsible for less than 10 per cent of human malformations detected during the first year of life. 8 Malformations resulting from gene or chromosome abnormalities are determined prior to differentiation and, although they may be modified by environmental factors, the genetic pathology is the major determinant of the developmental defect. In contrast, the effects of environmental teratogens are determined by several factors that illustrate the principles of teratogenesis as described by Wilson. 104 1. The maternal-fetal genotype: Fetal susceptibility to a potential teratogen is influenced by maternal absorption, metabolism and distribution, placental transfer, and fetal metabolism-characteristics unique to each maternal-fetal pair as a result of genetic heterogeneity. The clinical relevance of this phenomenon is that for the same teratogen some individuals will prove especially susceptible whereas others will be unusually resistant. 2. The developmental stage at the time of exposure: The timing of teratogenic exposure is critical with respect to subsequent fetal effects; three stages of development are generally acknowledged: (1) from fertilization through early postimplantation (days 11 to 12 post-conception), the embryo is relatively resistant to teratogenic insults due to the totipotential nature of cells at this stage. Because the fate of early embryonic cells is not irrevocably determined, if one cell is destroyed another can resume its function. Exposures at this stage are thus thought to be allor-none in effect-that is either embryo-lethal or without demonstrable organ-specific abnormalities; (2) days 18 to 60 post-conception are when the majority of human embryonic development occurs and this represents the period of maximum susceptibility to teratogens; specific structural defects are most easily induced during this time. Finally, (3) following the period of organ differentiation, further development is characterized by an increase in organ size. Fetal growth retardation, unaccompanied by visible malformations, is a hallmark of second and third trimester teratogen exposure. 3. Dose-response relationships: Manifestations of aberrant development may range from no effect at low doses, to organ-specific malformations at intermediate doses, and to embryo-fetal toxicity at high doses. These phenomenona are influenced by the stage of development, route of administration, and species. 4. Specificity of agent: Adverse environmental influences on developing tissues depend on the agent involved. Some agents have greater teratogenic potential than others due in part to factors such as dosage, maternal metabolism, and placental transfer. 5. Drug interactions: Two teratogens administered simultaneously may not have the same effect as when either is administered individually; possible mechanisms include induction or inhibition of enzyme systems and competition for binding sites that could influence levels of unbound and active teratogen.

Although the phenotypic effects of teratogen exposure may be readily apparent, the exact means by which such insults pervert normal structure and

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function remain ill-defined. Proposed mechanisms of teratogenesis include gene mutation, chromosome breaks and nondisjunction, mitotic interference, altered nucleic acid integrity or function, lack of precursors, substrates or coenzymes for biosynthesis, altered energy sources, changes in membrane characteristics, enzyme inhibition, and osmolar imbalance. lOoS Regardless of the specific mechanism(s) involved or their manifestations, the ultimate result is an organ with too few cells. The critical mass necessary for organ differentiation is lacking, resulting in disturbed development. By virtue of its unique location and architecture, the placenta is the ultimate arbiter of nutrient and xenobiotic transfer from mother to fetus. As an organ of fetal origin, the placenta ideally functions on behalf of the fetus to enhance growth and development while preventing or limiting pejorative environmental exposures. However, the concept of the placenta as a selective barrier, while appealing, is imperfect. Although it possesses the ability to modify xenobiotic transfer through metabolism and binding, the issue is not if a given drug will traverse the placenta, but rather, the kinetics of transfer and subsequent distribution in the fetus. Placental drug transfer is influenced by a variety of factors including molecular weight, lipid solubility, degree of ionization, and spatial configuration. Drugs having a molecular weight less than 400 readily cross the placenta; the larger the size, the more importance other factors assume. Mechanisms of placental transport include simple diffusion, facilitated diffusion, active transport, and pinocytosis. Most drugs are transported via simple diffusion down an electrochemical gradient with the result that the placenta is relatively impermeable to poorly lipid soluble and highly ionized drugs, such as turbocurarine. Such obstruction to transfer is seldom absolute however, in that most drugs-if present in high concentrations for a prolonged period of time-will manage passage to the fetus. Drugs are rarely transported via facilitated diffusion or active transport unless bearing a structural resemblance to compounds so handled by the placenta. For example, drugs containing amino acids that are similar in configuration to essential amino acids, may utilize the same active transport carrier mechanisms. Such is the case for alpha-methyldopa which may achieve higher fetal than maternal concentrations. 94 Other relevant factors whose ultimate influence on placental drug transfer remains to be determined include the progressive placental structural changes associated with advancing gestation. The placenta is known to decrease in thickness and increase in surface area as it matures, although such changes are not invariably associated with an increased permeability to drugs. Another consideration is placental drug biotransformation potential. In vitro studies involving human placental homogenates suggest it possesses both oxidation and reduction capabilities, although the ultimate drug biotransformation potential of the placenta in vivo is poorly defined. 73 Finally, there is the net effect of uterine blood flow. Although the rate of placental drug transfer is known to be heavily influenced by uteroplacental blood flow, precise estimates of normal baseline uterine blood flow are lacking as are the effects of various maternal and fetal conditions, such as hypertension, diabetes, and hypoxia. Under these circumstances, uterine blood flow is

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known to be decreased albeit the effect of such reductions on drug transfer is unknown. Just as our understanding of the rate and mechanism of placental drug transport is incomplete, our knowledge of drug effects on the fetus is imprecise owing to the relative paucity of specific information regarding drug distribution, metabolism, and excretion in the fetus. However, certain relevant data have been gleaned from animal and human studies. Drugs crossing the placenta commonly achieve fetal levels that are 50 to 100 per cent those in maternal serum. Certain agents including local anesthetics and diazepam ultimately reach fetal levels that exceed those in the mother.64 In assessing potential drug effects on the fetus, the total exposure to a drug and its metabolites is more significant than the ease with which it crosses the placenta. Unlike brief exposures, chronic drug ingestion can potentially affect fetal cell growth during stages of both early (hyperplasia) and later (hypertrophy) ,development. 2.5 Normal fetal growth and development is characterized by a number of changes in body composition affecting drug distribution. The preterm fetus contains less fat and more extracellular water than its term counterpart, thereby enlarging the volume of distribution of many drugs. Other changes influencing the amount of unbound drug in the fetus include decreased drug binding to maternal plasma proteins during pregnancy as well as less binding to fetal than to neonatal plasma proteins. Following transfer across the placenta, 20 to 40 per cent of umbilical blood flow bypasses the fetal liver being shunted directly to the inferior vena cava via the ductus venosus. This means that a significant percentage of any drug crossing the placenta has access to the fetal heart and brain undiluted by the portal circulation and prior to potential metabolism by the fetal liver. Unlike nonprimate species which lack drug-metabolizing potential until late in gestation, enzymes capable of oxidation have been demonstrated in human fetal liver during the first trimester.78 In contrast to the adult, however, there is evidence to suggest the fetal adrenal gland may be a more important site of drug metabolism; it is an active site of steroid biotransformations, contains drug-metabolizing enzymes having higher specific activities than in the liver, and is proportionately much larger in size than in the adult. 94 While most fetal waste products, including drugs and their metabolites, are eliminated via the placenta, other excretory routes also exist that may retard drug disappearance rate. Conjugated compounds excreted by the fetal kidney may be reabsorbed by the fetal intestine, the net effect of such recirculation being prolonged fetal exposure. Having reviewed pertinent aspects of teratology, placental drug transfer, and fetal drug distribution, some of the more commonly known teratogens are discussed below.

ALCOHOL Widely consumed as a drug of predilection, ethyl alcohol consumption in pregnancy has been associated with a spectrum of structural and neurologic

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defects. The fetal alcohol syndrome (F AS) consists of intra- and extrauterine growth retardation, central nervous system dysfunction, including mental retardation and developmental delay, and midline facial defects such as maxillary hypoplasia, micrognathia, cleft lip or palate, and epicanthal folds among others ..5 ] Accurate risk assessment is problematic in that unreliable estimations of dose, duration, and exposure to other recreational drugs influence the risk and type of congenital malformations observed. In women consuming a minimum of 2 to 2.5 oz of absolute alcohol (4 to 5 drinks) per day, the risk of affected offspring is estimated to be 40 per cent. The risk associated with lesser consumption is not clearly defined, although ingestion of as little as 1 oz of alcohol (2 drinks) per day has been related to a reduction in birth weight. 19 Moderate drinking, defined as more than 1 oz of absolute alcohol twice per week, has also been associated with a two- to fourfold increased risk of second trimester spontaneous abortions. 52 Alcohol's mechanism of teratogenesis is unclear but is thought to involve a direct cytotoxic effect of alcohol and potentially, its metabolite, acetaldehyde,19 in addition to the indirect effects of genetic susceptibility and environmental factors such as poor nutrition. Despite sporadic reports indicating paternal alcoholism increases the risk for poor pregnancy outcome, this association has not been confirmed by larger epidemiologic studies. J03 Ethanol achieves levels in breast milk similar to those in maternal serum. 106 At a maternal concentration of 100 mg per dl (a biochemical definition of intoxication), the infant is exposed on a mg per kg basis to the equivalent of one quarter of an alcoholic beverage. While this amount is not normally associated with adverse effects on the infant, J08 higher concentrations could be expected to result in sedation. Excess maternal consumption has also been associated with inhibition of the milk-ejection reflex. 17 Considering the relatively low potential for newborn toxicity with moderate maternal consumption, the American Academy of Pediatrics does not consider ethanol use a contraindication to breast-feeding. 18 ANTICOAGULANTS Coumarin derivatives (warfarin, dicumarol, phenindione) cause decreased synthesis of the vitamin K-dependent clotting factors 11, VII, IX, and X and also interfere with protein-binding of calcium. This interference with calcium binding is thought to be responsible for the principal features of warfarin embryopathy, which include nasal hypoplasia due to the lack of development of the nasal septum and calcific stippling of the epiphyses. 7 Other features that have been reported include growth and developmental retardation, scoliosis, deafness, and congenital heart disease. 37 Fetal coumarin exposure between 6 and 9 weeks has been associated with as high as a 25 per cent risk for such abnormalities. 1 Maternal therapy with these agents during the second and third trimesters has been associated with eye anomalies, hydrocephaly, and other central nervous system defects. Exposure during this time also results in a higher-than-expected incidence of spontaneous abortions, stillbirth, and neonatal hemorrhage. 37 Unlike other known or suspected human teratogens, these agents have not been shown to be

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teratogenic in laboratory animals. 8 In studies involving limited numbers of lactating women,56 warfarin was not detected in breast milk and is not considered a contraindication to breast-feeding in normal term infants. Phenindione, however, does cross into breast milk and has been associated with an increased risk for neonatal hemorrhage. It is, therefore, not recommended for use in breast-feeding women. 18 Because of their potential fetal toxicity throughout gestation, pregnancy is currently considered a contraindication to the use of coumarin derivatives. ANTICONVULSANTS Phenytoin (Dilantin) is a hydantoin antiepileptic commonly used for the treatment of tonic-clonic and psychomotor seizures. Although it has been well-documented that the progeny of epileptic women treated with anticonvulsant medications have a two- to threefold increased risk for congenital anomalies,68 assignment of teratogenic potential under these circumstances is problematic due to a number of confounding variables. Epilepsy and anomalies may be interrelated, as suggested by the finding that epileptics and their relatives have higher-than-expected incidence of anomalies. 99 In another study of children with facial clefts, there were three times the predicted number of of epileptics among their parents. 30 There is also evidence to suggest that the children of epileptic fathers have a greater-thanexpected number of birth defects. 90 A further consideration is the potential effect of seizure-related hypoxia and acidosis on the developing embryofetus. Such factors notwithstanding, there is substantial evidence supporting the human teratogenic potential of phenytoin. The fetal hydantoin syndrome (FRS), as described by Ranson, includes intra- and extrauterine growth retardation, mental impairment, congenital heart lesions, facial dysmorphisms (cleft lip and/or palate, low set ears, depressed nasal bridge, and short nose among others), hernias, and limb anomalies. 39 While all of the above are relatively nonspecific malformations, distal digital and nail hypoplasias are more unusual malformations considered peculiar to phenytoin. 7 Although some published estimates indicate that as many as 10 per cent of exposed infants manifest the full syndrome with approximately 30 per cent displaying some features,38 other studies have demonstrated a much lower or no increased risk of birth defects relative to phenytoin use. 20 .9J The teratogenic potential of phenytoin is thought to be related to the production of arene oxides, unstable metabolites theoretically capable of inducing cell death or mutation by covalently binding cell micromolecules. These compounds are metabolized by the enzyme epoxide hydrolase, which is normally present in low concentrations in the fetus. The variability in the quantity of enzyme actually present, a function of genetic heterogeneity, could be expected to influence the effects of phenytoin on the individual fetus. 98 In addition to the structural abnormalities, other serious potential complications attributable to maternal phenytoin therapy include an increased risk for childhood neuroectodermal tumors and neonatal coagulopathy. Nine cases of tumors including neuroblastoma, mesencyoma, ganglioneuroblas-

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toma, and ependyoma have been reported in antenatally exposed children. 2 ,74,89 While a small number in absolute terms and lacking a control population, this is a substantially larger number than would be expected by chance based on the rarity of these conditions in the general population. Anticonvulsant-associated coagulopathy has been reported to occur in approximately one half of all neonates exposed to phenytoin in utero and is secondary to a deficiency of vitamin K-dependent clotting factors.66 Intramuscular vitamin K (AquaMEPHYTON) administration will usually prevent this complication. If cord blood clotting studies are markedly abnormal, additional vitamin K and factor replacement therapy may also be necessary. Phenytoin is excreted in breast milk, achieving levels one quarter to one third those in maternal serum. 63 Because such concentrations have not been associated with clinical effects in the neonate, phenytoin therapy is not a contraindication to breast-feeding. 6.3 Valproic acid (Depakene) is indicated for the treatment of simple and complex absence seizures. It crosses the placenta, with levels in cord serum at term I. I to 4.6 times those in maternal serum. 31 This is thought to be a result of drug displacement from maternal proteins by free fatty acids and more avid binding in the fetal compartment. A fetal valproate syndrome has been described, many features of which are similar to the fetal hydantoin syndrome. 22 Of special relevance to the use of this agent, however, are multiple reports linking its use in the first trimester with an increased risk for neural tube defects. The Centers for Disease Control currently estimates the risk for spina bifida in the offspring of exposed women to be I to 2 per cent. 13 This is similar to that for an unexposed woman who has had a previous child with a neural tube defect. If at an appropriate stage in gestation (15 to 20 weeks), exposed women should be offered alpha-fetoprotein screening and fetal ultrasound evaluation. Valproic acid has been detected in breast milk in small amounts unassociated with clinical effects in the newborn. Therefore, it is considered compatible with breast-feeding. IS Trimethadione and paramethadion are oxazolidinedione anticonvulsants used for the treatment of petit mal epilepsy. They are uniformly distributed throughout the body and affect the vitamin K-dependent clotting factors and cell membrane permeability. Although experience with their use in pregnancy is limited, it has been associated with a fetal trimethadione syndrome consisting of developmental delay, mental impairment, and craniofacial abnormalities (low set ears, palate defects, and V-shaped eyebrows among others). 109 There are reports of several families in which maternal therapy resulted in multiple affected infants or spontaneous abortions, while discontinuation of treatment subsequently resulted in consecutive normal children. 29 ,32 Owing to the limited number of documented exposures, estimates of risk vary but are substantial, ranging between 60 to 80 per cent for malformations or pregnancy loss with first trimester exposure. I Because their teratogenic potential is greater than other anticonvulsants, use of these agents is contraindicated in pregnancy. ANTINEOPLASTICS Aminopterin is an antimetabolite similar in structure to methotrexate by which it has been replaced. A variety of malformations have been reported

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secondary to its use as an abortifacient including hydrocephaly, cleft palate, meningomyelocele, and cranial abnormalities. 33 Second and third trimester exposures are unassociated wtih congenital malformations. fi9 Methotrexate is the methylderivative of aminopterin, a folate antagonist. Such compounds inhibit dihydrofolate reductase causing cell death during the S phase of the cycle. 93 Experience with its use in pregnancy is limited, although embryotoxicity is suggested by the report of its use for the resorption of an ectopic gestation. 16 First trimester exposure has been related in three cases to children with multiple, unrelated anomalies,IO·62.77 although there are also cases of unaffected offspring following similar exposures. 21.69.75 An additional consideration is that methotrexate may persist for extended periods in maternal tissues. 14 It is currently not possible to accurately assign the risk associated with first trimester exposure. Gonadal toxicity in adult males and females is suggested by reports of oligospermia and amenorrhea. This is reversible in many cases and there are reports of normal offspring born to men and women following therapy with methotrexate-containing regimens. 26.65 The potential for normal reproduction is thought to be a function of whether adjuvant chemotherapy or radiation is employed. Methotrexate does pass into breast milk in small concentrations, the significance of which is unknown. 50 Since it may potentially accumulate in neonatal tissues, its use is a relative contraindication to breast-feeding.

ANTITHYROID DRUGS The thioureas propylthiouracil (PTU) and methimazole (Tapazole) are the two antithyroid preparations commonly administered to inhibit the excess production of thyroid hormone. PTU, considered by many to be the preferred agent for use during pregnancy, also inhibits the peripheral conversion of thyroxine to the more metabolically active tri-iodothyronine. 85 This agent crosses the placenta and is capable of inducing mild fetal hypothyroidism which usually resolves spontaneously within several days. 15 Approximately 10 per cent of fetuses so exposed develop elevated thyroidstimulating hormone (TSH) levels and compensatory mild enlargement of the thyroid gland. 80 Comparisons between exposed and nonexposed siblings have revealed no differences in physical or intellectual development relative to PTU -related hypothyroidism. l l Because this effect is felt to be at least partially dose-dependent, the minimum effective dose is recommended, especially in the third trimester. PTU is excreted in breast milk albeit in small amounts that have not been associated with changes in neonatal thyroid function. Its use is not considered a contraindication to breast feeding by the American Academy of Pediatrics. 18 Methimazole is also an effective antithyroid agent, although its use in pregnancy is associated with a number of disadvantages compared to PTU. It more readily crosses the placenta, is more slowly metabolized, and does not prevent the peripheral conversion of thyroxin to tri-iodothyronine. 80 Additionally, in utero exposure has been associated with aplasia cutis, a midline ulcer-like scalp defect. 61 Methimazole is also excreted in breast milk

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in amounts potentially capable of causing thyroid dysfunction in the neonate; therefore, its use is not recommended during lactation. ls Radioactive iodine (sodium iodide 1-131) is normally used for the diagnosis and treatment of hyperthyroidism in the nonpregnant state. Its use in pregnancy is contraindicated because it readily crosses the placenta and in millicurie doses can damage or ablate the developing fetal thyroid, which begins to concentrate iodine at 10 to 12 weeks. 92 The relative affinity of the fetal thyroid for iodine is 20 to 50 times that of the maternal thyroid. 10 This leads to a greater concentration of radio iodine per g of tissue in the fetus than in the mother. Of additional concern is the increased radiosenSitivity of fetal versus maternal tissues. 10 In a retrospective review of pregancies in which 1-131 was inadvertently administered during the first or second trimester, six neonates out of 178 live borns were born with congenital liypothyroidism although other structural malformations were not significantly increased. 97 1-131 concentrates in breast milk requiring up to 14 days for elimination and transmission ofI-131 to infants through breast milk has been reported. 70 Therefore, breast-feeding is contraindicated until radioactivity is no longer detected in the milk. 18

DIETHYLSTILBESTROL Diethylstilbestrol (DES) is a potent, synthetic nonsteroidal estrogen. This agent was widely used between 1940 and 1971 for the treatment of various pregnancy complications including threatened spontaneous abortion, premature delivery, intrauterine fetal demise, and pregnancy-induced hypertension. While ineffective for the treatment of these disorders, it was subsequently linked to a variety of reproductive tract anomalies in male and female offspring. One of the first such defects reported was clitoromegaly in female infants following in utero exposure. 9 Twelve years later, in 1971, Herbst described the occurrence of vaginal adenocarcinoma (an otherwise unusual malignancy) in young women whose mothers were treated with DES in the first trimester.46 Data from a registry established for the study of this phenomenon indicate that the risk for malignancy in women exposed to DES in utero, while increased relative to a nonexposed population, remains low and is estimated to be approximately 1 in 700 to 1 in 7000 for women less than 25 years of age. 82 In most reported cases, exposure occurred prior to the 18th week and the tumors were diagnosed after age 14 years. 45 Evidence suggests the risk is unrelated to maternal dose. While the risk of frank malignancy is low, the risk for other female reproquctive tract abnormalities, including uterine cavity malformations, cervical and fallopian tube anomalies, and vaginal adenosis, is estimated to be at least 25 per cent. 49 The risk of vaginal adenosis in particular has been reported to be as high as 75 per cent.7Z Adenosis refers to replacement of the normal squamous epithelium of the vaginal wall with columnar (glandular) epithelium resembling that normally found in the endocervix and endometrium. This may be a result of DES interference with normal differentiation and development of the cervix and vagina. The observation that areas of adenosis are often adjacent to foci of adenocarcinoma lends credence to speculation that the

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carcinogenic potential of DES is indirect, deriving from the presence of misplaced columnar epithelium. Such aberrant tissue is thought to have a greater potential for malignant transformation. While these structural defects of the genital tract appear to have little effect on conception rate,6 it is less clear whether they significantly increase the risk for poor reproductive outcomes such as first and second trimester pregnancy loss and prematurity. 100 Male reproductive tract defects, including epididymal cysts, hypotrophic testes, varicocele, and altered semen, have been described by some while others have found no increase in genitourinary abnormalities over controls. 54 There are no data on the use of DES in breast-feeding women.

ISOTRETINOIN (ACCUTANE) Isotretinoin is an oral vitamin A isomer used for the treatment of chronic cystic acne. Approved for human use in 1982, it is now considered one of the most potent known human teratogens. Major fetal malformations involving the face (absent external ear, malformed skull, cleft palate), central nervous system (micro-hydrocephaly), and cardiovascular system (septal defects, tetralogy of Fallot, transposition) have been documented following in utero exposure to this compound. 28 The incidence of spontaneous abortion is also increased over that expected. 28 The risk for fetal malformations with first trimester exposure is estimated to be 25 per cent.! Discontinuation of isotretinoin early in pregnancy may not necessarily preclude fetal toxicity as it persists in maternal stores with a residual potential for embryopathy over a period of days to weeks. 84 Accordingly, it is the manufacturer's recommendation that two reliable forms of contraception be used simultaneously for at least 1 month before initiation of therapy, during therapy, and for 1 month following discontinuation of therapy. There are no data regarding isotretinoin's excretion into breast milk although the manufacturer suggests that it not be used in lactating women.

LITHIUM Lithium carbonate, commonly used for the treatment of manic depression, readily crosses the placenta with similar maternal and fetal concentrations reported. 78 Case reports documenting the potential fetal effects of this agent led to the establishment of an international registry from which current estimates of fetal toxicity are derived. Of the known malformations associated with first trimester lithium exposure, approximately 75 per cent are cardiovascular in origin with a preponderance of these being E bstein' s anomaly, 4.79 an otherwise rare (spontaneous incidence 1 in 20,000) congenital lesion. The estimated risk of a fetal cardiac defect due to maternal lithium therapy ranges from a low of 2 per cenP to a high of 7 to 8 per cent.47 This compares to a risk of 0.8 per cent in the general population. Such women are candidates for midtrimester ultrasound evaluation of fetal cardiac anatomy. In a study of unaffected exposed children and unexposed siblings, there was no difference in the incidence of physical and neurologic defects. 86 When used near

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term, neonatal toxicity includes hypotonia, cyanosis, cardiac arrhythmias, and disturbances of renal and thyroid function. l ,g6 Most of these effects spontaneously resolve over 7 to 14 days, corresponding to the renal excretion of lithium from the newborn, The serum half-life of lithium in the neonate is extended, averaging 3 to 4 days versus 10 to 20 hours in the adult, 79 Lithium enters breast milk with serum levels in the infant one third to one half those in the mother.88 In that such concentrations are no known risk to the newborn, lithium is not contraindicated in lactating women. 18 METHYLMERCURY The association of motor and mental deficiencies with methylmercury exposure was first noted in 1953 involving the inhabitants of the Japanese fishing village of Minamata. Consumption of fish tainted with methylmercury was followed by an increase in the incidence of cerebral palsy and microcephaly in their offspring. In this population, 6 per cent of live born exposed infants were so affected. 67 Psychomotor retardation and cerebral palsy were also reported in the Iraqi population following consumption of bread prepared from grain treated with a mercurial fungicide. 3 Susceptibility of the developing central nervous system is not limited to the first trimester as cerebral palsy may result from third trimester exposure as well. l In vitro, methylmercury induces cell death by inhibiting red blood cell and lipoprotein enzymes, especially sulfhydryl enzymes,48 Evidence suggests the above effects pertain only to organic mercurials. Inorganic mercury, as might be encountered in dental amalgams and mercurial ointments, does not cross the placenta and has not been reported to have adverse reproductive effects. STREPTOMYCIN Streptomycin is an amino glycoside antibiotic frequently used in combination chemotherapy for tuberculosis. Placental passage has been demonstrated with fetal levels usually less than one half those of the mother. 42 Despite its potential for ototoxicity in the adult, demonstration of similar toxicity in prenatally exposed offspring is unusual. There are isolated case reports of deaf childen born to women treated with streptomycin in pregnancy,57,83 although a number of surveys have revealed the risk of congenital ototoxicity to be minimal. 23,43 Other studies of infants exposed to antituberculosis regimens, including streptomycin, have not revealed an increase in other structural malformations versus normal controls. 58 Streptomycin is present in breast milk in small amounts,107 although the low levels and poor gastrointestinal absorption suggest its potential for neonatal toxicity via this route is small. TETRACYCLINE The tetracyclines are antimicrobials that inhibit bacterial protein synthesis by interfering with transfer ribonucleic acid (RNA) function. These

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agents cross the placenta3 and were at one time routinely prescribed for maternal infections. In 1962, the first report appeared of yellow staining of deciduous teeth in a child exposed to tetracycline in utero. 40 Subsequent investigators described similar abnormalities that are due to the chelation of calcium orthophosphate by tetracycline and the deposition of this complex in bones and teeth when present during periods of calcification. 34 In the fetus, the deciduous (but not permanent) teeth calcify at 5 to 6 months; therefore, use of tetracycline after this time will result in yellow discoloration and fluorescence under ultraviolet light with an intensity proportional to tetracycline dosage. Following years of exposure to light, stained teeth change from yellow to gray to brown. Such changes commonly involve only the deciduous teeth but exposure close to term may also discolor crowns of the permanent teeth. 92 In the reports of children so affected, infant growth and development were normal and tetracycline has not been linked to any major malformations. 43 Fetal bones, which begin calcifying at 2 months, can also incorporate tetracycline. While such. bones are not more susceptible to fracture, in utero exposure has been associated with impaired growth of the fibula in premature infants. 81 Tetracycline passes into breast milk in low concentrations although serum levels in exposed infants are undetectable. 76 Its use is therefore not a contraindication to breast-feeding. (j

THALIDOMIDE The most infamous of known human teratogens, thalidomide was widely used as a sedative in other countries but never approved for use in the United States. The first report of thalidomide-induced phocomelia appeared in 196J59 and it was ultimately linked to over 5000 cases in West Germany as well as others worldwide. Subsequent analysis has revealed that induction of limb defects was confined to a critical period of no more than 14 days between the 22nd and 36th days of gestation. Exposures at 27 to 30 days were associated with upper extremity defects and those at 30 to 33 days with both upper and lower extremity abnormalities. 60 Associated malformations included facial hem angioma, esophageal-du~denal atresia, deafness, and cardiovascular and renal abnormalities. 60 Anomalies were reported in approximately 20 per cent of the offspring exposed during the critical period, some to as little as a single dose. 92 Despite the precise timing and characteristic nature of the defects induced, the mechanism of action of thalidomide remains unclear. Theories have included changes in the peripheral nerves of affected limbs,60 metabolite toxicity, and inhibition of the normal interaction between nephric tissue and mesenchymal tissue necessary for normal limb development. 53 An additional finding obscuring the nature of thalidomide embryopathy is the marked variability in species susceptibility. In contradistinction to the obvious sensitivity of humans, monkeys,5 and rabbits, 10i the mouse and rat were found to be relatively insensitive to its teratogenic potential. 12

SUMMARY Gross anomalies of structure and/or function affect 2 to 4 per cent of all human newborns and are the leading cause of perinatal mortality in this

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country. Despite their significance, the etiology of most such defects remains unclear. A majority are unassociated with any identifiable cause; a small but significant percentage are attributed to heritable disorders of either a Mendelian (single gene) or chromosomal nature. Drugs and environmental exposures are currently implicated in only a small percentage of affected pregnancies. Nevertheless, an awareness of the principles of teratogenesis, an appreciation for the role-though imprecise-of placental transfer and fetal drug disposition, and avoidance of known teratogens currently offers our best hope for the study and prevention of birth defects.

REFERENCES 1. ACOG Technical Bulletin: Teratology. Number 84, February 1985 2. Alien RW, Ogden B, Bentley FL, et al: Fetal hydantoin syndrome, neuroblastoma, and hemorrhagic disease in a neonate. JAMA 244:1464, 1980 3. Amin-Zaki L, Elhassana S, Majeed MS, et al: Intra-uterine methylmercury poisoning in Iraq. Pediatrics 54:587, 1974 4. Arnon RG, Marin-Garcia J, Peeden IN: Tricuspid valve regurgitation and lithium carbonate toxicity in a newborn infant. Am J Dis Child 135:941, 1981 5. Axelrod LR: Advances in Teratology. New York, Academic Press, 1970, p 217 6. Barnes AB, Colton T, Gundersen J, et al: Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. N Engl J Med 302:609, 1980 7. Barr M, Pozanski AK, Schmickel RD: Digital hypoplasia and anticonvulsants during gestation, a teratogenic syndrome. J Pediatr 4:254, 1974 8. Brent RL: The complexities of solving human malformations. Clin Perinatol 13:491, 1986 9. Bongiovanni AM, DiGeorge AM, Grumbach MM: Masculinization of the female infant associated with estrogenic therapy alone during gestation: Four cases. J Clin Endocrinol Metab 19:1004, 1959 10. Burrow GN: Medical Complications During Pregnancy. Philadelphia, WB Saunders, 1988, p 243 11. Burrow GN, Klatskin EH, Jenel M: Intellectual development in children whose mothers received propylthiouracil during pregnancy. Yale J Bioi Med 51:151, 1978 12. Cahen RL: Experimental and clinical chemoteratogenesis. Adv Pharmacol 4:263, 1966 13. Centers for Disease Control: Valproate: A new cause for birth defects-report from Italy and follow-up from France. MMWR 32:438, 1983 14. Charache S, Condit PT, Humphreys SR: Studies on the folic acid vitamins. IV. The persistence of amethopterin in mammalian tissues. Cancer 13:236, 1960 15. Cheron RG, Kaplan MN, Larsen PR, et al: Neonatal thyroid function after propylthiouracil therapy for maternal Graves' disease. N Engl J }'led 304:52.5, 1981 16. Chotiner HC: Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstet Gynecol 66:740, 198.5 17. Cobo E: Effect of different doses of ethanol on the milk-ejecting reflex in lactating women. Am J Obstet Gynecol 11.5:817, 1973 18. Committee on Drugs, American Academy of Pediatrics: The transfer of drugs and other chemicals into human breast milk. Pediatrics 72:37.5, 1983 19. Council on Scientific Affairs, American Medical Association: Fetal effects on maternal alcohol use. JAMA 249:2.517, 1983 20. Dalessio DJ: Current concepts: Seizure disorders in pregnancy. N Engl J Med 312:559, 198.5 21. Dara P, Slater LM, Armentrout SA: Successful pregnancy during chemotherapy for acute leukemia. Cancer 47:84.5, 1981 22. DiLiberti JH, Farndon PA, Dennis NR, et al: The fetal valproate syndrome. Am J Med Genet 19:473, 1984 23. Donald PR, Sellars SL: Streptomycin ototoxicity in the unborn child. S Afr Med J 60:316, 1981

580

JEFFREY

M.

DICKE

24. Edmunds LD, Layde PM, James LM, et al: Congenital malformations surveillance: Two American systems. Int J Epidemiol 10:247, 1981 25. Enesco M, Lebond CP: Increase in cell number as a factor in the growth of the organs and tissues of thc young male rat. J Embryol Exp Morphol 10:.530, 1962 26. Evenson DP, Arlin Z, Welt S, et al: Male reproductivc capacity may recover following drug treatment with L-lO protocol for acute lymphocytic leukemia. Cancer 53:30, 1984 27. Fabro SE: Clinical Obstetrics. New York, John Wiley & Sons, 1987, p 317 28. FDA Drug Bulletin: Update on birth defects with isotretinoin. 14:15, 1984 29. Feldman GL, Weaver DD, Lovrien EW: The fetal trimethadione syndrome. Am J Dis Child 131:1389, 1977 30. Friis ML: Epilepsy among parents of children with facial clefts. Epilepsia 20:69, 1979 3l. Froescher W, Gugler R, Niesen M, et al: Protein binding of valproic acid in maternal and umbilical cord serum. Epilepsia 25:244, 1984 32. German J, Ehlers KH, Kowal A, et al: Possiblc teratogenicity of trimethadione and paramcthadione. Lancet 2:261, 1970 33. Goetsch C: An evaluation of aminopterin as an abortifacient. Am J Obstet GyneeoI83:1474, 1962 34. Golbus MS: Teratology for the obstetrician: Current status. Obstet Gynecol 55:269, 1980 35. Gordon GB, Spielberg SP, Lake DA, et al: Thalidomide teratogenesis: Evidence for a toxic arenen oxide metabolite. Proc Natl Acad Sci 78:2545, 1981 36. Guilbeau JA, Schoenbach EG, Schaub IC, et al: Aureomycin in obstetrics: Therapy and prophylaxis. JAMA 143:520, 1950 37. Hall JE, Pauli RM, Wilson KM: Maternal and fetal sequelae of anti-coagulation during pregnancy. Am J Med 68:122, 1980 38. Hanson JW, Myrianthopoulos NC, Sedgwick MA, et al: Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. J Pediatr 89:662, 1976 39. Hanson JW, Smith DW: The fetal hydantoin syndrome. J Pediatr 87:285, 197.5 40. Harcourt JK, Johnson NW, Storey E: In vivo incorporation of tetracycline in the teeth of man. Arch Oral Bioi 7:4.31, 1962 4l. Hays DP: Teratogenesis: A review of the basic principles with a discussion of selected agents: Part 1. Drug Intell Clin Pharm 15:444, 1981 42. Heilman D, Heilman F, Hinshaw H, et al: Streptomycin: Absorption, diffusion, excretion and toxicity. Am J Med Sci 210:.576, 1945 43. Heinonen OP, Sloane D, Shapiro S: Birth Defects and Drugs in Pregnancy. Littieton, Publishing Sciences Group, 1977, p 297 44. Herbst AL, Cole P, Colton T, et al: Age incidence and risk of DES-related clear cell adenocarcinoma. Am J Obstet Gynecol 128:4.3, 1977 45. Herbst AL, Postkanzer DC, Robboy SJ, et al: Prenatal exposure to stilbestrol: A prospective comparison of exposed female offspring with unexposed controls. N Engl J Med 292:334, 1975 46. Herbst AL, Ulfelder H, Postkanzer DC: Adenocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearancc in young women. N Engl J Med 284:878, 1971 47. Hoffman JIE, Christianson R: Congenital heart disease in a cohort of 19,502 births with long term follow-up. Am J Cardiol 42:641, 1978 48. Hughes WL: A physiochemical rationale for the biological activity of mercury and its compounds. Ann NY Acad Sci 65:454, 1957 49. Jefferies JA, Robboy SJ, O'Brien PC, et al: Structural anomalies of the cervix and vagina in women enrolled in the diethylstilbestrol adenosis (DESAD) project. Am J Obstet Gynecol 148:59, 1984 50. Johns DG, Rutherford LD, Keighton PC, et al: Secretion of methotrexate into human milk. Am J Obstet Gynecol 112:978, 1972 51. Jones KL, Smith DW, Ulleland CN, et al: Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1: 1267, 1973 52. Kline J, Shrout P, Stein Z, et al: Drinking during pregnancy and spontaneous abortion. Lancet 2: 176, 1980 53. Lash JW, Saxen L: Human teratogenesis: In vitro studies on thalidomide-inhibited chondrogenesis. Dev Bioi 28:61, 1972

TER'
581

54, Leary FJ, Ressequi LI, Kurland LT, et al: Males exposed in utero to diethylstilbestrol. JAMA 252:2984, 1984 55, Lenz W, Knapp K: Thalidomide embryopathy. Arch Environ Health 5:100, 1962 56, L'E Orme M, Lcwis PJ, DeSwiet M, et al: May mothers given warfarin breast-feed their infants? Br '>fed J 1:1564, 1977 57, Lerox ML: Existe-t-il une surdite congcnitale aC'luise due a la streptomycine? Am Otolaryngol 67:194, 1950 58, '>1arynowski A, Sianozecka E: Comparison of the incidence of congenital malformations in neonates from healthy mothers and from patients treated because of tuberculosis, Ginekol Pol 43:713, 1972 59, McBride WG: Thalidomide and congenital abnormalities, Lancet 2:1358, 1961 60, McBride WG: Thalidomide embryopathy, Teratology 16:79, 1977 61. Milharn S, Elledge W: Maternal methimazole and congenital defects in children, Teratology 5:125, 1972 62, Milunsky A, Graef JW, Gaynor MF: '>1ethotrexate-induced congenital malformations, J Pediatr 72:790, 1968 63, Mirkin BL: Diphenylhydantoin: Placental transport, fetal localization, neonatal metabolism, and possible teratogenic effects, J Pediatr 78:329, 1971 64, Mirkin BL, Singh S: Perinatal Pharmacology and Therapeutics, New York, Academic Press, 1976, p 30 65, Moe pJ, Lethinen M, Wegelius R, et al: Progeny of survivors of acute lymphocytic leukemia, Acta Paediatr Scand 68:301, 1979 66, Mountain KR, Hirsh J, Gallus AS: Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy, Lancet 1:26.5, 1970 67, Murakami U: Advances in Experimental Medicine and Biology, New York, Plenum Press, 1972, p 301 68, N akane Y, Okuma T, Takahashi R, et al: Multi-institutional study on the teratogenicity and fetal toxicity of anti epileptic drugs: A report of a collaborative study group in Japan, Epilepsia 21:663, 1980 69, Nicholson HO: Cytotoxic drugs in pregnancy: review of reported cases, J Obstet Gynaecol Br Commonw 75:307, 1968 70, Nurnberger CE, Lipscomb A: Transmission of radioiodine (1-131) to infants through human maternal milk. JAMA 1.50:1398, 1952 71. Oakley GP: Frequency of human congenital malformations. Clin Perinatol 13:54.5, 1986 72. O'Brien PC, Noller KL, Robboy SJ, et al: Vaginal epithelial changes in young women enrolled in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. Obstet Gynecol .53:300, 1979 73, Pelkonen 0, Moilanen ML: The specificity and multiplicity of human placental xenobioticmetabolizing monoxygenase system studied by potential substrates, inhibitors, and gel electrophoresis, Med Bioi .57:306, 1979 74. Pendergrass TW, Hanson JW: Fetal hydantoin syndrome in neuroblastoma. Lancet 2:1.50, 1976 75. Pizzuto J, Aviles A, Noriega L, et al: Treatment of acute leukemia during pregnancy: Presentation of nine cases. Cancer Treat Rep 64:679, 1980 76, Posner AC, Prigot A, KonicoffNG: Antibiotics Annual. New York, Medical Encyclopedia, 1954-55, p 345 77. Powell HR, Ekert H: Methotrexate-induced congenital malformations. Med J Aust 2:1076, 1971 78. Rane A, Tomson G: Prenatal and neonatal drug metabolism in man. Eur J Clin Pharmacol 18:9, 1980 79. Rane A, Tomson G, Bjarke B: Effects of maternal lithium therapy in newborn infant. J Pediatr 93:296, 1978 80, Rayburn WF, McNulty RM, O'Shaughnessy RW: Drug Therapy in Obstetrics and Gynecology, Norwalk, CT, Appleton-Century-Crofts, 1986, p 103 81. Rendle-Short TJ: Tetracyclinc in teeth and bone, Lancet 1:118, 1962 82. Robboy SI, Noller KL, Kaufman RH, et al: Information for physicians. Prenatal diethylstilbestrol (DES) exposure: Recommendations of the diethylstilbestrol-adenosis (DESAD) project for the identification and management of exposed individuals. NIH Publication No. 81-2049, 1981

582

JEFFREY

\1.

DICKE

83. Robinson GC, Cambon KG: I-Iearing loss in infants with tuberculous mothers trcated with streptomycin during pregnancy. N Engl J ~1ed 271:949, 1964 84. Hosa FW: Retinoic acid embryopathy. N Engl J Mcd 315:262. 1986 85. Saberi M. Sterling FH, Utiger HD: Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man. J Clin Invest 55:218, 1975 86. Schou M: What happened later to the lithium babies? A follow-up study of children born without malformations. Acta Psychiatr Scand .54:193, 1976 87. Schou M, Amdisen A: Lithium and placenta. Am J Obstet Gynecol 122:541, 1975 88. Schou M, Amdisen A: Lithium in pregnancy. Ill. Lithium ingestion by children hreastfed by women on lithium treatment. Br Med J 2:138, 1973 89. Seeler RA, Israel IN, Royal JE, et al: Ganglioneuroblastoma and fetal hydantoin-alcohol syndromes. Pediatrics 63:524, 1979 90. Shapiro S, Hartz SC, Siskind V, et al: Anticonvulsants and parental epilcpsy in the development of birth defects. Lancet 1:272, 1976 91. Shapiro S, Slone D, Hartz SC, et al: Are hydantoins (phenytoins) human tcratogcns? J Pediatr 90:673, 1977 92. Shepard TH: Catalog of Teratogenic Agents. Baltimore, The Johns Hopkins University Press, 1986, p 324 93. Skipper HT, Schabel FM: Cancer Medicine. Philadelphia, Lca & Febiger, 1973, p 629 94. Sonawane BR, Yaffee SJ: Drug and Chemical Action in Pregnancy: Pharmacologic and toxicologic principles. New York, Marcel Dekker, 1986, p 103 95. Stenchever MA, Williamson RA, Leonard J, et al: Possible relationship between in utero diethylstilbestrol exposure and male fertility. Am J Obstet Gynecol 140:186, 1981 96. Stevens D, Burman D, Midwinter A: Transplacental lithium poisoning. Lancet 2:59.5, 1974 97. Stoffer SS, Amburger JI: Inadvertent 1-131 therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 17:146, 1976 98. Strickler SM, Dansky LV, Miller .vIA, et al: Genetic predisposition to phenytoin-induced birth defects. Lancet 2:746, 1985 99. Stumpf DA, Frost M: Seizures, anticonvulsants, and pregnancy. Am J Dis Child 132;746, 1978 100. Veridiano NP, Delke I, Rogers J, et al: Reproductive performance of DES-exposed female progeny. Obstet Gynecol 58:58, 1981 101. Vickers TH: Concerning the morphogenesis of thalidomide dysmelia in rabbits. Br J Exp Pathol 48:579, 1967 102. Warkany J: Teratogenicity of folic acid antagonists. Cancer Bull 33:76, 1981 103. Warner HH, Rosett HO: The effects of drinking on offspring. J Stud Alcohol 36:1395, 1975 104. Wilson JG: Handbook of Teratology. New York, Plenum Press, 1977, p 47 105. Wilson JG: Mechanisms of teratogenesis. Am J Anat 136:129, 1973 106. Wilson JT: Drugs in Breast Milk. Ncw York, ADIS Press, 1971, p 110 107. Wilson JT: Drugs in Breast Milk. Balgowlah, Australia, ADIS Press, 1981, p 79 108. Wilson JT, Brown RD, Chcrek DR, et al: Drug excretion in human breast milk. Principles, pharmacokinetics and projected consequences. Clin Pharmacol 5:1, 1980 109. Zackae EH, Mellman WJ, Neiderer B, et al: The fetal trimethadione syndrome. J Pediatr 87:280, 1975 Department of Obstetrics and Gynecology Washington University School of Medicine Jewish Hospital 216 S. Kingshighway St. Louis, MO 63110