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Teratogenic Agents

Major congenital anomalies occur in about 3% of all births. Maternal exposure to drugs or environmental chemicals may be responsible for 4-6% of these anomalies, or approximately 1 in 400 liveborn infants.

Whether birth defects occur in a conceptus exposed to a potentially teratogenic agent depends in large part on two factors: 1) gestational timing of the exposure and 2) the genetic makeup of the conceptus and the mother. Morphogenetic stage of the organism's development is a key factor in susceptibility to a potential teratogen. Exposure to a teratogenic agent during organogenesis may result in a gross defect involving the organ undergoing formation at that time. Conversely, exposure to such an agent during histogenesis may produce finer structural defects within the target organ system. Substantial evidence suggests that, second only to the gestational timing of exposure, the most important variable is difference in the genetically determined activity of the enzymes involved in the metabolism of drugs and chemicals. This difference is termed pharmacogenetic variation. An important determinant of teratogenic potential is mode of exposure. The teratogenic agent may reach the developing embryo or fetus either by direct passage through maternal tissues (eg, ionizing radiation) or by placental transfer (eg, drugs or chemicals) teratogen, teratagen, teratogenic, birth defects, birth injury, medicine, chemical, fetus.

Drugs and Chemicals


Danazol and other androgenic hormone agents may produce clitoral enlargement or labioscrotal fusion in the female fetus when they are given before 13 weeks of gestation. Studies have failed to demonstrate a significant relationship between congenital anomalies and first-trimester use of oral contraceptive agents or medroxyprogesterone acetate.


Warfarin and other coumarin-derived anticoagulants inhibit the synthesis of vitamin K-dependent coagulation factors, and use during gestation can produce major and minor congenital anomalies in as many as 25% of


Thyroid medications such as propylthiouracil, methimazole, and iodide cross the placenta and may occasionally produce transient fetal hypothyroidism and goiter. Infants exposed to methimazole in utero also


Each of the commonly used anticonvulsant medications has been implicated as teratogenic. Diphenylhydantoin may produce a syndrome characterized by abnormal facies, microcephaly, growth deficiency, mental retardation, and hypoplastic nails and distal phalanges in as many as 10% of exposed offspring. However, as many as 30% of exposed newborns may demonstrate some aspects of the syndrome. Intrauterine exposure to diphenylhydantoin is also associated with a three- to fourfold increase in

Both valproic acid and carbamazepine have been associated with NTDs. Exposure during embryogenesis poses approximately a 1% risk of spina bifida to exposed fetuses. Specific syndromes have been described.

Trimethadione and paramethadione have been associated with abnormalities similar to those observed with the hydantoins. The risk for congenital anomalies or spontaneous abortion is 60-80% with first-trimester


Lithium may produce malformations in 1% of offspring exposed prenatally. The anomalies frequently involve the heart and great vessels, with Ebstein's anomaly of the tricuspid valve being observed most


The synthetic estrogen diethylstilbestrol produces structural defects of the genital tract, as well as reproductive problems in prenatally exposed females. Vaginal adenosis has been detected in more than


Isotretinoin. The vitamin A isomer isotretinoin is a potent teratogen, with serious congenital anomalies reported among approximately 35% of exposed fetuses. The specific congenital anomalies observed after oral administration of isotretinoin during early pregnancy include heart disease, thymic agenesis, microphthalmia, hydrocephalus, microtia, cleft palate, deafness and blindness, and an increased risk of

Tretinoin. Topical tretinoin does not result in an increased risk of congenital anomalies because skin metabolizes the drug and no detectable systemic concentrations result.

Etretinate. Etretinate is an oral agent used to treat psoriasis. Case reports link the use of this agent to birth defects similar to those observed after the use of isotretinoin during pregnancy. Unlike vitamin A and its congeners, etretinate has been detected in serum of patients at therapeutic levels for as long as 7 years

High-Dose Vitamin A. The Centers for Disease Control and Prevention recently evaluated the use of vitamin A during pregnancy. Daily supplementation with 5,000 IU of vitamin A should be considered the maximum

Occupational and Environmental Agents

Pregnant women may be occupationally or environmentally exposed to a variety of chemicals that are associated with poor reproductive outcomes, including spontaneous abortion, low birth weight, neurologic abnormalities, and congenital anomalies. These chemicals include methyl mercury, lead, polychlorinated biphenyls, polybrominated biphenyls, and organic solvents. Verified human teratogens in this class of agents

Ionizing Radiation

Embryonic or fetal radiation exposure usually results from diagnostic radiologic studies. Diagnostic radiation usually exposes the conceptus to less than 5 cGy (5 rads), depending on the number of radiographs taken

Thyrotoxic (therapeutic) radioisotope (131I) exposure is considerably more hazardous to the fetus than diagnostic studies that use iodine I 121. The fetal thyroid is not susceptible to radioisotope damage before 9-11 weeks of gestation. Dosimetry calculations should be made by experienced professionals, and risks

Social and Illicit Drugs


Maternal alcohol ingestion during pregnancy may result in a recognizable pattern of congenital anomalies known as fetal alcohol syndrome. Fetal alcohol syndrome features include prenatal and postnatal growth restriction, characteristic facial anomalies (ie, short palpebral fissures, microphthalmia, indistinct or absent philtrum, thin upper lip, midfacial hypoplasia), microcephaly, joint contractures, and cardiac defects. Fetal

It is difficult to correlate the amount of alcohol consumed to the risk of fetal alcohol syndrome. Among pregnant women who consume four or more drinks per day during pregnancy, the risk for fetal alcohol syndrome may be as high as 20%, with risks increasing to perhaps 40% with six drinks per day. Women


Smoking tobacco poses a threat to reproductive function and pregnancy outcome in women. The prevalence of smoking among adults has decreased from approximately 40% in 1965 to approximately 25% in the

The pregnant smoker may be at increased risk for the spontaneous abortion of an otherwise normal fetus, fetal death associated with placental abruption or placenta previa, preterm delivery, and PROM. A dose-response relationship has been shown between the amount of maternal smoking and reduced birth


Marijuana, the most frequently used illicit drug, has been associated with poor perinatal outcome in some studies but not in others. It is particularly difficult to identify the effects of a single illicit drug on perinatal outcome because the lifestyle associated with the use of any illicit drug usually includes co-use of other drugs (ie, tobacco, alcohol, other psychoactive drugs).


Cocaine (street names "coke," "snow" "lady") use is a major public health concern. Use of cocaine in the 1970s was primarily limited to the intranasal route. In the 1980s, a decrease in the street cost and wider availability of cocaine resulted in an increasing prevalence of intravenous and smoked ("free-base" or "crack") routes of use. Consequently, the prevalence of cocaine-associated medical complications has increased

The drug is metabolized primarily by plasma and hepatic cholinesterases to water-soluble metabolites (benzoylecgonine and ecgonine methyl ester). The most commonly used urine test detects benzoylecgonine at a sensitivity of 300 ng/mL. The elimination half-life of the parent drug is approximately 4-5 hours. Cocaine metabolites can be detected in urine for 24-48 hours. Pharmacokinetics of perinatal cocaine use are poorly


Maternal use of heroin, methadone, methamphetamine, or phencyclidine may produce a neonatal withdrawal syndrome characterized by increased muscle tone, tremors, and a high-pitched cry. The teratogenicity of lysergic acid diethylamide (LSD) has been suggested, but no conclusive evidence exists at present. It is important to note that lysergide analogues, even those...