Hormonal Agents
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. Recent studies, however, have failed to demonstrate a significant relationship between congenital anomalies and first-trimester use of oral contraceptive agents or medroxyprogesterone acetate.
Anticoagulants
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 fetuses exposed during the first trimester. Abnormalities characteristic of warfarin include hypoplastic nose, epiphyseal stippling, optic atrophy, microcephaly, IUGR, and other central nervous system anomalies. Heparin and low-molecular-weight heparin are not associated with an increased frequency of congenital anomalies.
Antithyroid Drugs
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 may develop scalp defects, but this association is rare. Thyroid replacement therapy (ie, thyroxine) does not cross the placenta and is not associated with congenital anomalies, fetal abnormalities, or neonatal abnormalities.
Anticonvulsants
Each of the commonly used anticonvulsant medications has been implicated as teratogenic, but there is no clear consensus concerning which one has the most teratogenic potential. 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 the incidence of cleft lip or cleft palate and congenital heart disease. Mild to moderate mental retardation is observed in two thirds of children who have the most severe malformations associated with the syndrome. The syndrome was recently linked to lowered maternal epoxide hydrolase activity, an enzyme involved in the metabolism of hydantoin.
Drugs and Chemicals Associated with Birth Defects
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 exposure. A syndrome including V-shaped eyebrows, low-set ears, high arched palate, and irregular dentition was identified.
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