DELAYED TERATOGENIC EXPRESSION OF ANTICONVULSANTS

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While the target for drugs administered during pregnancy is the mother, the fetus often becomes an unwanted recipient. The great danger with drugs administered during pregnancy relates to the fact that what is non-toxic and therapeutic to the mother may be a powerful teratogen in the fetus. It has been shown that drugs taken during pregnancy may act as teratogens producing structural malformations in the fetus. Many drugs also can produce more subtle biochemical and physiological teratogenic defects in the fetus. While these may be "delayed" defects that are not apparent at birth or even during childhood, they are both longterm and permanent defects. Almost by definition, teratogenic induced defects in reproductive function can be defined as delayed or "latent" birth defects. While reprodductive capabilities are not exhibited until adulthood, they are under the control of the hypothalamic-pituitery-gonadal axis which is sensitive to the teratogenic effects of drugs during the critical period of sexual differentiation. The fact that 0.3 to 0.5 percent of pregnant women are epileptic and are therefore likely recipients of anticonvulsants raises important concerns about possible teratological effects of the therapy. Because of their CNS actions, we have proposed that anticonvulsants can disrupt normal differentiation of the neuroendocrine axis and thus become likely teratogenic candidates capable of producing longterm reproductive abnormalities. We have proposed to test the hypothesis that commonly used anticonvulsants administered after the period of organogenesis can produce latent and permanent biochemical birth defects in sexual differentiation and reproduction. By exposing fetuses during the last few days of gestation to therapeutic-like doses of the most often prescribed anticonvulsants for pregnant women, neonates, infants and young children, i.e., diazepam, phenytoin, carbamazepine, valproic acid, etc., we shall determine whether early treatment with some or all of these agents exposes developing mammals to the risks of sexual and reproductive birth defects. Furthermore, by describing the reproductive and hormonal effects of the drugs, we may gain some biochemical insights into the longterm teratogenic consequences of prenatal exposure to anticonvulsants.