Verification of the fetal valproate syndrome phenotype

Valproic acid (VPA) is a relatively new anticonvulsant, having been approved for use in the United States in 1978. The main indication for its use is in treatment of absence seizures although it has been used in a variety of seizure disorders, often in combination with other anticonvulsants. Although VPA, as a carboxylic acid, is structurally unrelated to other kinds of anticonvulsant drugs, prenatal exposure to it, like other prenatal anticonvulsant exposures, has been associated with congenital malformations in laboratory animals [Brown et al., 1980; Kao et al., 1981: Diaz and Shields, 1981; Bruckner et al., 1983; Paulson et al., 19851. VPA is known to cross the human placenta and is present in higher concentration in the infant than in the mother [Dickinson et al., 1979; Nau et al., 19811. Single case reports of birth defects occurring in offspring of women taking VPA during pregnancy have been published since 1980 suggesting that VPA might have teratogenic properties in humans as well [Dalens et al., 1980; Gomez, 1981; Thomas and Buchanan, 1981; Clay et al., 1981; Stanley and Chambers, 1982: Bailey et al., 1983; Blaw and Woody, 1983; Bantz, 1984: Garden et al., 1985; Tein and MacGregor, 19851. In September, 1982, utilizing data from the Birth Defects Surveillance Program in Lyon, France, for the years 1976 and 1978-1982, Robert and Guibaud [ 19821 reported that an unusually high proportion of infants with spina bifida were born to women with epilepsy treated with VPA. Further analysis of these data [Robert et al., 19841 and data from other birth defect registries [Bjerkedal et al., 1982; CDC, 19821 has confirmed this association and has led to an estimated risk of spina bifida of 1-2% in children of women using VPA during pregnancy. The risk is similar to the recurrence risk