Behavioral Teratology of Antiepileptic Drugs

Pizzi, William

Abstract

In the United States, it is estimated that approximately 18,000 children are born to women with diagnosed epilepsy each year (Vorhees, 1987a). These women are regularly treated with a wide variety of antiepileptic drugs (AED's). Concern about the effects AED's may exert on the developing fetus have been reported in the literature for over 20 years, and today it is generally accepted that some, if not most, of the AED's put the fetus and the offspring at an increased risk for teratological outcome and developmental problems (Hanson, 1986 for recent review). It is currently estimated that AED's result in 1,100 - 2,200 birth defects per year in the U.S.A. If one adds the estimated incidence of behavioral teratology, as many as 5,000 children per year may be affected in the U.S.A. alone. The studies proposed here will attempt to validate an animal model of the Fetal Anticonvulsant Therapy Syndrome (FACTS). As was the case with the Fetal Alcohol Syndrome, an animal model of FACTS would constitute strong evidence that anticonvulsants are capable of inducing behavioral deficits independent of an epileptic disorder. Further, several widely used anticonvulsants will be screened for their safety in treating pregnant women and the subsequent effects on their offspring. This step is important since the physician needs all the information possible in selecting the safest and most efficacious drug for use in pregnant epileptic women. Four AED's will be screened at two dose levels calculated to produce circulating Blood levels within the human therapeutic range and at approximately 1.5 times the high end of the therapeutic range. Standard reproduction and behavioral teratology screens, along with selected experiments aimed at elucidating the mechanisms underlying the deficits will be carried out.