BENZODIAZEPINE AMPLIFICATION OF VALPROATE TERATOGENIC EFFECTS IN CHILDREN OF MOTHERS WITH ABSENCE EPILEPSY

Valproate (VPA) is one of the most frequently used antiepileptic drugs (AEDs). Concern has recently been raised regarding VPA medication dur ing pregnancy and teratogenic effects in the offspring. Both neural tu be defects (5, 18, 34) and a constellation of signs termed the fetal v alproate syndrome (1, 12) have been reported. Benzodiazepines (BZDs) a re also widely used and sometimes as effective adjunctives in AED ther apy. Both VPA and BZD have close connections to GABA transmission. Rec ently, clinical and epidemiological human studies (26, 27, 37, 39), su pported by animal studies (17, 24, 40), have indicated that BZDs may a ct as human teratogens. We report on 7 children with congenital malfor mations, dysmorphism and abnormal neurological signs from birth. The m others had well controlled primary generalized absence epilepsy withou t major seizures during pregnancy. Five children had been exposed to V PA monotherapy and two children to VPA and BZD combined during the fir st trimester. Those two infants had myelomeningoceles and the most pro nounced dysmorphism in the group. We propose that these observations i ndicate a possible amplifying action of BZDs on VPA teratogenicity. Un recognized BZD use during pregnancies exposed to VPA may be of importa nce when estimating the teratogenic risks of VPA therapy.