MATERNAL USE OF ANTIEPILEPTIC DRUGS AND THE RISK OF MAJOR CONGENITAL-MALFORMATIONS - A JOINT EUROPEAN PROSPECTIVE-STUDY OF HUMAN TERATOGENESIS ASSOCIATED WITH MATERNAL EPILEPSY

Purpose: To quantify the risks of intrauterine antiepileptic drug (AED ) exposure in monotherapy and polytherapy. Methods: Data from five pro spective European studies totaling 1,379 children were pooled and rean alyzed. Data were available for 1,221 children exposed to AED during p regnancy and for 158 children of unexposed control pregnancies. Result s: Overall, when comparing a subgroup of 192 children exposed to AED w ith 158 children of matched nonepileptic controls, there was an increa sed risk of major congenital malformations (MCA) in children exposed t o AED during gestation [relative risk (RR) 2.3; 95% confidence interva l (CI): 1.2-4.7]. A significant increase in risk was found for childre n exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepi ne (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing dif ferent AED regimens during all 1,221 pregnancies, risks of MCA were si gnificantly increased for the combination of phenobarbital (PB) and et hosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin , PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers u sing >1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed less tha n or equal to 600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 m g/day and less than or equal to 600 mg/day. Conclusions: This reanalys is shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based stud ies are needed to evaluate the risks of many other less frequently pre scribed treatment regimens, including newly marketed AEDs.