Antiepileptic drug regimens and major congenital abnormalities in the offspring

To assess the risk of major congenital abnormalities associated with specif ic antiepileptic drug regimens, a large retrospective cohort study was perf ormed. The study comprised 1,411 children born between 1972 and 1992 in fou r provinces in the Netherlands who were born to mothers with epilepsy and u sing antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of m ajor congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose-response relationship for valproate. T he risk of major congenital abnormalities was nonsignificantly increased fo r phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoi n monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination wit h other antiepileptic drugs, showed a significantly increased relative risk Furthermore, there were significantly increased relative risks for the com bination of carbamazepine and valproate and the combination of phenobarbita l and caffeine with other antiepileptic drugs. This study shows that most a ntiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose-re sponse relationship) and carbamazepine monotherapy, benzodiazepines in poly therapy, and caffeine comedication in combinations with phenobarbital.