Teratogenic effects of antiepileptic drugs: Use of an international database on malformations and drug exposure (MADRE)

Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants wi th malformations. Methods: Information on all malformed infants (1990-1996) with maternal fir st-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as i nfants presenting with a specific malformation, and controls were defined a s infants presenting with any other birth defect. Exposure was defined by t he use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios w ith 95% confidence intervals and testing their homogeneity among registries . Results: Among 8005 cases of malformations, 299 infants were exposed in ute ro to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbit al, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs, Associations were found for spina bifi da with valproic acid. Infants exposed to phenobarbital and to methylphenob arbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic a cid, and carbamazepine. Hypospadias was associated with valproic acid. Pore ncephaly and other specified anomalies of brain, anomalies of face, coarcta tion of aorta, and limb reduction defects were found to be associated with valproic acid. Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never be en reported associated with AEDs or for which the association was suggested by case reports.