Teratogenic Effects of Antiepileptic Drugs: Use of an International Database on Malformations and Drug Exposure (MADRE)

Abstract

Summary:Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations.Methods: Information on all malformed infants (1990)(1991)(1992)(1993)(1994)(1995)(1996) with maternal first-trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries.Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation 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 been reported associated with AEDs or for which the association was suggested by case reports. Key Words: Antiepileptic drugs-Teratogenesis- Malformation registries-Risk factorsThe assessment of the teratogenic effects of antiepileptic drugs (AEDs) through epidemiological studies has often provided conflicting results (1-5). Cohort studies are limited by the low incidence of congenital malformations and thus reach adequate power only if a large multicenter approach is adopted. On the other hand, case-control studies on birth defects usually select Accepted June 1, 2000. Address correspondence and reprint requests to Prof. Pierpaolo Mastroiacovo at International Centre for Birth Defects, via Pilo Albertelli 9, 00195 Roma, Italy. E-mail: icbd@icbd.org healthy infants as controls, and there is a major risk of recall bias (i.e., the quality of the information given by the mothers regarding exposures during pregnancy differs between cases and controls). A registry-based system represents a relatively simple and inexpensive way of gathering information on intrauterine drug exposure in a large number of malformed infants (6). The use of controls presenting with malformations other than the malformation under study may reduce the recall bias and thus the overestimation of the effect.The main objective of our study was to test the effe...

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes [RETIRED]

“…Therefore, three studies used in answering these questions [7][8][9] include the offspring of mothers who took AEDs for various indications.…”

Unilateral multicystic dysplastic kidney in infants exposed to antiepileptic drugs during pregnancy

“…There could be genetic differences in the prevalence of people with low activity of epoxide hydrolase, which may explain the different rates of CBZ-induced congenital anomalies. Among urogenital defects, the association between AED therapy during pregnancy and hypospadia has been reported [13]. There is less evidence about kidney involvement (hydronephrosis, renal dysplasia) [14] and prenatal AED exposure.…”

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

“…This is a critical period when fusion of embryonic processes forming the upper lip and palate takes place. Studies have shown a positive association between formation of cleft lip/palate and maternal medication, 6 maternal smoking, 7 and alcohol use. 8 Moreover, maternal infection, 9 and folic acid deficiency 10 may also contribute to orofacial malformations.…”