Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case–control study


Dr D Kjær, The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark. Email


Objective  To investigate whether folic acid supplementation in early pregnancy modifies the association between the prevalence of congenital abnormalities in the offspring and maternal use of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and primidone (PRI).

Design  A population-based case–control study.

Setting  The Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA) (1980–1996) and its information on children from the Hungarian Congenital Abnormality Registry and the Hungarian National Birth Registry.

Population  Children with congenital abnormalities (cases; n= 20 792, of whom 148 had been exposed to antiepileptic drugs [AEDs]) and unaffected children (controls; n= 38 151, of whom 184 had been exposed to AEDs).

Methods  Information on drug exposure and background variables for the mothers were collected from antenatal logbooks, discharge summaries, and structured questionnaires completed by the mothers at the time of HCCSCA registration.

Main outcome measures  Congenital abnormalities detected at termination of pregnancy, at birth or until 3 months of age according to CBZ, PB, PHT, or PRI exposure at 5–12 weeks from first day of the last menstrual period (LMP), stratified by folic acid supplementation.

Results  Compared with children unexposed to AEDs and folic acid, the odds ratio of congenital abnormalities was 1.47 (95% CI 1.13–1.90) in children exposed to AEDs without folic acid supplementation and 1.27 (95% CI 0.85–1.89) for children exposed to AEDs with folic acid supplementation.

Conclusion  The results indicate that the risk of congenital abnormalities in children exposed in utero to CBZ, PB, PHT, and PRI is reduced but not eliminated by folic acid supplementation at 5–12 weeks from LMP. The statistical precision in our study is limited due to rarity of the exposures, and further studies are needed.