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Updated: Jul 10, 2026
Modifying Levels of Maternal Dietary Folic Acid or Choline to Study the Impact of Deficiencies on Offspring Health Outcomes
Published on: June 28, 2024
Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control
D Kjaer1, E Horvath-Puhó, J Christensen
1The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, Aarhus, Denmark.
Insights
Folic acid supplementation during early pregnancy may reduce, but not eliminate, the risk of congenital abnormalities in offspring exposed to certain antiepileptic drugs. Further research is needed to confirm these findings on drug safety in pregnancy.
Area of Science:
- Obstetrics and Gynecology
- Pharmacology
- Pediatrics
Background:
- Maternal use of antiepileptic drugs like carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and primidone (PRI) is associated with an increased risk of congenital abnormalities.
- Folic acid supplementation is recommended during pregnancy, but its effect on modifying this association is not fully understood.
Purpose of the Study:
- To determine if folic acid supplementation in early pregnancy alters the risk of congenital abnormalities in infants born to mothers using CBZ, PB, PHT, or PRI.
- To investigate the protective role of folic acid against antiepileptic drug-induced teratogenicity.
Main Methods:
- A population-based case-control study utilizing data from the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) between 1980-1996.
- Involved analysis of 20,792 cases with congenital abnormalities and 38,151 controls, examining maternal drug exposure (CBZ, PB, PHT, PRI) and folic acid use during 5-12 weeks from the last menstrual period.
Main Results:
- Children exposed to antiepileptic drugs (AEDs) without folic acid supplementation had an odds ratio of 1.47 for congenital abnormalities compared to unexposed children.
- Children exposed to AEDs with folic acid supplementation showed a reduced odds ratio of 1.27, indicating a potential protective effect, though not statistically significant in this study.
Conclusions:
- Folic acid supplementation during early pregnancy appears to reduce, but not completely eliminate, the risk of congenital abnormalities associated with maternal use of specific antiepileptic drugs.
- The study highlights the need for further research with larger sample sizes to confirm these findings due to the rarity of the exposures and limited statistical precision.
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.
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