Maternal Use of Antiepileptic Drugs and the Risk of Major Congenital Malformations: A Joint European Prospective Study of Human Teratogenesis Associated with Maternal Epilepsy
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Summary: Purpose: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and poly‐therapy. Methods : Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. Results : Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2–4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6–15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3–18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4–67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1–57.6). Offspring of mothers using > 1,000 mg VPNday were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed ≥600 mg VPNday (RR 6.8; 95% CI: 1.4–32.7). No difference in risk of MCA was found between the offspring exposed to 601–1,000 mg/day and ≥600 mg/day. Conclusions : This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population‐based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.
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AED use during pregnancy is associated with adverse neurodevelopment outcomes in children.
“AED use during pregnancy is associated with risks to the fetus as these drugs can cross the placenta or may be transferred to the infant through breast feeding and may be associated with adverse neurodevelopment outcomes.2–4”
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- Authors
- Samrén, E. B., van Duijn, C. M., Koch, S., Hiilesmaa, V. K., Klepel, H., Bardy, A. H., Mannagetta, G. B., Deichl, A. W., Gaily, E., Granström, I. L., Meinardi, H., Grobbee, D. E., Hofman, A., Janz, D., & Lindhout, D.
- Affiliations
- Erasmus MC (NL)
- Helsinki University Hospital (FI)
- University Hospital Magdeburg (DE)
- University of Helsinki (FI)
- Stichting Epilepsie Instellingen Nederland (NL)
- Corresponding author
- Lindhout, D.
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 1997-09
- Volume
- 38
- Issue
- 9
- Pages
- 981-990
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W2143268844
- Cited by
- 406
- References
- 46
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 22 · 2014: 16 · 2013: 17 · 2012: 16
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Sanofi
- Deutsche Forschungsgemeinschaft
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Keywords
- antiepileptic drugs, major congenital malformations, maternal epilepsy, valproic acid, carbamazepine, phenytoin, phenobarbital, ethosuximide, polypharmacy, monotherapy, neural tube defects, prenatal drug exposure, dose-response relationship, pregnancy outcomes
- MeSH terms
- Abnormalities, Drug-Induced, Adolescent, Adult, Anticonvulsants, Dose-Response Relationship, Drug, Drug Therapy, Combination, Epilepsy, Female, Humans, Infant, Newborn, Male, Maternal-Fetal Exchange, Middle Aged, Pregnancy, Pregnancy Complications, Prospective Studies, Risk Factors, Cohort Studies, Multicenter Studies as Topic
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