The DOI matches its Crossref record; 45 of the 46 references it cites were found in a registry or an index.
Maternal Use of Antiepileptic Drugs and the Risk of Major Congenital Malformations: A Joint European Prospective Study of Human Teratogenesis Associated with Maternal Epilepsy
Open accessAbstract
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 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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Cites
MATERNAL VALPROIC ACID AND CONGENITAL NEURAL TUBE DEFECTS
Robert, E., & Guibaud, P. (1982) · The Lancet · doi:10.1016/s0140-6736(82)90908-4 · Cited by 537
Nearly ubiquitous tissue distribution of the scrapie agent precursor protein
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Spina Bifida in Infants of Women Treated with Carbamazepine during Pregnancy
Rosa, F. W. (1991) · New England Journal of Medicine · doi:10.1056/nejm199103073241006 · Cited by 457
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IN-UTERO EXPOSURE TO VALPROATE AND NEURAL TUBE DEFECTS
Lindhout, D., & Schmidt, D. (1986) · The Lancet · doi:10.1016/s0140-6736(86)91711-3 · Cited by 300
Self-citationNatural History of Lactic Acidosis after Grand-Mal Seizures
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ANTICONVULSANTS AND PARENTAL EPILEPSY IN THE DEVELOPMENT OF BIRTH DEFECTS
Shapiro, S., Hartz, S. C., Siskind, V., Mitchell, A. A., Slone, D., Rosenberg, L. A., Monson, R. R., Heinonen, O. P., Idänpään-Heikkilä, J. J., Häró, S., et al. (1976) · The Lancet · doi:10.1016/s0140-6736(76)91403-3 · Cited by 270
The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort.
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Self-citationANTICONVULSANTS AND PARENTAL EPILEPSY IN THE DEVELOPMENT OF BIRTH DEFECTS
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Self-citation
Research works printed but not linked: 4
- Hiilesmaa VK., 1982, A prospective study on maternal and fetal outcome in 139 women with epilepsy. Academic dissertation
- Klepel H, 1986, Untersuchungen zum pranatalen Wachsurn von Kindern anfallskranker Mutter, Psychiatr Neurol Med Psycho1, 38, 55
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Items 401–403 of 403
Age-Related Counseling Requirements for Women with Epilepsy
Zweig, L., Kelly, K., & Puntambekar, P. (2026) · Journal of Women s Health · doi:10.1177/15409996261429028
Therapeutic Drug Monitoring Considerations in Pregnancy
Krasowski, M. D. (2026) · Clinics in Laboratory Medicine · doi:10.1016/j.cll.2026.07.001
Metadata
- 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 › Clinical Neurology › 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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