Main Article Content

Koby Brosh
Ilan Matok
Eyal Sheiner
Gideon Koren
Arnon Wiznitzer
Rafael Gorodischer
Amalia Levy


Antiepileptic medications, folic acid antagonists, birth defects, monotherapy, polytherapy, valproic acid, phenobarbital



To investigate the potential impact of exposure to anti epileptic medications during the first-trimester of pregnancy on major malformations.


Study Design

A retrospective cohort study comparing all pregnancies of women with and without exposure to antiepileptic medications during pregnancy was performed. A computerized database of medications dispensed from 1998 to 2008 to all women registered in the "Clalit" health maintenance organization, was linked with computerized and non computerized databases containing maternal and infant hospitalization records from the district hospital. Exposed women were further analyzed by mono and poly- antiepileptic therapy during pregnancy. Stratified analyses, using multiple logistic regression models were performed to control for confounders.



During the study period 99,724 deliveries and 1012 pregnancy terminations occurred; of those, 421 (0.42%) were exposed to one or more antiepileptic medications during the first trimester. A higher rate of major congenital malformations was detected among women who were exposed, as compared to those unexposed to antiepileptic medications during the first trimester (10.0% vs. 7.0%; P=0.02). The association remained significant after adjusting for maternal age, ethnicity, smoking, diabetes and parity (adjusted OR= 1.50; 95% CI 1.06-2.12; p=0.02). Specifically, the risk was significant for antiepileptic anti folate drugs (n=210; adjusted OR= 1.95; 95% CI 1.25-3.03; P=0.003). Poly-antiepileptic therapy was significantly associated with major congenital malformations (26.5% vs. 5.7%, P<0.001). Using a multiple logistic regression model, controlling for ethnicity, diabetes, smoking, maternal age and parity, poly-antiepileptic therapy was an independent risk factor for major congenital malformations (adjusted OR= 7.98; 95% CI 3.4-18.7; P<0.001), while mono-therapy lost its independent association with major congenital malformations (adjusted OR= 1.23; 95% CI 0.8-1.8; P=0.28).



First-trimester exposure to antiepileptic medications is an independent risk factor for major congenital malformations. The risk is significantly higher for anti folate antiepileptic drugs and for poly-antiepileptic therapy.

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