Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations

Arch Neurol. 2011 Oct;68(10):1275-81. doi: 10.1001/archneurol.2011.133. Epub 2011 Jun 13.


Objective: To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy.

Design: A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews.

Setting: United States and Canada.

Patients: A total of 6857 pregnant women taking an AED for any reason.

Main outcome measures: Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs).

Results: The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results.

Conclusions: The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology*
  • Abnormalities, Drug-Induced / etiology*
  • Anticonvulsants / adverse effects*
  • Canada / epidemiology
  • Carbamazepine / adverse effects
  • Cohort Studies
  • Drug Therapy, Combination / adverse effects
  • Epilepsy / drug therapy
  • Female
  • Humans
  • Infant, Newborn
  • International Cooperation
  • Lamotrigine
  • Pregnancy
  • Pregnancy Complications
  • Pregnancy Trimester, First / drug effects
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / epidemiology*
  • Prospective Studies
  • Reference Values
  • Retrospective Studies
  • Triazines / adverse effects
  • United States / epidemiology


  • Anticonvulsants
  • Triazines
  • Carbamazepine
  • Lamotrigine