A recent evidence-based review of prospective cohort studies of major congenital malformations (MCMs) after exposure to antiepileptic drugs (AEDs) concluded that intrauterine, first-trimester exposure to valproic acid (VPA) is highly likely to increase the risk for MCMs compared with use of either no AED or a few other individual AEDs (JW Womens Health June 11 2009). However, associations with specific MCMs were statistically limited by the designs of the studies. Now, researchers have employed a reverse approach, using the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, a population-based registry of congenital anomalies from 14 countries.

Using data from eight published cohort studies of outcomes after first-trimester valproic acid exposure, the investigators identified 14 MCMs that occurred at a greater frequency in these studies than in the EUROCAT reference group (3.8 million pregnancies). Then, the investigators used the EUROCAT antiepileptic-study database to conduct a case-control study to test their hypotheses. They compared the odds of exposure to VPA monotherapy among cases (for each of the 14 MCMs) with the odds in two control groups (a group with MCMs other than those under study and a group with chromosomal abnormalities).

Pregnancies involving spina bifida had an adjusted odds ratio (OR) of 12.7 for VPA exposure versus no AED exposure and an OR of 5.7 for VPA exposure versus exposure to other-AED monotherapy. Five other MCMs — atrial septal defect, cleft palate, hypospadias, polydactyly, and craniosynostosis — had significantly higher adjusted ORs for VPA exposure versus no AED exposure (range, 2.2 to 6.8). In an analysis of the adjusted OR for VPA monotherapy versus monotherapy with another AED, the findings were almost identical, except that craniosynostosis was no longer significantly associated with VPA exposure, but ventricular septal defect was.

Comment: The consistently higher risk for MCMs with VPA, echoed throughout several pregnancy studies around the world and now supported by a different methodological approach, is remarkable. This study more clearly identifies which MCMs are likely to occur with the use of VPA. These findings further underscore the message that, by choosing to prescribe any AED other than VPA, the clinician is likely lowering the risk for some MCMs in current and future pregnancies. Avoiding VPA use should be a guiding principle when treating adolescent girls and women with epilepsy.

— Page B. Pennell, MD

Dr. Pennell is Director of Research for the Division of Epilepsy and Sleep, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston.

Published in Journal Watch Neurology July 13, 2010