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28-06-2011 | Article

Specific antiepileptic drug risks determine polytherapy effect on birth defects


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MedWire News: The risk for birth defects associated with prenatal exposure to a combination of antiepileptic drugs is determined by the risks associated with each individual drug, a large registry study shows.

Relative to monotherapy, polytherapy significantly increased women's risk for having a baby with congenital abnormalities only if the combination of drugs included valproate, the researchers report in the Archives of Neurology.

This report is the third major study on the risk for birth defects associated with antiepileptic drugs to appear in recent weeks, with the other reports appearing in JAMA and The Lancet Neurology.

The JAMA study showed that exposure to the newer generation of antiepileptic drugs did not raise the risk for birth defects, whereas the Lancet Neurology study revealed a dose-dependent relationship between exposure and birth defect risk, even for the newer-generation drugs.

The latest study, by Lewis Holmes (MassGeneral Hospital for Children, Boston, Massachusetts, USA) and colleagues, includes 6857 pregnant women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2010. All the women received one or more antiepileptic drugs during the first 16 weeks of pregnancy, with the two therapies most commonly prescribed being lamotrigine and carbamazepine.

In all, 1.9% of the 1441 infants exposed to lamotrigine as monotherapy had a major congenital malformation, identified up to 12 weeks after delivery.

This rate was not significantly different to the 1.5% rate among an internal comparison cohort of 408 unexposed infants born to women drawn from friends and family of women enrolled in the registry. It was also no different to the 1.6% rate among an external comparison cohort of 69,277 infants in the Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, Massachusetts.

The 55 infants exposed to lamotrigine plus valproate had a 9.1% birth defect rate, or a five-fold increase relative to lamotrigine monotherapy exposure. But the risk for birth defects associated with exposure to lamotrigine plus any other antiepileptic (450 infants) was 2.9% - not a significant increase relative to lamotrigine monotherapy.

The birth defect rate among 1012 infants exposed to carbamazepine monotherapy was 2.9%. This remained low, at 2.5%, among 326 infants exposed to carbamazepine plus any other antiepileptic drug except valproate, but was markedly higher, at 15.4%, among those exposed to carbamazepine plus valproate, or a 6.2-fold increase relative to carbamazepine monotherapy.

"Counseling for fetal risks from exposure to [antiepileptic drug] polytherapy should be based on the specific drugs included in the combinations," conclude Holmes and team.

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Eleanor McDermid