NEW YORK (Reuters Health) – In pregnancy, antiepileptic drug (AED) polytherapy that includes valproate poses a higher risk of fetal malformations than therapy without this drug, according to results of study published online June 13 in Archives of Neurology.

It’s been well-documented that women taking more than one AED while pregnant are at much higher risk of having a fetus with a major malformation than those taking only one AED while pregnant, Dr. Lewis Holmes from MassGeneral Hospital for Children in Boston and colleagues note in their report.

Their study of women in the North American AED Registry showed a significantly increased risk of malformations in infants exposed to polytherapy of carbamazepine or lamotrigine that included valproate, but not when carbamazepine or lamotrigine were paired with other AEDs.

“The findings confirm an important warning to busy clinicians that they should not be prescribing valproate to women in the child-bearing age group as either monotherapy or polytherapy,” Dr. Holmes noted in an e-mail to Reuters Health.

“I find that many still have not heard that explicit warning.”

The study included 6,857 women taking an AED during some portion of pregnancy and 441 unexposed women enrolled in the North American AED Registry who delivered between February 1997 and June 2010.

“The North American AED Pregnancy Registry is compiling useful information and could always use more enrollees,” Dr. Holmes commented.

Based on their analysis, the risk of malformations was 1.9% among the 1,441 infants exposed to lamotrigine monotherapy. However, among the 505 infants exposed to lamotrigine as polytherapy, the risks were 9.1% for lamotrigine plus valproate (odds ratio 5.0) versus 2.9% for lamotrigine plus any other AED (odds ratio 1.5).

The risk of malformations was 2.9% for the 1,012 infants exposed to carbamazepine monotherapy. For the 365 infants exposed to carbamazepine polytherapy, the risks were 15.4% for carbamazepine plus valproate (odds ratio 6.2) versus 2.5% for carbamazepine plus any other AED (odds ratio 0.8).

“Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use and chronic maternal diseases did not explain the results,” Dr. Holmes and colleagues note in their report.

They also note that their observations are similar to those published by the UK Epilepsy and Pregnancy Register and the International Lamotrigine Pregnancy Registry. “The comparable findings in these 2 separate pregnancy registries suggest that the fetal risks for malformations vary for the specific drugs used in polytherapy,” they conclude.

Arch Neuro 2011.