Valproate Linked to Increased Prenatal Risks

Valproate, an epilepsy drug also used to treat bipolar disorder, is linked to lower IQ scores at age 3 in children exposed to the drug before birth than in children whose mothers took other antiepileptic drugs during pregnancy, a study published in the April 4 New England Journal of Medicine showed.

From 1999 to 2004, U.S. and U.K. researchers enrolled 303 pregnant women with epilepsy who were taking lamotrigine, phenytoin, carbamazepine, or valproate in a prospective, observational study known as the Neurodevelopmental Effects of Antiepileptic Drugs study. The researchers conducted follow-up assessments, especially in terms of neurological development, in the children. Women who were not taking any antiepileptic drugs during pregnancy were not included.

The average IQ score of 3-year-old children who had in utero exposure to valproate was 92, which was statistically significantly lower than that of children exposed to lamotrigine (average IQ 101), phenytoin (99), or carbamazepine (98). The comparisons among lamotrigine, phenytoin, and carbamazepine were not statistically different. The authors also found a dose-dependent relationship between valproate and IQ score.

That valproate exposure carries a higher risk of birth defects than other antiepileptics, such as lamotrigine and carbamazepine, is not new knowledge, Torbjorn Tomson, M.D., a professor of clinical neuroscience at the Karolinska Institute in Sweden, pointed out in an editorial. The worthwhile discovery of this study was the differential effects on children's long-term cognitive development associated with various antiepileptics. This was the largest prospective study so far on the effects of antiepileptics on cognitive development.

This study was reported in several media outlets, including the New York Times and the Associated Press, with broad headlines such as“ I.Q. Harmed by Epilepsy Drug in Utero,” without clearly presenting the context that the study was a comparison between valproate and other antiepileptic drugs.

Untreated epilepsy, as well as untreated bipolar disorder, poses a significant risk of harm to pregnant women and their fetuses. For many pregnant patients, stopping medication is not an option. Therefore, accurately describing the different risks among drugs in the same class is critically important for physicians and patients. The authors concluded that valproate should not be used as a first-line treatment for women who are pregnant or may become pregnant. In addition, “discussion of the risks of valproate should be balanced with consideration of the risks of uncontrolled seizures,” Tomson recommended.

An abstract of “Cognitive Function at 3 Years of Age After Fetal Exposure to Antiepileptic Drugs” is posted at<content.nejm.org/cgi/content/short/360/16/1597>.▪