Lasting impact of fetal valproate exposure

Fetal exposure to the antiepileptic drug (AED) valproate has a dose-dependent negative impact on children's IQ at age 6 years, shows a study in The Lancet Neurology.

"IQ at age six is strongly predictive of adult IQ and school performance, so our research suggests that valproate use during pregnancy is likely to have long-term negative effects on a child's IQ and other cognitive abilities," said lead researcher Kimford Meador (Emory University, Atlanta, Georgia, USA) in a press statement.

There were 311 children in the study. When assessed at 6 years of age, average IQ among the 62 children whose mothers took valproate during pregnancy was 97. This was significantly lower than the average IQs of the 94 children with fetal carbamazepine exposure, the 100 with lamotrigine exposure, and the 55 with phenytoin exposure, which were 105, 108, and 108, respectively.

This primary analysis included imputed IQs for 87 children who did not complete the 6-year assessment and was adjusted for maternal IQ, AED dose, periconceptional folate, and gestational age at delivery.

The apparent adverse effect of valproate exposure on IQ was dose dependent; the average daily valproate dose was 1032 mg, ranging from 133 to 3583 mg. AED dose did not correlate with IQ for any of the other drugs, although the team notes that the dose range was smaller for phenytoin than for the other drugs.

Valproate dose inversely correlated with children's performance on verbal, nonverbal, executive function, and memory tests.

The researchers observe that IQs of children exposed to valproate doses lower than 1000 mg per day did not differ from those of children exposed to other AEDs. However, they caution that a larger study could still reveal adverse effects, particularly given suggestions from laboratory studies that valproate adversely effects the immature brain at subtherapeutic doses. "Thus, a safe dose of valproate is unknown," they say.

There was a strong positive relationship between maternal and child IQ for children exposed to carbamazepine, lamotrigine, and phenytoin, but not for children exposed to valproate.

"Based on anatomical and cognitive risks, we propose that valproate is a poor first-choice antiepileptic drug for most women of childbearing potential," say Meador et al. "However, a few women with generalised epilepsy can only be controlled by valproate."

Meador commented: "Given that many women do not have the option of stopping medication during pregnancy, more research in this area is urgently needed."

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