Drugs, pregnancy, and lactation: valproic acid.(Obstetrics)

For more than 20 years, the risk of neural tube defects (NTDs) associated with first-trimester exposure to valproic acid has been well known: The estimated risk is 2%, about 10- to 20-fold higher than the baseline risk. With more widespread use of valproic acid, partly due to increasing use of the drug for psychiatric conditions, more data and larger controlled studies on its teratogenic effects have accumulated over the past 3-4 years, revealing an association with major malformations that previously had been reported anecdotally. The main anomalies that have been identified are cardiac and limb malformations.

The results of these studies reflect what we found in a metaanalysis of data from 13 cohort studies in the medical literature, published between 1982 and 2005. The studies in the metaanalysis, which will be published next month in a Canadian journal, compared rates of major malformations among women who reported taking valproic acid during the first trimester with rates among pregnant women who were taking other antiepileptic drugs (AEDs) and among women who were not taking any such drugs.

Nearly 1,000 pregnant women were exposed to valproic acid in the 13 studies. The risk of major malformations, including NTDs, associated with exposure to valproic acid was twofold greater than the risk with exposure to other AEDs. The risk was 4.4-fold greater than in the healthy controls, representing a highly significant increase in risk among valproic acid-exposed pregnancies.

We could not include three studies comparing the neurobehavioral risks of in utero exposure to valproic acid and other AEDs in the metaanalysis, because of their different designs and the variety of cognitive tests used. Still, all three reported an association between valproic acid and developmental delays and cognitive deficits. The most prominent effect was on verbal IQ. More studies on the neurodevelopmental effects of in utero exposure that control for maternal education and other confounding factors need to be conducted to further examine these associations.

On the positive side, in 3 of the 13 studies that also looked at the dose-dependent effects of valproic acid, the threshold dose needed to cause malformations was about 1,000 mg/day, as reported over the past few years. This is true for all malformations associated with valproic acid, including NTDs. In one study, first-trimester valproic acid plasma levels in women were higher among those who had a child with a malformation; in another, a daily dose of 1,000 mg was ...