Valproate sodium and related drugs should never be used to prevent migraines in pregnant women, according to a Food and Drug Administration warning. The safety advisory cites the final results of a study indicating that prenatal exposure to these drugs "can cause decreased IQ scores" in children whose mothers took them during pregnancy.
The pregnancy category for valproate for the migraine indication will be changed from a "D" – designated for drugs where the potential benefit for a pregnant woman might be acceptable despite its potential risks – to a category "X," designating that the risk of the drug in a pregnant woman "clearly outweighs any possible benefit of the drug," according to the advisory, issued May 6 by the FDA.
Valproate products include valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and generic versions of these products. They also are used to treat epilepsy and manic episodes associated with bipolar disorder, and for these indications, they will remain in category "D" and "should only be prescribed if other medications are not effective in treating the condition or are otherwise unacceptable." Women who can become pregnant should not use valproate unless it is essential to managing their medical condition, the FDA states.
"Valproate medications should never be used in pregnant women for the prevention of migraine headaches because we have even more data now that show the risks to the children outweigh any treatment benefits for this use," Dr. Russell Katz, director of the division of neurology products in the FDA’s Center for Drug Evaluation and Research, said in a May 6 statement issued by the FDA to announce the advisory.
The data cited by the FDA are the final results of the Neurodevelopmental Effects of Antiepileptic Drugs study, published in March 2013, which found that at age 6, children whose mothers had taken valproate products while pregnant had lower IQs, compared with those whose mothers took other antiepileptic drugs. In the study, the mean IQ among the children exposed to valproate in utero was 97, compared with a mean of 105 among those exposed to carbamazepine, 108 among those exposed to lamotrigine, and 108 among those exposed to phenytoin (Lancet Neurol. 2013;12:244-52).
In June 2011, the FDA issued an alert when interim results of this study found that at age 3 years, children exposed to valproate had lower scores on cognitive tests, information that was added to the labels at that time.
The FDA notes that the results of the study are similar to other epidemiologic studies that have associated in utero exposure to valproate to lower IQ scores, when compared with children exposed to another AED or no AED in utero.
Since women in the study were taking antiepileptic drugs throughout pregnancy, it is unclear whether the effects on IQ are related to the timing or duration of prenatal valproate exposure, so "exposure to valproate at any time during pregnancy should be considered to have the potential to result in decreased IQ in children," the advisory says.
The prescribing information for valproate medications already include a boxed warning about the fetal risks, especially neural tube defects and other major malformations, associated with prenatal exposure.
Adverse events associated with valproate products should be reported to the FDA’s MedWatch program or at 800-332-1088. In addition, the agency is asking physicians to encourage their pregnant patients on valproate to enroll in the North American Antiepileptic Drug Registry online or at 888-233-2334.