Valproate: A Mixed Bag

The next (June 10th) issue of The Medical Letter will include a brief article elaborating on an FDA warning against the use of Depacon, Depakene, Depakote or their generic equivalents by pregnant women for prevention of migraine. All of these drugs end up as valproate in the gastrointestinal tract, and all are approved by the FDA not only for prevention of migraine, but also for use in epilepsy and in bipolar disorder. The first approval was for epilepsy, and valproate is still thought of principally as an antiepileptic drug.

The reason for the FDA warning was the publication of the third of a series of articles evaluating the intellectual development of children exposed to antiepileptic drugs during pregnancy. The news about valproate was not good: by the age of 6 years, children whose mothers took the drug during pregnancy had IQ scores 6-11 points lower than those whose mothers took any one of 3 other antiepileptic drugs. All of these studies enrolled women taking these drugs for epilepsy. So why warn so specifically against taking them to prevent migraine? Good question: women taking valproate for migraine might be using different doses and might have some other significant differences in baseline characteristics from women with epilepsy. But apparently the FDA felt that migraine prophylaxis could be interrupted during pregnancy, while the consequences of not treating bipolar disorder or epilepsy could be more severe.

The consequences of taking valproate during pregnancy for any indication can also be severe. In addition to the apparent IQ-lowering effect, the risk of major malformations, including neural tube defects, is well documented.  Accordingly, the FDA hedged its bets by putting the drug in category X for use against migraine (the benefits do not outweigh the risks) while keeping it in category D for epilepsy and bipolar disorder (the benefits may outweigh the risks). These are difficult decisions, but all parties agree that, if at all possible, women of childbearing age should not take any formulation of valproate.

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