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Valproate Should Not Be Used in Pregnant Women with Migraines, the FDA Warns

Rukovets, Olga

doi: 10.1097/01.NT.0000431954.54127.89
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Migraine experts say that a new FDA warning against the use of valproate-based drugs for migraine confirms a widely-held view that the drugs should be avoided, and they offer tips on alternative approaches for treating migraine in women of childbearing age.

In May, the Food and Drug Administration (FDA) issued a warning against the use of valproate-based drugs for migraine, based on updated findings from a recent Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study that identified a lower IQ in children of mothers who took those drugs during pregnancy. The FDA noted that the following products are contraindicated for pregnant women with migraines: valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics.

[The alert came on the heels of an earlier FDA warning about an associated risk between valproate and autism in children of mothers who took the drug during pregnancy. See our June 6 story, “Valproate Associated with Increased Risk of Autism in Maternal Epilepsy.”]

These medications had already been labeled with a box warning indicating fetal risk and potential birth defects, and now the medications will feature labels with stronger warnings against use during pregnancy and “valproate's pregnancy category for migraine use will be changed from ‘D’ (the potential benefit of the drug in pregnant women may be acceptable despite its potential risks) to 'X' (the risk of use in pregnant women clearly outweighs any possible benefit of the drug),” the FDA stated. For valproate's other approved uses — epilepsy and bipolar disorder — the pregnancy category for the drug will remain a “D” at this point, “but it should only be taken if other medications have not controlled the symptoms or are otherwise unacceptable. Women who can become pregnant should not use valproate unless it is essential to managing their medical condition,” the agency said.



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Several migraine experts told Neurology Today they were aware of the warning and the drug's associated risks. As migraine specialists, “we've long been concerned about the use of [valproate] as a prophylactic medication in pregnant women and in women who might become pregnant,” Gretchen Tietjen, MD, professor and chair of neurology, and director of University of Toledo Medical Center (UTMC) Headache Treatment and Research Program told Neurology Today. “Migraine, unlike epilepsy, is not a life-threatening condition, so valproate is pretty much avoided by most neurologists starting a preventive therapy in women of childbearing age. But [this warning from the FDA] might lean epileptologists further away from the drug.”

Stephen Silberstein, MD, a professor of neurology at Jefferson University Medical Center, and lead author of the AAN's 2012 evidence-based guidelines for migraine treatment, agreed that valproate is never the drug of first choice for women with migraine. He noted that “there are [other] issues with divalproex sodium independent of this warning in women who are young: polycystic ovarian syndrome, obesity, tremor, and hair loss.”

“In all women of childbearing potential, independent of what drug we put them on, you have to be sure that they are either on contraception or are remaining abstinent,” he said. If the patients are not on contraception, he continued, “we would likely not prescribe any drugs at all because 3 percent of all births have a major malformation, and 10 percent may have a minor malformation, so there's a one in 10 chance that a birth defect may result.”

Topiramate (Topamax), for example, the commentators noted, was once considered safe for women in pregnancy, “and now we know that it may cause teratogenicity. With [topiramate] there's also the concern that it lowers the efficacy of the birth control pill,” though this seems to be only in high daily doses (200 mg or more), Dr. Tietjen pointed out.

So, how do you determine which migraine patients do require daily medication? Usually, Dr. Tietjen said, the woman determines it — “if she feels that her quality of life has gone down despite the use of acute medications and she really can't tolerate it.

“But I have a lot of pregnant women referred to me when they have trouble with migraines, and I usually find that I am able to get things under control without a daily medication. If I do use a preventive treatment, it is usually magnesium supplements. Better acute treatment of each individual headache may lead to fewer headaches, and I also use some other strategies,” she said.

For instance, Dr. Tietjen advises nonpharmacologic preventative treatments, like self-management strategies, such as learning biofeedback and making healthy lifestyle changes, to see if those practices help to ward off headaches in her patients of childbearing age. Thankfully, she said, for many women, migraine frequency tends to improve during pregnancy — at least in the second and third trimesters. When necessary, in women who experience severe migraines, Dr. Tietjen will sometimes use occipital nerve blocks — a mixture of local anesthetic and steroids injected into the area of the occipital nerves at the base of the skull — as a mitigation strategy during pregnancy, adding that she usually uses a combination that is mostly anesthetic and only a small amount of steroid. The relief provided by these injections may last from four to six weeks.

Dr. Silberstein, however, is hesitant to use complementary drug therapy. “You may advise them to use it now, but then in a few years, we may find that it is not safe,” as was the case for topiramate, he noted. But biofeedback, meditation, yoga, and exercise are safe and effective in all women, he added.

One notable and significant problem with identifying safe treatments for pregnant women or women of childbearing age, the commentators said, is the inability to perform controlled studies. Thus, most safety data is gathered from registries, which may take a very long time, Dr. Silberstein said. Added Dr. Tietjen: Going forward, “I think that we need more comparative effectiveness trials of different strategies in migraine, and also development of new migraine-specific medications.”

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•. FDA press release warning against use of valproate in pregnant migraineurs:
    •. Holland S, Silberstein SD, Ashman E Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Part I. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1346–1353.
      •. Meador KJ, Baker GA, Browning N Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3): 244–252.
        •. Neurology Today's archive on valproate:
          •. Neurology's archive on valproate:
            © 2013 American Academy of Neurology