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Valproate Associated with Increased Risk of Autism in Maternal Epilepsy

Moran, Mark

doi: 10.1097/01.NT.0000431662.09511.43
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The latest finding of an association between valproate and autism adds to a list of major congenital malformations associated with maternal use of valproate, and argues for more judicious use of the drug — still regarded as effective for epilepsy, as well as bipolar disorder and migraine headaches — in women of childbearing age, experts say.

Maternal use of valproate during pregnancy appears to be associated with a significantly increased risk of autism spectrum disorder and childhood autism in offspring, even after adjusting for maternal epilepsy, according to a population-based study in Denmark published in the Apr. 24 issue of the Journal of the American Medical Association (JAMA).

The study offers the strongest evidence to date for an association that has previously been suspected on the basis of case reports and animal research. Using a large population database from the Danish birth registry, the investigators were able to control for a range of possible confounding factors, including maternal or paternal psychiatric illness as well as maternal epilepsy; they found an increased risk from valproate use in the offspring of mothers both with and without an epilepsy diagnosis, thereby suggesting a biological effect of valproate.



The finding of an association with autism adds to a list of major congenital malformations associated with maternal use of valproate, and argues for more judicious use of the drug — still regarded as effective for epilepsy, as well as bipolar disorder and migraine headaches — in women of childbearing age. “For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control,” the lead author Jakob Christensen, PhD, of the department of neurology at Aarhus University Hospital in Denmark, and colleagues.

[On May 6, the US Food and Drug Administration (FDA) issued a safety alert specifically recommending that clinicians avoid prescribing valproate medications for pregnant women for prevention of migraine headaches and that they only prescribe it for pregnant women with epilepsy or bipolar disorder if other treatments have failed to provide adequate symptom control or are otherwise unacceptable. According to the FDA statement: “Stronger warnings about use during pregnancy will be added to the drug labels, 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).”]

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In the JAMA study, Dr. Christensen and colleagues used birth registries to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism, Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders).

Of 655,615 children born from 1996 through 2006, the 508 children exposed to valproate had an absolute risk of 4.42 percent for autism spectrum disorder and an absolute risk of 2.50 percent for childhood autism. When restricting the cohort to the 6,584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15 percent, and the absolute risk of childhood autism was 2.95 percent. This is compared with 1.02 percent for childhood autism among 6152 children not exposed to valproate.

The researchers also found that the children of women who had previously used valproate and stopped it at least 30 days prior to conception were not at increased risk for autism.

In an editorial accompanying the study, Kimford J. Meador, MD, and David W. Loring, PhD, of the department of neurology at Emory University, said valproate is an effective drug, but appears to be prescribed for women of childbearing potential “at a rate that does not fully consider the ratio of benefits to risks.” They added: “Given the accumulating evidence linking fetal valproate exposure to congenital malformations, cognitive impairments, and autism, the use of valproate in women of childbearing potential should be minimized.”

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Neurologists who reviewed the report for Neurology Today concurred. Cynthia Harden, MD, said the JAMA study adds new weight to an association that has been widely suspected. “There has been a link between valproate use and autism put forth in the scientific and lay communities, but it seemed to have been widely accepted without much clear proof,” she said. “This study is important because it provides more solid evidence in patients that in utero valproate exposure increases the risk of autism spectrum disorders, Asperger's, and pervasive developmental disorders. So the previous literature is weak, and the association is greatly strengthened by this new finding.”

Dr. Harden, chief of the Division of Epilepsy and Electroencephalography at Hofstra North Shore-Long Island Jewish School of Medicine, noted that AAN guidelines for the management of women with epilepsy during pregnancy recommend caution in the use of the drug for women of childbearing age. “There are probably still too many prescriptions of this drug in women of childbearing age, and not enough emphasis on making sure these women are using and have access to adequate birth control if they must remain on valproate,” she said.

She said the findings require clinicians to balance risk and benefit in the selection of an appropriate antiepileptic for the individual patient. “Sometimes, valproate is the only medication that controls seizures,” she said. “Primary generalized seizure types are sometimes exquisitely sensitive to valproate, and less susceptible to other antiseizure medications. It becomes a clinical trial and error process to find the medication that works for some patients with ongoing seizures.”



She noted that there are several antiseizure medications that can be used successfully when a woman is taking valproate and needs to be tapered off prior to pregnancy. “There are many unplanned pregnancies in women with epilepsy, just as in the population at large, so not using valproate in a woman of child-bearing potential is a good strategy, when possible,” she told Neurology Today. “If the patient must remain on valproate for her own safety, using adequate birth control should be ensured. Folic acid should be taken by all women planning pregnancies to reduce the risks of both structural and cognitive teratogenesis.”

Mark Yerby, MD, MPH, associate clinical professor of neurology and public health at Oregon Health and Sciences University and chair of the Scientific Advisory Committee for the North American Epilepsy and Pregnancy Registry, agreed that the choice of using valproate or another medication is not clear-cut, but will depend on multiple factors related to the patient's clinical status. “Valproate, because of its potency, is generally used in persons with more severe epilepsies,” he said. “So it is customary for physicians to start with alternative medications first and use valproate if the `first line' drugs fail.”

Dr. Yerby said lamotrigine, levetiracetam and lacosamide are reasonable alternatives for epilepsy, though there is little or no safety information on lacosamide in pregnancy.

He emphasized that the association between maternal valproate use and autism is correlative, not causative, and pointed out that though the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study demonstrated lower IQ scores in children exposed to valproate, most children in that study were still within the normal range of IQ measurements.

“The disease state and effects of maternal seizures may also be an important factor in these outcomes,” he said. “One must carefully balance the risks and benefits of valproate's use and not refrain from its use for those patients for whom it may be the best medication for their seizure control.”

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•. Christensen J, Grønborg TK, Vestergaard M, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 2013; 309(16):1696–1703.
    •. Meador KJ, Loring DW. Editorial: Risks of in utero exposure to valproate. JAMA 2013; 309(16):1730–1731.
      •. FDA safety alert on valproate for migraine prevention:
        •. Neurology Today archive on gender specific issues for epilepsy management:
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