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FDA Warns That Topiramate Could Cause Birth Defects: What to Tell Patients

Fitzgerald, Susan

doi: 10.1097/01.NT.0000397214.67211.35
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IN ONE REGISTRY, the prevalence of oral cleft palates and lips was 1

IN ONE REGISTRY, the prevalence of oral cleft palates and lips was 1

The FDA issued a warning about the use of topiramate by childbearing woman based on data from two registries, which showed an increased risk of oral clefts in infants exposed to monotherapy during the first trimester of pregnancy.

A new FDA warning about birth defects linked to the antiseizure drug topiramate is likely to change how clinicians treat epilepsy in women of childbearing age. The agency warned on Mar. 4 that new data from two pregnancy registries showed an elevated risk for cleft lip and cleft palate in babies born to women who took topiramate during pregnancy.

“The benefits and the risks of topiramate should be carefully weighed when prescribing this drug to women of childbearing age, particularly for conditions not usually associated with permanent injury or death,” a statement from the agency said. “Alternative medications that have a lower risk of oral clefts and other adverse birth outcomes should be considered for these patients.”

Topiramate, which is sold under the brand name Topamax, is approved for use in epilepsy, as well as for the prevention of migraine headaches. It is also sometimes used off-label as part of “drug cocktails” to treat certain psychiatric conditions. The FDA said that from 2007-2010, approximately 32.3 million topiramate prescriptions were dispensed in the US to 4.3 million patients.

The FDA said topiramate would now be classified as a “Pregnancy Category D” drug, meaning there is evidence of human fetal risk based on human data, but that the use of the drug in pregnant women might still be acceptable under certain circumstances. The drug previously was classified as a “Pregnancy Category C” drug, which meant that data from animal studies had suggested potential fetal risk, but there was not enough data from humans at the time of its approval to make a determination.

“The decision to issue the warning at this time resulted from the FDA review of the most recent data available pertaining to topiramate and teratogenicity, including the data contained in the 2010 report from the North American Antiepileptic Drug Pregnancy Registry, which was corroborated by data from the UK Epilepsy and Pregnancy Register,” a spokesperson for the FDA said. “The decisions to add this information to the topiramate prescribing information, change topiramate's pregnancy category to D, and issue an FDA Drug Communication were made upon completion of the FDA review of all available data.”



The North American Antiepileptic Drug Pregnancy Registry showed that there was an increased risk of oral clefts in infants who were exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.4 percent in those infants, compared to 0.38 to 0.55 percent in infants exposed to other antiepileptic drugs and 0.7 percent in mothers without epilepsy or treatment with other antiepileptic drugs.



The UK Epilepsy and Pregnancy Register found a prevalence of oral clefts of 3.2 percent among infants exposed to topiramate monotherapy, compared to a rate of 0.2 percent in a background population, the FDA said.

“If the decision is made to use topiramate in women of childbearing age, effective birth control should be used,” the FDA said. “Oral clefts occur in the first trimester of pregnancy before many women know they are pregnant.”

The FDA said in a written statement to Neurology Today that it “will continue to monitor the occurrence of oral clefts, other birth defects and other adverse outcomes in babies born to mothers who took topiramate during pregnancy as additional data from pregnancy registries and other sources accrue.”

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The latest FDA warning on topiramate follows a December 2009 warning by the agency about the heightened risk of neural tube defects and other major birth defects in babies exposed to vaproate sodium and related products (valproic acid and divalproex sodium).

Kimford J. Meador, MD, professor of neurology and director of the Epilepsy Center at Emory University, said this latest warning from the FDA on topiramate “adds another piece of information” to a growing body of literature on the risks and benefits of various antiseizure medications.

“Women need to know about this and doctors need to know about this, but they need to put it in perspective,” Dr. Meador said, noting that most women who take the drug will have healthy babies. He said the FDA warning on topiramate “doesn't mean you should never use this drug,” but rather that the potential risks of the drug needs to be weighed against potential benefits in any given patient. “Epilepsy is not a minor disease. It can cause morbidity and death,” he said. He added, however, that keeping dosage as low as possible might be a good idea.

Dr. Meador is doing research on the cognitive effects of antiseizure drugs on babies born to women who took the medications during pregnancy. He published a paper in 2009 in The New England Journal of Medicine that found that the children of women who took valproate during pregnancy had lower IQs than children whose mothers took carbamazepine, lamotrigine or phenytoin.

Jacqueline French, MD, professor of neurology at New York University, said that the latest data on topiramate to emerge from the pregnancy registries should be helpful to doctors in a couple of ways. “One of them is if you are faced with a woman who is about to initiate therapy,” she said. “Obviously, if she is contemplating pregnancy in the future, you want to select a drug that is safe.” Dr. French, a member of the Neurology Today editorial advisory board, includes lamotrigine in that category.

A more complicated dilemma, she said, is what to do for a patient whose seizures are well controlled by topiramate and wants to get pregnant. If the woman has already tried other options that didn't work out, sticking with topiramate might make sense.



“Now at least you can identify the risk to them: ‘If you stay on the drug, here is what the risk is,'” she said. “We don't want women taking matters into their own hands,” she said. The FDA advised women against discontinuing medication without consulting with their health care provider.

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Alison Pack, MD, associate professor of clinical neurology at Columbia University, told Neurology Today that she has one patient in particular who does very well on topiramate after failing multiple other antiepileptic drugs, and she has been talking to her about the data on the risk of cleft lip or cleft palate. “I tell women that the percentage (of birth defects) is certainly higher than the background rate. Most women, however, will go on to have healthy pregnancies. When treating a woman with epilepsy you must consider both the teratogenic potential of the drug as well as seizure control for the woman.”

Dr. Pack said that she probably could not justify the use of the drug for women with migraines who may have pregnancy in their future. “While migraine headaches can be debilitating and awful for a person, you don't want to take the risk in pregnancy.”

Clinicians said the key is to start talking to women from the start about their various options for epilepsy drugs, even if they are at a young age and parenthood seems like a distant possibility.

The FDA advised patients to tell their clinician immediately if they become pregnant. The agency advised clinicians to inform patients of the NAAED Pregnancy Registry and encourage those who become pregnant to enroll by calling 1-888-233-2334. It also advised healthcare professionals to report adverse events involving topiramate to the FDA MedWatch program at 1-800-332-1088.

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Meador KJ, Baker GA, Loring DW, et al, for the NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360(16):1597–1605.
©2011 American Academy of Neurology