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Topiramate in early pregnancy increases risk of oral clefts

Study finds that taking a higher dose of the drug in the first trimester increases risk of cleft lip or cleft palate more than taking a lower dose

Brigham and Women's Hospital

The anti-epileptic drug topiramate has been increasingly prescribed over the last decade not only to prevent seizures, but also to treat bipolar disorder and migraine headaches. In addition, topiramate is a component of a recently FDA-approved drug for weight loss. Past studies have found that women taking topiramate during early pregnancy to prevent epileptic seizures had a two- to five-fold greater chance of giving birth to a baby with an oral cleft, but such studies did not focus on women taking the drug at a lower dose for non-seizure related conditions. A new study by investigators from Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health suggest that using topiramate in early pregnancy, particularly at the high doses used for epilepsy, increases the risk of oral clefts.

Their results are published in . "Our results suggest that the increased risk of oral clefts is most pronounced in women taking higher doses of topiramate to treat epilepsy. Low doses of topiramate may also increase the risk of oral clefts but to a lesser extent," said last author Elisabetta Patorno, MD, DrPH, of the BWH Division of Pharmacoepidemiology & Pharmacoeconomics. "We hope that this work gives important information to women and their clinicians as they determine the best course of treatment and options available to individuals."

The new work leverages nationwide Medicaid data on more than 1 million live births from between 2000 and 2010. The team examined the risk of oral clefts - including cleft palate or cleft lip - among three groups: infants born to women who had taken topiramate in their first trimester; infants born to women who had taken the drug lamotrigine (an unrelated drug used to treat bipolar disorder and epilepsy); and infants who had not been exposed to anti-epileptic medications in utero. They found that the risk of oral clefts was approximately three times higher for the topiramate group than for either the lamotrigine or the unexposed group. Approximately one out of every 1,000 infants are born with an oral cleft, but among infants exposed to low doses of topiramate (median 100-mg daily dose) in the first trimester, that risk was 2.1 out of every 1,000 live births. Among women taking higher dose topiramate (median 200-mg daily dose), the risk was much higher - 12.3 for every 1,000 live births.

"Our results suggest that women with epilepsy on topiramate have the highest relative risk of giving birth to a baby with cleft lip or cleft palate, likely due to the higher doses of topiramate when used for controlling seizures," said corresponding author Sonia Hernandez-Diaz, MD, DrPH, of the Harvard T.H. Chan School of Public Health. "The best course may be to avoid prescribing high doses of topiramate to women of childbearing age unless the benefits clearly outweigh the risks."


Funding for this work was provided by an R01 grant (R01 MH100216) from the National Institute of Mental Health, a career development grant (K08HD075831) from the National Institute of Child Health & Human Development and a career development grant (K01MH099141) from the National Institute of Mental Health. Paper cited: Hernandez-Diaz S et al. "Topiramate use early in pregnancy and the risk of oral clefts" Neurology DOI: 10.1212/WNL.0000000000004857

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