Study: Epilepsy and Migraine Drug, Topiramate, Associated With Risk of Clefting in Newborns

The higher the dose, the higher the probability of cleft lip or palate in the child, new paper says; fortunately, topiramate is not prescribed for dieting purposes in Israel

A child with cleft lip being lifted from a scale at a foster home on the outskirts of Beijing, China, October 2017.
Ng Han Guan/AP

Higher doses of the anticonvulsant drug topiramate when used during the first trimester exacerbates the risk of clefting in newborns, says a new study published in the medical journal of the American Academy of Neurology.

Doctors may not mean to prescribe it to pregnant women, but unplanned pregnancies are common, points out paper co-author Dr. Sonia Hernandez-Diaz.

“Our study found that when pregnant women took topiramate during the first trimester, baby’s risk of cleft lip or palate was three times greater than if mom was not taking the drug,” said Hernandez-Diaz, from the Harvard School of Public Health. “The risk was higher when the mother took high doses of the drug than when she took lower doses.”

Generally, topiramate is used to treat epilepsy, migraine and, in combination with other chemicals, to lose weight.

In fact, the Israeli Health Ministry has been aware of topiramate for a year now. Because of the risks the drug poses to newborns, the decision was made at the start of 2017 that it shouldn’t be given to pregnant women for either migraine prevention or epilepsy, certainly when other treatments are possible, the ministry told Haaretz.

Israeli doctors are not allowed to prescribe topiramate for weight loss, the ministry noted. Elsewhere, topiramate may be given for weight loss along with phentermine, though some find the side effects – such as a burning sensation around the mouth or a bad taste in the mouth – as troubling as the initial obesity.

There is also work being done on using topiramate to treat addiction to alcohol, cocaine, and so on, partially through dulling the sense of craving.

In Israel, the drug may be prescribed as a monotherapy for epilepsy, from age 7, and to treat “partial” seizures and tonic-clonic seizures in adults and children from age 2. It may also be prescribed to prevent migraines in nonpregnant adults, though the Health Ministry points out its use to actually treat acute migraine has not been studied.

Hernandez-Diaz’s paper is based on Medicaid data from a 10-year period on nearly 1.4 million American women who gave birth to live babies.

Among women not taking anti-seizure drugs, 1.1 per 1,000 births had cleft lip or cleft palate. Among mothers taking the anticonvulsant medication lamotrigine in their first trimester, the risk rose to 1.5 per 1,000 births.

In the group of mothers who filled a prescription for topiramate during the first trimester (there’s no telling if they actually took the drug) for all uses, the risk rose to 4.1 per 1,000 births.

But when the drug was taken specifically for epilepsy, the probability shot up. Women taking topiramate for epilepsy (not, say, migraine prevention) had a roughly 800 percent greater risk of giving birth to a baby with clefting. Among women taking the drug for other reasons, the risk was 50 percent higher.

Why? Because treating epilepsy requires big doses, the doctors concluded.

Women with epilepsy averaged 200 milligrams a day, while women taking it for other conditions averaged half that.

“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 Hernandez-Diaz.

The recommendations in Israel are to start with low doses of the drug and to gradually increase based on clinical reaction, until reaching 200 to 400 milligrams a day (in total), explains the Health Ministry.

The directive to doctors is to assess the necessity of treatment before giving topiramate to women planning pregnancy, let alone already pregnant.

One problem is that suddenly halting an anticonvulsant regimen isn’t recommended, the ministry said, because that in and of itself can cause seizures, which can harm mother and baby.

In general, anti-epileptic treatment for pregnant women is best given as a monotherapy when possible, “because combined therapy has been associated with heightened risk of birth defects,” the ministry told Haaretz.

In fact, clefting isn’t the only risk associated with topiramate. The ministry points out that not only does it increase the risk of birth defects including clefting when taken in the first trimester; it is teratogenic in animals.

The ministry’s recommendation is that premenopausal women be meticulous about using contraceptives while taking topiramate. At the end of the day, it’s up to the woman’s doctor to evaluate the potential risks to the fetus versus the known risks of epilepsy – and if the juxtaposition of circumstances involves pregnancy and use of the drug, prenatal monitoring is important.