Side effects of prescription drugs are of particular concern during pregnancy.

Two medicines used to control epileptic seizures -- and prescribed to patients with migraine, pain and bipolar disorder -- are associated with an increased risk of birth defects, new research indicates.

Women who took valproic acid or topiramate in the early months of their pregnancies had a higher-than-usual chance of having babies with birth defects, including spina bifida and cleft lip, according to a study published Wednesday in Neurology.

2% of pregnant Americans use anti-epilepsy drugs

Anti-epileptic drugs, particularly the newest ones, are increasingly prescribed for medical conditions unrelated to epilepsy. Prevalence of epilepsy medicine use for any reason during pregnancy is reported as 21.9 per 1,000 expectant women in the United States, 6.7 per 1,000 in France and 4.3 per 1,000 in the Netherlands, according to a 2018 study cited by the researchers.

For the study, researchers used data from the French national health care system to identify pregnancies that resulted in live births between January 2011 and March 2015. Among the 1,886,825 pregnancies, the researchers looked for the mothers' use of 10 anti-seizure drugs before and after conception and searched for 23 birth defects in the children born to these women.

A total 8,794 women had been prescribed a single anti-epileptic drug, the researchers found.

Women prescribed valproic acid (10.4% of the group of pregnant women prescribed anti-epileptic medication) had a 19 times greater risk of having a baby with spina bifida compared with women who did not take an epilepsy drug. Among the 913 women prescribed valproic acid, six babies (0.66%) had spina bifida, compared with 616 babies (0.03%) born to women not taking an epilepsy drug. Valproic acid also increased the risk of seven other birth defects, including cleft palate and four types of heart defects.

Women prescribed topiramate (5.9%) had a seven times greater risk of having a baby with cleft lip (with or without cleft palate), the study indicated. Among the 517 women prescribed topiramate, three babies (0.60%) had cleft lip, compared with 1,637 babies (0.09%) born to women not taking an epilepsy drug.

No elevated risks for birth defects were associated with lamotrigine, levetiracetam, carbamazepine, oxcarbazepine and gabapentin.

The researchers caught weak signals linking clonazepam to a higher risk of microcephaly (a small head circumference that is associated with lower IQ), while individually, phenobarbital and pregabalin were linked to higher risks of different types of heart defects. These associations were based on very few babies and so cannot be considered statistically significant, they said.

Alternative medications

Dr. David Ficker, chairman-elect of the professional advisory board of the Epilepsy Foundation, said the new study "confirms other large-scale studies where similar findings were found. It reinforces the risks associated with these particular two medications."

"We've been concerned about valproic acid for many years," said Ficker, who was not involved in the new research. He recalled a study from the early 2000s that found an association between the drug and a higher risk of major congenital malformations. After these revelations, "use of valproic acid in women of childbearing age decreased considerably," he said.

There are different levels of care for patients with epilepsy, with some treated by their primary care providers, others treated by neurologists and still others receiving treatment from epilepsy specialists -- neurologists with special training in the disease.

"Definitely in the epilepsy physician community, we are well aware of the risks of valproic acid during pregnancy. I think even in the neurology community," said Ficker, who is also a professor of neurology at University of Cincinnati Gardner Neuroscience Institute. However, the primary care community may not recognize potential safety risks, he said.

"I also know that there are some women with difficult-to-control epilepsy that valproic acid may be the only medication that might be effective for them. All these different medicines have different ways of working in the brain, and they're not necessarily completely interchangeable."

"Fortunately, for many women, there are alternative medications that can be used that have a better safety profile during pregnancy," he said.

Guidelines from the Academy of Neurology recommend that doctors prescribe a medicine that poses no risk to a developing fetus and, if possible, only one seizure medicine at a time: "If someone is on more than one seizure medicine, the risk of birth defects increases," Ficker said.

Still, it is important to control seizures because they pose dangers -- such as falling, miscarriage, reduced oxygen to the fetus and fetal distress -- to a developing baby as well, he said.

Ultimately, Ficker cautions women with epilepsy who are of childbearing age or pregnant, "do not stop your medication without speaking to your treating physician."

Interactions with birth control

American Epilepsy Society President Dr. Page Pennell agreed that the study's findings are not new, as most of these associations between anti-epilepsy drug use during pregnancy and birth defects were known based on "many studies" of populations in North America, Australia and other countries in Europe.

Yet previous studies have found evidence of additional negative associations, wrote Pennell, who was not involved in the new research, in an email: "Most notable, valproic acid use during pregnancy has been associated with higher risk for lower IQ, autism and autism spectrum disorder, and need for special education in the children who were exposed during pregnancy. Topiramate has also been associated with increased risk for low birth weight."

Though the evidence is not substantial, she also highlighted the study's "relatively new findings" of an association with clonazepam use and microcephaly and pregabalin use and a heart defect. Of the total women prescribed anti-epileptic drugs, 11.1% had received a script for clonazepam and 19.0% for pregabalin, the study found.

The new research also suggests that neurologists are proactive about ensuring patients of childbearing age take supplemental folic acid, which "has been associated with lowering the risk for neurodevelopmental disorders including autism in children of women with epilepsy," Pennell said.

Like Ficker, she recommends counseling for young women prescribed anti-epileptic drugs, since "over 50% of the pregnancies are unplanned in the US," and women taking anti-epileptic drugs "still have a high unplanned pregnancy rate," despite the known risks.

Not all of these pregnancies are due to a lack of forethought, though. Carbamazepine, she explained, and some of the other drugs for controlling seizures may interact with birth control and "can increase the rate of unplanned pregnancies."

At dosages greater than 200 milligrams a day, topiramate may also diminish the effectiveness of some hormonal contraceptives.

Pennell concluded that "a planned pregnancy allows the health care provider and the woman to decide on the best plan for her individually ... to lower fetal risk while keeping her seizures under optimal control."