When the FDA warned about the teratogenic risks of valproate in 2013, epilepsy experts understood the agency's concern. But the next year, when European regulators put out a stronger statement against use of the drug in women with childbearing potential, some worried the warnings may have gone too far, according to Torbjörn Tomson, MD, PhD, of the department of clinical neuroscience at the Karolinska Institutet in Stockholm, Sweden.
Dr. Tomson spoke on this subject at the annual meeting of the American Epilepsy Society, held in Philadelphia in December. Earlier in the year, he also chaired a task force on valproate in the treatment of epilepsy in women and girls, convened by the International League Against Epilepsy—Commission on European Affairs and the European Academy of Neurology.
The European regulators had advised physicians “not to prescribe valproate for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant, or in girls unless other treatments are ineffective or not tolerated,” said Dr. Tomson. “These were the restrictions that actually prompted the appointment of the task force …to provide recommendations on how valproate can be used within the remit of these new restrictions.”
The FDA's warning, in contrast, allowed for prescription of valproate if it is essential to the management of a woman of childbearing age's medical condition. “A more flexible statement,” said Dr. Tomson.
That flexibility is important to epilepsy experts for a number of reasons, he explained. “The first concern is that treatment alternatives are few for generalized idiopathic or genetic epilepsies,” he said. In addition, it's not certain whether those alternatives are safe during pregnancy. “The other concern is an ethical concern. With these restrictions, unlike men, women—and girls in particular—risk being denied the most effective treatment for their epilepsy,” said Dr. Tomson.
Experts were also concerned that the European warning, depending on how it is interpreted, might lead to harmful treatment discontinuation or medication changes. “There was an impression that the regulations underestimated the risks associated with uncontrolled seizures,” he said. “It's important to remember that this is perhaps particularly important during pregnancy.”
Studies in the U.S. and U.K. have found that women with epilepsy face about a 10-fold risk of maternal death compared to the general population, he reported. “In addition, there's also possibility that uncontrolled maternal seizures may have adverse effects on the fetus,” said Dr. Tomson. Valproate is sometimes the most effective way to prevent such seizures.
Of course, the FDA and European warnings were based on convincing data, too. “The other side of the coin is teratogenicity and the development of toxicity on valproate. We've known for many, many years that the risk for major malformations is increased in offspring of women that take valproate during pregnancy,” he said.
Pregnancy registries from the U.S., Europe, and the U.K. have shown higher rates of malformations like neural tube defects and hypospadias with valproate than with other epilepsy drugs, including carbamazepine, lamotrigine, and newer-generation drugs.
The risk does seem to be dose-dependent, but unfortunately, it's not clear what the dose cutoff should be, Dr. Tomson said. “From Europe, [there are registry data] showing that the risk of major malformations with valproate is lower if you have a dose under 700 mg per day. You have data from the U.K./Irish pregnancy registry … those exposed to doses below 600 mg had lower malformation rates. In the American pregnancy registry, the cutoff was defined as below 500 mg per day. From the Australian pregnancy registry … the increase in the risk of malformations comes above 800 mg per day or more,” he reported.
Researchers have also followed pregnant women on more than 1 epilepsy drug. Malformation rates were similar in those taking valproate alone or along with another drug, “suggesting that if one could, by adding 1 other antiepileptic drug to valproate, keep the valproate dose lower, that might be beneficial,” Dr. Tomson said.
Lower doses might not eliminate the adverse effects of valproate on cognitive development, however. Studies have shown that children of mothers on higher doses have lower IQ than those on lower doses but also that even the lower doses are associated with verbal and educational difficulties. There are also data showing increased rates of autism after in utero exposure to valproate, Dr. Tomson reported. “We cannot really define completely safe dose categories of valproate,” he said.
A Cochrane review on the subject, published in 2014, expressed concerns about the risks but also found insufficient data regarding alternative medications. It concluded that most women with epilepsy should continue their medication during pregnancy, as uncontrolled seizures also carry maternal risk.
While stressing that valproate, wherever possible, should be avoided in the treatment of women of childbearing potential, the recent European task force was also significantly more specific in its advice, offering recommendations for newly diagnosed patients and those who are already pregnant, considering pregnancy, or not likely to become pregnant (see sidebar). It also offered some general recommendations, including that women should be informed of the teratogenic risks and uncertainties of the drug, that valproate should generally not be used for women with focal epilepsy, that it should be prescribed at the lowest effective dose, and that women taking it and not planning to become pregnant should use birth control.
“However, the overriding principle in this discussion was the informed patient's right to express a preference and the principle of shared decision making between physician and patient,” said Dr. Tomson. “Risks and benefits of reasonable treatment alternatives have to be assessed and discussed with the woman. The choice of treatment is a shared decision between the well-informed patient and the physician.”