PHILADELPHIA—Valproate should be avoided in girls and women of childbearing potential whenever possible because of its teratogenicity, which raises important clinical questions and an ethical concern for neurologists.
Valproate has the best-documented efficacy for certain generalized idiopathic or genetic epilepsies that have few treatment alternatives, such as juvenile myoclonic epilepsy. “Unlike men, women and girls with epilepsy risk being denied the most effective treatment,” said Torbjörn Tomson, MD, PhD, at the 69th Annual Meeting of the American Epilepsy Society.
Torbjörn Tomson, MD, PhD
A Joint Task Force
The European Medicines Agency issued strengthened warnings in 2014 about the use of valproate in patients of childbearing potential to highlight the risk of malformations and developmental problems among children exposed to valproate in utero. The warnings prompted the Commission on European Affairs of the International League Against Epilepsy and the European Academy of Neurology to convene a joint task force to provide guidance on situations when it might be appropriate to prescribe valproate to this population.
Professional societies had expressed concern that the European regulations neglected the risks associated with uncontrolled seizures. Neurologists also worried that the warnings might encourage women to rapidly discontinue or switch treatment during pregnancy without any evidence that discontinuing valproate during pregnancy reduces teratogenic risk, said Dr. Tomson, Professor of Neurology and Epileptology at Karolinska Institutet in Stockholm. In addition, some alternative antiepileptic drugs (eg, topiramate) have limited safety data in pregnant women.
The overriding principle in the task force’s discussion was that the informed patient has the right to express a treatment preference. “The choice of treatment is a shared decision between the well-informed patient and the clinician,” Dr. Tomson said.
Maternal Risk
An audit in the UK found that 4–7% of all maternal deaths were epilepsy-related—10 times more than the researchers had expected. Studies also have shown that uncontrolled maternal seizures may adversely affect the fetus. Valproate exposure in utero, however, increases the risk of major malformations (eg, neural tube defects and hypospadias) and neurodevelopmental problems (eg, lower IQ), compared with other medications. These risks are dose-dependent. Baker et al found that exposure to low doses of valproate in utero (ie, less than 800 mg/day) was associated with impaired verbal abilities and the need for educational interventions, “indicating that we cannot really define a completely safe dose,” Dr. Tomson said.
A Cochrane evaluation concluded that the reduction in IQ associated with valproate exposure is “sufficient to affect education and occupational outcomes in later life.” The evaluation also noted that further research about newer antiepileptic drugs is needed and that “most women with epilepsy should continue their medication during pregnancy, as uncontrolled seizures also carry a maternal risk.”
Consensus-Based Recommendations
The joint task force concluded that, “wherever possible, valproate should be avoided in the treatment of girls and women of childbearing potential,” said Dr. Tomson. The task force made the following general recommendations. Patients on valproate, it suggested, should be informed of the drug’s teratogenic effects and of the limitations of prenatal screening as a means to identify children whose neurodevelopment will be affected. Valproate should not be prescribed as a first-line treatment for focal epilepsy. When valproate is prescribed, it should be used at the lowest effective dose. Women of childbearing potential who are not planning pregnancy and who continue treatment with valproate should use effective birth control.
Among patients of childbearing potential who are newly diagnosed with generalized epilepsies for which valproate may be more effective than other drugs, “alternatives, as well as valproate, should be considered for treatment,” Dr. Tomson said. “The vast majority of cases leads to treatment with other drugs, such as lamotrigine or levetiracetam. But the exception might be the woman who has a strong preference for valproate and a clear statement that she is not planning to become pregnant.”
Valproate also might be considered for girls when it is the most appropriate drug for their seizure or epilepsy type and the patient has a “very high likelihood of remission and antiepileptic drug withdrawal before puberty,” such as in myoclonic epilepsy in infancy or atypical benign focal epilepsy, said Dr. Tomson. Valproate also can be considered when it is the most appropriate drug for a woman’s seizure type or epilepsy and “the epilepsy or comorbidity is so severe that future pregnancies are extremely unlikely.”
Patients Already Taking Valproate
In situations where the woman is taking valproate, in remission, and not considering pregnancy, withdrawal should be considered if the likelihood of relapse is acceptable to the patient. In this scenario, the neurologist should explain to the patient that there “is a risk that you will have a relapse,” Dr. Tomson said. “What do you think about that? What are the alternatives? This is the complicated discussion that we have to have with that specific person, given her individual circumstances.”