Restrict Valproate, EMA Committee Urges

October 14, 2014

The European Medicine Agency (EMA)'s Pharmacovigilance and Risk Assessment Committee has recommended strengthening the restrictions on the use of valproate in women of childbearing age.

This is because of the risk for malformations and developmental problems in children exposed to valproate during pregnancy.

The committee recommends that valproate not be used to treat epilepsy or bipolar disorder in girls and women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated.

It adds that women for whom valproate is the only option should use effective contraception and that a doctor experienced in treating these conditions should start and supervise treatment.

The advice also applies to the use of valproate for the prevention of migraine.

The EMA committee also recommends that doctors who prescribe valproate provide women with full information to ensure understanding of the risks and to support their decisions.

These recommendations follow a review of available data on the effects of valproate exposure during pregnancy. During the review the committee also consulted representatives of patients and families who have been affected, as well as a group of experts and specialists.

While valproate remains an option for patients in whom other treatments have failed or are not tolerated, the committee concluded that women and healthcare professionals need to be better informed about the risks of valproate exposure in utero and the need for effective contraception.

High Rate of Developmental Problems

Recent studies have shown that preschool children exposed to valproate during pregnancy have up to a 30% to 40% risk for developmental problems, including delayed walking and talking, memory problems, difficulty with speech and language, and lower intellectual ability, the EMA statement notes.

In addition, data show that children exposed to valproate in the womb are at an approximately 11% risk for malformations at birth (such as neural tube defects and cleft palate) compared with a 2% to 3% risk among children in the general population. Available data also suggest that children exposed to valproate in the during pregnancy have a 3-fold increased risk for an autistic spectrum disorder and a 5-fold increased risk for childhood autism.

Limited data also indicate that children exposed to valproate in the womb may be more likely to develop symptoms of attention-deficit/hyperactivity disorder.

The committee recommended that educational materials should be provided to all healthcare professionals in the EU and to women prescribed valproate to inform them of these risks. Doctors will be required to regularly review the treatment of girls and women, including at puberty and when a woman plans to become pregnant.

The recommendations of the committee will now be sent the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human, which will adopt a final position. In the meantime, women currently taking valproate who have any questions about their treatment should speak with their doctor, the EMA says.

The review of valproate was started in October 2013 after the publication of new data on the risks of valproate exposure in the womb.

Poor Choice

Kimford J. Meador, MD, Stanford University School of Medicine, California, who has conducted several studies in this area, told Medscape Medical News that if adopted, the new restrictions will help reduce the number of children exposed to valproate in utero.

"Given the multiple increased risks of fetal valproate exposure and that about half of pregnancies are not planned, valproate is a poor choice for the large majority of women of childbearing age irrespective of the indication. I agree that its use should be limited to those women who have failed other available therapies, and all women receiving valproate should be fully informed of the risks," he said.

Also commenting on the EMA's recommendations for Medscape Medical News, Stacey Rennard, public relations and campaigns manager for the United Kingdom advocacy group Epilepsy Action, said the organization supports the recommendation that sodium valproate should not be the first-line treatment for epilepsy in women of childbearing potential or in girls who will need treatment into their childbearing years.

"We also agree that women need to be better informed about the risks of the drug during pregnancy. In recent years we have campaigned for women of childbearing age with epilepsy to receive preconception counseling to make sure they are made aware of the risks associated with epilepsy medicines. We have also produced resources to support women with epilepsy of childbearing age," said Rennard.

While other epilepsy medicines are available, Epilepsy Action points out that for some women who are pregnant or who may become pregnant, sodium valproate at the lowest effective dose will be the most appropriate medicine to use.

"This may be because alternative medicines fail to give seizure control, cause significant side effects, or the risk of uncontrolled seizures outweighs the risks associated with sodium valproate. In this case, after discussing all the risks and benefits, the patient and their doctor may decide that the drug is the safest option for them," Rennard added.

"If adopted, the recommendations should help ensure that women are made aware of the risks of sodium valproate and, alongside healthcare professionals, are able to make informed decisions about their treatment," she said.

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