MDs urged to avoid valproate in fertile women: risk of major fetal malformations cited.(News)

NEW ORLEANS -- Valproate should not be prescribed as first-line therapy for any indication in women of childbearing age because it significantly increases the risk of major malformations in exposed infants, the American Epilepsy Society's pregnancy outcomes forum panel has recommended.

Converging data from six studies that were presented at the annual meeting of the American Epilepsy Society and two recently published studies prompted the recommendation, said Kimford Meador, M.D., who is the director of the epilepsy program at the University of Florida, Gainesville, and a member of the panel.

"This isn't class I evidence--we're never going to have that--but what is the chance that seven different studies in seven different populations would all come to this same conclusion?" he asked. "In my opinion, this drug should not be used as first-line therapy for this population."

The studies presented linked valproate with up to a sevenfold increased relative risk of major malformation, compared with the general population; the rate of malformations among these infants was 10%, compared with 1.6% in the general population.

Five studies were hospital-based pregnancy registries conducted in the United States, United Kingdom, Europe, and Australia. The other two were international drug company registries for lamotrigine and gabapentin. (See box.)

Cardiac, neural tube, and multiple anomalies were among the malformations noted. None of the registries had high enough power to determine the risks for any particular malformation, however, said Lewis Holmes, M.D., chief of the genetics and teratology unit at Massachusetts General Hospital, Boston, and the director of the Antiepileptic Drug Pregnancy Registry, which is managed by the hospital and targets pregnant women in the United States and Canada who are on an AED.

The registry was established in 1977; as of July 2004, it included 3,708 women. Sixteen infants with major malformations have been born to 149 valproate-exposed women (10.7% and a relative risk of 7.3).