Higher-dose antiepileptics increase risk of congenital malformations

The risk of major congenital malformations increases dose-dependently with 4 common antiepileptic drugs, according to the results of a study published online June 5 in The Lancet Neurology. However, “the risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential,” the authors wrote.

Researchers prospectively evaluated pregnancy outcomes using data from the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), which represents a collaboration of physicians from 42 countries. Researchers evaluated 1,402 patients who were prescribed carbamazepine, 1,280 prescribed lamotrigine, 1,010 prescribed valproic acid, and 217 on phenobarbital at the time of conception and found an increase in malformations with higher doses for all drugs.

A multivariable analysis, which included 10 covariates in addition to treatment with antiepileptic drugs, showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4.4, 95% CI 2.06-9.23). With regard to drug treatment, researchers noted that the lowest rates of malformation occurred with less than 300 mg lamotrigine per day and less than 400 mg carbamazepine per day. Risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day compared to lamotrigine monotherapy at doses less than 300 mg per day.

“Our findings suggest that many women can enter pregnancy at comparatively low doses and maintain seizure control. Our study gives the prescriber the possibility of assessing, before pregnancy, how teratogenic risks with an individual woman's treatment compare with the risks associated with alternative treatments at various doses,” the researchers stated.