Topiramate is associated with a significantly increased risk of major congenital malformations, whether given as monotherapy or as part of a polytherapy antiepileptic regimen, Dr. Stephen Hunt and his colleagues have reported.
Although the associations were strong—an 11-fold increase in the risk of oral clefts and a 14-fold increase in the risk of hypospadias, compared with background rates in the United Kingdom—the confidence intervals surrounding them were wide, noted Dr. Hunt of the Royal Group of Hospitals, Belfast, Ireland. Therefore, the data “should be interpreted with caution,” he and his colleagues wrote (Neurology 2008;71:272-6).
The U.K. registry is one of three national registries that track pregnancy outcomes in women taking antiepileptic drugs. Neither of the others—a North American and an Australian registry—has reported an association between topiramate and birth defects, said Dr. Kimford Meador, the Melvin Greer Professor of Neurology at the University of Florida, Gainesville.
“The U.K. data are the first data on topiramate risks during pregnancy,” Dr. Meador said in an interview. “The data suggest an association of increased malformations with topiramate exposure during pregnancy. However, the sample is small and the confidence intervals are large, so no definitive conclusion can be drawn.”
Because the results are preliminary, clinicians and their patients should be cautious about medication changes, said Dr. Martha Morrell, director of the Columbia Comprehensive Epilepsy Center, New York.
The analysis was drawn from the U.K. Epilepsy and Pregnancy Register. The present study included outcomes for 203 pregnancies with exposure to topiramate during the first trimester. Most of the women (133) were taking the drug as part of a polytherapy regimen (mean topiramate dose, 299 mg/day); the rest were on topiramate monotherapy (mean dose 245 mg/day).
Of all these pregnancies, 178 (88%) resulted in a live birth; there were a total of 31 congenital anomalies among these infants (16 major and 15 minor).
Among women on monotherapy, there were eight infants born with anomalies, three of which were considered major. Two infants had a cleft lip/palate, and one had hypospadias. The average daily dose of topiramate for the mothers of these infants was 400 mg/day, compared with the average 238 mg dose among women on monotherapy who had normal pregnancy outcomes.
The five minor anomalies in the monotherapy group were sacral dimple, “clicky” hips, plagiocephaly, webbed toes, and immature hip joints.
The combination of valproate with topiramate was associated with the highest rate of major congenital malformations (36%; 12 cases), followed by a regimen of three or more antiepileptic drugs (24%; 23 cases). Conversely, only 8% of polytherapy regimens that did not include valproate resulted in a major anomaly.
Janssen-Cilag, U.K. manufacturer of topiramate (Topamax), and other pharmaceutical firms provided unrestricted educational grants to help support to study. Several of the study authors have received honoraria from Janssen-Cilag and other pharmaceutical firms.