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, Northern 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 when they consider medication changes, said Dr. Martha Morrell, director of the Columbia Comprehensive Epilepsy Center, New York.
“The first objective of treatment is to control seizures,” she said in an interview. “Seizures during pregnancy place the mother at risk for injury and may also pose risk for the fetus. These results will be compared to data coming from other pregnancy registries as they become available. In the meantime, women taking topiramate should not make any adjustment in medications without consulting a physician.”
The analysis was drawn from the U.K. Epilepsy and Pregnancy Register, a prospective observational registry and follow-up study that tracks pregnancy outcomes among women in the United Kingdom who are taking antiepileptic medications. 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. Dosage had no significant effect on gestational age or birth weight.
The five minor anomalies in the monotherapy group were sacral dimple, “clicky” hips, plagiocephaly, webbed toes, and immature hip joints.
In the polytherapy group, there were 23 malformations, 13 of which were considered major. The major anomalies included pyloric stenosis, anal atresia, hypospadias, cleft palate, talipes, and dislocated hips. The average daily dosage for mothers of infants with a major anomaly was 342 mg, which was not significantly higher than the average dose of 294 mg/day for mothers on polytherapy who had normal infants. As in the monotherapy group, there were no significant dosage associations with gestational age or birth weight.
The combination of valproate with topiramate as duotherapy 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.
“It is not clear if this is a consequence of an interaction between the drugs, a reflection of unidentified patient characteristics, or due to valproate, which has increasingly been shown to be associated with a high risk of major congenital malformations,” Dr. Hunt and his colleagues wrote.
The results are particularly compelling in light of the rapid expansion of indications for topiramate, which in 2004 was approved for prophylaxis of migraine—a condition that is much more common than epilepsy among women of childbearing years, the authors noted.
Janssen-Cilag, U.K. manufacturer of topiramate (Topamax), and other pharmaceutical firms provided unrestricted educational grants to help support the study. Several of the study authors have received honoraria from Janssen-Cilag and other pharmaceutical firms.