High Doses of Topiramate for Epilepsy in Pregnancy Increase Risks for Oral Clefts in Offspring

baby with cleft lip
baby with cleft lip
Women receiving topiramate for epilepsy were exposed to high cumulative doses, increasing the risk for oral clefts in offspring.

Data suggest that the use of topiramate in the first trimester of pregnancy increases the risk for oral clefts in offspring, particularly infants born to women with epilepsy because of higher drug doses, according to the results of a population-based cohort study published in Neurology.

The study included a cohort of 1,360,101 pregnant women with a live-born infant who were enrolled in Medicaid from 3 months prior to conception through 1 month following delivery. The number of pregnancies eligible for analysis was  2425 in the topiramate-exposed arm, 1,322,955 in the unexposed arm, and 2796 in the lamotrigine reference group.

The risk for development of oral clefts was 4.1 per 1000 live births in the topiramate group, 1.1 per 1000 live births in the unexposed group, and 1.5 per 1000 live births in the lamotrigine group. This translates to an adjusted risk ratio (aRR) for oral clefts linked to topiramate exposure of 2.90 (95% CI, 1,56-5.40) compared with the unexposed group, and 2.38 (95% CI, 0.71-7.96) compared with the lamotrigine-exposed group.

In addition, in women with epilepsy the risk for having a child with an oral cleft at birth was 12.3 per 1000 topiramate-exposed newborns (aRR 8.30; 95% CI, 2.65-26.07), and  in women without epilepsy the risk for oral clefts was 2.1 per 1000 topiramate-exposed infants (aRR 1.45; 95% CI, 0.54-3.86).

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In women with epilepsy, the median daily dose for the initial topiramate prescription filled in the first trimester was 200 mg compared with 100 mg in women without epilepsy. In women receiving first-trimester topiramate monotherapy, the risk for oral clefts in women treated with daily doses ≤100 mg was 2.4 per 1000 live births (aRR 1.64; 95% CI, 0.53-5.07). In women receiving daily topiramate doses >100 mg, the risk for oral clefts was 7.3 per 1000 live births (aRR 5.16; 95% CI, 1.94-13.73). The results were similar compared with the lamotrigine group.

The investigators concluded that the study findings support avoiding high doses of topiramate in women of childbearing age in order to prevent exposure early in pregnancy, unless the benefits clearly outweigh the risks. The observed risk ratios reported in this study translate to a risk of approximately 5 cases of oral clefts per 1000 pregnancies exposed to topiramate at daily doses >100 mg in the first trimester.


Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study [published online December 27, 2017]. Neurology. doi:10.1212/WNL.0000000000004857