Use of topiramate in relation to the risk of orofacial clefts

Background: The use of topiramate (TPM) has been increased among pregnant women. Safety data for TPM in human pregnancy are limited. Recent studies have suggested that exposure to TPM early in gestation has a higher risk of orofacial clefts (OCs), particularly cleft lip with or without palate, and there has been a Food Drug Administration (FDA) alert. Objectives: The aim of this study was to assess the risk of OCs relative to other malformations in infants whose mothers had taken TPM during the first trimester of pregnancy. Methods: A population-based case-control study with malformed controls was performed using the EUROCAT Antiepileptic (AED) Drug Database including data from 19 population-based registries of congenital anomaly in Europe with a total coverage of 8.0 million births from 1995 to 2011. Cases were 10 802 nonsyndromic OC registrations, of whom 8919 were isolated, and 6827 were cleft lip with or without cleft palate (CL/P). Controls were 136 838 nonchromosomal, non-OC registrations. We compared first trimester TPM use versus no-AED use, for monotherapy and polytherapy. Results: Exposure to TPM monotherapy was recorded for a total of 12 registrations, with one registration in the case group (isolated cleft palate) and 11 in the control group (odds ratio (OR) 1.15, 95% CI 0.03-7.95 for OC relative to other malformations, OR 4.03, 95%CI 0.09-27.8 for isolated cleft palate). No registration of CL/P was in TPM monotherapy exposure. There were 36 registrations exposed to TPM polytherapy, of whom six with isolated CL/P, three with cleft palate. Out of 36 of TPM polytherapy, 19 included valproic acid, 8 included carbamazepine and 4 included lamotrigine. The OR for TPM polytherapy versus no-AED use was 4.23 (95%CI 1.75-9.28) for OC, 4.35 (95%CI 1.31- 11.5) for isolated CL/P and 3.85 (95%CI 0.75- 12.5) for isolated cleft palate. Conclusions: The prevalence of TPM monotherapy exposure was five times lower in these data than reported in the United States, which limited our ability to confirm or refute previous findings. We found an excess of OCs, particularly CL/P, associated with TPM polytherapy. Further attention to TPM polytherapy is warranted.