Lamotrigine use in pregnancy and risk of orofacial cleft, an update of eurocat lamotrigine study

Background: Lamotrigine (LTG) is increasingly used during pregnancy. A FDA warning was issued for an association of LTG exposure and increased risk of orofacial clefts (OCs), based on data from the North American Antiepileptic Drug Pregnancy Registry (Holmes, 2006; Holmes et al., 2008). The signal was examined in the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database (Dolk, 2008). No significantly increased risk of OCs was found relative to other malformations, either for isolated orofacial clefts or for isolated cleft palate. There has been no independent confirmation of increased risk of OCs in relation to LTG from all studies in the literature combined (Dolk et al., 2012). Objectives: To investigate whether first trimester exposure to LTG monotherapy is specifically associated with an increased risk of OCs, using the EUROCAT antiepilepticstudy database including birth years up to 2010. Methods: A population-based case-control study with malformed controls was performed. The updated EUROCAT antiepileptic-study dataset included 226,806 live births, stillbirths, or terminations with malformations among 7.6 million births in 20 European countries from 1995 to 2010, more than twice the population of the original study. Cases were 10,523 nonsyndromic OC registrations, of whom 8,771 were isolated, and 3,789 cleft palate (CP) of whom 2,984 were isolated. Controls were 144,914 non-chromosomal, non-OC registrations. We compared first trimester LTG vs no antiepileptics (non- AED use), for mono and polytherapy. Results: There were 181 LTG exposed (109 mono- and 72 polytherapy) registrations. Thematernal age adjusted odds ratios (ORs) for LTG monotherapy vs non-AED use were 0.84 (95% CI 0.37-1.92) for OC relative to other malformations, 1.01 (95% CI 0.44-2.30) for isolated OC; 1.18 (95% CI 0.38-3.72) for CP, and 1.49 (95% CI 0.47-4.72) for isolated CP. Conclusions: This update does not change the conclusion of the original study: we found no evidence of an increased risk of isolated orofacial clefts relative to other malformations for LTG monotherapy exposure in the first trimester, nor any evidence of an increased risk for isolated cleft palate