The anticonvulsant lamotrigine (Lamictal) is being used with increasing regularity for the treatment of women with bipolar disorder.  Back in 2006, we reported on preliminary data indicating an increased risk of oral clefts among infants exposed to lamotrigine during the first trimester of pregnancy.  It has been a while since we reviewed the data regarding the reproductive safety of lamotrigine, so this seems like a good time to review the data we have and to highlight the findings of a new study.

Just to review, Holmes and colleagues (2008) reported on 684 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry.  In this analysis, 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations identified at birth. Five infants (7.3/1,000) had oral clefts. This represented a 10.4-fold increase in comparison to a sample of 206,224 unexposed infants, where the prevalence of oral clefts was 0.7/1,000. The North American Registry did not find a dose-dependent effect on risk for oral clefts or overall malformations.

A comparison was also made to 1,623 infants exposed to lamotrigine as monotherapy who had been enrolled in five other registries. In this comparison group, there were four infants with oral clefts, representing a lower prevalence of 2.5/1,000, or a 3.8-fold increase in risk when compared to the unexposed controls.

The most recent study from Dolk and colleagues was a population-based case-control study utilizing data from the EUROCAT congenital malformation registries which included 10.1 million births from 21 registries between the years 1995 and 2011. (Note: This study is an extension of the study from Dolk and colleagues which included 3.9 million births from 19 registries between 1995 and 2005.)

First-trimester lamotrigine monotherapy exposure in oral cleft cases was compared to exposure in children with other non-syndromic congenital malformations (controls).  For all oral clefts, the adjusted odds ratio was 1.31 (95% confidence interval [CI] 0.73-2.33), 1.45 for isolated oral cleft (95% CI 0.80-2.63), and 1.69 for isolated cleft palate (95% CI 0.69-4.15). (When the 95% confidence interval includes the null value 1, there is insufficient evidence to conclude that there is a statistically significant difference between the two groups.)

The researchers also assessed risk for clubfoot, as an increased risk was associated with lamotrigine exposure in a previous study.  The adjusted odds ratio for clubfoot was 1.83 (95% CI 1.01-3.31) and 1.43 (95% CI 0.66-3.08) in the independent study population. No other specific congenital malformations were significantly associated with lamotrigine exposure.

The estimate of the risk for oral clefts relative to other malformations was statistically nonsignificant with an upper confidence limit of 2.3.  In their discussion, the authors note that we cannot rule out a small increase in risk; they estimate — based on the European oral cleft prevalence rate of 1.4 per 1,000 and an upper confidence limit of OR of 2.3 — exposure to lamotrigine would result in oral clefts in less than 1 out of every 550 exposed babies.  This study does not support the 6-fold risk suggested by the North American AED Registry and is more consistent with other studies published since the original report, studies which do not find an increased risk of oral clefts in lamotrigine-exposed children.

Ruta Nonacs, MD PhD

Dolk H, Wang H, Loane M, Morris J, et al.  Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016 Apr 6.. [Epub ahead of print]