Clinical Update 2020: Lamotrigine (Lamictal) and Pregnancy
Ruta Nonacs, MD PhD, MGH Center for Women's Mental Health
July 28th, 2020

Maintenance treatment with a mood stabilizer during pregnancy can significantly reduce the risk of relapse in women with bipolar disorder; however, many of the mood stabilizers commonly used in this setting, including lithium and valproic acid, carry some degree of teratogenic risk. In contrast, lamotrigine (Lamictal) appears to be a much safer option for use during pregnancy.

Initial reports raised concerns about an increased risk of oral clefts in children exposed to lamotrigine. In 2006, Holmes and colleagues reported on 684 women enrolled in the North American AED Pregnancy Registry who had received lamotrigine as monotherapy during pregnancy. 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.

In a comparison analysis including 1,623 lamotrigine-exposed infants from five other registries, 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.

However, more recent (and larger) studies have not documented an association between lamotrigine exposure and risk for oral clefts or any other types of malformations. Dolk and colleagues conducted 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. First-trimester lamotrigine monotherapy exposure in oral cleft cases was compared to exposure in children with other non-syndromic congenital malformations (controls). This study did not observe any increase in risk of oral clefts in infants exposed to lamotrigine monotherapy.

In the most recent meta-analysis, researchers analyzed a total of 21 studies describing pregnancy outcomes and rates of congenital malformations (Pariente et al, 2017). Compared with disease-matched controls (n = 1412) and healthy controls (n = 774,571), prenatal exposure to lamotrigine (LTG) monotherapy was not associated with an increased risk of major malformations.

References:
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]

Pariente G, Leibson T, Shulman T, Adams-Webber T, Barzilay E, Nulman I. Pregnancy Outcomes Following In Utero Exposure to Lamotrigine: A Systematic Review and Meta-Analysis. CNS Drugs. 2017 Apr 22.