A new analysis of registry data from European countries does not support a risk of orofacial cleft and clubfoot with exposure to lamotrigine monotherapy, in contrast to signals from previous studies of the antiepileptic drug.
First author Helen Dolk, Dr.P.H., professor of epidemiology and health services research and the head of the center for maternal, fetal, and infant research at the University of Ulster in Coleraine, Northern Ireland, and her colleagues analyzed data from 10.1 million births exposed to antiepileptic drugs including lamotrigine (Lamictal) as a monotherapy during the first trimester between 1995 and 2011. The births were recorded in 21 population-based registries from 16 European countries. The outcomes of interest were major congenital malformations in general, as well as orofacial clefts and clubfoot (Neurology. 2016 April 6. doi: 10.1212/WNL.0000000000002540).
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Assessment of all antiepileptic drug-exposed congenital malformation registrations revealed that 12% of pregnant registrants were exposed to lamotrigine monotherapy, with an additional 7% exposed to lamotrigine as part of polytherapy. A total of 77.1% of pregnant women exposed to lamotrigine monotherapy had records indicative of a diagnosis of epilepsy. The proportion of lamotrigine monotherapy exposures was observed to have increased over the study period, likely based on a movement away from the traditional use of valproate because of teratogenic concerns.
A total of 147 lamotrigine monotherapy-exposed babies with congenital malformations not attributable to chromosomal irregularities were identified from the total sample. The odds ratio for having a child with orofacial clefts after exposure to lamotrigine monotherapy was 1.31 (95% confidence interval, 0.73-2.33). Based on these data, the authors said they estimated exposure to lamotrigine would result in orofacial clefts in fewer than 1 in every 550 exposed babies.
The odds ratio for having a child with clubfoot after exposure to lamotrigine monotherapy was 1.83 (95% CI, 1.01-3.31). Although the study results confirmed the statistically significant signal for an overall excess of clubfoot risk found in a previous study conducted by this research team that analyzed births during 1995-2005, the investigators could not reproduce this result in an independent study population of 6.3 million births during 2005-2011(odds ratio, 1.43; 95% CI, 0.66-3.08). There were no significant differences in the risk for developing any other congenital malformations associated with lamotrigine monotherapy, the investigators said.
The authors said their results were in accord with those from several previous studies that did not detect an increased risk of orofacial clefts. In addition, they said statistically significant independent evidence of a clubfoot excess was not detected in the current study, despite findings from their previous study suggesting an increased risk.
The EUROCAT Central Database was funded by the EU Public Health Programme. GlaxoSmithKline, which markets lamotrigine, provided a grant for additional funding of this study. Dr. Dolk and her coauthors reported that their institutions received funding from GlaxoSmithKline for data or staff time contributed to this study.