While anticonvulsants, such as lamotrigine (Lamictal), topiramate (Topamax), and gabapentin (Neurontin), are being used with increasing regularity for the treatment of women with bipolar disorder, we have limited information with respect to the reproductive safety of the newer anticonvulsant agents.  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.

In this study from Lewis Holmes and his colleagues (which was published in 2008), 684 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were included in the 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.

In another study, Dolk and colleagues assessed the association between oral clefts and exposure to lamotrigine using a population-based case-control study utilizing data from the EUROCAT congenital malformation registries. The study population included 3.9 million births from 19 registries from 1995 to 2005. Registrations included congenital anomalies among live births, stillbirths, and terminations of pregnancy following prenatal diagnosis.

The authors identified 5,511 cases of non-syndromic oral cleft.  The control group consisted of 80,052 cases of non-chromosomal, non-oral cleft malformations.  There were 72 lamotrigine-exposed (40 mono- and 32 polytherapy) cases.  In this study, there was no evidence of an increased risk of isolated oral clefts relative to other malformations among infants exposed to lamotrigine.

In an editorial comment, Meador and Penovich note that these discrepancies seen in these various studies may reflect the small numbers of lamotrigine-exposed cases with oral clefts used to calculate these estimates of risk. They also point out some of the limitations of AED registries; they are not randomized trials, and selection bias may occur. Further, important factors are not always assessed, including anticonvulsant dose and levels and potential confounders, such as race/ethnicity, smoking, alcohol use, and exposure to other medications.  Clearly more data are essential to better evaluate the reproductive safety of lamotrigine; important questions regarding the safety of lamotrigine and other anticonvulsants might be best addressed by collaboration between multiple registries, including EURAP and the North-American Anti-Epileptic Drug Registry.

Overall the data are reassuring.  While these data may signal an increase in risk of malformations in children exposed to lamotrigine, it is important to put this risk into perspective. If we assume that the findings from the North American registry are true, the absolute risk of having a child with cleft lip or palate is about 0.7%. While some women may elect to discontinue treatment with lamotrigine given the magnitude of this risk, many women with more brittle bipolar illness may require treatment with some type of mood stabilizer during pregnancy.

The alternatives to lamotrigine may carry an ever greater risk. For example, exposure to valproic acid during the first trimester carries an unacceptably high risk of major malformations (over 10% in some samples), including neural tube defects. First trimester exposure to lithium has been associated with an increased risk of cardiovascular malformation estimated to be between 1 in 2000 (0.05%) and 1 in 1000 (0.1%).  At this point, data regarding the reproductive safety of the newer anticonvulsants and atypical antipsychotic agents is sparse. Thus, some women may elect to continue treatment with lamotrigine, acknowledging that, while there may be risks associated with this exposure, other treatment options also carry some risk.

Ruta M. Nonacs, MD PhD

Holmes LB et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology. 2008 May 27;70(22 Pt 2):2152-8. Epub 2008 Apr 30.

Dolk H et al. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology. 2008 Sep 2;71(10):714-22. Epub 2008 Jul 23.

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