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Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations?

From EUROCAT Central Registry (H.D., M.L.), Faculty of Life and Health Sciences, University of Ulster, UK; Social Pharmacy (J.J., L.T.W.d.J.-v.d.B.), Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands; Wolfson Institute of Preventive Medicine (J.M.), Barts and the London, Queen Mary’s School of Medicine and Dentistry, UK.

Address correspondence and reprint requests to Prof. Dr. Lolkje de Jong–van den Berg, Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands, Ant. Deusinglaan 1, 9713 AV Groningen l.t.w.de.jong-van.den.berg{at}rug.nl

Objective: To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk.

Methods: Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995–2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use.

Results: There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10–2.34) for OC relative to other malformations, 0.80 (95% CI 0.11–2.85) for isolated OC, 0.79 (95% CI 0.03–4.35) for CP, and 1.01 (95% CI 0.03–5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03–1.93) for OC, 1.21 (95% CI 0.82–1.72) for isolated OC, 2.37 (95% CI 1.54–3.43) for CP, and 1.86 (95% CI 1.07–2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed.

Conclusion: We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

Abbreviations: AED = antiepileptic drug; ATC = Anatomic Therapeutic Chemical; CP = cleft palate; FDA = Food and Drug Administration; LTG = lamotrigine; OC = orofacial cleft.

Editorial, page 706

e-Pub ahead of print on July 23, 2008, at www.neurology.org.

*Members of The EUROCAT Antiepileptic Drug Working Group are listed in appendix 1.

Disclosure: The EUROCAT Central Database is funded by the EU Public Health Programme. The additional funding for this study was obtained from Glaxo Smith Kline. GSK approved the design of the study before funding it, but was not involved in the conduct or management of the study, or analysis or interpretation of data or preparation of the manuscript. GSK commented on the draft manuscript, but the authors were free to publish their own interpretation. There are no other conflicts of interest.

Received November 2, 2007. Accepted in final form March 6, 2008.

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				Risk for Orofacial Cleft with Lamotrigine Use in Pregnancy Journal Watch Neurology, November 25, 2008; 2008(1125): 4 - 4. [Full Text]

				K. J. Meador and P. Penovich What is the risk of orofacial clefts from lamotrigine exposure during pregnancy? Neurology, September 2, 2008; 71(10): 706 - 707. [Full Text] [PDF]