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Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy

From the North American AED Pregnancy Registry (L.B.H., E.J.B., C.R.S., E.H., L.G., S.L.W.), Genetics and Teratology Unit, MassGeneral Hospital for Children, Boston; and Genetics Program (D.F.W.), Department of Medicine, Boston University School of Medicine, MA.

Address correspondence and reprint requests to Dr Holmes, Genetics Unit, MassGeneral Hospital for Children, CPZS-504, 175 Cambridge Street, Boston, MA 02114 holmes.lewis{at}mgh.harvard.edu

Background: Pregnancy registries for women taking anticonvulsant drugs have been developed to determine more efficiently the fetal risks of each drug. A total of 722 drug-exposed pregnancies are needed to identify a sevenfold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1,000.

Methods: The infants with major malformations born to the 791 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were identified. Medical records were obtained from the affected infants' doctors. A total of 107 of the 791 infants or pregnancies were excluded.

Results: A total of 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations that were identified at birth. Five infants (7.3/1,000) had oral clefts: isolated cleft palate (3), isolated cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine-exposed infants showed a 10.4-fold increase (95% CI: 4.3–24.9) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Women's Hospital in Boston, where the prevalence of isolated oral clefts was 0.7/1,000. A comparison was made also to 1,623 infants exposed to lamotrigine, as monotherapy, who had enrolled in five other registries. There were four infants with oral clefts: prevalence 2.5/1,000 (RR: 3.8, 95% CI: 1.4–10.0).

Conclusions: The infant exposed in the first trimester of pregnancy to the anticonvulsant drug lamotrigine has an increased risk to have an isolated cleft palate or cleft lip deformity.

GLOSSARY: AED = antiepileptic drug; BWH = Brigham and Women's Hospital; CL = cleft lip without cleft palate; CLP = cleft lip and palate; CP = cleft palate; LMP = last menstrual period.

e-Pub ahead of print on April 30, 2008, at www.neurology.org.

The North American AED Pregnancy Registry is supported by funds provided by Abbott, Eisai, GlaxoSmithKline, Novartis, Ortho-McNeil, and Pfizer Pharmaceuticals.

Disclosure: Each of the authors received salary support from funds provided since 1997 by the six sponsors of the Registry. At the time this manuscript was written, the sponsors were Abbott, Eisai, GlaxoSmithKline, Novartis, Ortho-McNeil, and Pfizer.

Received April 4, 2007. Accepted in final form November 19, 2007.

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