Lamotrigine exposure linked to oral clefts.(Obstetrics)

After several years of little indication that lamotrigine was linked to specific birth defects, a major pregnancy registry has found a significant increase in the risk of oral clefts associated with first-trimester use of lamotrigine monotherapy.

Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry detected "an elevated prevalence" of isolated, non-syndromic oral clefts in infants exposed to lamotrigine monotherapy during the first trimester, when compared with a reference population, according to a "Dear Health Care Professional" letter issued by the drug's manufacturer, GlaxoSmithKline (GSK), last month.

The letter reports that there were five cases of oral clefts (three cleft palates and two cleft lips) among 564 pregnancies exposed to lamotrigine monotherapy in the first trimester, for a rate of 8.9/1,000. Based on these numbers, the prevalence of oral cleft is 24 times higher among lamotrigine-exposed neonates than the prevalence of 0.37/1,000 in the general population at the Brigham and Women's Hospital surveillance program, the letter says.

The letter notes that the prevalence of oral clefts in the Massachusetts General Hospital-run NAAED registry is also greater than the background prevalence of nonsyndromic oral clefts ranging from 0.50 to 2.16 per 1,000 reported in the literature, including studies from the United States, Australia, and Europe.

Lamotrigine, marketed as Lamictal by GSK, is approved as a treatment for seizures and for maintenance therapy in bipolar I disorder. It is classified as a pregnancy category C drug, and its label reads that while no evidence of teratogenicity has been found in animals, the drug has been found to reduce folate concentrations in rats, an effect "known to be associated with teratogenesis in animals and humans."

Because there are no adequate and well-controlled studies in pregnant women, lamotrigine "should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus," according to the label.

The five cases described in the GSK letter were reported by Dr. Lewis B. Holmes, chief of the genetics and teratology unit at Massachusetts General Hospital for Children, Boston, and director of the North American AED pregnancy registry, at the Teratology Society meeting in June.