Lamotrigine Exposure Linked to Oral Clefts


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, nonsyndromic 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.

“This was the first study big enough to be able to look at the frequency of specific major malformations,” Dr. Holmes said in an interview. He pointed out that earlier studies from the company registry and the United Kingdom registry with smaller sample sizes looked at all malformations and showed a modest increase in the rate of major malformations but did not have enough patients to pick up increases in specific malformations.

At the meeting, he reported that a greater risk of oral clefts was also detected in five other registries, suggesting the same association. In those registries, there were four oral clefts reported among 1,623 lamotrigine-exposed infants, for a frequency of 2.5/1,000 compared with 0.37/1,000 in the comparison group. “So this is something that women have to be told about,” Dr. Holmes said.

This information has to be put into a practical perspective, and physicians should discuss the absolute risk with patients, Dr. Holmes said. Based on the data he presented, the absolute risk of having an infant with an oral cleft is close to 1%—and is much less than 1% based on the other data—so “it's still a very small risk and it is a very treatable problem,” he pointed out.

Gerald G. Briggs, B.Pharm., a pharmacist clinical specialist at the Women's Pavilion, Miller Children's Hospital, Long Beach, Calif., who was at the Teratology Society meeting, said that this information “is significant because this is the first report of teratogenicity in a second-generation anticonvulsant.” All of the first-generation anticonvulsants are known to have teratogenic effects.

Furthermore, none of the women whose infants had oral clefts was a smoker, which has been associated with isolated oral clefts in some studies, and all were taking folic acid supplements at conception, so folic acid did not appear to be protective, he pointed out.

GSK's letter says the company is discussing the new data with the Food and Drug Administration and regulatory officials in other countries. GSK is encouraging physicians to register pregnant women exposed to lamotrigine before the fetal outcome is known.

GSK's Lamotrigine Pregnancy Registry can be contacted for more information at 800-336-2176. Women can enroll themselves in the NAAED registry by calling 888-233-2334.

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