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), in June. The letter reports that there were 5 cases of oral clefts (3 cleft palates and 2 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 points out 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, which includes 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 MassGeneral 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, Dr. Holmes said.
“So this is something that women have to be told about,” and physicians “need to know this is a serious issue that's been raised and it is not a trivial sample size,” facts that should be brought up with their patients.
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. The abstract notes that the findings in a pregnancy registry “are the first step in developing the hypothesis of possible teratogenicity” (Birth Defects Res. A. Clin. Mol. Teratol. 2006;76:318).
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 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—phenytoin, phenobarbital, carbamazepine, and valproic acid—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. He added, however, that the folic acid dose was not specified, leaving open the possibility that women might not have been compliant.
Although he considers the findings significant, at this point, they “can only raise a hypothesis,” said Mr. Briggs, a professor of pharmacy at the University of California, San Francisco. “Consequently, women taking lamotrigine should be advised that exposure in the first trimester might increase the risk for isolated oral clefts [lip or palate], but the absolute risk [is] still low,” he said in an interview.
Mr. Briggs said he would counsel women who are on lamotrigine monotherapy and who may become pregnant that seizures can also have adverse effects on them and on the embryo and fetus, and he would recommend that they take 4–5 mg of folic acid with multivitamins and to abstain from smoking or drinking. “Changing to another second-generation anticonvulsant before conception is an option but no guarantee, because the other agents have not been adequately studied,” he said, noting that the same recommendations apply to a woman with bipolar disorder, if there is no other drug that can control her symptoms.
The GSK letter says that the company is currently discussing the new data with the Food and Drug Administration and regulatory officials in other countries, and when those discussions are concluded, GSK will update the label, pregnancy category, and other information. For now, GSK is encouraging physicians to register pregnant women exposed to lamotrigine before the fetal outcome is known.
The Lamotrigine Pregnancy Registry (the company's registry) can be contacted for more information at 800-336-2176. Women can enroll themselves in the NAAED registry by calling 888-233-2334.
FULL TEXT