WASHINGTON — There is no evidence that lamotrigine monotherapy increases the risk of major congenital malformations in infants exposed prenatally to the drug, according to updated data from the International Lamotrigine Pregnancy Registry.
However, when the drug was used as adjunctive therapy along with valproate, the rate of major congenital malformations was significantly higher than the rate for the background population, reported Dr. John A. Messenheimer of GlaxoSmithKline, Research Triangle Park, N.C.
Since its inception in 1992, the lamotrigine registry has recorded 2,000 pregnancies exposed to the drug in the first trimester. The interim report on data up to September 2005 was presented as a poster at the joint annual meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society.
Most of the women (707) were taking lamotrigine as monotherapy, 256 were on polytherapy with lamotrigine but without valproate, and 119 were on polytherapy with lamotrigine and valproate.
Of the 20 major congenital malformations reported, two were club feet, two were cases of anencephaly, and three were ventricular septal defects. The remaining malformations included midline defects, urogenital defects, cortical dysplasia, hypoplastic left heart syndrome, hypoplasia of the left ventricle, and diaphragmatic hernia with abdominal organ displacement.
The malformation rate in women on lamotrigine monotherapy was 2.8%; the rate in those on polytherapy without valproate was 2.7%. The rate in women on polytherapy with valproate was 11.8%—significantly higher than the background population rate of 2%–3%.
There was no significant relationship between lamotrigine dosage and the incidence of malformation, Dr. Messenheimer said. The rate of malformations in women taking more than 400 mg/day was slightly elevated at 4%. But only 100 women were taking such a high dose, and the confidence intervals were wide
Published reports have identified a significantly increased risk of major congenital malformations among women taking valproate as monotherapy (10.7%). These studies prompted the American Epilepsy Society's pregnancy outcomes forum panel to recommend last year that valproate be avoided as a first-line therapy for any indication in women of childbearing age.
The lamotrigine registry could not determine whether valproate exposure alone could explain the higher rate of defects in the lamotrigine/valproate group. The numbers of antiepileptic drugs used may be inextricably tied to the frequency and severity of seizures, making it difficult to assess the contribution of each factor, he said.
In adults, lamotrigine is approved as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome and for conversion to monotherapy in adults with partial seizures who are receiving treatment. It is also approved for maintenance treatment of bipolar disorder, and it is a pregnancy category C drug.
Physicians are asked to report exposed pregnancies to the international registry by calling 800–336–2176 as soon as the pregnancy is identified. The complete interim report of the registry is available by calling the same number.