The International Registry, established in 1992, forms part of an epidemiologic safety program monitoring pregnancy outcomes in women exposed to lamotrigine (LTG). This primarily prospective observational study aims to assess the risk of all major malformations associated with first trimester exposure to LTG monotherapy. Data on LTG polytherapy and patterns of specific malformation types also are reviewed.
Physicians from around the world (31 countries) report exposure to LTG during pregnancy (therapy type, dose, and treatment duration) and subsequent outcomes to the registry on a voluntary basis. Details of how to enroll patients are available at http://www.inveresk.com/activereg/activereg.asp. Prospective reporting early in pregnancy is encouraged to increase the accuracy of treatment history and to avoid the bias associated with retrospective reporting. Physicians are then approached close to the expected delivery date to confirm treatment and epilepsy history during pregnancy and to ascertain the health of the infant. Major congenital malformations (MCMs) are almost always ascertained at birth or during the hospital stay by the attending physician. Malformations are classified according to the Centers for Disease Control (CDC) criteria, and the reports are reviewed by an independent pediatrician.
The percentage of MCMs is calculated for prospective first trimester LTG monotherapy and polytherapy exposures separately. Chromosomal abnormalities are not included in the numerator, as these are unlikely to be related to AED exposure during pregnancy. Retrospective cases are excluded from risk estimates but are reviewed to determine any patterns of malformation types. Conclusions are developed by a scientific advisory committee.
Between September 30, 1992, and March 31, 2004, 12 MCMs were observed among 414 monotherapy exposures, giving a risk of 2.9%[12 of 414; 95% confidence interval (CI), 1.6–5.1%]. This compares with risks of 2 to 3% in the general population (1) [as estimated through the Metropolitan Atlanta Congenital Defects Program (MACDP), which also uses CDC malformation classification criteria] and 3.3 to 4.5% in cohorts of women with epilepsy exposed to AED monotherapy reported in the literature (2–4). The Lamotrigine Registry currently has the power to detect a 1.79- to 2.00-fold increase in the risk of MCMs, assuming a baseline of 2 to 3%, as estimated from the MACDP.
The observed risk among 88 LTG and valproate (VPA) polytherapy exposures was 12.5% (11 of 88; 95% CI, 6.7–21.7%) and was 2.7% (five of 182; 95% CI, 1.0–6.6%) among 182 exposures to LTG polytherapy without VPA. No consistent pattern of malformation types was observed among monotherapy or polytherapy exposures.
The Lamotrigine Registry represents substantial data on one of the newer AEDs. The risk of MCMs after LTG monotherapy exposure appears to be similar to that in the general population, although the sample size is insufficient to allow definitive conclusions. The higher frequency of major malformations after LTG-VPA polytherapy exposure was consistent with that in publications on VPA monotherapy, although the registry is not powered to determine the individual contribution of each medication. Continued registration of exposed pregnancies will enhance the statistical power of the study and the data available for physicians to assess the benefit–risk ratio of LTG use in pregnancy.