Search

Purpose: The International Lamotrigine Pregnancy Registry monitored for a signal of a substantial increase in the frequency of major congenital malformations associated with lamotrigine exposures in pregnancy over an 18-year period. Key methodological lessons are discussed., Methods: The strengths and weaknesses of the Registry were assessed using quantifiable methodological and operational parameters including enrollment, completeness of exposure and outcome data reporting, and lost to follow-up. The choice of comparator groups and stopping rules for registry closure were critically evaluated., Results: The reliance on voluntary reporting was associated with a clustered geographical distribution of registered pregnancies. The enrollment rate increased over time with new approvals and indications for lamotrigine and publication of interim data. Reporter burden was minimized through a streamlined data collection approach resulting in a high level of completeness of exposure and primary outcome data. Lost to follow-up rates were high (28.5% overall) representing a major limitation; incentives to increase the completeness of reporting failed to reduce rates. A lack of an internal comparator group complicated data interpretation; but external comparisons with multiple external groups allowed an assessment of consistency of outcome data across multiple data sources. A lack of a priori closure criteria prolonged the life of the Registry, and consideration of regulatory guidelines on this subject is encouraged at the time of conception of future registries., Conclusions: A successful pregnancy exposure registry requires ongoing flexibility and continuous re-assessment of enrollment, recruitment, and retention methods and the availability of comparison data, throughout its lifecycle., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure., Methods: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates., Results: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed., Discussion: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

The chronic nature of epilepsy treatment, as well as the peak in incidence in children and adolescents, makes it likely that women of childbearing age will be exposed to antiepileptic drugs (AEDs). This has led to the establishment of several pregnancy registries to monitor the safety of anticonvulsants in terms of the risk of major birth defects following in utero exposure. Many registries are now approaching their second decade of data collection. With the release of substantial information on a range of AEDs (both older and newer generation drugs), it becomes increasingly important to understand how the methodological variations between cohorts may affect the risks of major birth defects being reported. This chapter explores the key methodological elements of these registries in terms of patient enrolment, the source of exposure and outcome information, outcome definition and ascertainment and comparator groups and how these elements may influence the reported risk estimates. With multiple registries collecting and releasing substantial data on AED safety in pregnancy, the chapter also reflects on how an increasing number of "signals" around increased risk of specific birth defects is likely. Possible methods for interpreting such signals, that the registries were not originally designed to detect and interpret, are also discussed.