Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations

Abstract

Background: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). Methods: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. Results: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE)

“…Children exposed to LEV in the womb showed rates of MCMs comparable to those of control children [2,3,107], to the expected background rate, and to the rates of children exposed to low doses of LTG [4]. No dose-response association was found [2][3][4].…”

Contraception, fecundity, and pregnancy in women with epilepsy: an update on recent literature

“…In order to better understand the discrepancy, study personnel from EURAP and North American Antiepileptic Drug Pregnancy Registry (NAAPR) reviewed this report. Using the criteria of EURAP or NAAPR, the MCM rates with monotherapy exposure dropped to 3.6 and 1%, respectively [31]. This discordance was largely because of the levetiracetam registry classifying abnormalities that would be minor anomalies in the other registries or including abnormalities caused by a known genetic condition.…”

Assuring Access to Safe Medicines in Pregnancy and Breastfeeding

“…For example, the registries for lamotrigine and levetiracetam helped establish these products as lower risk to fetuses in mothers treated for epilepsy compared with valproate, carbamazepine, and topiramate, which has since been corroborated by data from the UK epilepsy in pregnancy registry. 22 Table 2 Physiologic changes in pregnancy that may alter pharmacokinetics and pharmacodynamics of medicines 17 Parameter Increase Decrease Comments The Antiretroviral Pregnancy Registry, which is supported by manufacturers of antiretrovirals, publishes their data every 6 months and has been useful in generating pregnancy safety data that have been added to labeling. Regulatory systems must be examined and optimized to ensure timely and efficient use of all available data resources, especially new tools applied to large healthcare databases to promote integrated approaches and cross-disciplinary activities.…”

“…As pregnancies are not rare events, more efficient and effective approaches should be considered by product developers to facilitate recruitment and retention, such as developing partnerships with disease registries, linking to electronic health record systems, incorporating new tools (e.g., mobile apps), and using advanced social and behavioral science techniques to overcome barriers. For example, the registries for lamotrigine and levetiracetam helped establish these products as lower risk to fetuses in mothers treated for epilepsy compared with valproate, carbamazepine, and topiramate, which has since been corroborated by data from the UK epilepsy in pregnancy registry 22 . The Antiretroviral Pregnancy Registry, which is supported by manufacturers of antiretrovirals, publishes their data every 6 months and has been useful in generating pregnancy safety data that have been added to labeling.…”

“…For example, the registries for lamotrigine and levetiracetam helped establish these products as lower risk to fetuses in mothers treated for epilepsy compared with valproate, carbamazepine, and topiramate, which has since been corroborated by data from the UK epilepsy in pregnancy registry. 22 The Antiretroviral Pregnancy Registry, which is supported by manufacturers of antiretrovirals, publishes their data every 6 months and has been useful in generating pregnancy safety data that have been added to labeling.…”