Gabapentin and Pregabalin Use in First Trimester of Pregnancy and Risk of Specific Congenital Anomalies: An IMI ConcePTION European Case-Malformed Control Study.

Abstract

Introduction and objective: Given the increasing use of gabapentinoids and ongoing safety concerns, we assessed the association between first-trimester exposure to gabapentin and pregabalin and the risk of specific congenital anomalies (CAs) in the offspring.

Methods: Using EUROmediCAT data, we conducted a case-malformed control study based on 170,126 registrants with major CAs from livebirths, fetal deaths (≥20 weeks), and terminations of pregnancy for fetal anomaly in nine European countries (2000-2020), covering 10.6 million births. We compared gabapentinoid use in registrants with a specific CA with those among other registrants with non-genetic CA (main control group) and among registrants with a genetic condition (secondary control group). We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for registry, birth year, and maternal age. Analyses included specific subgroups of CA with ≥3 exposed registrants.

Results: First-trimester gabapentinoid exposure was identified in 37 registrants, with most registered in the Valencian region (Spain) (37.8%), EFEMERIS (France) (13.5%) and three other registries (8.1% each). Over 60% of the exposures were observed during 2015-2020. Seven out of 91 EUROCAT subgroups had ≥3 exposed registrants: congenital heart defects, ventricular septal defects, severe congenital heart defects, limb anomalies, urinary anomalies, genital anomalies, and hypospadias. A significantly higher proportion of exposure (0.4‰, 12 exposed cases) was observed among cases with ventricular septal defect compared with registrants in the non-genetic control group (0.2‰, 17 exposed cases), with an adjusted OR of 2.5 (95% CI 1.1-5.3); and the adjusted OR was elevated but non-significant compared with the registrants in the genetic group (2.3; 95% CI 0.8-6.9).

Conclusions: We observed an association between first trimester exposure to gabapentinoids and ventricular septal defect, the most common cardiac anomaly, although this finding is based on only 37 exposed registrants. While our findings align with some previous studies suggesting teratogenic risks associated with gabapentinoids, they also reveal the challenges of studying rare exposures and rare outcomes.