Pregnancy and Fetal Outcomes Following Prenatal Exposure to Modafinil and/or Armodafinil: A 14-Year Registry Study

An interim analysis of the modafinil/armodafinil Pregnancy Exposure Registry (PER) revealed a potential increased risk of major congenital malformations (MCMs) associated with maternal exposure to these products. To further investigate this safety signal, a 14-year safety update was conducted using the final PER data. The aim of this study was to evaluate pregnancy and fetal outcomes associated with modafinil/armodafinil exposure.

This was a prospective, observational longitudinal cohort study conducted from 2010 to 2024. Women exposed to modafinil/armodafinil during pregnancy or within 6 weeks before becoming pregnant were included. Women enrolled before the knowledge of pregnancy outcome or birth defect detection were classified as prospective, whereas those enrolled after such knowledge were classified as retrospective. MCMs were adjudicated and classified based on the Metropolitan Atlanta Congenital Defects Program (MACDP). Descriptive statistics were used to analyze pregnancy outcomes including births, spontaneous abortions, elective terminations, fetal death, neurodevelopmental abnormalities, low/very low birth weight (LBW/very LBW), small for gestational age (SGA), and intrauterine growth restriction. Follow-up growth measurements were evaluated. MCM prevalence was compared with the MACDP population-based rate.

A total of 191 pregnancies (83.2% prospective and 16.8% retrospective) were enrolled. The mean maternal age was 31 years (SD = 4.5), and 182 (95.3%) had exposure during the first trimester. Outcomes were known for 179 pregnancies (93.7%). Among 156 prospective fetuses with known outcomes (83.0%), 137 (87.8%) resulted in live births, 17 (10.9%) in spontaneous abortions, and 2 (1.3%) in elective terminations. Among prospective live births, the prevalence of MCM was 13.1% (18/137, 95% CI, 8.0-20.0) overall and 13.7% after first trimester exposure, compared with the MACDP population-based rate of 3%. Other reported outcomes included 23 (16.8%) minor congenital malformations, 14 (10.2%) preterm births, 3 (2.2%) cases of IUGR, and 11 (8.0%) cases of LBW/VLBW; all were within the expected range of background rates. SGA was not reported. Growth parameters were within normal limits.

This 14-year prospective study of pregnant women exposed to modafinil/armodafinil reveals a higher prevalence of MCMs among live births compared with the general population. The study limitations and conflicting results across the literature highlight the need for future research to further investigate the potential teratogenic risks of modafinil/armodafinil.