Assessment of non-cardiac congenital malformations and in utero exposure to modafinil/armodafinil in the Sentinel Distributed Database

Background: PROVIGIL® (modafinil, U.S. FDA approval 1998) and NUVIGIL® (armodafinil, U.S. FDA approval 2007) are wakefulness promoting agents. Some but not all previous studies have reported an association between in utero exposure to modafinil/armodafinil and increased risk of major congenital malformations.

Objectives: Compare the risk of non-cardiac malformations among pregnancies exposed to modafinil/armodafinil in the first trimester to pregnancies exposed to methylphenidate, amphetamines, or unexposed.

Methods: We conducted a retrospective cohort study among four participating Data Partners with mother-infant linkage data in the United States Sentinel Distributed Database. The study period included data from January 1, 2000, to December 31, 2022. We included females aged 10-54 years with evidence of a live birth linked to an infant record, who had no evidence of known teratogen use or chromosomal abnormalities in the current pregnancy. Patients could contribute multiple pregnancies.

We evaluated the occurrence of non-cardiac congenital malformations and compared the exposed (modafinil/armodafinil) and referent groups matched 1:1 on propensity score. For each comparison, we used conditional logistic regression models to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). We also considered musculoskeletal and urinary malformations separately.

Results: We identified 813 modafinil/armodafinil exposed pregnancies that were propensity matched to referent pregnancies. The prevalence of non-cardiac malformations was 4.51%, among modafinil/armodafinil exposed pregnancies and 4.23%, 5.58%, and 4.95% among unexposed, methylphenidate, and amphetamine exposed pregnancies, respectively. Modafinil/armodafinil exposure was not associated with non-cardiac malformations when compared to unexposed (OR 0.93, 95% CI 0.68, 1.26) or amphetamines exposed (OR 1.09, 95% CI 0.78, 1.52) and inversely associated when compared to methylphenidate exposed (OR 0.67, 95% CI 0.50, 0.89). There was no association with modafinil/armodafinil exposure and increased risk of non-cardiac malformations when stratified by age. Modafinil/armodafinil exposure was not associated with musculoskeletal (OR vs. amphetamines 0.89, 95% CI 0.45, 1.75) or urinary malformations (OR vs. amphetamines 1.50, 95% CI 0.60, 3.74).

Conclusions: Our study has several strengths including the use of a validated outcome algorithm and relatively large sample size. However, the study is limited by potential exposure and outcome misclassification. Overall, our results do not indicate that modafinil/armodafinil exposure during the first trimester is associated with increased risk of non-cardiac congenital malformations.