IMPORTANCE: Current evidence of the association between prenatal exposure to glucocorticoids and long-term mental disorders is scarce and has limitations. OBJECTIVE: To investigate the association between prenatal exposure to systemic glucocorticoids and mental disorders in offspring at the age of 15 years, comparing exposed vs unexposed offspring born to mothers with the same underlying disease (risk of preterm delivery and autoimmune or inflammatory disorders). DESIGN, SETTING, AND PARTICIPANTS: This nationwide population-based cohort study used data from registries in Denmark with follow-up until December 31, 2018. Participants included all Danish infants born alive from 1996 to 2016. Analyses were performed from January to December 2023. EXPOSURES: Prenatal exposure to systemic glucocorticoids. MAIN OUTCOMES AND MEASURES: Fifteen-year crude and adjusted risks, risk differences, and risk ratios (RR) for mental disorders using Kaplan-Meier estimator comparing exposed vs unexposed offspring born to mothers with the same underlying disease. RESULTS: A total of 1 061 548 infants (52% male) were included in the final study cohort, including 31 518 born to mothers at risk of preterm delivery and 288 747 born to mothers with autoimmune or inflammatory disorders. Among offspring born to mothers at risk of preterm delivery, the adjusted risks for exposed vs unexposed were 6.6% vs 4.3% (RR, 1.5 [95% CI, 1.2-1.9]) for autism spectrum disorders
1.6% vs 1.3% (RR, 1.3 [95% CI, 0.8-1.8]) for intellectual disabilities
5.8% vs 4.3% (RR, 1.3 [95% CI, 1.0-1.7]) for attention-deficit hyperactivity disorder (ADHD)
and 7.2% vs 4.6% (RR, 1.5 [95% CI, 1.1-2.0]) for mood, anxiety, and stress-related disorders. Among offspring born to mothers with autoimmune or inflammatory disorders, the adjusted risks for exposed vs unexposed were 4.8% vs 3.8% (RR, 1.3 [95% CI, 1.1-1.5]) for autism spectrum disorders
1.1% vs 0.8% (RR 1.4, [95% CI, 0.9-2.0]) for intellectual disabilities
5.5% vs 4.4% (RR, 1.3 [95% CI, 1.0-1.5]) for ADHD
and 6.6% vs 4.6% (RR, 1.4 [95% CI, 1.2-1.8]) for mood, anxiety, and stress-related disorders. Findings were confirmed through an active comparator and sibling design. However, confounding by disease severity could not be ruled out. CONCLUSIONS AND RELEVANCE: In this cohort study, prenatal exposure to glucocorticoids was associated with higher risk of some mental disorders. These data support continued caution in the use of glucocorticoids in pregnant people.