Mental Disorders Among Offspring Prenatally Exposed to Systemic Glucocorticoids

Abstract

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.

Figure 1.. Study Flow Diagram

The cohorts of offspring born to mothers at risk of preterm birth and offspring born to mothers with autoimmune or inflammatory disorders were not mutually exclusive.

Figure 2.. Fifteen-Year Risks, Risk Differences, and Relative Risks for Mental Disorders

Adjusted for year of conception; parity; maternal and paternal age at conception; maternal smoking during pregnancy; specific maternal autoimmune or inflammatory disorders; maternal and paternal neurodevelopmental disorders; maternal and paternal mood, anxiety, and stress-related disorders; maternal and paternal schizophrenia spectrum disorders; maternal and paternal substance use disorders; maternal polycystic ovarian syndrome; maternal use of comedications during pregnancy, including nonsteroidal anti-inflammatory drugs, other immunosuppressive agents, opioids, antiepileptic medications, antidepressants, antipsychotics, and stimulants; highest maternal educational level at conception; maternal country of origin; and civil status. For offspring born to mothers at risk of preterm delivery, we additionally adjusted for singleton/multiple pregnancy, gestational diabetes, preeclampsia, and maternal infections during pregnancy. Underlying number at risk and number of outcomes are provided in eTable 5 in Supplement 1. Kaplan-Meier curves are not presented due to Danish legislation regarding individual-level data. ADHD indicates attention deficit hyperactivity disorder; PEQ, prednisolone equivalents; RD, risk difference; RR, relative risk.