Report on the Association Between Prenatal Exposure to Systemic Glucocorticoids and Offspring Mental Disorders

Academic Background

Glucocorticoids are widely used among pregnant women, particularly those at high risk of preterm birth or with autoimmune disorders. These treatments can reduce neonatal morbidity and mortality or alleviate symptoms by suppressing inflammation. While glucocorticoids play an important role in fetal development, especially in the central nervous system (CNS), excessive exposure may increase the risk of mental disorders in offspring through various mechanisms. Although prior studies have explored this association, many suffer from small sample sizes, short follow-up durations, or insufficient control of confounding factors. Thus, the medical and obstetric communities have called for further research to clarify the risks of using glucocorticoids in pregnant women.

Source of the Paper

This study was conducted by Dr. Kristina Laugesen, Dr. Nils Skajaa, Dr. Irene Petersen, and other scholars from institutions such as Aarhus University Hospital in Denmark, University College London, and Odense University Hospital. The research was published on January 3, 2025, in the JAMA Network Open journal and is titled “Mental Disorders Among Offspring Prenatally Exposed to Systemic Glucocorticoids.”

Study Design and Methods

Study Design

This nationwide, population-based cohort study was conducted using Denmark’s national registry data, covering all live births from 1996 to 2016, with follow-up until December 31, 2018. The primary objective was to compare the risk of mental disorders at age 15 between offspring prenatally exposed to systemic glucocorticoids and those unexposed.

Study Population

The study ultimately included 1,061,548 live births. Among these, 31,518 were born to mothers at risk of preterm delivery, and 288,747 were born to mothers with autoimmune or inflammatory diseases. Exposure groups were compared to unexposed groups, with the exposed group defined as offspring of mothers who used systemic glucocorticoids during pregnancy and the unexposed group consisting of offspring of mothers who did not.

Exposure Definition

For women with preterm risk, exposure was defined as the use of glucocorticoids (e.g., betamethasone) during pregnancy. For mothers with autoimmune or inflammatory diseases, exposure was defined as using glucocorticoids (e.g., prednisolone) at least once during pregnancy. Exposure was further categorized by cumulative dose into low (<250 mg), medium (250-499 mg), and high (≥500 mg).

Primary Outcomes

The study assessed the risk of four categories of mental disorders: autism spectrum disorders (ASD), intellectual disabilities, attention deficit hyperactivity disorder (ADHD), and mood, anxiety, and stress-related disorders. Diagnoses were based on inpatient and outpatient hospital records in Denmark’s national patient registry.

Statistical Analysis Methods

The study used Kaplan-Meier estimators to calculate 15-year crude and adjusted risks and employed standardized morbidity ratio weighting to control for confounders. Sensitivity analyses included sibling-matched comparisons, dose-response analysis, and active comparator assessments to ensure the robustness of the findings.

Key Results

Outcomes in the Preterm Risk Group

For women at risk of preterm delivery, the adjusted risks for exposed versus unexposed offspring were as follows:
- ASD: 6.6% vs. 4.3% (Relative Risk [RR], 1.5; 95% CI, 1.2-1.9)
- Intellectual Disabilities: 1.6% vs. 1.3% (RR, 1.3; 95% CI, 0.8-1.8)
- ADHD: 5.8% vs. 4.3% (RR, 1.3; 95% CI, 1.0-1.7)
- Mood, Anxiety, and Stress-related Disorders: 7.2% vs. 4.6% (RR, 1.5; 95% CI, 1.1-2.0)

Outcomes in the Autoimmune/Inflammatory Disorder Group

For women with autoimmune or inflammatory diseases, the adjusted risks for exposed versus unexposed offspring were:
- ASD: 4.8% vs. 3.8% (RR, 1.3; 95% CI, 1.1-1.5)
- Intellectual Disabilities: 1.1% vs. 0.8% (RR, 1.4; 95% CI, 0.9-2.0)
- ADHD: 5.5% vs. 4.4% (RR, 1.3; 95% CI, 1.0-1.5)
- Mood, Anxiety, and Stress-related Disorders: 6.6% vs. 4.6% (RR, 1.4; 95% CI, 1.2-1.8)

Sensitivity Analyses

Through sibling-matched analysis and comparisons to active controls, the findings were confirmed to be robust. The sibling-matched analysis indicated a composite relative risk of 1.4 (95% CI: 0.5-3.9) in the preterm group and 1.3 (95% CI: 1.0-1.6) in the autoimmune/inflammatory group.

Conclusions and Relevance

This study found that prenatal exposure to systemic glucocorticoids is associated with an increased risk of certain mental disorders in offspring. Although the absolute risk increases were small to moderate, these findings support cautious use of glucocorticoids in pregnant women. Future studies should focus on minimizing unnecessary glucocorticoid exposure, especially among women with a low risk of preterm birth, and exploring safer alternative therapies for autoimmune or inflammatory disorders during pregnancy.

Research Highlights

1. Innovative Design: The study reduced confounding by comparing exposed and unexposed offspring born to mothers with the same underlying disease.
   
2. Large Sample Size: Over 1 million infants were included, lending significant statistical power.
   
3. Long Follow-up Duration: The study tracked mental health outcomes up to 15 years.
   
4. Comprehensive Analyses: Sensitivity and dose-response analyses confirmed the robustness of the findings.
   

Study Limitations

1. Confounding Factors: Despite multiple strategies to control for confounding, residual confounding from disease severity cannot be ruled out.
   
2. Exposure Classification: Medication adherence could not be measured, potentially leading to exposure misclassification.
   
3. Follow-up Duration: While follow-up duration was extensive, even longer follow-up may provide additional insights into lifelong risks.
   

Summary

This study provides new evidence linking prenatal glucocorticoid exposure to an increased risk of mental disorders in offspring, emphasizing the need for caution in its use during pregnancy. Future research should focus on reducing unnecessary exposure and evaluating alternative therapeutic options.