Evaluation of Long-term Outcomes Associated With Preterm Exposure to Antenatal Corticosteroids: A Systematic Review and Meta-analysis

Abstract

Importance: Animal studies have found that antenatal corticosteroids affect many organs across multiple stages of life. However, the long-term outcomes in human children are not well understood.

Objective: To conduct a systematic review and meta-analysis of long-term outcomes associated with preterm exposure to antenatal corticosteroids compared with no exposure in all children as well as children with preterm and full-term birth.

Data sources: Academic databases were searched for articles published from January 1, 2000, to October 29, 2021, including Ovid MEDLINE, Ovid Embase, PsycInfo, CINAHL (Cumulative Index of Nursing and Allied Health Literature), Web of Science, ClinicalTrials.gov, and Google Scholar. References of articles were also searched for relevant studies.

Study selection: Randomized clinical trials (RCTs), quasi-RCTs, and cohort studies that assessed long-term neurodevelopmental, psychological, or other outcomes at 1 year or older in those who had preterm exposure to antenatal corticosteroids were included. No language restrictions were set.

Data extraction and synthesis: Two reviewers independently extracted data using a piloted data extraction form. Data on study population, pregnancy characteristics, exposure to antenatal corticosteroids, and outcomes were collected. Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines were followed, and random-effects models were used for the meta-analysis.

Main outcomes and measures: The primary outcome was an author-defined composite of any adverse neurodevelopmental and/or psychological disorder. The secondary outcomes included specific measures of psychological disorders; neurodevelopmental delay; and anthropometric, metabolic, and cardiorespiratory outcomes.

Results: A total of 30 studies met the inclusion criteria, and involved more than 1.25 million children who were at least 1 year of age when the outcomes were assessed. Exposure to a single course of antenatal corticosteroids for children with extremely preterm birth was associated with a significant reduction in risk of neurodevelopmental impairment (adjusted odds ratio, 0.69 [95% CI, 0.57-0.84]; I2 = 0%; low certainty). For children with late-preterm birth, exposure to antenatal corticosteroids was associated with a higher risk of investigation for neurocognitive disorders (n = 25 668 children; adjusted hazard ratio [aHR], 1.12 [95% CI, 1.05-1.20]; low certainty). For children with full-term birth, exposure to antenatal corticosteroids was associated with a higher risk of mental or behavioral disorders (n = 641 487 children; aHR, 1.47 [95% CI, 1.36-1.60]; low certainty) as well as proven or suspected neurocognitive disorders (n = 529 205 children; aHR, 1.16 [95% CI, 1.10-1.21]; low certainty).

Conclusions and relevance: Results of this study showed that exposure to a single course of antenatal corticosteroids was associated with a significantly lower risk of neurodevelopmental impairment in children with extremely preterm birth but a significantly higher risk of adverse neurocognitive and/or psychological outcomes in children with late-preterm and full-term birth, who made up approximately half of those with exposure to antenatal corticosteroids. The findings suggest a need for caution in administering antenatal corticosteroids.

Figure 1.. PRISMA Diagram of Study Selection

Figure 2.. Primary and Adjusted Long-term Neurodevelopmental and Psychological Outcomes After Exposure to a Single Course of Antenatal Corticosteroids

The forest plots show the comparison between a single course of antenatal corticosteriods and no exposure. Each star represents 1 point and half of a star represents one-half point in the modified Newcastle-Ottawa Scale for assessing risk of bias across domains. Squares represent effect size estimates and the whiskers correspond to the 95% CIs. The diamonds represent the overall effect based on pooled data from all included studies for each outcome. OR indicates odds ratio.

Figure 3.. Primary and Adjusted Long-term Neurodevelopmental and Psychological Outcomes After Exposure to an Unspecified Number of Courses of Antenatal Corticosteroids

The forest plots show the comparison between an unspecified number of antenatal corticosteriod courses and no exposure. Each star represents 1 point and half of a star represents one-half point in the modified Newcastle-Ottawa Scale for assessing risk of bias across domains. On each forest plot, squares represent effect size estimates and the whiskers correspond to the 95% CIs. The diamonds represent the overall effect based on pooled data from all included studies for each outcome. HR indicates hazard ratio; OR, odds ratio.