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

Pregnancies at risk for preterm birth are treated with antenatal corticosteroids, which have been found to lower the morbidity and mortality of preterm babies. Clinical guidelines advocate for the use of antenatal corticosteroids, although studies in animals have found an association between exposure to antenatal corticosteroids and harmful neurological outcomes, including diminished cortical surface, alterations to hypothalamic-pituitary-adrenal axis, decreased blood flow in specific brain areas, and loss of essential synaptic proteins. In addition, outcomes such as decreased hippocampal development have been reported in animals born at full-term after antenatal corticosteroids. Both preterm and full-term animals experienced effects on additional organs, such as reduced glomerular filtration rates. These concerning outcomes necessitate the critical research priority of understanding long-term implications for children after preterm exposure to antenatal corticosteroids. Thus, this study was a meta-analysis and systematic review of long-term outcomes resulting from (1) preterm exposure to a singular course of antenatal corticosteroids, or (2) preterm exposure to unspecified numbers of courses (although likely 1 course), both compared with no exposure. Because approximately half of children were exposed to antenatal corticosteroids and delivered at or after 35 gestational weeks, the authors conducted a meta-analysis and review of long-term outcomes in children with both preterm and full-term birth. Databases were used searching for observational studies, randomized clinical trials (RCTs), and quasi-randomized clinical trials assessing long-term neurodevelopment, psychological, and other outcomes post 1 year of age. The primary outcome entailed author-defined composite of adverse neurodevelopmental and/or psychological disorders. Secondary outcomes included psychological developmental disorders (eg, disorders of language and speech); mixed conduct and emotional disorders; autism spectrum disorders; social functioning, emotional, and tic disorders; mood, neurotic, stress-related, or psychotic disorders; clinical measures of anxiety; clinical measures of depression; eating disorders; special education needs; cerebral palsy, Bayley Scales of Infant and Toddler Development-II (BSID-II) Mental Development Score of less than 70 points; BSID-II scale psychomotor Developmental Index score of less than 70 points; BSID-III cognitive score less than 85 points; BSID-III language score less than 85 points; IQ scores; intellectual impairment, intellectual disability; and any other included neurodevelopmental and/or psychological outcomes. A total of 8577 titles and abstracts were screened for review, with 342 full-text articles chosen for assessment. Of these, 30 cohort studies met the final inclusion criteria, which held data for over 1.25 million children. Of these 30, 26 focused on neurodevelopmental and/or psychological outcomes, 3 included data on neurodevelopmental and/or psychological outcomes, and 1 included other outcomes data. The authors found that exposure to a single course of antenatal corticosteroids for children with extremely preterm birth was associated with a significantly reduced risk of neurodevelopmental impairment (adjusted odds ratio, 0.69; 95% CI, 0.57-0.84). In those with late-preterm birth, antenatal corticosteroids were associated with a higher risk of investigation for neurocognitive disorders (adjusted hazards ratio [aHR], 1.12; 95% CI, 1.05-1.20). For children with full-term birth, antenatal corticosteroids were associated with a higher risk of mental or behavioral disorders (aHR, 1.47; 95% CI, 1.36-1.60) as well as neurocognitive disorders (aHR, 1.16; 95% CI, 1.10-1.21). The strengths of the study included its comprehensive search via several academic sources, resulting in a thorough synthesis of long-term outcomes in preterm and full-term births. The inclusion of studies involving births that occurred in or after 2000 provided relevance to current neonatal care practice. In addition, the consideration of both single courses of antenatal corticosteroids and unspecified numbers of antenatal corticosteroid courses provided a comprehensive view of the long-term impacts. However, the study also has limitations, such as scarcity of follow-up data and possible bias from using observational data (which affects data quality). The authors of the study conclude that this systematic review and meta-analysis found an association between single course-exposure to antenatal corticosteroids and a significantly lower risk for neurodevelopmental impairment in extremely preterm birth, along with a substantially higher risk of adverse psychological and/or neurocognitive outcomes in full-term and late-preterm birth. As approximately 50% of children with preterm exposure to antenatal corticosteroids were born full-term, both dose and timing of steroid administration should be carefully considered.