Impact of Antenatal Corticosteroids on Brain Function and Underlying Mechanisms in Preclinical Studies: Protocol for a Systematic Review

Background Antenatal corticosteroid (ACS) treatment matures the fetal lung and reduces risks of neonatal morbidity and mortality in babies born preterm. However, ACS treatment also impacts the brain and stress regulatory systems, with increasing clinical evidence for adverse long-term impacts. Preclinical studies are important to investigate the mechanisms for these impacts. Objective This systematic review aims to synthesize the best available evidence describing how in utero exposure to ACS affects brain function, the underlying mechanisms, and the hypothalamic-pituitary-adrenal axis in nonhuman mammalian species. Methods This review will include peer-reviewed, primary studies that report measures of brain function (eg, learning, behavior) and the underlying mechanisms (eg, brain size, neuron number, myelination, hypothalamic-pituitary-adrenal axis function) in nonhuman mammals exposed in utero to ACS in the second half of pregnancy, in comparison to unexposed individuals. Initial search terms include (corticosteroid* OR glucocorticoid*) AND (antenatal OR fetal* OR pregnan*) AND (brain OR neurodevelopment*). We searched PubMed, Embase, MEDLINE (Ovid), Web of Science, Scopus, and ProQuest for English language publications without date restrictions. Two independent reviewers will perform abstract screening, data extraction, and quality assessment. Antenatal corticosteroid treatment information, study design, methods, and outcomes will be reported for each study. Results A narrative synthesis will be presented following standard guidelines. A dose-response meta-analysis will be performed where at least three studies report the same outcome following in utero exposure to the same steroid. As of February 21, 2026, title and abstract screening were completed for 42,024 of 56,493 records, with 40,795 records excluded. Searches will be updated in June-July 2026 to include sources published to the end of 2025. Publication is planned for 2027. Conclusions This review will inform future research including intervention studies to reduce the adverse effects of antenatal corticosteroids on the brain.