Efficacy and safety of antenatal corticosteroids in twin gestations at risk of late preterm birth: a systematic review and meta-analysis with trial sequential analysis

Late preterm birth (34⁰/⁷–36⁶/⁷ weeks) is associated with significant neonatal morbidity, with twin gestations carrying an approximately 50% higher risk compared to singletons. While antenatal corticosteroids (ACS) are well established before 34 weeks, their use in late preterm twins remains debated, with limited evidence to guide practice. From inception through March 2026, PubMed, Embase, Scopus, and Cochrane Library were systematically searched for studies evaluating antenatal corticosteroids in twin gestations at risk of late preterm birth. Eligible study designs included randomized controlled trials and observational studies; the included evidence comprised five retrospective cohorts and one randomized controlled trial. A random-effects model was applied across all analyses, and trial sequential analysis (TSA) was performed for each outcome. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool for randomized trials and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. PROSPERO (CRD420261374857). Six studies involving 9,109 mothers were included. ACS exposure was associated with a significantly increased incidence of neonatal hypoglycemia (RR = 1.60; 95% CI: 1.16, 2.22) and neonatal intensive care unit (NICU) admission (RR = 1.38; 95% CI: 1.02, 1.87), and with a small reduction in birthweight (MD = − 0.08 kg; 95% CI: −0.15, − 0.01). TSA confirmed conclusive evidence for hypoglycemia alone, with the required information size exceeded and the monitoring boundary for harm crossed. No significant differences were observed in respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), jaundice, mechanical ventilation, continuous positive airway pressure (CPAP) requirement, or composite respiratory morbidity, and TSA indicated absent evidence for all outcomes other than hypoglycemia. In late preterm twin gestations, ACS increased neonatal hypoglycemia, the only outcome with conclusive TSA evidence; NICU admission and a modest birthweight reduction were inconclusive, and no respiratory benefit was demonstrated. These data do not support routine ACS use in twins at risk of late preterm birth, and where it is given, neonatal hypoglycemia and NICU-level care should be anticipated. Adequately powered twin-specific randomized trials are needed.