Surfactant-budesonide combination to prevent death or bronchopulmonary dysplasia: a systematic review and meta-analysis

Introduction: Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity. We aimed to assess whether intratracheal administration of budesonide mixed with surfactant reduces mortality and BPD in preterm infants. Methods: We conducted a systematic review and meta-analysis of randomized and observational studies enrolling preterm neonates. PubMed, Scopus, and Web of Science were searched from inception to October 2025 without language or year restrictions. Studies comparing bolus administration of bovine or porcine surfactant mixed with budesonide versus surfactant alone were included. Random-effects meta-analyses using inverse variance weighting were performed to estimate risk ratios (RRs) with 95% confidence intervals (CIs). Certainty of evidence was assessed using GRADE. Results: Twenty randomized and five observational studies were included. Surfactant–budesonide combination therapy reduced mortality (RR 0.83, 95% CI 0.69–0.99; 18 studies, 5,117 infants) and BPD (RR 0.84, 95% CI 0.75–0.94; 25 studies, 5,732 infants). Mortality reduction was observed when all studies were pooled, with no significant difference between study designs. Prenatal steroid exposure was associated with greater mortality reduction. Reduction in BPD remained significant when restricted to randomized trials, irrespective of surfactant type. Sensitivity analyses excluding studies at high risk of bias yielded similar results. Certainty of evidence was moderate for both outcomes. Conclusions: Surfactant combined with budesonide may reduce mortality and BPD in preterm infants. However, the evidence remains insufficient to recommend the combination as generalized primary treatment for all preterm neonates. Future studies should incorporate pathophysiological phenotyping to identify infants most likely to benefit.