Timing of intratracheal administration of budesonide mixed with surfactant to prevent bronchopulmonary dysplasia: a systematic review and meta-analysis.

UNLABELLED: The aim of this study was to evaluate whether intratracheal budesonide mixed with surfactant prevents bronchopulmonary dysplasia (BPD) and whether timing contributes to heterogeneity. We searched MEDLINE, Embase, CENTRAL, Web of Science, and trial registries for randomised controlled trials of budesonide-surfactant versus surfactant alone. Random-effects meta-analyses yielded risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias with RoB 2 and certainty of evidence with GRADE. A post hoc subgroup analysis classified trials by whether treatment was restricted to within 4 h after birth or permitted after 4 h. We included 15 trials (3522 infants); 14 trials (3494 infants) reported BPD at 36 weeks' postmenstrual age (BPD36). The overall analysis suggested a reduction in BPD36 (RR 0.71; 95% CI, 0.59-0.86; I2 = 68%), although heterogeneity was substantial. BPD36 was reduced in trials restricting treatment to within 4 h (RR 0.58; 95% CI, 0.46-0.72; eight trials; 1065 infants), but not in trials permitting later treatment (RR 0.98; 95% CI, 0.91-1.06; four trials; 2011 infants; P for subgroup difference < 0.00001). The composite outcome of BPD or death showed a similar pattern. Mortality and most other neonatal outcomes did not differ between groups. CONCLUSION: In trials restricting treatment to within 4 h after birth, budesonide-surfactant therapy may reduce BPD36; however, this post hoc, trial-level finding is hypothesis-generating and may reflect differences between earlier small and contemporary large trials. Current evidence does not support routine budesonide-surfactant therapy. A large prospective trial of early administration is needed to determine whether timing modifies benefit. TRIAL REGISTRATION: PROSPERO (CRD42024547670). WHAT IS KNOWN: • Earlier small trials suggested that budesonide mixed with surfactant reduces BPD, whereas recent large multicentre trials found little or no benefit. • The source of the marked heterogeneity among trials remains uncertain. WHAT IS NEW: • Trials restricting treatment to within 4 h showed reductions in BPD36 and BPD or death, whereas trials permitting later treatment showed no benefit. • This post hoc association with timing may reflect study-level confounding and small-study effects and requires confirmation.