Efficacy and safety of azithromycin in preventing bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis

Introduction Ureaplasma colonization in preterm infants is linked to pulmonary inflammation and bronchopulmonary dysplasia (BPD). Evidence regarding the effectiveness of macrolides, including their prophylactic role in preventing BPD, remains limited. This review aimed to assess whether azithromycin reduces the incidence of BPD or death in preterm infants, with or without Ureaplasma colonization, compared with placebo or no intervention. Methods We followed PRISMA guidelines and searched PubMed, Cochrane Library, Embase, and Google Scholar for randomized controlled trials (RCTs) evaluating azithromycin in preterm infants with unknown or confirmed Ureaplasma infection. Primary outcomes were death and BPD, while secondary outcomes included hospital stay, adverse events, and ventilation or oxygen duration. Studies not focused on preterm infants, lacking Ureaplasma status, or not randomized were excluded. Results A meta-analysis of six randomized controlled trials, including 1,446 preterm infants with unknown or confirmed Ureaplasma status and sample sizes ranging from 80 to 796, compared azithromycin with placebo. No significant reduction was observed in BPD incidence [risk ratio (RR) = 0.92, 95% CI: 0.78–1.09, p = 0.35] or mortality (RR = 0.88, 95% CI: 0.66–1.18, p = 0.39). Heterogeneity was low for mortality ( I 2 = 0%) and moderate for BPD ( I 2 = 61%). Secondary outcomes showed no significant differences in mechanical ventilation days (mean difference=0.07, 95% CI: −0.78 to 0.33, p = 0.58), supplemental oxygen requirement (mean difference=−0.45, 95% CI: −0.98 to 0.07, p = 0.09), or hospitalization duration (mean difference=−0.02, 95% CI: −0.19 to 0.15, p = 0.85). Heterogeneity ( I 2 ) was 94% for supplemental oxygen, 71% for mechanical ventilation, and 0% for hospitalization duration. Risk-of-bias assessment identified two studies with low risk and four with unclear risk, indicating acceptable methodological quality. Conclusion This systematic review and meta-analysis evaluated azithromycin efficacy and safety in preventing BPD and reducing mortality in preterm infants. No significant reduction in BPD or mortality was observed with azithromycin compared with placebo. Secondary outcomes, including ventilation duration, supplemental oxygen use, and hospitalization length, showed no improvement. However, heterogeneity among secondary outcomes was moderate to high, and included studies were limited. Systematic Review Registration PROSPERO CRD42024572847.