Macrolides for the prevention of bronchopulmonary dysplasia in preterm neonates.

rationaleBronchopulmonary dysplasia (BPD) continues to be the most frequent complication of prematurity despite advances in neonatal care. It occurs from interactions between antenatal exposures, postnatal oxygen, ventilation-mediated injury as well as other postnatal injuries that induce a proinflammatory state in an immature developing lung. Macrolides, particularly azithromycin, have anti-inflammatory actions that may play a role in preventing BPD. A current review is required to investigate whether macrolide use in the highest-risk patient population, intubated and ventilated very preterm and very low-birthweight infants, have benefits that outweigh any harms when used for the prevention of BPD.

objectivesTo evaluate the benefits and harms of: 1. macrolide antibiotics in the prevention of BPD in preterm neonates compared to no intervention; and 2. different subtypes of macrolides in preventing BPD in preterm neonates compared to other macrolides. SEARCH

methodsWe searched CENTRAL, MEDLINE, Embase, and trial registries. We conducted reference checking. The latest search date was June 2025. ELIGIBILITY CRITERIA: We included randomised and quasi-randomised trials in very and extremely preterm infants (less than 32 weeks' gestational age) or very and extremely low-birthweight infants (less than 1500 g), or both, requiring mechanical ventilation, and at risk of developing BPD, who received either a macrolide or placebo/no intervention. This included studies comparing macrolide versus macrolide. We excluded trials that enrolled: 1. only infants with Ureaplasma colonisation (and not all 'at risk' ventilated infants); 2. a broader group of infants, most of whom were not ventilated, who were only at risk because of their size and birthweight, and where specific outcome data for ventilated preterm infants were unobtainable. OUTCOMES: Our outcomes were BPD at 36 weeks' postmenstrual age (PMA); death before discharge; adverse effects including gastrointestinal upset, hepatic dysfunction, prolonged corrected QT interval (QTc) and cardiac arrhythmias, pyloric stenosis; and use of postnatal steroids to prevent or treat BPD prior to discharge. RISK OF BIAS: We used the Cochrane RoB 1 tool to assess risk of bias. SYNTHESIS

methodsWe synthesised results for each outcome using meta-analysis where possible, calculating risk ratios (RR) and risk difference with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Where MD was not calculable, we summarised the results using the Synthesis Without Meta-analysis (SWiM) method. We used GRADE to assess the certainty of evidence. INCLUDED STUDIES: We included six studies involving a total of 1108 infants providing macrolide or placebo (saline)/no intervention from 72 hours of age. Five studies (1033 infants) investigated the effects of intravenous azithromycin compared to placebo. The included studies were conducted in high- and upper-middle-income countries. Studies varied in the i) macrolide prescribed (azithromycin (five studies) and erythromycin (one study)) and ii) duration of intervention (three days to six weeks). All participants were very preterm and very low-birthweight infants requiring intubation and ventilation at the time of randomisation. SYNTHESIS OF

resultsWe judged all six studies as at low risk of bias for most domains; one study was at unclear risk of bias for selective reporting, and another study was at unclear risk of bias for blinding. We downgraded the overall certainty of evidence for all outcomes due to serious or very serious concerns regarding imprecision (e.g. small number of infants, and the 95% CI including the possibility of both important benefit and harm). Any macrolide compared with placebo or no intervention Use of any macrolide may result in little to no difference in BPD at 36 weeks' PMA (RR 0.95, 95% CI 0.86 to 1.06; 6 studies, 1041 participants; low-certainty evidence). Macrolides may result in a slight reduction in death before discharge (RR 0.89, 95% CI 0.66 to 1.19; 6 studies, 1108 participants; low-certainty evidence). Macrolides may result in a reduction in gastrointestinal upset (RR 0.47, 95% CI 0.20 to 1.11; 2 studies; 91 participants; low-certainty evidence). Macrolides may result in little to no difference in hepatic dysfunction (RR 1.09, 95% CI 0.59 to 1.99; 4 studies, 391 participants; low-certainty evidence); prolonged QTc and cardiac arrhythmias (Not estimable; 2 studies, 136 participants; low-certainty evidence); and pyloric stenosis (Not estimable; 2 studies, 136 participants; low-certainty evidence). Macrolides may reduce the use of postnatal steroids to prevent or treat BPD prior to discharge (RR 0.74, 95% CI 0.54 to 1.02; 4 studies, 391 participants; low-certainty evidence). In a subgroup analysis restricted to the use of azithromycin compared with placebo (five studies), azithromycin may result in little to no difference in BPD at 36 weeks' PMA (RR 0.93, 95% CI 0.84 to 1.04; 5 studies, 966 participants; low-certainty evidence). Azithromycin may result in a slight reduction in death before discharge (RR 0.92, 95% CI 0.68 to 1.24; 5 studies, 1033 participants; low-certainty evidence). Azithromycin may result in a reduction in gastrointestinal upset (RR 0.47, 95% CI 0.20 to 1.11; 2 studies, 91 participants; low-certainty evidence). Azithromycin may result in little to no difference in hepatic dysfunction (RR 1.09, 95% CI 0.59 to 1.99; 4 studies, 391 participants; low-certainty evidence); prolonged QTc and cardiac arrhythmias (Not estimable; 2 studies, 136 participants; low-certainty evidence); and pyloric stenosis (Not estimable; 2 studies, 136 participants; low-certainty evidence). Azithromycin may reduce the use of postnatal steroids to prevent or treat BPD prior to discharge (RR 0.74, 95% CI 0.54 to 1.02; 4 studies, 391 participants; low-certainty evidence). AUTHORS'

conclusionsThe use of macrolides, specifically azithromycin, for the prevention of BPD in very preterm infants at high risk of developing BPD, may result in little to no difference in BPD at 36 weeks' PMA, defined as requiring oxygen or respiratory support at 36 weeks' PMA. They may result in a slight reduction in death before discharge and a reduction in gastrointestinal upset. There may be little to no difference between groups in hepatic dysfunction, prolonged QTc and cardiac arrhythmias, or pyloric stenosis. Importantly, azithromycin may reduce the use of postnatal steroids to prevent or treat BPD prior to discharge.

fundingThis Cochrane review had no dedicated funding. REGISTRATION: Protocol (2022) DOI: 10.1002/14651858.CD015063.