Ureaplasma positivity and respiratory outcomes in very low birth weight infants: a cohort study with a nested double-blind randomized pilot trial of azithromycin

Background Ureaplasma spp. colonization/infection has been implicated in the inflammatory pathogenesis of bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW) infants, but the benefit of targeted macrolide therapy remains uncertain. We evaluated respiratory outcomes associated with early Ureaplasma positivity in VLBW infants and assessed feasibility and preliminary efficacy of a standardized intravenous azithromycin regimen in a nested pilot randomized trial. Methods This single-center study comprised (1) a retrospective cohort of inborn VLBW infants (< 1,500 g) born between July 2017 and December 2021 who underwent Ureaplasma screening within 24 h after birth, and (2) a prospective, double-blind, randomized, placebo-controlled pilot trial nested among Ureaplasma -positive infants requiring significant respiratory support. In the cohort, outcomes included moderate-to-severe and severe BPD at 36 weeks’ postmenstrual age and home oxygen therapy. Multivariable logistic regression adjusted for gestational age, sex, preterm premature rupture of membranes, histologic chorioamnionitis, antenatal steroid exposure, patent ductus arteriosus treatment, and sepsis. In the trial, infants were randomized 1:1 to intravenous azithromycin for 14 days (10 mg/kg/day for 7 days, then 5 mg/kg/day for 7 days) or placebo. Microbiologic response at 2 weeks and safety, including QTc, were assessed. Results Among 536 VLBW infants, 34 (6.3%) were Ureaplasma positive. Ureaplasma -positive infants had higher rates of moderate-to-severe BPD (76.5% vs. 41.0%), severe BPD (67.6% vs. 36.0%), and home oxygen therapy (46.2% vs. 19.1%). After adjustment, Ureaplasma positivity remained associated with moderate-to-severe BPD (adjusted odds ratio [aOR] 3.86, 95% confidence interval [CI] 1.44–10.35) and severe BPD (aOR 2.93, CI 1.21–7.10). In the pilot trial ( n = 26; 13 per group), moderate-to-severe BPD occurred in 61.5% (8/13) with azithromycin versus 84.6% (11/13) with placebo, and severe BPD in 46.2% (6/13) versus 76.9% (10/13). Loss of detectable Ureaplasma by culture at 2 weeks occurred in 13/13 azithromycin-treated infants, while 5/13 placebo infants remained positive. No QTc prolongation or clinically significant safety concerns attributable to azithromycin were observed. Conclusion Early Ureaplasma positivity in VLBW infants was associated with substantially worse respiratory outcomes. A two-week intravenous azithromycin regimen was feasible, microbiologically active, and showed directionally favorable estimates for BPD without an observed safety signal. Larger microbiology-guided trials are warranted. Trial registration KCT0002373 (registered 7 July 2017).