There have long been questions about the possible role of ureaplasma in the pathogenesis of BPD. Studies have shown a statistical association between maternal colonization and BPD, between placentas showing evidence of the germ, and between neonatal endotracheal colonization and BPD.

Unfortunately it is not that easy to get rid of it, older therapies such as erythromycin were very poor at eliminating the organism, it often being still present at the end of a course of treatment, and previous RCTs have shown little efficacy of routine treatment with erythromycin. But, there are RCTS which have suggested a benefit of azithromycin, which is much more effective at eliminating the organism. One RCT, which had a null result, suggested a positive impact in the subgroup who subsequently turned out to have been colonized with ureaplasma. A systematic review from a couple of years ago suggested that ureaplasma-colonized babies had a reduction in BPD when treated with azithromycin, but the total sample size of the included studies was only 126, and the RR of the outcome “BPD among survivors at 36 weeks” was 0.8 (95% CI 0.66-1.03), and therefore was consistent with both a potential substantial benefit, as well as with no difference.

There was therefore a need for an adequately powered RCT, with a sample size large enough to include a significant number of babies colonized with ureaplasma. One has just been published, the AZTEC trial. Lowe J, et al. Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Respir Med. 2024. In this 796 trial babies <72 hours of age <30 weeks GA who had received some positive pressure support were randomized to a 10 day course of azithromycin (20 mg/kg/d for 3 days then 10).

The primary outcome was “death or BPD at 36 weeks”, with BPD being diagnosed if the baby was on O2 or respiratory support at 36 weeks. Sigh. I will bore you all again by reiterating that death and needing oxygen at 36 weeks are not equivalent, and, even if they are competing outcomes, it is easy to design and analyze such studies differently. Also, it is not necessary to censor mortality at 36 weeks, death after and before 36 weeks are equally important, and it is easy to include death before discharge, and a more appropriate measure of lung injury, in outcomes.

Nevertheless, the trial was registered in 2018, and therefore designed prior to that, I just hope that things are changing, and that future trials are designed to recognize the relative importance of different outcomes, and include outcomes that are of interest to families and to society as a whole.

Despite that caveat, this was a high-quality masked multi-centre trial, large enough to answer the major question, and large enough to include many ureaplasma positive infants. The results showed absolutely nothing! There was a 1% absolute increase in deaths with azithromycin, and a 2% absolute increase in BPD, which are clearly consistent with random effects. All subgroups, in particular the culture positive babies, of which there were 148, 66 azithromycin vs 82 controls, had no benefit from azithromycin,

All the other common NICU complications were also similar between groups, including late-onset sepsis, NEC and RoP.

Early azithromycin to eliminate ureaplasma and improve pulmonary outcomes in preterm infants is now a dead issue. I guess there could still be a role for azithromycin in infants who are developing BPD, still intubated, and in whom ET cultures are positive. That is something I have a done a few times over the last few years, but even in those infants, these data make me wonder if it is really indicated. In the supplemental data one can see that the primary outcome was only slightly higher among infants who were colonized with ureaplasma (65% in the azithromycin group and 56% in controls), compared to those who were not colonized (59% vs 56%).

Ureaplasma spp, and the less commonly found mycoplasma organisms, seem to have no important role in the pathogenesis of chronic lung disease of the preterm infant, probably being just an innocent bystander.