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Ureaplasma, Azithromycin, and Varying Definitions of BPD (Bronchopulmonary Dysplasia) in Preterm Infants: Challenges for Clinical Care and Drug Development

Maher Ajour, Yasir Alsiraj, Aric Schadler, Hong Huang, Brandon Schanbacher, Kori Williams, Hubert O. Ballard, John Anthony Bauer*

Rationale: Bronchopulmonary Dysplasia (BPD) is the major pulmonary morbidity in preterm infants, with the defining criteria for this condition changing several times. Perinatal Ureaplasma infection has been implicated in BPD risks and known to be prevalent in Neonatal Intensive Care Unit (NICU) patient populations. Some studies have suggested the use of Azithromycin can reduce BPD risks in Ureaplasma positive cases.

Objectives: The goal of this study was to conduct a secondary data analysis using a completed clinical trial to compare the incidence and severity of BPD in preterm infants using multiple BPD definitions.

Methods and results: Secondary data analysis including 220 preterm infants enrolled at birth and randomized to receive Azithromycin or placebo daily up to 6 weeks was evaluated. Categorical variables were compared using Pearson Chi-square or Fisher’s Exact tests, as appropriate. Distributions of BPD grade outcomes and the benefits of Azithromycin using four historically different scoring systems (VON-1988, NIH-2001, NICHD-2018, and Jensen-2019) on the same patient data set were compared. Among 176 survivors of this population, grade II/moderate BPD was significantly different at 43.8% and 47.1% compared with 17% according to NIH- 2001, Jensen-2019 and NIH-2018 definitions, respectively. In addition, shifts in BPD grades according to these classifications were seen in grade III/severe BPD, significantly different at 35.8%, 35.8% and 9% according to NIH-2001, NIH-2018 and Jensen-2019 definitions. Only VON-1988 and NIH-2001 BPD grading resulted in an association of Ureaplasma positivity with BPD severity and Azithromycin treatment, showing overall reduction in BPD outcomes. In contrast, the two most recent BPD scoring systems showed no statistically significant differences between Ureaplasma positive vs. negative cases nor azithromycin benefits.

Conclusion: The incidence of BPD, a major morbidity of premature birth, differs based on the definition applied. The impact of Ureaplasma positivity on BPD outcomes, and the potential benefit of Azithromycin in patients with this infection, were also highly dependent on the BPD grading system employed. This issue has a great effect on clinical trial design to address consistency of diagnosis in BPD. The study illustrates how crucial BPD grading is for defining potential causative agents and therapeutic strategies.