Upper Airway Manifestations and Otolaryngologic Management of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review

Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens. To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials. Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded. Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence. Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I² = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I² = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regimen.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

Free oxygen radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. Superoxide dismutase (SOD) is a naturally occurring enzyme which provides a defense against such oxidant injury. Providing supplementary SOD has been tested in clinical trials to prevent BPD in preterm infants. To determine the efficacy and safety of SOD in the prevention and treatment of BPD on mortality and other complications of prematurity in infants at risk for, or having BPD. We searched CENTRAL, PubMed, Embase, and three trials registers on 22 September 2022 together with reference checking, citation searching and contact with study authors to identify additional studies. Randomized, quasi-randomized and cluster-randomized controlled trials (RCTs) where the participants were preterm infants who had developed, or were at risk of developing BPD, and who were randomly allocated to receive either SOD (in any form, by any route, any dose, anytime) or placebo, or no treatment. We used standard Cochrane methods. Our primary outcomes were BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality, mortality prior to discharge, and BPD or death at 36 weeks' postmenstrual age. We reported risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for the dichotomous outcomes. We used GRADE to assess certainty of evidence for each outcome. We included three RCTs (380 infants) on SOD administration in preterm infants at risk for BPD, and no studies in preterm infants with evolving BPD / early respiratory insufficiency. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days (RR 1.09, 95% CI 0.94 to 1.26; RD 0.06, 95% CI -0.05 to 0.16, 1 study, 302 infants; I2 for RR and RD not applicable), BPD defined as oxygen at 36 weeks' postmenstrual age (RR 0.96, 95% CI 0.72 to 1.29; RD -0.01, 95% CI -0.11 to 0.09, 2 studies, 335 infants; I2 for RR and RD = 0%), neonatal mortality (RR 0.98, 95% CI 0.57 to 1.68; RD -0.00, 95% CI -0.08 to 0.07, 2 studies, 335 infants; I2 for RR and RD = 0%), and mortality prior to discharge (RR 1.20, 95% CI 0.53 to 2.71; RD 0.04, 95% CI -0.14 to 0.23, 2 studies, 78 infants; I2 for RR and RD = 0%). No studies reported BPD or death at 36 weeks' postmenstrual age. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage (RR 0.95, 95% CI 0.78 to 1.15; RD -0.03, 95% CI -0.15 to 0.08, 2 studies, 335 infants; I2for RR = 0%, I2 for RD = 8%), and severe retinopathy of prematurity (ROP) (RR 0.97, 95% CI 0.57 to 1.65; RD -0.01, 95% CI -0.10 to 0.09, 1 study, 244 infants; I2 for RR and RD not applicable). No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. Certainty of evidence was very low for all outcomes. We identified no ongoing trials. The evidence is very uncertain about the effect of SOD on BPD defined as an oxygen requirement at 28 days, BPD defined as oxygen at 36 weeks' postmenstrual age, neonatal mortality and mortality prior to discharge compared to placebo. No studies reported BPD or death at 36 weeks' postmenstrual age and need for supplemental oxygen. The evidence is very uncertain about the effect of SOD on retinopathy of prematurity any stage and severe retinopathy of prematurity. No studies reported moderate to severe neurodevelopmental outcome at 18 to 24 months. The effects of SOD in preterm infants has not been reported in any trial in the last few decades, considering that the most recent trial on SOD in preterm infants was conducted in 1997/1998, and no new studies are ongoing. In the light of the limited available evidence, new data from preclinical and observational studies are needed to justify the conduction of new RCTs. Observational studies might report how SOD is administered, including indication, dose and association with relevant outcomes such as mortality, BPD and long-term neurodevelopment.

To investigate the risk factors for moderate/severe bronchopulmonary dysplasia (BPD) in preterm infants with a gestational age of <32 weeks. A retrospective analysis was performed on the medical data of preterm infants with a gestational age of <32 weeks and a length of hospital stay of ≥28 days who were admitted to the neonatal intensive care unit (NICU) of 17 institutions of Jiangsu Neonatal Perinatal Cooperation Network from January 1, 2019 to December 31, 2020 and were diagnosed with BPD. The preterm infants were grouped according to gestational age and severity of BPD. A multivariate logistic regression analysis was used to investigate the risk factors for moderate/severe BPD in various gestational age groups. During the two-year period, a total of 2 603 preterm infants with a gestational age of <32 weeks were admitted to the NICU of the 17 institutions, among whom 961 were diagnosed with BPD, and the incidence rates of BPD and moderate/severe BPD were 36.92% (961/2 603) and 8.64% (225/2 603), respectively. The incidence rate of moderate/severe BPD was 56.5% (26/46) in preterm infants with a gestational age of 24+0-25+6 weeks, 31.0% (66/213) in those with a gestational age of 26+0-27+6 weeks, 16.9% (75/445) in those with a gestational age of 28+0-29+6 weeks, and 22.6% (58/257) in those with a gestational age of 30+0-31+6 weeks. The multivariate logistic regression analysis showed that there were different risk factors for moderate/severe BPD in preterm infants with different gestational ages: patent ductus arteriosus requiring treatment as risk factors in preterm infants with a gestational age of 24+0-25+6 weeks; premature rupture of membranes ≥18 hours, positive pressure ventilation for resuscitation, clinical sepsis, and duration of mechanical ventilation ≥14 days as risk factors in preterm infants with a gestational age of 26+0-27+6 weeks; duration of mechanical ventilation ≥14 days, neonatal pneumonia, and patent ductus arteriosus requiring treatment as risk factors in preterm infants with a gestational age of 28+0-29+6 weeks; positive pressure ventilation for resuscitation, neonatal pneumonia, and anemia of prematurity as risk factors in preterm infants with a gestational age of 30+0-31+6 weeks (P<0.05). The development of moderate/severe BPD is multifactorial in preterm infants with a gestational age of <32 weeks, and there are different risk factors in different gestational age groups. Targeted preventive measures for preterm infants of different gestational ages may be useful to reduce the severity of BPD.

The aim of the study is to determine clinical correlates of moderate to severe bronchopulmonary dysplasia (BPD) in preterm infants following surgical necrotizing enterocolitis (NEC). This is a retrospective, single-center cohort study comparing patients with moderate to severe BPD to patients with non/mild BPD among surgical NEC infants. BPD was defined by NIH 2001 consensus definition. Of 92 consecutive neonates with surgical NEC, 77% (71/92) had moderate/severe BPD and 22% (21/92) had non/mild BPD. The patent ductus arteriosus (PDA) was significantly higher in those developing moderate/severe BPD (67.6% [48/71]) than non/mild BPD (28.6% [6/21]; p = 0.001). Postoperatively, infants with moderate/severe BPD had more severe acute kidney injury (AKI; 67.6 [48/71] vs. 28.6% [6/21]; p = 0.001), were intubated longer (40.5 [interquartile (IQR): 12, 59] vs. 6 days [IQR: 2, 13]; p <0.001), received more parenteral nutrition (109 [IQR: 77, 147] vs. 55 days [IQR: 19, 70]; p <0.001), developed higher surgical morbidity (46.5 [33/71] vs. 14.3% [3/21]; p = 0.008), had more intestinal failure (62.5 vs. 13.3%; p <0.001), required a longer hospital stay (161 [IQR: 112, 186] vs. 64 days [IQR: 20, 91]; p <0.001), and were more likely to need home oxygen. In a multivariable analysis, lower birth weight (OR = 0.3, [95% confidence interval (CI): 0.1-0.5]; p = 0.001), PDA (OR = 10.3, [95% CI: 1.6-65.4]; p = 0.014), and longer parenteral nutritional days (OR = 8.8; [95% CI: 2.0-43.0]; p = 0.005) were significantly and independently associated with higher odds of moderate/severe versus non-/mild BPD. Development of moderate/severe BPD occurred in the majority of preterm infants with surgical NEC in this consecutive series. Preterm infants with moderate/severe BPD were more likely to have a PDA before NEC. Development of moderate/severe BPD was associated with significantly greater burden and duration of postoperative morbidity following surgical NEC. Identifying surgical NEC infants at increased risk of moderate/severe BPD and developing lung protection strategies may improve surgical NEC outcomes. · Three-fourths of preterm infants experienced severe lung injury following surgical NEC.. · The infants with severe moderate/severe BPD were most likely associated with greater duration of postoperative morbidity.. · There is need to understand and develop lung protective strategies in infants with surgical NEC..

We previously demonstrated the safety and feasibility of mesenchymal stem cell (MSC) transplantation for bronchopulmonary dysplasia (BPD) in preterm infants in a phase I clinical trial. We thus investigated the therapeutic efficacy of MSCs for BPD in premature infants. A phase II double‐blind, randomized, placebo‐controlled clinical trial was conducted on preterm infants at 23 to 28 gestational weeks (GW) receiving mechanical ventilator support with respiratory deterioration between postnatal days 5 and 14. Infants were stratified by 23 to 24 GW and 25 to 28 GW and randomly allocated (1:1) to receive stem cells (1 × 107 cells/kg, n = 33) or placebo (n = 33). Although the inflammatory cytokines in the tracheal aspirate fluid were significantly reduced with MSCs, the primary outcome of death or severe/moderate BPD in the control group (18/33, 55%) was not significantly improved with MSC transplantation (17/33, 52%). In the subgroup analysis, the secondary outcome of severe BPD was significantly improved from 53% (8/15) to 19% (3/16) with MSC transplantation in the 23 to 24 GW group but not in the 25 to 28 GW subgroup. In summary, although MSC transplantation might be safe and feasible, this small study was underpowered to detect its therapeutic efficacy in preterm infants at 23 to 28 GW. Accordingly, we are now conducting an additional larger and controlled phase II clinical trial focusing on infants at 23 to 24 GW (NCT03392467). ClinicalTrials.gov identifier: NCT01828957.

Objective: To study the association between Sirtuin1 (Sirt1), a class III histone deacetylator, in tracheal aspirate (TA) leukocytes and the development of bronchopulmonary dysplasia (BPD) in premature infants and modulation of Sirt1 with dexamethasone (Dex) use. Design/methods: Serial TA samples were collected on days 1, 3, 5 and 7 from ventilated premature neonates. Sirt1 was localized by immunocytochemistry and quantified on a scale of 0–4 by blinded observers. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). Results: A total of 130 TA samples were collected from 51 infants (mean ± SD: GA 25.5 ± 1.4 w, BW 762 ± 174 g). Eleven infants survived without BPD and 40 infants died before 36 weeks PMA or developed BPD. Sirt1 was localized in the cytoplasm and nuclei of mononuclear (MONO) as well as polymorphonuclear cells. Sirt1 was significantly more localized in the nuclei of MONO cells in infants without BPD compared to infants who developed BPD or died before 36 weeks PMA. Twenty six infants received Dex. There was no significant change in Sirt1 localization with steroid therapy. Conclusions: Lower Sirt1 in TA leukocytes is associated with the development of BPD or death in premature infants. Dex use had no effect on Sirt1.

Association of increased cord blood soluble endoglin with the development of bronchopulmonary dysplasia in preterm infants with maternal preeclampsia.

To determine whether angiopoietin-1 and endostatin levels in the cord blood could predict the subsequent development of bronchopulmonary dysplasia (BPD) in preterm infants. A total of 102 preterm (gestational age ≤ 32 weeks) infants (28 infants developed BPD and 74 had no BPD) were enrolled in the study. Cord plasma levels of angiopoietin-1 and endostatin were measured by enzyme-linked immunosorbent assay. Preterm infants who subsequently developed BPD had significantly lower cord plasma levels of angiopoietin-1 than those who did not (p < 0.001). Our results showed that cord plasma levels of endostatin were significantly higher in infants with BPD than in those without (p < 0.001). In infants with BPD, angiopoietin-1 levels in cord plasma correlated negatively with endostatin (r = -0.48; p = 0.008). In preterm infants, low-angiopoietin-1 and high-endostatin levels in cord plasma at birth predict the subsequent development of BPD.

To study the influencing factors for the development and severity of bronchopulmonary dysplasia (BPD) in preterm infants with a gestational age of <32 weeks and a birth weight of <1 500 g. A retrospective analysis was performed on the medical data of preterm infants with a gestational age of <32 weeks and a birth weight of <1 500 g who were admitted to Women and Children's Hospital Affiliated to Xiamen University from January 1, 2017 to December 31, 2021. According to oxygen dependence on day 28 after birth, they were divided into two groups: BPD (n=218) and non-BPD (n=142). According to disease severity based on oxygen concentration required at the corrected age of 36 weeks or at discharge, the infants with BPD were divided into two groups: mild BPD (n=154) and moderate/severe BPD (n=64). Indices such as perinatal data and nutritional status were compared between groups. The multivariate logistic regression analysis was used to determine the influencing factors for BPD and its severity. The incidence rate and severity of BPD increased with the reduction in gestational age and birth weight (P<0.05). The multivariate logistic regression analysis showed that a long duration of invasive mechanical ventilation (OR=1.320, P<0.05), hemodynamically significant patent ductus arteriosus (OR=2.032, P<0.05), and a prolonged time to reach oral calorie goal of 110 kcal/(kg·d) (OR=1.041, P<0.05) were risk factors for BPD, while an older gestational age was a protective factor against BPD (OR=0.535, P<0.05). Early-onset sepsis (OR=2.524, P<0.05) and a prolonged time to reach oral calorie goal of 110 kcal/(kg·d) (OR=1.029, P<0.05) were risk factors for moderate/severe BPD, while a high mean weight growth velocity was a protective factor against moderate/severe BPD (OR=0.906, P<0.05). The incidence rate and severity of BPD in preterm infants with a gestational age of <32 weeks and a birth weight of <1 500 g can be reduced by shortening the duration of invasive mechanical ventilation, giving early treatment of early-onset sepsis and hemodynamically significant patent ductus arteriosus, adopting active enteral nutritional strategies, and increasing mean weight growth velocity.

Objective:Vitamin D deficiency is associated with asthma and reactive airway disease in childhood but its potential contribution to bronchopulmonary dysplasia (BPD) in preterm infants is unknown. Preterm infants have lower levels of 25-hydroxyvitamin D (25(OH)D) at birth and are at risk for nutritional deficiencies after birth. The objective of the study was to evaluate the association of 25(OH)D concentrations at birth and at 36 weeks' corrected gestational age with BPD in preterm infants born before 29 completed weeks of gestation.Study Design:We collected umbilical cord blood samples from 44 preterm infants (gestational age <29 weeks) delivered at Brigham and Women's Hospital in Boston. In addition, with parental consent we collected venous samples at 36 weeks' corrected age from 20 preterm infants born before 29 weeks' gestation (including 6 infants with previously collected cord blood). Samples were frozen at −80 °C until subsequent measurement of 25(OH)D levels by chemiluminescence. We used multivariable logistic models to adjust for gestational age and considered other confounding variables, including maternal race, age, mode of delivery and infant sex.Results:Among 44 infants, 41 (93.2%) survived and 3 (6.8%) died before 36 weeks' corrected age. Median 25(OH)D levels at birth were 30.4 ng ml−1 in preterm infants who subsequently died or developed BPD and 33.8 ng ml−1 in infants who survived without BPD (P=0.6). Median 25(OH)D levels at corrected age of 36 weeks were 59.0 ng ml−1 among survivors without BPD and 64.2 ng ml−1 among survivors with BPD (P=0.9). Neither cord blood nor 36 weeks' corrected 25(OH)D levels were associated with odds of death or BPD (adjusted odds ratio (OR) 1.00, 95% confidence interval (CI): 0.73 to 1.37; and OR 0.93, 95% CI: 0.61 to 1.43, respectively).Conclusions:Among this population of extremely preterm infants neither cord blood nor the 36 weeks' corrected age 25(OH)D levels were associated with development of BPD. Notably, at the current level of supplementation, all extremely preterm infants in our cohort had achieved 25(OH)D levels >30 ng ml−1 by 36 weeks' corrected age, which is thought to represent sufficiency in adult and pediatric populations.

This research will explore non-linear relationship between vitamin D status on admission and bronchopulmonary dysplasia (BPD) in preterm infants. Data were retrospectively collected on preterm infants ≤32 weeks gestation and ≥28 weeks gestation hospitalized in our hospital between Jan. 2019 and Jul. 2022, which were classified into BPD and non-BPD groups according to BPD diagnostic criteria. Independent influences between the two groups were staged using comparison of differences between groups, univariate analysis, multivariate analysis, smoothed curve fitting, and threshold effect staging. 255 preterm infants were enrolled in this research, including 135 males and 120 females, with a mean gestational age of 30.59 ± 0.86 weeks. Vitamin D status on admission was an independent protective factor for BPD in preterm infants, with a 6% reduction in the probability of BPD for every 1 ng/ml increase in vitamin D status on admission (p = 0.036). There was also a non-linear relationship, with each 1 ng/ml increase in vitamin D status on admission being associated with an 87% reduction in the incidence of BPD when vitamin D status was <12.82 ng/ml (p = 0.010). Vitamin D status on admission and BPD are non-linearly in preterm infants at 28-32 weeks gestation. Analyzing the relationship between vitamin D status on admission and BPD. A nonlinear relationship and turning point between vitamin D status on admission and BPD was derived by curve fitting and threshold effect. We provide a new reference point for vitamin D supplementation for the prevention of neonatal BPD and to avoid ineffective overmedication.

RationaleThe chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-877) is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown.ObjectivesTo study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia.MethodsTotal interleukin-8 and interleukin-877 were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function.Main ResultsPeak total interleukin-8 and interleukin-877 concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05). Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-877 to shorter isoforms (p<0.001). Conversion was greater in bronchopulmonary dysplasia infants (p<0.05). This conversion was inhibited by α-1 antitrypsin and antithrombin III (p<0.01). Purified neutrophil serine proteases efficiently converted interleukin-877 to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001). Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01).ConclusionsShorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.

Azithromycin has anti-Ureaplasma and anti-inflammatory properties that might help reduce lung injury in preterm infants. To test the efficacy and safety of prophylactic or therapeutic azithromycin in preventing bronchopulmonary dysplasia (BPD) in preterm infants with unknown or proven Ureaplasma status. We searched PubMed, Web of Science, and Cochrane Library until 13 September 2020. Two authors independently assessed the eligibility, risk of bias, and extracted the data. We performed a random-effects model meta-analysis to yield pooled relative risk (RR) or mean difference (MD) with 95% confidence interval (CI). We used the Cochrane GRADE methodology for summarizing the results. We included five randomized clinical trials. The meta-analysis revealed no significant differences in BPD (RR, 0.92; 95% CI,0.71, 1.19; low-quality evidence), death (RR,0.75; 95% CI, 0.52, 1.10; low-quality evidence), and BPD or death (RR, 0.90; 95% CI, 0.74, 1.10; low-quality evidence). However, a significantly lower BPD or death (RR, 0.83; 95% CI, 0.70, 0.99) and a trend towardlower BPD (RR, 0.83; 95% CI, 0.66, 1.03) with azithromycin therapy was noted in Ureoplasma positive neonates. No differences in secondary outcomes were noted, except for significantly lower supplemental oxygen days with azithromycin (MD, -6.06; 95% CI, -7.40, -4.72; moderate-quality evidence). The test for subgroup differences between short (<7 days) and long (>7 days) course of azithromycin were nonsignificant for all the outcomes. Low-quality evidence suggests azithromycin therapy reduces BPD or death in preterm infants with positive Ureoplasma, but not in all preterm infants.

To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure. The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age). Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity. The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.