Bronchopulmonary Dysplasia

ImportanceBronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies.ObjectiveTo explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies.Data sourcesPubMed and Embase were searched up to April 2023. Key search terms included BPD and PH.Study selectionStudies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH.Data extraction and synthesisThis study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA.Main outcomes and measuresThe primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0).ResultsA total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable.Conclusions and relevanceIn this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.

ImportanceLarge-scale estimates of bronchopulmonary dysplasia (BPD) are warranted for adequate prevention and treatment. However, systematic approaches to ascertain rates of BPD are lacking.ObjectiveTo conduct a systematic review and meta-analysis to assess the prevalence of BPD in very low birth weight (≤ 1,500 g) or very low gestational age (Data sourcesA search of MEDLINE from January 1990 until September 2019 using search terms related to BPD and prevalence was performed.Study selectionRandomized controlled trials and observational studies evaluating rates of BPD in very low birth weight or very low gestational age infants were eligible. Included studies defined BPD as positive pressure ventilation or oxygen requirement at 28 days (BPD28) or at 36 weeks postmenstrual age (BPD36).Data extraction and synthesisTwo reviewers independently conducted all stages of the review. Random-effects meta-analysis was used to calculate the pooled prevalence. Subgroup analyses included gestational age group, birth weight group, setting, study period, continent, and gross domestic product. Sensitivity analyses were performed to reduce study heterogeneity.Main outcomes and measuresPrevalence of BPD defined as BPD28, BPD36, and by subgroups.ResultsA total of 105 articles or databases and 780,936 patients were included in this review. The pooled prevalence was 35% (95% CI, 28-42%) for BPD28 (n = 26 datasets, 132,247 neonates), and 21% (95% CI, 19-24%) for BPD36 (n = 70 studies, 672,769 neonates). In subgroup meta-analyses, birth weight category, gestational age category, and continent were strong drivers of the pooled prevalence of BPD.Conclusions and relevanceThis study provides a global estimation of BPD prevalence in very low birth weight/low gestation neonates.

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.

ImportanceIn randomized trials, early prophylactic hydrocortisone improved survival without bronchopulmonary dysplasia (BPD) with few adverse effects in extremely preterm infants. Large scale implementation data are needed to evaluate clinical effects and safety.ObjectiveTo examine the association between early prophylactic hydrocortisone and survival without BPD at 36 weeks' postmenstrual age (PMA) in extremely preterm infants in Sweden after guideline implementation and to assess treatment safety.Design, setting, and participantsA national historical cohort study with prospectively collected data from the Swedish Neonatal Quality register from 4 Swedish centers where hydrocortisone prophylaxis was implemented. The study included infants born between 22 and 27 weeks' gestation between 2018 and 2023. Infants were divided into exposed and nonexposed groups according to the intention-to-treat principle.ExposureHydrocortisone, 1 mg/kg/d, for the first 7 days of life, followed by 0.5 mg/kg/d from days 8 through 10.Main outcomes and measuresThe primary outcome was survival without BPD at 36 weeks' PMA. A predefined statistical analysis plan with logistic regression was used to calculate unadjusted and adjusted odds ratios.ResultsAmong 1106 infants (median [IQR] gestational age, 25 weeks, 6 days [24 weeks, 3 days to 27 weeks]; median [IQR] birth weight, 780 [610-964] g), 474 received hydrocortisone prophylaxis and 632 did not. Survival without BPD occurred in 154 of 474 exposed (32.5%) and 185 of 632 nonexposed (29.3%) infants (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27). BPD occurred in 233 exposed (49.2%) and 345 nonexposed (54.6%) infants (adjusted odds ratio, 0.65; 95% CI, 0.49-0.86). Death before 36 weeks' PMA occurred in 87 exposed (18.4%) and 102 nonexposed (16.1%) infants. Late-onset bacterial infection was more common in exposed infants, but not significant after adjustment. No other severe neonatal morbidities differed significantly between the 2 groups.Conclusions and relevanceIn this cohort study of extremely preterm infants, the introduction of prophylactic hydrocortisone was associated with increased survival without BPD, after adjusting for covariates. There was no significant increase in severe neonatal morbidities, except that late-onset bacterial infection was more common in the exposed group before adjustments.