Search

Background: Bronchopulmonary dysplasia (BPD) affects up to half of extremely preterm infants, and is associated with adverse long-term respiratory, neurodevelopmental, and educational sequelae and costly health service and family economic outcomes. The NICHD Neonatal Research Network Hydrocortisone for Bronchopulmonary Dysplasia (BPD) Trial evaluated the efficacy and safety of hydrocortisone treatment to prevent BPD in high-risk infants. The trial enrolled 800 very preterm infants with respiratory failure and followed the participants until 2 years corrected age to assess safety of the trial intervention. Longer-term impacts of hydrocortisone exposure and severity of BPD on functional outcomes of high-risk infants remain unknown. The HYdrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study extends follow-up of all surviving children enrolled in the Hydrocortisone for BPD Trial until early school age. It aims to characterize the childhood functional motor, cognitive, academic, and pulmonary outcomes of this large, well-phenotyped trial cohort., Methods: Parents of surviving trial participants complete telephone questionnaires when their children are 3 and 4 years corrected age. A single in-person study visit takes place at early school age (5 years, 0 months to 7 years, 11 months corrected age). Children undergo a multidimensional assessment of functional outcomes and parents complete a battery of questionnaires. In 5 of 19 participating centers, respiratory mechanics are evaluated with impulse oscillometry., Discussion: The HYBRiD Outcomes Study will be the largest and most comprehensive evaluation to date of the functional early school age outcomes of children with a history of severe neonatal lung disease and of children exposed to HC during infancy. This will substantially improve understanding of the longer-term implications of severe neonatal lung disease; provide data to facilitate the development of future randomized intervention trials in this population; and inform public policy by enhancing knowledge about school age resource requirements in children with a history of prematurity and lung disease., Trial Registration: clinicaltrials.gov ID NCT01353313. Primary trial registration 5/11/11 modified to include followup through school age 12/13/17. This manuscript reflects version 3 of the trial manuscript, dated 10/12/2020., Competing Interests: Declarations Ethics approval and consent to participate The HYBRiD Outcomes Study was approved by the local IRB at each participating center and written informed consent to participate was provided by a parent or legal guardian of each child. Competing interests The authors declare no competing interests. IRB reference numbers for each participating center are: Case Western Reserve University: FWA00004428, U Hosps Cleveland Med Ctr: FWA00003937, University of Texas Southwestern Med Ctr: FWA00005087, Wayne State U: FWA00002460, Emory U: FWA00005792, Cincinnati Children’s Hosp Med Ctr: FWA00002988, Indiana University: FWA00003544, Women & Infants Hosp of Rhode Island: FWA00000056, Leland Stanford Junior U: FWA00000935, UAB Hospital: FWA00005960, The University of Texas Health Science Center at Houston: FWA00000667, Duke University: FWA 00009025, University of North Carolina at Chapel Hill: FWA00004801, WakeMed Health & Hospitals: FWA00000213, U of Iowa (The): FWA00003007, MercyOne Des Moines Medical Center: FWA00000046, University of Utah: FWA00003745, Intermountain Healthcare: FWA00007905, U of New Mexico Hlth Sciences Ctr (UNMHSC) (aka): FWA00003255, University of Pennsylvania: FWA00004028, Children’s Hosp of Philadelphia: FWA0000459, U of Rochester: FWA00009386, University at Buffalo - State University of New York: FWA00008824, U of California Los Angeles (UCLA): FWA00004642, Nationwide Children’s Hosp: FWA00002860, The Children’s Mercy Hospital: FWA00002496, Research Triangle Institute International LLC: FWA00003331. Consent for publication Not applicable. Results of the HYBRiD Outcomes Study will be shared at a major academic pediatric meeting and then submitted to a peer-reviewed medical journal as soon as possible after completion of the study. All members of the study subcommittee will be named as authors on the primary study publication, given their contributions throughout the conduct of the study, as long as they meet ICJME authorship criteria at the time of publication. No professional writers will be used. Results will also be shared with the families of study participants through a paper mail or e-mail study newsletter., (© 2024. The Author(s).)

Bronchopulmonary dysplasia (BPD) poses a significant challenge as the most common late morbidity of preterm infants. This study aimed to evaluate airway abnormalities in infants with BPD who underwent flexible bronchoscopy (FB) to gain insights into the prevalence of upper airway obstruction and associated complications. A retrospective case-control study was conducted on BPD patients who underwent FB at a tertiary center between 2013 and 2023. BPD patients were matched (1:3) with a reference group based on age, gender, and ethnicity, who also had undergone FB. Demographic data, comorbidities, indications for FB, findings, and complications during and after FB were collected. The study included 50 BPD patients (mean age 1.26 ± 0.9 years, 58% males), and 150 controls. As expected, BPD patients had a lower gestational age, lower birth weight, and longer hospitalizations and were treated with more medications. Abnormal bronchoscopy findings were significantly more common in the BPD group compared to the reference group, with an increased rate of turbinate hypertrophy (OR [95% CI]: 3.44 [1.27-9.37], P = 0.014), adenoid hypertrophy (OR: 2.7 [1.38-5.29], P = 0.004), lingual tonsils (OR: 5.44 [1.29-27.4], P = 0.0024), subglottic stenosis (OR: 6.95 [2.08-27.1], P = 0.002), and tracheomalacia (OR: 2.98 [1.06-8.19], P = 0.034). Complications including desaturation (OR: 3.89 [1.32-11.7], P = 0.013) and PICU admission (OR: 16.6 [2.58-322], P = 0.011) were more frequent in the BPD than in the reference group., Conclusion: The study revealed a high prevalence of structural anomalies leading to upper airway obstruction and complications in infants with BPD undergoing FB. These findings emphasize the importance of careful consideration and preparation for bronchoscopic procedures in this vulnerable population., What Is Known: • Bronchopulmonary dysplasia (BPD) represents the most prevalent late morbidity among preterm infants. • Preterm infants diagnosed with BPD frequently undergo diagnostic procedures, including flexible and rigid bronchoscopies, to identify structural pathologies within the respiratory tract., What Is New: • A significantly higher prevalence of structural anomalies leading to upper airway obstruction was observed in the BPD group compared to controls. • The incidence of complications during flexible bronchoscopy was higher in the BPD group than in controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Preterm infants, particularly those with bronchopulmonary dysplasia (BPD), are at risk of lung development problems. Over the last decades, lung protective strategies have been used, decreasing the risk of chronic lung disease., Objective: To evaluate the pulmonary function test (PFT) of preterm infants born after the introduction of lung protective strategies and to assess perinatal determinants of impaired lung function in this population., Methods: A prospective, observational, single-center study was conducted in the neonatal unit of a high-complexity hospital. The study included newborns with less than 32 weeks gestational age born between 2012 and 2014, who were followed up until they reach school age. For the main outcome, two groups were stablished: no BPD or grade 1 BPD (no BPD/1) and grade 2 or 3 BPD (BPD 2/3)., Results: Out of 327 patients, 116 were included. BPD was diagnosed in 49.1% (47), with 50.9% (29) classified as grade 1, 35.1% (20) as grade 2, and 14.0% (8) as grade 3. Mean age at PFT was 8.59 years (SD 0.90). Mean FEV1% was 95.36% (SD 13.21) and FEV1 z-score -0.36 (SD 1.12); FVC% 97.53% (SD 12.59) and FVC z-score -0.20 (SD 1.06); FEV1/FVC ratio 85.84% (SD 8.34) and z-score -0.24 (SD 1.34). When comparing patients with no BPD/1 and BPD 2/3, we observed differences in all pulmonary function parameters, which persisted after adjusting for gestational age. No differences in PFT were observed between patients without BPD and those with grade 1 BPD. Most patients (76.7%, 89) had normal spirometry pattern, with obstructive pattern observed in 12.9% (15), restrictive pattern in 9.5% (11), and mixed pattern in 0.9% (1) of patients., Conclusion: Preterm infants with BPD 2/3 showed a decrease in all pulmonary function parameters compared to preterm infants with no BPD/1; an effect that was independent of gestational age. Among patients with BPD who had an altered PFT pattern, the most common pattern was obstructive, followed by restrictive and then, mixed., (© 2024 Wiley Periodicals LLC.)

Bronchopulmonary dysplasia (BPD) is characterized by impaired lung alveolar and vascular growth. We investigated the hypothesis that neonatal exposure to hyperoxia leads to persistent BPD phenotype caused by decreased expression of liver kinase B1 (LKB1), a key regulator of mitochondrial function. We exposed mouse pups from Postnatal Day (P)1 through P10 to 21% or 75% oxygen. Half of the pups in each group received metformin or saline intraperitoneally from P1 to P10. Pups were killed at P4 or P10 or recovered in 21% O 2 until euthanasia at P21. Lung histology and morphometry, immunofluorescence, and immunoblots were performed to detect changes in lung structure and expression of LKB1; downstream targets AMPK, PGC-1α, and electron transport chain (ETC) complexes; and Notch ligands Jagged 1 and delta-like 4. LKB1 signaling and in vitro angiogenesis were assessed in human pulmonary artery endothelial cells (exposed to 21% or 95% O 2 for 36 hours. Levels of LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes were decreased in lungs at P10 and P21 in hyperoxia. Metformin increased LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes at P10 and P21 in pups exposed to hyperoxia. Radial alveolar count was decreased, and mean linear intercept increased in pups exposed to hyperoxia at P10 and P21; these were improved by metformin. Lung capillary density was decreased in hyperoxia at P10 and P21 and was increased by metformin. In vitro angiogenesis was decreased in human pulmonary artery endothelial cells by 95% O 2 and was improved by metformin. Decreased LKB1 signaling may contribute to decreased alveolar and vascular growth in a mouse model of BPD.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease, associated with premature birth, that arises during the infantile period. It is an evolving disease process with an unchanged incidence due to advancements in neonatal care which allow for the survival of premature infants of lower gestational ages and birth weights. Currently, there are few effective interventions to prevent BPD. However, careful attention to BPD phenotypes and comprehensive care provided by an interdisciplinary team have improved care. Interventions early in the disease course hold promise for improving long-term survival and outcomes in adulthood for this high-risk population., Competing Interests: Disclosure The authors have no financial or commercial conflicts of interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate associations between neonatal risk factors and pulmonary vein stenosis (PVS) among infants born preterm with severe bronchopulmonary dysplasia (sBPD)., Study Design: We performed a case-control study of infants born from 2010 to 2022 at <32 weeks' gestation with sBPD among 46 neonatal intensive care units in the Children's Hospitals Neonatal Consortium. Cases with PVS were matched to controls using epoch of diagnosis (2010-2016; 2017-2022) and hospital. Multivariable logistic regression analyses were utilized to evaluate PVS association with neonatal risk factors., Results: From 10 171 preterm infants with sBPD, we identified 109 cases with PVS and matched those to 327 controls. The prevalence of PVS (1.07%) rose between epochs (0.8% in 2010-2016 to 1.2% in 2017-2022). Relative to controls, infants with PVS were more likely to be <500 g at birth, to be small for gestational age <10th%ile, or have surgical necrotizing enterocolitis, atrial septal defects, or pulmonary hypertension. In multivariable models, these associations persisted, and small for gestational age, surgical necrotizing enterocolitis, atrial septal defects, and pulmonary hypertension were each independently associated with PVS. Among infants on respiratory support at 36 weeks' postmenstrual age, infants with PVS had 4.3-fold higher odds of receiving mechanical ventilation at 36 weeks' postmenstrual age. Infants with PVS also had 3.6-fold higher odds of in-hospital mortality relative to controls., Conclusions: In a large cohort of preterm infants with sBPD, multiple independent, neonatal risk factors are associated with PVS. These results lay important groundwork for the development of targeted screening to guide the diagnosis and management of PVS in preterm infants with sBPD., Competing Interests: Declaration of Competing Interest Children's Hospitals Neonatal Consortium 2022 Mentored Fellow Research Award Recipient. K.M., M.A.P., and T.G. are Board Members of CHNC. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Survival of preterm-born infants, especially at extremes of prematurity (less than 28 weeks gestation), is now common, particularly in the developed world. Despite advances in neonatal care, short-term respiratory morbidity, termed bronchopulmonary dysplasia (also called chronic lung disease of prematurity), remains an important clinical outcome. As survival during the neonatal period has improved, preterm-born individuals are now entering childhood, adolescence and adulthood in far greater numbers, and adverse longer-term respiratory outcomes following birth at an immature stage of lung development are becoming increasingly apparent. In this article, we shall review the background of the major respiratory complications in the neonatal period, bronchopulmonary dysplasia, and the current evidence regarding its prevention and management. In addition, we shall review the emerging literature on the respiratory morbidity experienced in childhood, adolescence, and adulthood by preterm-born survivors, with reduced lung function and a risk of developing chronic obstructive pulmonary disease in early adult life. As this population of preterm-born individuals increases, an understanding of the respiratory consequences of preterm birth will become increasingly important not only for neonatologists, paediatricians and paediatric pulmonologists but also for physicians and healthcare professionals involved in the care of adults who were born preterm.

Objectives: To determine the incidence, risk factors, and accuracy of a previously published risk estimator in predicting Bronchopulmonary dysplasia (BPD) in a very preterm cohort from India., Methods: A single-center prospective observational study was conducted in preterm neonates born at 23-30 wk of gestation with a birth weight of 501-1249 g. The incidence and risk factors of BPD were evaluated, and the accuracy of BPD prediction at six pre-specified time points using the National Institute of Child Health and Human Development (NICHD) BPD risk estimator was assessed by comparing the estimated risk with the observed rates., Results: A total of 310 neonates with mean gestation age of 28.7±1.5 wk and birth weight of 1023.6±171.4 g were enrolled in the study. The study cohort had 49.7% males and 32.3% neonates requiring resuscitation. Any BPD was observed in 54 (17.4%) neonates with severity being mild, moderate, and severe in 29 (53.7%), 17 (31.5%), and 8 (14.8%) neonates respectively. Hundred (32.3%) neonates died before discharge from the hospital. Sepsis, patent ductus arteriosus, retinopathy of prematurity, intraventricular hemorrhage, and blood transfusion were significant risk factors for the development of BPD. The calculator was accurate for the prediction of death or moderate-severe BPD on days 1 and 3 with the area under the curve of 0.82 and 0.77 respectively., Conclusions: The NICHD BPD estimator helped to accurately predict moderate-severe BPD early in Indian preterm infants., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Objective: To investigate the neurodevelopmental outcomes for preterm infants born < 29 weeks gestation with/without bronchopulmonary dysplasia (BPD)., Study Design: Preterm infants < 29 weeks' gestation born 2007-2018 in New South Wales and the Australian Capital Territory, Australia, were included. Infants who died < 36 weeks' postmenstrual age and those with major congenital anomalies were excluded. Subjects were assessed at 18-42 months corrected age using the Bayley Scales of Infant Development, 3rd edition., Results: 1436 infants without BPD (non-BPD) and 1189 infants with BPD were followed. The BPD group, 69 % infants were discharged without respiratory support (BPD1), 29 % on oxygen (BPD2) and 2 % on pressure support/tracheostomy (BPD3). Moderate neurodevelopmental impairment (NDI) was evident in 5.7 % of non-BPD infants, 11 % BPD1, 15 % BPD2, 15 % BPD3 infants. Severe NDI was seen in 1.7 % non-BPD infants, 3.4 % BPD1, 7.3 % BPD2, 35 % BPD3 infants. After adjusting for confounders, infants with BPD2 (OR 2.24, 99.9 % CI 1.25 to 5.77) or BPD3 (OR 5.99, 99.9 % CI 1.27 to 46.77) were more likely to have moderate-severe NDI compared to non-BPD infants., Conclusion: The majority of infants with BPD were discharged home without respiratory support and had better neurocognitive outcomes in early childhood compared to those that required home-based oxygen or respiratory support., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Data on static compliance of the chest wall ( C cw ) in preterm infants are scarce. We characterized the static compliance of the lung ( C L ) in very preterm infants at 36 wk postmenstrual age (PMA). We also aimed to investigate how these compliances were influenced by the presence of bronchopulmonary dysplasia (BPD) and impacted breathing variables. Airway opening pressure, esophageal pressure, and tidal volume ( C cw to determine their relative contribution to static compliance of the respiratory system ( C rs ) in very preterm infants at 36 wk postmenstrual age (PMA). We also aimed to investigate how these compliances were influenced by the presence of bronchopulmonary dysplasia (BPD) and impacted breathing variables. Airway opening pressure, esophageal pressure, and tidal volume ( V T ) were measured simultaneously during a short apnea evoked by the Hering-Breuer reflex. We computed tidal breathing variables, airway resistance ( R ), and dynamic lung compliance (C L,dyn ), inspiratory capacity (IC), and C rs , C L , and C cw . Functional residual capacity was assessed by the multiple breath washout technique (FRC mbw ). Breathing variables, compliances, and lung volumes were adjusted for body weight. Twenty-three preterm infants born at 27.2 ± 2.0 wk gestational age (GA) were studied at 36.6 ± 0.6 wk PMA. Median and interquartile range (IQR) C rs /kg is 0.69 (0.6), C L /kg 0.95 (1.0), and C cw /kg 3.0 (2.4). Infants with BPD ( n = 11) had lower C rs /kg ( P = 0.013), C L /kg ( P ) in preterm infants with and without bronchopulmonary dysplasia (BPD) in the postsurfactant era.C cw /kg ( P = 0.027) compared with infants without BPD. C cw / C L ratio was equal between groups. FRC mbw /kg ( P = 0.044) and IC/kg ( P = 0.005) were decreased in infants with BPD. Infants with BPD have reduced static compliance of the respiratory system, the lungs, and chest wall. Decreased C rs , C L , and C cw in infants with BPD explain the lower FRC and IC seen in these infants. NEW & NOTEWORTHY Data on chest wall compliance in very preterm infants in the postsurfactant era are scarce. To our knowledge, we are the first group to report data on static respiratory system compliance ( C rs ), lung compliance ( C L ), and chest wall compliance ( C cw ) in preterm infants with and without bronchopulmonary dysplasia (BPD) in the postsurfactant era.

Introduction: This retrospective study describes characteristics of serial polysomnograms (PSGs) of BPD patients on home oxygen therapy and describes PSG parameters associated with discontinuation of supplemental oxygen., Methods: A single-center study was performed at Children's Hospital Los Angeles, where serial PSGs for 44 patients with BPD infants discharged on home oxygen therapy were extracted for maximum of five PSGs or until oxygen discontinuation. Clinical and polysomnography data was collected. Characteristics of PSG1 were compared amongst the patients who were weaned from oxygen after PSG2 and PSG3., Results: Of 44 patients, 68.2% of patients were males with median birth gestational age of 26 weeks (IQR: 24.6-28.1), median birthweight of 777.5 g (IQR: 632.5-1054 g) and 77.3% of the cohort had severe BPD. A total of 138 PSGs were studied between all 44 patients serially. When comparing PSG1 and PSG2 parameters, statistically significant improvement was noted in multiple parameters. Median baseline SpO 2 , peak RR, and average PETCO 2 were found to be potential predictors of prolonged oxygen use. Gestational age and birth weight were not associated with prolonged oxygen use after PSG3. The median age of oxygen discontinuation was calculated to be about 2 years of age., Conclusions: The severity of hypoxia and tachypnea on initial infant PSG are associated with prolonged oxygen therapy past 2 years of age. Growth and development of lungs with maturation of control of breathing help improve these parameters over time regardless of BPD severity. The study may inform discussions between providers and parents for patients discharged home on oxygen therapy., (© 2024 Wiley Periodicals LLC.)

Introduction: Bronchopulmonary disease (BPD) is associated with long-term neurodevelopmental and cardiorespiratory complications, often requiring significant use of resources. To reduce this healthcare burden, it is essential that those at high risk of BPD are identified early so that strategies are introduced to prevent disease progression. Our aim was to discuss potential methods for improving early diagnosis in the first week after birth., Areas Covered: A narrative review was undertaken. The search strategy involved searching PubMed, Embase and Cochrane databases from 1967 to 2024. The results of potential biomarkers and imaging modes are discussed. Furthermore, the value of scoring systems is explored., Expert Opinion: BPD occurs as a result of disruption to pulmonary vascular and alveolar development, thus abnormal levels of factors regulating those processes are promising avenues to explore with regard to early detection of high-risk infants. Data from twin studies suggests genetic factors can be attributed to 82% of the observed difference in moderate to severe BPD, but large genome-wide studies have yielded conflicting results. Comparative studies are required to determine which biomarker or imaging mode may most accurately diagnose early BPD development. Models which include the most predictive factors should be evaluated going forward.

Background: Respiratory Syncytial Virus (RSV) infections may lead to severe consequences in infants born preterm with breathing problems (such as bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS)) or congenital heart diseases (CHD). Since studies investigating the influence of different gestational age (WGA) and concomitant specific comorbidities on the burden of RSV infections are scarce, the present study aimed to better characterize these high-risk populations in the Italian context., Methods: This retrospective, longitudinal and record-linkage cohort study involved infants born between 2017 and 2019 in Lazio Region (Italy) and is based on data extracted from administrative databases. Each infant was exclusively included in one of the following cohorts: (1) BPD-RDS (WGA ≤35 with or without CHD) or (2) CHD (without BPD and/or RDS) or (3) Preterm (WGA ≤35 without BPD (and/or RDS) or CHD). Each cohort was followed for 12 months from birth. Information related to sociodemographic at birth, and RSV and Undetermined Respiratory Agents (URA) hospitalizations and drug consumption at follow-up were retrieved and described., Results: A total of 8,196 infants were selected and classified as 1,084 BPD-RDS, 3,286 CHD and 3,826 Preterm. More than 30% of the BPD-RDS cohort was composed by early preterm infants (WGA ≤ 29) in contrast to the Preterm cohort predominantly constitute by moderate preterm infants (98.2%), while CHD infants were primarily born at term (83.9%). At follow-up, despite the cohorts showed similar proportions of RSV hospitalizations, in BPD-RDS cohort hospitalizations were more frequently severe compared to those occurred in the Preterm cohort (p<0.01), in the BPD-RDS cohort was also found the highest proportion of URA hospitalizations (p<0.0001). In addition, BPD-RDS infants, compared to those of the remaining cohorts, received more frequently prophylaxis with palivizumab (p<0.0001) and were more frequently treated with adrenergics inhalants, and glucocorticoids for systemic use., Conclusions: The assessment of the study clinical outcomes highlighted that, the demographic and clinical characteristics at birth of the study cohorts influence their level of vulnerability to RSV and URA infections. As such, continuous monitoring of these populations is necessary in order to ensure a timely organization of health care system able to respond to their needs in the future., (© 2024. The Author(s).)

Background: Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among preterm infants. Human induced pluripotent stem cells (hiPSCs) have shown promise in repairing injury in animal BPD models. Evidence suggests they exert their effects via paracrine mechanisms. We aim herein to assess the effectiveness of extracellular vesicles (EVs) derived from hiPSCs and their alveolar progenies (diPSCs) in attenuating hyperoxic injury in a preterm lung explant model., Methods: Murine lung lobes were harvested on embryonic day 17.5 and maintained in air-liquid interface. Following exposure to 95% O 2 for 24 h, media was supplemented with 5 × 10 6 particles/mL of EVs isolated from hiPSCs or diPSCs by size-exclusion chromatography. On day 3, explants were assessed using Hematoxylin-Eosin staining with mean linear intercept (MLI) measurements, immunohistochemistry, VEGFa and antioxidant gene expression. Statistical analysis was conducted using one-way ANOVA and Multiple Comparison Test. EV proteomic profiling was performed, and annotations focused on alveolarization and angiogenesis signaling pathways, as well as anti-inflammatory, anti-oxidant, and regenerative pathways., Results: Exposure of fetal lung explants to hyperoxia induced airspace enlargement, increased MLI, upregulation of anti-oxidants Prdx5 and Nfe2l2 with decreased VEGFa expression. Treatment with hiPSC-EVs improved parenchymal histologic changes. No overt changes in vasculature structure were observed on immunohistochemistry in our in vitro model. However, VEGFa and anti-oxidant genes were upregulated with diPSC-EVs, suggesting a pro-angiogenic and cytoprotective potential. EV proteomic analysis provided new insights in regard to potential pathways influencing lung regeneration., Conclusion: This proof-of-concept in vitro study reveals a potential role for hiPSC- and diPSC-EVs in attenuating lung changes associated with prematurity and oxygen exposure. Our findings pave the way for a novel cell free approach to prevent and/or treat BPD, and ultimately reduce the global burden of the disease., (© 2024. The Author(s).)

Background: Bronchopulmonary dysplasia (BPD) is a significant contributor to morbidity and death in infants who are born premature. Male sex is an independent risk factor for the development of BPD. However, whether male sex is associated with adverse outcomes that occur after formal diagnosis of severe BPD prior to hospital discharge remains unclear., Research Question: Is male sex associated with a higher risk of adverse outcomes in infants with established severe BPD?, Study Design and Methods: A retrospective, multicenter cohort study of infants enrolled in the BPD Collaborative Registry from January 1, 2015, to June 29, 2022, was performed. Demographics, clinical characteristics, and outcomes were stratified by sex (ie, male vs female). Regression modeling was used to estimate the association of sex with the primary composite outcome of death or tracheostomy at hospital discharge., Results: We identified 1,156 infants with severe BPD, defined at 36 weeks postmenstrual age by the National Institutes of Health 2001 consensus definition. The cohort was predominantly male (59% male infants, 41% female infants). However, rates of mechanical ventilation at 36 weeks postmenstrual age (ie, type 2 severe BPD) did not differ by sex. Overall mortality rates within the cohort were low (male infants, 5.3%; female infants, 3.6%). The OR of death or tracheostomy for male-to-female infants was 1.0 (95% CI, 0.7-1.5)., Interpretation: Our results lead us to speculate that, although sex is an important variable that contributes to the development and pathogenesis of severe BPD, it does not appear to be associated with adverse outcomes in this cohort of infants with established disease. The surprising results raise important questions surrounding the temporal role of biological sex in the development of severe BPD and its progression during the neonatal ICU stay. As we explore the phenotypes and endotypes of BPD, it is imperative to consider how sex modulates the disease from birth through hospital discharge., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024. Published by Elsevier Inc.)

Background: The survival of smaller and more immature premature infants has been associated with lifelong cardiorespiratory comorbidities. Infants with bronchopulmonary dysplasia (BPD) undergo routine screening echocardiography to evaluate for development of chronic pulmonary hypertension, a late manifestation of pulmonary vascular disease., Methods: Our aim was to evaluate left ventricular (LV) performance in infants with BPD and pulmonary vascular disease who developed systemic hypertension. We hypothesized that infants with hypertension were more likely to have impaired LV performance. We present a single-center cross-sectional study of premature infants born at less than 28 0/7 weeks' gestational age with a clinical diagnosis of BPD. Infants were categorized by the systolic arterial pressure (SAP) at time of echocardiography as hypertensive (SAP ≥90 mm Hg) or normotensive (SAP <90 mm Hg). Sixty-four patients were included., Results: Infants with hypertension showed altered LV diastolic function with prolonged tissue Doppler imaging-derived isovolumic relaxation time (54.2 ± 5.1 vs 42.9 ± 8.2, P < .001), lower E:A, and higher E:e'. Indices of left heart volume/pressure loading (left atrium:aorta and LV end-diastolic volume [6.1 ± 2 vs 4.2 ± 1.2, P < .001]) were also higher in the hypertensive group. Finally, infants in the hypertensive group had higher pulmonary vascular resistance index (4.42 ± 1.1 vs 3.69 ± 0.8, P = .004)., Conclusions: We conclude that extremely preterm infants with BPD who develop systemic hypertension are at risk of abnormal LV diastolic dysfunction. Increased pulmonary vascular resistance index in the hypertensive group may relate to pulmonary venous hypertension secondary to LV dysfunction. This is an important consideration in this cohort when selecting the physiologically most appropriate treatment., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: To determine how bronchopulmonary dysplasia (BPD) affects health-related quality of life (HRQL) among infants from NICU hospitalization through 1-year postdischarge., Study Design: This was a prospective cohort study of infants with BPD and their parents. Parent HRQL was measured with the PedsQL Family Impact Module before NICU discharge and 3- and 12-months post-discharge. At 12 months, parent-reported child health outcomes included questions from the Test of Respiratory and Asthma Control in Kids, Warner Initial Developmental Evaluation of Adaptive and Functional Skills, and National Survey of Children with Special Health Care Needs. HRQL change over time was assessed by multivariable linear regression., Results: Of 145 dyads, 129 (89%) completed 3-month follow-up, and 113 (78%) completed 12-month follow-up. In the NICU, lower HRQL was associated with earlier gestational age, postnatal corticosteroids, outborn status, and gastrostomy tubes. At 3 months, lower HRQL was associated with readmissions and home oxygen use. At 12 months, lower HRQL was associated with parent-reported difficulty breathing, lower developmental scores, and not playing with other children. At 3 and 12 months, 81% of parents reported similar or improved HRQL compared with the NICU period. Parents reporting infant respiratory symptoms experienced less improvement., Conclusions: BPD affects parent HRQL over the first year. Most parents report similar or better HRQL after discharge compared with the NICU stay. Less improvement is reported by parents of infants experiencing respiratory symptoms at 12 months. Efforts to improve parent HRQL should target respiratory symptoms and social isolation., Competing Interests: Declaration of Competing Interest None to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Bronchopulmonary dysplasia (BPD) is the most common long term pulmonary morbidity in premature infants and is characterized by impaired lung growth and development. We hypothesized that lung mass growth is a critical factor in determining outcomes in infants with BPD., Objectives: To measure regional lung density and mass in infants with BPD and compare to clinical variables., Methods: We conducted a retrospective cohort study of neonates (n = 5 controls, n = 46 with BPD). Lung mass and lung density were calculated using ultrashort echo time (UTE) magnetic resonance imaging (MRI)., Measurements and Main Results: Lung mass increased with increasing corrected gestational age at the time of MRI in all patients. Total, right, and left lung mass in infants with BPD trended higher than control infants (65.7 vs. 49.9 g, 36.2 vs. 26.8 g, 29.5 vs. 23.1 g, respectively). Babies with BPD who survived to discharge had higher relative lung mass than control infants and infants with BPD that did not survive to discharge (21.6 vs. 15.7 g/kg, p = .01). There was a significant association between the rate of lung mass growth and linear growth at the time of MRI (p = .034)., Conclusions: Infants with BPD are capable of building lung mass over time. While this lung mass growth in infants with BPD may not represent fully functional lung tissue, higher lung mass growth is associated with increased linear growth., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

We aimed to assess the determinants of diaphragmatic function in term and preterm infants. 149 infants (56 term; 93 preterm, of whom 14 were diagnosed with bronchopulmonary dysplasia-BPD) were studied before discharge. Diaphragmatic function was assessed by measurement of the maximum transdiaphragmatic pressure (Pdimax)-a measure of diaphragmatic strength, and the pressure-time index of the diaphragm (PTIdi)-a measure of the load-to-capacity ratio of the diaphragm. The Pdimax was higher in term than preterm infants without BPD (90.1 ± 16.3 vs 81.1 ± 11.8 cmH 2 O; P = 0.001). Term-born infants also had lower PTIdi compared to preterms without BPD (0.052 ± 0.014 vs 0.060 ± 0.017; P = 0.006). In term and preterm infants without BPD, GA was the most significant predictor of Pdimax and PTIdi, independently of the duration of mechanical ventilation and oxygen support. In infants with GA < 32 weeks (n = 30), the Pdimax was higher in infants without BPD compared to those with BPD (76.1 ± 11.1 vs 65.2 ± 11.9 cmH 2 O; P = 0.015). Preterms without BPD also had lower PTIdi compared to those with BPD (0.069 ± 0.016 vs 0.109 ± 0.017; P < 0.001). In this subgroup, GA was the only significant independent determinant of Pdimax, while BPD and the GA were significant determinants of the PTIdi.  Conclusions: Preterm infants present lower diaphragmatic strength and impaired ability to sustain the generated force over time, which renders them prone to diaphragmatic fatigue. In very preterm infants, BPD may further aggravate diaphragmatic function. What is Known: • The diaphragm of preterm infants has limited capacity to undertake the work of breathing effectively. • The maximum transdiaphragmatic pressure (a measure of diaphragmatic strength) and the pressure-time index of the diaphragm (a measure of the load-to-capacity ratio of the muscle) have not been extensively assessed in small infants. What is New: • Preterm infants have lower diaphragmatic strength and impaired ability to sustain the generated force over time, which renders them prone to diaphragmatic fatigue. • In very preterm infants, bronchopulmonary dysplasia may further impair diaphragmatic function., (© 2023. The Author(s).)

Background: Bronchopulmonary dysplasia (BPD) is a multifactorial disease with neurodevelopmental implications. This study aims to quantify the risks of adverse neurodevelopmental outcomes for each BPD grade among preterm infants born at less than 30 weeks' gestation., Methods: We retrospectively studied infants who received care in our institution until at least 36 weeks postmenstrual age and had a formal neurodevelopmental assessment in our infant follow-up clinic using the Bayley Scales for Infant and Toddler Development (BSID). We assessed the association between BPD grade and adverse neurodevelopmental outcomes using descriptive statistics and regression models., Results: Two hundred and fifty infants, including 89 (35.6%), 87 (34.8%), 65 (20.6%), and 9 (3.6%) with No BPD, Grade 1, Grade 2, and Grade 3 BPD, were included in the study. Small for gestational age, late pulmonary hypertension, dexamethasone administration, and adverse neurodevelopmental outcomes were more common as BPD grade increased. In a logistic regression analysis, Grades 2 and 3, but not Grade 1, BPD were associated with increased odds of a composite adverse neurodevelopmental outcome by 2.7 and 7.2 folds, respectively. A BSID domain-specific analysis showed that higher grades were associated with lower scores in the cognitive, gross motor, and fine motor domains., Conclusions: Grades 2 and 3 BPD, but not Grade 1, correlate with risks of adverse neurodevelopmental outcomes at a grade-dependent manner in our single-center cohort retrospective study. Further validation using a multi-center large cohort is warranted.

Background: Neonatal leukemoid reaction is associated with higher risk of mortality, chronic lung disease and has been associated with chorioamnionitis. Literature on extremely low birth weight infants with leukemoid reaction is limited., Objectives: The aim of our study was to characterize the maternal and placental factors associated with neonatal leukemoid reaction and to describe outcomes of these ELBW infants. Our objective was to assess if there were maternal factors that would assist the decision-making process regarding the delivery of preterm infants at risk of chorioamnionitis and the sequelae of this inflammatory process., Methods: This was a retrospective case-control study performed in a single, tertiary Maternity Hospital in Dublin. Two matched controls were identified for each case based on gestation and year of birth and data was collected on both the infants and their mothers., Results: 7 extremely preterm neonates were identified as having a leukemoid reaction, defined as a total white cell count of >50,000 or in the first seven days of life. Baseline characteristics between the groups were similar. The median gestational age in the cases group was 24 + 4 weeks and in the control group was 24 + 1. The mean birthweight was 650 g in the cases group vs. 655 g in the control group. There was a higher percentage of males in the control group, 42.9% vs 28.6% in the cases. The preterm infants with leukemoid reaction had a longer duration of ventilation with a median of 18 days (7.5-23.5 days) compared to 6.5 days (2.8-24.5 days) in the control group. More infants in the leukemoid reaction group required inotropes for hypotension in the first 72 h after delivery (42.9% vs 7.1% in the controls, p value .169). Death or Bronchopulmonary dysplasia (BPD) occurred in 85.7% of the cases identified with a leukemoid reaction vs 71.4% of the controls matched. Median maternal CRP was higher in cases prior to delivery vs the controls (66 vs 18.1 mg/L, p -value = .2151). There was histological evidence of maternal inflammatory response in all cases with fetal inflammatory response in 71% of cases., Conclusions: Leukemoid reaction in ELBW infants with evidence of maternal and fetal inflammatory response syndrome on placental histology is associated with a longer duration of initial ventilation, increased need for inotropes in the first 72 h after birth, higher rates of death, and BPD. Prospective studies are required to identify potential biomarkers such as proinflammatory cytokines, IL-6, which might aid the decision-making process in delivery.

Objective: To describe current treatment practices of preterm infants with early hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) and their association with patient outcomes., Study Design: We developed a prospective, observational, multicenter clinical registry of preterm newborns <34 weeks' gestation with HRF and PH, based on either clinical or echocardiographic evidence during the first 72 hours of life, from 28 neonatal intensive care units in the US from 2017 through 2022. The primary end point was mortality among those who did or did not receive PH-targeted treatment, and the secondary end points included comparisons of major morbidities. Variables were compared using t tests, Wilcoxon rank-sum tests, Fisher exact tests, and χ² tests., Results: We analyzed the results of 224 preterm infants enrolled in the registry. Of which, 84% (188/224) received PH-targeted treatment, most commonly inhaled nitric oxide (iNO). Early mortality in this cohort was high, as 33% (71/224) of this sample died in the first month of life, and 77% of survivors (105/137) developed bronchopulmonary dysplasia. Infants who received PH-targeted treatment had higher oxygenation indices at the time of enrollment (28.16 [IQR: 13.94, 42.5] vs 15.46 [IQR: 11.94, 26.15]; P = .0064). Patient outcomes did not differ between those who did or did not receive PH-targeted therapy., Conclusions: Early-onset HRF with PH in preterm infants is associated with a high early mortality and a high risk of developing bronchopulmonary dysplasia. iNO is commonly used to treat early-onset PH in preterm infants with HRF. In comparison with untreated infants with lower oxygenation indices, iNO treatment in severe PH may prevent poorer outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. This study was sponsored by an investigator-initiated research grant from Mallinckrodt Pharmaceuticals (grant number IIR-USA-003947 to J.P.K.). The study was also supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. The manuscript's contents are the authors' sole responsibility and do not necessarily represent the sponsors' views. The sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Surfactant protein-D (SP-D) is a hydrophilic protein with multiple crucial anti-inflammatory and immunological functions. It might play a role in the development and course of pulmonary infections, acute respiratory distress syndrome, and other respiratory disorders. Only few small neonatal studies have investigated SP-D: we aimed to investigate the links between this protein, measured in the first hours of life in extremely preterm neonates, and clinical outcomes, as well its relationship with pulmonary secretory phospholipase A2 (sPLA2). Bronchoalveolar lavage fluids were obtained within the first 3 h of life. SP-D and sPLA2 were measured with ELISA and radioactive method, respectively; epithelial lining fluid concentrations were estimated with urea ratio. Clinical data were prospectively collected. One hundred extremely preterm neonates were nonconsecutively studied. SP-D was significantly raised with increasing gestational age (24-26 wk: 68 [0-1,694], 27 or 28 wk: 286 [0-1,328], 29 or 30 wk: 1,401 [405-2,429] ng/mL, overall P = 0.03). SP-D was significantly higher in cases with clinical chorioamnionitis with fetal involvement (1,138 [68-3,336]) than in those without clinical chorioamnionitis with fetal involvement (0 [0-900] ng/mL, P < 0.001). SP-D was lower in infants with bronchopulmonary dysplasia (BPD) (251 [0-1,550 ng/mL]) compared with those without bronchopulmonary dysplasia (BPD) or who died before its diagnosis (977 [124-5,534 ng/mL], P = 0.05) and this was also significant upon multivariate analysis [odds ration (OR): 0.997 (0.994-0.999), P = 0.024], particularly in neonates between 27- and 28-wk gestation. SP-D significantly correlated with the duration of hospital stay (ρ = -0.283, P = 0.002), invasive ventilation (ρ = -0.544, P = 0.001), and total sPLA2 activity (ρ = 0.528, P = 0.008). These findings help understanding the role of SP-D early in life and support further investigation about the role of SP-D in developing BPD. NEW & NOTEWORTHY Surfactant protein-D increases with gestational age and is inversely associated with BPD development. These results have been obtained in the first hours of life of extremely preterm neonates with optimal perinatal care.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Brady, Zhang, Anderson and Popova.)

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15 -/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% [Formula: see text]) for 5 days after birth. The mice were euthanized on postnatal day 21 (PND 21). Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Hyperoxia exposure adversely impacted alveolarization and lung vascular development, with a greater impact in Gdf15 -/- mice. Interestingly, Gdf15 -/- mice showed lower macrophage count in the lungs compared with WT mice both under room air and after exposure to hyperoxia. Analysis of the lung transcriptome revealed marked divergence in gene expression and enriched biological pathways in WT and Gdf15 -/- mice and differed markedly by biological sex. Notably, pathways related to macrophage activation and myeloid cell homeostasis were negatively enriched in Gdf15 -/- mice. Loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15 -/- mice. NEW & NOTEWORTHY We show for the first time that loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15 -/- mice. We also highlight the distinct pulmonary transcriptomic response in the Gdf15 -/- lung including pathways related to macrophage recruitment and activation.

Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.

Background: Less invasive forms of ventilation have evolved aiming to decrease bronchopulmonary dysplasia (BPD) morbidity. It is unclear whether changes in ventilation practices have been associated with improvements in respiratory outcomes., Objective: To examine the changes in ventilation modes in preterm neonates between two periods during the last decade and their impact on BPD prevalence., Methods: A retrospective chart review of very low birth weight infants and those born at less than 32 weeks gestation hospitalized during two periods: the years 2012-2013 and 2018-2019. The primary outcome was the prevalence of BPD. Study variables included the mode and duration of ventilation, duration of oxygen need, and perinatal clinical parameters., Results: Four hundred eighty-one infants were enrolled. Between the two study periods, a significant increase was observed in invasive (33%-47%, p = 0.002), and noninvasive ventilation rates (44%-72%, p < 0.001). The average duration of noninvasive ventilation increased significantly (from 9.24 to 14.08 days, p = 0.016). The total duration of respiratory support remained unchanged. The overall prevalence of moderate and severe BPD at 36 weeks corrected age remained approximately 40% in preterm infants born at less than 28 weeks gestation., Conclusion: The increasing use of non-invasive ventilation was not accompanied by a reduction in the use of invasive ventilation, nor by a reduced prevalence of BPD. The high prevalence of BPD remains a significant problem in extreme prematurity. Other interventions, in addition to less aggressive ventilation, need to be explored., (© 2023 Wiley Periodicals LLC.)

Aim: Systemic postnatal corticosteroids are used to treat or prevent bronchopulmonary dysplasia (BPD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants but are associated with long-term harm. We aimed to assess the relationship between cumulative postnatal corticosteroid dose and neurodevelopmental outcomes., Methods: Longitudinal cohort study of all EP/ELBW livebirths in Victoria, Australia 2016-2017. Perinatal data were collected prospectively. Neurodevelopmental assessment was performed at 2 years' corrected age. Linear and logistic regression were used to determine relationships between cumulative corticosteroid dose and neurodevelopment, adjusted for gestational age, birth weight, sex and major intraventricular haemorrhage., Results: Seventy-six EP/ELBW infants received postnatal corticosteroids to treat or prevent BPD, 62/65 survivors were seen at 2 years. Median (IQR) cumulative postnatal corticosteroid dose was 1.36 (0.92-3.45) mg/kg dexamethasone equivalent. Higher cumulative corticosteroid dose was associated with increased odds of cerebral palsy, adjusted OR (95% CI) 1.47 (1.04, 2.07). Higher cumulative corticosteroid dose was also associated with lower cognitive and motor developmental scores, however, this weakened after adjustment for confounding variables: cognitive composite score adjusted coefficient (95% CI) -1.3 (-2.7, 0.1) and motor composite score adjusted coefficient (95% CI) -1.3 (-2.8, 0.2)., Conclusion: Higher cumulative postnatal corticosteroid dose in EP/ELBW infants is associated with increased odds of cerebral palsy at 2 years' corrected age. Adequately powered studies are needed to assess the independent effects of cumulative steroid dose on neurodevelopmental outcomes., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Aminophylline use and the association between clinical outcomes and therapy timing have been less investigated. The objective of this study was to determine the efficacy of early aminophylline use (within the first two days of life) in premature infants., Method: A retrospective observational cohort of infants weighing <1500 g and <30 weeks of gestational age at Kaohsiung Veterans General Hospital received aminophylline either within the first two days of life (EA, early aminophylline group), after the third day of life (LA, late aminophylline group), or without aminophylline during the first month of life (WA, without aminophylline group). Demographic data and neonatal clinical outcomes were compared among the three groups., Results: This study included 89 preterm infants (EA = 33, LA = 38, WA = 18). The EA group had a lower incidence of bronchopulmonary dysplasia (BPD) than the WA group (adjusted odds ratio [aOR] = 8.86(1.56-59.32); P = 0.024). Although there was no significant difference in BPD incidence between the EA and LA groups (aOR = 2.66(0.51-13.81), P = 0.244), a trend remained. Birth body weight less than 1000 g was also a significant risk factor for BPD (aOR = 8.86(1.32-47.41), P = 0.014). The duration of mechanical ventilation was shorter in the infants in the EA group compared to the WA group (estimated beta = -11.344(-19.57-3.12); P = 0.008)., Conclusion: Early aminophylline administration may be associated with a decreased incidence of BPD in preterm infants. However, the clinical benefits of aminophylline treatment require further investigation. In addition, a birth body weight of less than 1000 g was a crucial risk factor for BPD., Competing Interests: Declaration of competing interest The authors declare that they have no potential conflicts of interest., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Children with a history of bronchopulmonary dysplasia (BPD) may have lower physical activity levels, but evidence to date is mixed. This study compared physical activity levels between children born extremely preterm with and without history of BPD, and examined their associations with pulmonary magnetic resonance imaging (MRI) and pulmonary function test (PFT) indices., Methods: This multicentre cross-sectional study included children aged 7-9 years born extremely preterm, with and without BPD. Children wore a pedometer for 1 week, then completed the Physical Activity Questionnaire (PAQ), pulmonary MRI, and PFT. Spearman correlations and multivariable linear regression modeling were performed., Results: Of 45 children, 28 had a history of moderate-severe BPD. There were no differences in any physical activity outcomes by BPD status. Higher average daily step count and higher average daily moderate-to-vigorous physical activity (MVPA) were each correlated with greater forced vital capacity (r = 0.41 and 0.58), greater MRI lung proton density at full expiration (r = 0.42 and 0.49), and lower lung clearance index (r = -0.50 and -0.41). After adjusting for MRI total proton density and BPD status, a 5% increase in forced expiratory volume at 1 s was associated with 738 (95% CI: 208, 1268) more steps per day and 0.1 (0.0, 0.2) more hours of MVPA, respectively., Conclusion: School-aged children born extremely preterm have similar physical activity levels to their peers, regardless of history of BPD. MRI and PFT measures suggestive of gas trapping and/or airflow obstruction are associated with lower physical activity levels., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Aim: To describe pulmonary important outcomes (PIO) reported by parents of children born extremely preterm., Methods: Over 1-year, all parents of children aged 18 months-7-years born <29 weeks' GA were asked regarding their perspectives. The proportion of parents who described PIO and the themes they invoked were examined. Results were analysed using mixed methods., Results: Among parental responses (n = 285, 98% participation rate), 44% spoke about PIO, invoking 24 themes pertaining to NICU hospitalisation and/or long-term respiratory health. Some themes had an impact primarily on the child (e.g. exercise limitation), while the majority had an impact on the whole family (e.g. hospital readmissions). None mentioned oxygen at 36 weeks nor bronchopulmonary dysplasia (BPD). The proportion of responses invoking PIO were statistically similar between parents of children with and without BPD, born before or after 25 weeks or with birthweight < or ≥750 g. PIO were more likely to be mentioned in males and among those readmitted for respiratory problems., Conclusion: Parents describe many PIO, most related to the functional impact of lung disease on their child (and family), rather than the diagnosis of BPD itself. Most of these PIO are not primary outcomes in large neonatal trials nor collected in neonatal databases., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To determine if skin-to-skin contact (SSC) improved respiratory parameters in premature infants with evolving or established bronchopulmonary dysplasia (BPD) on non-invasive neutrally adjusted ventilator assist (NIV-NAVA)., Methods: Premature infants (<32 weeks gestational age) with BPD on NIV-NAVA were studied. Continuous readings from the Edi catheter (modified nasogastric feeding tube inserted for NAVA ventilation) were compared: pre-SSC (baby in incubator) and end-SSC (just before end of SSC)., Results: Sixty-five episodes of SSC were recorded in 12 premature infants with median gestational age at birth of 24.4 (23.1-27.0) weeks and birth weight of 642 (530-960) grams. Peak Edi (uV) in end-SSC 11.5 (2.7-38.7) was significantly lower compared to pre-SSC 15.8 (4.0-36.6), p < 0.001. P mean (cmH 2 O) was significantly lower in end-SSC 9.7 (7.3-15.4) compared to pre-SSC 10.3 (7.5-15.5), p = 0.008. Respiratory rate (breaths/min) was significantly lower in end-SSC 52.9 (31.1-78.1) compared to pre-SSC 53.4 (35.1-74.1), p = 0.031. There was no significant difference in inspired oxygen requirement or time on back-up mode in end-SSC 40.0 (22.1-56.1) and 5.9 (0.0-56.0) compared to pre-SSC 39.0 (26.0-56.1) and 5.1 (0.0-29.3), p = 0.556 and p = 0.853 respectively., Conclusion: SSC improved respiratory parameters in premature infants with evolving or established BPD on NIV-NAVA., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward., Competing Interests: Declaration of Competing Interest The authors indicated no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: We sought to investigate how race, ethnicity, and socioeconomic status relate to tracheostomy insertion and post-tracheostomy mortality among infants with bronchopulmonary dysplasia (BPD)., Methods: The Vizient Clinical Database/Resource Manager was queried to identify infants born ≤32 weeks with BPD admitted to US hospitals from January 2012 to December 2020. Markers of socioeconomic status were linked to patient records from the Agency for Healthcare Research and Quality's Social Determinants of Health Database. Regression models were used to assess trends in annual tracheostomy insertion rate and odds of tracheostomy insertion and post-tracheostomy mortality, adjusting for sociodemographic and clinical factors., Results: There were 40,021 ex-premature infants included in the study, 1614 (4.0%) of whom received a tracheostomy. Tracheostomy insertion increased from 2012 to 2017 (3.1%-4.1%), but decreased from 2018 to 2020 (3.3%-1.6%). Non-Hispanic Black infants demonstrated a 25% higher odds (aOR 1.25, 1.09-1.43) and Hispanic infants demonstrated a 20% lower odds (aOR 0.80, 0.65-0.96) of tracheostomy insertion compared with non-Hispanic White infants. Patients receiving public insurance had increased odds of tracheostomy insertion (aOR 1.15, 1.03-1.30), but there was no relation between other metrics of socioeconomic status and tracheostomy insertion within our cohort. In-hospital mortality among the tracheostomy-dependent was 14.1% and was not associated with sociodemographic factors., Conclusions: Disparities in tracheostomy insertion are not accounted for by differences in socioeconomic status or the presence of additional neonatal morbidities. Post-tracheostomy mortality does not demonstrate the same relationships. Further investigation is needed to explore the source and potential mitigators of the identified disparities., (© 2023 Wiley Periodicals LLC.)

Rationale: Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. Objective: To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. Methods: We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. Measurements and Main Results: A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 ( P  < 0.001) and 0.45 ( P  < 0.001), respectively. Conclusions: In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.

More and more very low birth weight (VLBW) infants around the world survive nowadays, with consequently larger numbers of children developing prematurity-related morbidities, especially bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and its rising incidence in recent years means that general pediatricians are much more likely to encounter a child born extremely preterm, possibly with BPD, in their clinical practice. Short- and long-term sequelae in VLBW patients may affect not only pulmonary function (principally characterized by an obstructive pattern), but also other aspect including the neurological (neurodevelopmental and neuropsychiatric disorders), the sensorial (earing and visual impairment), the cardiological (systemic and pulmonary hypertension, reduced exercise tolerance and ischemic heart disease in adult age), nutritional (feeding difficulties and nutritional deficits), and auxological (extrauterine growth restriction). For the most premature infants at least, a multidisciplinary follow-up is warranted after discharge from the neonatal intensive care unit in order to optimize their respiratory and neurocognitive potential, and prevent respiratory infections, nutritional deficiencies or cardiovascular impairments.  Conclusion: The aim of this review is to summarize the main characteristics of preterm and BPD infants, providing the general pediatrician with practical information regarding these patients' multidisciplinary complex follow-up. We explore the current evidence on respiratory outcomes and their management that actually does not have a definitive available option. We also discuss the available investigations, treatments, and strategies for prevention and prophylaxis to improve the non-respiratory outcomes and the quality of life for these children and their families, a critical aspect not always considered. This comprehensive approach, added to the increased needs of a VLBW subjects, is obviously related to very high health-related costs that should be beared in mind. What is Known: • Every day, a general pediatrician is more likely to encounter a former very low birth weight infant. • Very low birth weight and prematurity are frequently related not only with worse respiratory outcomes, but also with neurological, sensorial, cardiovascular, renal, and nutritional issues. What is New: • This review provides to the general pediatrician a comprehensive approach for the follow-up of former premature very low birth weight children, with information to improve the quality of life of this special population., (© 2023. The Author(s).)

Premature birth is a risk factor for bronchopulmonary dysplasia (BPD); both of which are associated with obstructive airway disease throughout childhood. Impulse oscillometry (IOS) is an effort-independent, passive measure of tidal breathing, which could have benefits in assessing lung function amongst younger patients unable to perform valid spirometry. A literature search was conducted to investigate the use of IOS in prematurely born children and young people. IOS results correlate with those of spirometry. Reversibility of airway obstruction in children with BPD is variable. IOS could have benefits in assessing individual patient response and suitability for bronchodilator therapy. More work, however, is required to establish multi-ethnic reference ranges and standardise commercially available devices prior to its routine incorporation into clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Over the last decade, there has been increased use of end-tidal carbon dioxide (ETCO 2 ) and oxygen saturation (SpO 2 ) monitoring during resuscitation of prematurely born infants in the delivery suite. Our objectives were to test the hypotheses that low end-tidal carbon dioxide (ETCO 2 ) levels, low oxygen saturations (SpO 2 ) and high expiratory tidal volumes (VT E ) during the early stages of resuscitation would be associated with adverse outcomes in preterm infants., Methods: Respiratory recordings made in the first 10 min of resuscitation in the delivery suite of 60 infants, median GA 27 (interquartile range 25-29) weeks were analysed. The results were compared of infants who did or did not die or did or did not develop intracerebral haemorrhage (ICH) or bronchopulmonary dysplasia (BPD)., Results: Twenty-five infants (42%) developed an ICH and 23 (47%) BPD; 11 (18%) died. ETCO 2 at approximately 5 min after birth was lower in infants who developed an ICH, this remained significant after adjusting for gestational age, coagulopathy and chorioamnionitis (p=0.03). ETCO 2 levels were lower in infants who developed ICH or died compared to those that survived without ICH, which remained significant after adjustment for gestational age, Apgar score at 10 min, chorioamnionitis and coagulopathy (p=0.004). SpO 2 at approximately 5 min was lower in the infants who died compared to those who survived which remained significant after adjusting for the 5-min Apgar score and chorioamnionitis (p=0.021)., Conclusions: ETCO 2 and SpO 2 levels during early resuscitation in the delivery suite were associated with adverse outcomes., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103 + DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11b hi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11b hi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Brady, Zhang, Fulton, Goldsmith and Popova.)

Preterm birth is a major contributor to neonatal morbidity and mortality. Complications of prematurity such as bronchopulmonary dysplasia (BPD, affecting the lung), pulmonary hypertension associated with BPD (BPD-PH, heart), white matter injury (WMI, brain), retinopathy of prematurity (ROP, eyes), necrotizing enterocolitis (NEC, gut) and sepsis are among the major causes of long-term morbidity in infants born prematurely. Though the origins are multifactorial, inflammation and in particular the imbalance of pro- and anti-inflammatory mediators is now recognized as a key driver of the pathophysiology underlying these illnesses. Here, we review the involvement of the interleukin (IL)-1 family in perinatal inflammation and its clinical implications, with a focus on the potential of these cytokines as therapeutic targets for the development of safe and effective treatments for early life inflammatory diseases.

Introduction: Advances in neonatal care have made possible the increased survival of extremely preterm infants. Even though there is widespread recognition of the harmful effects of mechanical ventilation on the developing lung, its use has become imperative in the management of micro-/nano-preemies. There is an increased emphasis on the use of less-invasive approaches such as minimally invasive surfactant therapy and non-invasive ventilation that have been proven to result in improved outcomes., Areas Covered: Here, we review the evidence-based practices surrounding the respiratory management of extremely preterm infants including delivery room interventions, invasive and non-invasive ventilation approaches, and specific ventilator strategies in respiratory distress syndrome and bronchopulmonary dysplasia. Adjuvant relevant respiratory pharmacotherapies used in preterm neonates are also discussed., Expert Opinion: Early use of non-invasive ventilation and use of less invasive surfactant administration are key strategies in the management of respiratory distress syndrome in preterm infants. Ventilator management in bronchopulmonary dysplasia must be tailored according to the individual phenotype. There is strong evidence to start caffeine early to improve respiratory outcomes, but evidence is lacking on the use of other pharmacological agents in preterm neonates, and an individualized approach has to be considered for their use.

Neonates born prematurely (<37 weeks of gestation) are at a significantly increased risk of developing inflammatory conditions associated with high mortality rates, including necrotizing enterocolitis, bronchopulmonary dysplasia, and hypoxic-ischemic brain damage. Recently, research has focused on characterizing the content of extracellular vesicles (EVs), particularly microRNAs (miRNAs), for diagnostic use. Here, we describe the most recent work on EVs-miRNAs biomarkers discovery for conditions that commonly affect premature neonates.

Exposure to supraphysiological concentrations of oxygen (hyperoxia) predisposes to bronchopulmonary dysplasia (BPD), which is characterized by abnormal alveolarization and pulmonary vascular development, in preterm neonates. Neonatal hyperoxia exposure is used to recapitulate the phenotype of human BPD in murine models. Male sex is considered an independent predictor for the development of BPD, but the main mechanisms underlying sexually dimorphic outcomes are unknown. Our objective was to investigate sex-specific and cell-type specific transcriptional changes that drive injury in the neonatal lung exposed to hyperoxia at single-cell resolution and delineate the changes in cell-cell communication networks in the developing lung. We used single-cell RNA sequencing (scRNAseq) to generate transcriptional profiles of >35,000 cells isolated from the lungs of neonatal male and female C57BL/6 mice exposed to 95% [Formula: see text] between PND1-5 (saccular stage of lung development) or normoxia and euthanized at PND7 (alveolar stage of lung development). ScRNAseq identified 22 cell clusters with distinct populations of endothelial, epithelial, mesenchymal, and immune cells. Our data identified that the distal lung vascular endothelium (composed of aerocytes and general capillary endothelial cells) is exquisitely sensitive to hyperoxia exposure with the emergence of an intermediate capillary endothelial population with both general capillaries (gCap) and aerocytes or alveolar capillaries (aCap) markers. We also identified a myeloid-derived suppressor cell population from the lung neutrophils. Sex-specific differences were evident in all lung cell subpopulations but were striking among the lung immune cells. Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure.

Growth and differentiation factor 15 (GDF15) is a stress-responsive cytokine, and its expression increases during inflammation, hyperoxia, and senescence. Significantly, GDF15 is secreted by the placenta, and maternal levels increase throughout pregnancy. Serum GDF15 level is a promising biomarker for many lung diseases like pulmonary hypertension and pulmonary fibrosis. However, circulating GDF15 levels in preterm infants and their role as a predictor of respiratory outcomes have not been studied. We hypothesized that GDF15 levels would increase with gestational age at birth, and that postnatal GDF15 will be correlated with adverse respiratory outcomes in preterm infants. Scavenged blood samples were retrieved from 57 preterm infants at five time points, from birth until 36-weeks postmenstrual age (PMA). GDF15 levels were measured using ELISA in 114 samples. We performed two-sample t-test, correlation and linear regression, logistic regression, and mixed-effects linear models for statistical analysis, and significance was identified when p < 0.05. Contrary to our hypothesis, for every 1-week increase in gestational age at birth, the predicted GDF15 level decreased by 475.0 pg/ml (p < 0.001). Greater PMA was significantly associated with lower serum GDF15 levels (p < 0.001). Interestingly, higher GDF15 levels were associated with a longer need for mechanical ventilation (p = 0.034), prolonged respiratory support need (p < 0.001), and length of hospital stay (p = 0.006). In conclusion, in preterm infants, GDF15 levels show an inverse correlation with gestational age at birth, with higher levels in more preterm babies, and levels trend down postnatally. Furthermore, longitudinal GDF15 levels through 36 weeks PMA predict adverse respiratory outcomes in preterm infants., (© 2022 Wiley Periodicals LLC.)

Introduction: Little is known about the interplay between neutrophil heterogeneity in neonates in health and disease states. Olfactomedin-4 (OLFM4) marks a subset of neutrophils that have been described in adults and pediatric patients but not neonates, and this subset is thought to play a role in modulating the host inflammatory response., Methods: This is a prospective cohort of neonates who were born between June 2020 and December 2021 at the University of Cincinnati Medical Center NICU. Olfactomedin-4-positive (OLFM4+) neutrophils were identified in the peripheral blood using flow cytometry., Results: OLFM4+ neutrophil percentage was not correlated with gestational age or developmental age. Neonates with sepsis had a higher percentage than those without the condition, 66.9% (IQR 24.3-76.9%) versus 21.5% (IQR 10.6-34.7%), respectively, p = 0.0003. At birth, a high percentage of OLFM4+ neutrophils was associated with severe chorioamnionitis at 49.1% (IQR 28.2-61.5%) compared to those without it at 13.7% (IQR 7.7-26.3%), p < 0.0001. Among neonates without sepsis, the percentages of OLFM4+ neutrophils were lower in the BPD/early death group compared to those without BPD, 11.8% (IQR 6.3-29.0%) versus 32.5% (IQR 18.5-46.1%), p = 0.003, and this retained significance in a multiple logistic regression model that included gestational age, birthweight, and race., Conclusion: This is the first study describing OLFM4+ neutrophils in neonates and it shows that this neutrophil subpopulation is not influenced by gestational age but is elevated in inflammatory conditions such as sepsis and severe chorioamnionitis, and lower percentage at birth is associated with developing bronchopulmonary dysplasia., (© 2022 S. Karger AG, Basel.)

Background: The long-term respiratory consequences for children with bronchopulmonary dysplasia (BPD) are well known. However, there is little emphasis on monitoring preterm infants without BPD. Few studies have explored the lung function status of infants with the symptoms of chronic lung disease of prematurity (CLD)., Objective: To evaluate functional lung deficits in preterm infants with CLD, and to assess the perinatal determinants of diminished lung function., Methods: In our cross-sectional study, 132 preterm infants with symptomatic CLD underwent infant pulmonary function testing (iPFT) at a median post-term age of 0.9 years. The iPFT included bodypletysmography, compliance measurement, tidal breath analysis, and rapid thoracoabdominal compression. The relationships between the respective z scores of the iPFT parameters and perinatal characteristics, postnatal treatment, and BPD status were investigated., Results: Seventy-three patients (55.3%) were born before the 28 th week of gestation, and 92 (69.7%) met the BPD criteria. Functional deficits were detected in 85.8%. The obstructive ventilatory pattern was more prevalent than restrictive (36.3 vs. 12.4%, p < 0.001). Infants with restriction had lower birth weight (BW) and required a longer duration of oxygenotherapy. In a univariate model, the lung function correlated with the duration of invasive mechanical ventilation, gestational week, and BW. In a general linear model, BPD status was not an additional determinant of the iPFT results., Conclusion: IPFT may reveal significant functional deficits in preterm infants with CLD even without BPD. The current symptoms and perinatal factors may be more important determinants of functional deficits than the BPD status itself., (© 2022 Wiley Periodicals LLC.)

Objective: To assess the clinical applicability of the current definitions of bronchopulmonary dysplasia (BPD) and their ability to predict subsequent respiratory outcomes., Study Design: In this retrospective cohort study, data were collected from 104 preterm infants (mean gestational age, 25.8 weeks) diagnosed with BPD between 2010 and 2018 at a single tertiary care center. The infants were classified according to the following definitions: 2001 National Institute of Child Health and Human Development (NICHD), 2017 Canadian Neonatal Network (CNN), 2018 NICHD, and 2019 Neonatal Research Network (NRN). Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to assess the predictive ability of each definition on mortality or severe respiratory morbidity at 18-24 months of age., Results: All patients could be adequately classified by each definition, except for the 2001 NICHD definition, in which 11.4% were unclassifiable. The prevalence of BPD was 49% by the 2017 CNN definition and 70% by the 2018 NICHD and 2019 NRN definitions. The best regression model was the one that included the 2018 NICHD definition, which had an accuracy of 85.6% and a significantly higher AUC compared with the 2001 NICHD (0.891 vs 0.824; P = .015) and 2017 CNN (0.891 vs 0.811; P = .036) definitions, but not compared with the 2019 NRN definition (0.891 vs 0.833; P = .09)., Conclusions: The current definitions of BPD showed a good predictive ability for mid-term respiratory outcomes, with the highest ability for the 2018 NICHD definition. Further studies are needed to establish the most appropriate definition of BPD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To test whether prospective classification of infants with bronchopulmonary dysplasia identifies lower-risk infants for discharge with home oxygen who have fewer rehospitalizations by 1 year after neonatal intensive care unit discharge., Study Design: This is a prospective single-center cohort that included infants from 2016 to 2019 with bronchopulmonary dysplasia, defined as receiving respiratory support at 36 weeks of postmenstrual age. "Lower-risk" infants were receiving ≤2 L/min nasal cannula flow, did not have pulmonary hypertension or airway comorbidities, and had blood gas partial pressure of carbon dioxide <70 mm Hg. We compared 3 groups by discharge status: lower-risk room air, lower-risk home oxygen, and higher-risk home oxygen. The primary outcome was rehospitalization at 1 year postdischarge, and the secondary outcomes were determined by the chart review and parent questionnaire., Results: Among 145 infants, 32 (22%) were lower-risk discharged in room air, 49 (32%) were lower-risk using home oxygen, and 64 (44%) were higher-risk. Lower-risk infants using home oxygen had rehospitalization rates similar to those of lower-risk infants on room air (18% vs 16%, P = .75) and lower rates than higher-risk infants (39%, P = .018). Lower-risk infants using home oxygen had more specialty visits (median 10, IQR 7-14 vs median 6, IQR 3-11, P = .028) than those on room air. Classification tree analysis identified risk status as significantly associated with rehospitalization, along with distance from home to hospital, inborn, parent-reported race, and siblings in the home., Conclusions: Prospectively identified lower-risk infants discharged with home oxygen had fewer rehospitalizations than higher-risk infants and used more specialty care than lower-risk infants discharged in room air., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)