Retrospective analysis of referrals for hypoxic challenge testing in children born preterm.

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may be at risk of hypoxaemia at altitude, such as during air travel. We have performed preflight hypoxic challenge testing (HCT) since 2006, incorporating British Thoracic Society (BTS) guidance since 2011, to determine which children may require oxygen during air travel. AIMS: We aimed to compare the outcome of HCTs in children with a history of BPD who met the 2011 BTS criteria and those who did not and, in addition to this, to interrogate the data for factors that may predict the outcome of HCT in this population. METHODS: We performed a retrospective analysis of data from HCTs of children with a history of BPD referred 2006-2020. Cases were excluded if the patient had a respiratory comorbidity, was still on oxygen therapy, if the test was a repeat or if the clinical record was incomplete. Descriptive and univariate analysis of the data was performed, and a binary logistic regression model was fitted. RESULTS: There were 79 HCTs, of which 24/79 (30%) did not meet BTS 2011 guidelines referral criteria. The analysis showed a greater proportion of desaturation in the group that did not meet criteria: 46% vs 27% (no statistical significance). Baseline oxygen saturations were higher in those who did not require oxygen during HCT and this variable was significant when adjusted for confounders. CONCLUSIONS: This study found that the current criteria for referral for preflight testing may incorrectly identify those most at risk and highlights the need for further investigation to ensure those most at risk are being assessed prior to air travel.

A comprehensive study on machine learning models combining with oversampling for bronchopulmonary dysplasia-associated pulmonary hypertension in very preterm infants.

BACKGROUND: Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) remains a devastating clinical complication seriously affecting the therapeutic outcome of preterm infants. Hence, early prevention and timely diagnosis prior to pathological change is the key to reducing morbidity and improving prognosis. Our primary objective is to utilize machine learning techniques to build predictive models that could accurately identify BPD infants at risk of developing PH. METHODS: The data utilized in this study were collected from neonatology departments of four tertiary-level hospitals in China. To address the issue of imbalanced data, oversampling algorithms synthetic minority over-sampling technique (SMOTE) was applied to improve the model. RESULTS: Seven hundred sixty one clinical records were collected in our study. Following data pre-processing and feature selection, 5 of the 46 features were used to build models, including duration of invasive respiratory support (day), the severity of BPD, ventilator-associated pneumonia, pulmonary hemorrhage, and early-onset PH. Four machine learning models were applied to predictive learning, and after comprehensive selection a model was ultimately selected. The model achieved 93.8% sensitivity, 85.0% accuracy, and 0.933 AUC. A score of the logistic regression formula greater than 0 was identified as a warning sign of BPD-PH. CONCLUSIONS: We comprehensively compared different machine learning models and ultimately obtained a good prognosis model which was sufficient to support pediatric clinicians to make early diagnosis and formulate a better treatment plan for pediatric patients with BPD-PH.

Large airway T cells in adults with former bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary Dysplasia (BPD) in infants born prematurely is a risk factor for chronic airway obstruction later in life. The distribution of T cell subtypes in the large airways is largely unknown. OBJECTIVE: To characterize cellular and T cell profiles in the large airways of young adults with a history of BPD. METHODS: Forty-three young adults born prematurely (preterm (n = 20), BPD (n = 23)) and 45 full-term-born (asthma (n = 23), healthy (n = 22)) underwent lung function measurements, and bronchoscopy with large airway bronchial wash (BW). T-cells subsets in BW were analyzed by immunocytochemistry. RESULTS: The proportions of both lymphocytes and CD8 + T cells in BW were significantly higher in BPD (median, 6.6%, and 78.0%) when compared with asthma (3.4% and 67.8%, p = 0.002 and p = 0.040) and healthy (3.8% and 40%, p < 0.001 and p < 0.001). In all adults born prematurely (preterm and BPD), lymphocyte proportion correlated negatively with forced vital capacity (r= -0.324, p = 0.036) and CD8 + T cells correlated with forced expiratory volume in one second, FEV1 (r=-0.448, p = 0.048). Correlation-based network analysis revealed that lung function cluster and BPD-birth cluster were associated with lymphocytes and/or CD4 + and CD8 + T cells. Multivariate regression analysis showed that lymphocyte proportions and BPD severity qualified as independent factors associated with FEV1. CONCLUSIONS: The increased cytotoxic T cells in the large airways in young adults with former BPD, suggest a similar T-cell subset pattern as in the small airways, resembling features of COPD. Our findings strengthen the hypothesis that mechanisms involving adaptive and innate immune responses are involved in the development of airway disease due to preterm birth.

Rates of bronchopulmonary dysplasia in very low birth weight neonates: a systematic review and meta-analysis.

IMPORTANCE: Large-scale estimates of bronchopulmonary dysplasia (BPD) are warranted for adequate prevention and treatment. However, systematic approaches to ascertain rates of BPD are lacking. OBJECTIVE: To 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 (< 32 weeks) neonates. DATA SOURCES: A search of MEDLINE from January 1990 until September 2019 using search terms related to BPD and prevalence was performed. STUDY SELECTION: Randomized 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 SYNTHESIS: Two 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 MEASURES: Prevalence of BPD defined as BPD28, BPD36, and by subgroups. RESULTS: A 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 RELEVANCE: This study provides a global estimation of BPD prevalence in very low birth weight/low gestation neonates.

Early cardiac function and death, severe bronchopulmonary dysplasia and pulmonary hypertension in extremely preterm infants.

BACKGROUND: Association between early cardiac function and neonatal outcomes are scarcely reported. The aim of the current study was to describe this association with death, severe bronchopulmonary dysplasia (BPD) and BPD-related pulmonary hypertension (PH). METHODS: Retrospective cohort study of infants <29 weeks born between 2015 and 2019. Infants with clinically acquired echocardiography at ≤21 days after birth were included and data were extracted by an expert masked to outcomes. RESULTS: A total of 176 infants were included. Echocardiogram was performed at a median of 9 days (IQR 5-13.5). Of these, 31 (18%) had death/severe BPD and 59 (33.5%) had death/BPD-related PH. Infants with death/severe BPD were of lower birth weight (745 [227] vs 852 [211] grams, p = 0.01) and more exposed to invasive ventilation, late-onset sepsis, inotropes and/or postnatal steroids. Early echocardiograms demonstrated decreased right ventricular [Tricuspid Annular Plane Systolic Excursion: 5.2 (1.4) vs 6.2 (1.5) cm, p = 0.03] and left ventricular function [Ejection fraction 53 (14) vs 58 (10) %, p = 0.03]. Infants with death/BPD-related PH had an increased Eccentricity index (1.35 [0.20] vs 1.26 [0.19], p = 0.02), and flat/bowing septum (19/54 [35%] vs 20/109 [18%], p = 0.021). CONCLUSIONS: In extremely premature infants, altered ventricular function and increased pulmonary pressure indices within the first 21 days after birth, were associated with the combined outcome of death/severe BPD and death/BPD-related PH. IMPACT: Decreased cardiac function on echocardiography performed during first three weeks of life is associated with severe bronchopulmonary dysplasia in extremely premature infants. In extreme preterm infants, echocardiographic signs of pulmonary hypertension in early life are associated with later BPD-related pulmonary hypertension close to 36 weeks post-menstrual age. Early cardiac markers should be further studied as potential intervention targets in this population. Our study is adding comprehensive analysis of echocardiographic data in infants born below 29 weeks gestational age.

Blood pressure in preterm infants with bronchopulmonary dysplasia in the first three months of life.

BACKGROUND: Neonatal hypertension is common in preterm infants with bronchopulmonary dysplasia (BPD). Our study aimed to examine blood pressure variation in the first three months of life in preterm BPD patients. METHODS: We conducted a retrospective, single-centre study at the Neonatal Intensive Care Unit of the University of Szeged, Hungary. We collected blood pressure data from 26 preterm infants (born at < 30 weeks gestation) with moderate or severe BPD over three years (2019-2021). We calculated the BPD group's daily average blood pressure values and used previously defined normal blood pressure values from a preterm patient group born at < 30 weeks gestation as a reference. We used 19,481 systolic, diastolic and mean blood pressure measurement data separately to calculate daily average blood pressures. RESULTS: We found a statistically significant correlation between the blood pressure values of the BPD patient group and the reference data. The difference between the blood pressure curve of the group with BPD and that of the reference group was also statistically significant. We also analysed individual patients' daily average blood pressure values and found that 11 patients (42%) had hypertensive blood pressure values for three or more days within the first 90 days of life. Within this group, our statistical analysis showed a 25% chance of acute kidney injury. CONCLUSION: The blood pressure of the BPD group not only correlated with but also significantly differed from the reference data. Hypertension lasting three or more days occurred more frequently in patients with acute kidney injury accompanied by BPD.

Right ventricular function indices and platelet parameters for early prediction value of bronchopulmonary dysplasia: a retrospective study.

BACKGROUND: To examine the value of early echocardiographic indices for the right ventricular function combined with platelet(PLT) parameters for predicting bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: This retrospective study included infants with gestational age (GA) below 32 weeks, who were admitted to the neonatal intensive care unit(NICU). The detection rate of tricuspid regurgitation jet velocity (TRVJ), ventricular septal flattening, pulmonary artery widening, right ventricular dilation, and right atrial enlargement on the 7th day of life (DOL 7) were compared between BPD and non-BPD infants. Echocardiographic indices of the right ventricular function including tricuspid annular plane systolic excursion (TAPSE) and right ventricular index of myocardial performance (RIMP) were measured on 1 day of life (DOL 1)、on DOL 7 and on 14 day of life (DOL 14) respectively. The PLT parameters including the PLT count, mean platelet volume (MPV), platelet hematocrit (PCT) level, and platelet distribution width (PDW) were measured on the DOL 1,DOL 7, and DOL 14. Multivariate logistic regression was used to analyze the relationship between these parameters and BPD. Receiver operating characteristic curve analysis was performed to assess the predictive value of the right ventricular function indices and PLT parameters for BPD. RESULTS: A total of 220 preterm infants were included in this study, and of these, 85 infants developed BPD among them. The RIMP of the BPD group on DOL 14 was higher than that of the non-BPD group (P < 0.05). The TAPSE of the BPD group on DOL 14 was lower than that of the non-BPD group (P < 0.05). The PLT count of the BPD group on DOL 1 was lower than that of the non-BPD group (P < 0.05), and the MPV of the BPD group on DOL 1 was higher than that of the non-BPD group (P < 0.05). Using multivariate logistic regression, GA、invasive mechanical ventilation duration ≥ 7 days、 PLT、 MPV、 TAPSE and RIMP were found to be independent risk factors for BPD. The area under the receiver operating characteristic curve was 0.846 (95CI: 0.794∼0.899), which improved when using right ventricular function indices combined with platelet parameters. CONCLUSION: TAPSE and RIMP combined with PLT count and MPV can help identify preterm infants at an increased risk of developing BPD.

Prediction of bronchopulmonary dysplasia by the chest radiographic thoracic area on day one in infants with exomphalos.

OBJECTIVES: To determine if infants with exomphalos had abnormal antenatal lung growth as indicated by lower chest radiographic thoracic areas (CRTA) on day one compared to controls and whether the CRTA could predict the development of bronchopulmonary dysplasia (BPD). METHODS: Infants with exomphalos cared for between January 2004 and January 2023 were included. The controls were term, newborn infants ventilated for absent respiratory drive at birth, without lung disease and had no supplemental oxygen requirement by 6 h of age. The radiographs were imported as digital image files by Sectra PACS software (Sectra AB, Linköping, Sweden). Free-hand tracing of the perimeter of the thoracic area was undertaken and the CRTA calculated by the software. RESULTS: Sixty-four infants with exomphalos and 130 controls were included. Infants with exomphalos had a lower median (IQR) CRTA (1,983 [1,657-2,471] mm2) compared to controls (2,547 [2,153-2,932] mm2, p<0.001). Following multivariable regression analysis, infants with exomphalos had lower CRTAs compared to controls (p=0.001) after adjusting for differences in gestational age and male sex. In the exomphalos group, the CRTAs were lower in those who developed BPD (n=14, 1,530 [1,307-1,941] mm2) compared to those who did not (2,168 [1,865-2,672], p<0.001). Following multivariable regression analysis, the CRTA was associated with BPD development (p=0.021) after adjusting for male sex and gestational age. CONCLUSIONS: Lower CRTAs on day one in the exomphalos infants compared to the controls predicted BPD development.

Evaluation of preterm infants having bronchopulmonary dysplasia with echocardiography and serum biomarkers.

BACKGROUND AND OBJECTIVES: Pulmonary hypertension is frequent in infants with bronchopulmonary dysplasia. Echocardiography is easy to perform, non-invasive, and recommended by guidelines even though solely it is not enough. Catheterisation is gold standard but invasive, expensive, and not cost effective. Therefore, we aimed to assess to find out the role of biomarkers besides echocardiography in the diagnosis of pulmonary hypertension in preterm with bronchopulmonary dysplasia. METHODS: This study is done during the time period January 2016-2017. The diagnosis of pulmonary hypertension was assessed by echocardiography at 36 weeks later repeated at 3rd and 6th months. We also repeated biomarkers at 3rd and 6th months. The infants born ≤ 28 weeks in Erciyes University hospital who were diagnosed bronchopulmonary dysplasia were included. Infants with genetic syndromes, structural lung, and CHDs were excluded. Patients without bronchopulmonary dysplasia but having pulmonary hypertension due to other reasons and patients having echocardiograms without adequate images were excluded. RESULTS: At initial, 21/59 patients had bronchopulmonary dysplasia-pulmonary hypertension (Group 1), 21/59 had no bronchopulmonary dysplasia-pulmonary hypertension (Group 2), and 17/59 had bronchopulmonary dysplasia without pulmonary hypertension (Group 3). Systolic pulmonary artery pressure and pulmonary vascular resistance were found high in Group 1 (36 mmHg; p <0.001, 1.25 Woods Unit; p < 0.0017, respectively). Tricuspid annular plane systolic excursion values of Group 1 were low. Median serum kallistatin levels of Group 1 were lower than the other groups (230.5 (114.5-300.5) µg/ml; p < 0.005). During the study period, pulmonary hypertension of 14/21 bronchopulmonary dysplasia-pulmonary hypertension resolved, six patients in Group 3 developed pulmonary hypertension. However, there was no difference in the biomarkers of these six patients. CONCLUSION: In the diagnosis and the follow-up of pulmonary hypertension in bronchopulmonary dysplasia patients, besides echocardiography kallistatin, gelsolin, NT-probrain natriuretic peptide, homocysteine, and cystatin-C levels can be used. Further studies were required with large sample sizes.

Development of a peripheral blood transcriptomic gene signature to predict bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common lung disease of extreme prematurity, yet mechanisms that associate with or identify neonates with increased susceptibility for BPD are largely unknown. Combining artificial intelligence with gene expression data is a novel approach that may assist in better understanding mechanisms underpinning chronic lung disease and in stratifying patients at greater risk for BPD. The objective of this study is to develop an early peripheral blood transcriptomic signature that can predict preterm neonates at risk for developing BPD. Secondary analysis of whole blood microarray data from 97 very low birth weight neonates on day of life 5 was performed. BPD was defined as positive pressure ventilation or oxygen requirement at 28 days of age. Participants were randomly assigned to a training (70%) and testing cohort (30%). Four gene-centric machine learning models were built, and their discriminatory abilities were compared with gestational age or birth weight. This study adheres to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) statement. Neonates with BPD (n = 62 subjects) exhibited a lower median gestational age (26.0 wk vs. 30.0 wk, P < 0.01) and birth weight (800 g vs. 1,280 g, P < 0.01) compared with non-BPD neonates. From an initial pool (33,252 genes/patient), 4,523 genes exhibited a false discovery rate (FDR) <1%. The area under the receiver operating characteristic curve (AUC) for predicting BPD utilizing gestational age or birth weight was 87.8% and 87.2%, respectively. The machine learning models, using a combination of five genes, revealed AUCs ranging between 85.8% and 96.1%. Pathways integral to T cell development and differentiation were associated with BPD. A derived five-gene whole blood signature can accurately predict BPD in the first week of life.

Discharge Practices for Infants with Bronchopulmonary Dysplasia: A Survey of National Experts.

OBJECTIVE: To establish consensus practices among a panel of national experts for the discharge of premature infants with bronchopulmonary dysplasia (BPD) from the hospital to home. STUDY DESIGN: We conducted a Delphi study that included US neonatologists and pediatric pulmonologists from the Bronchopulmonary Dysplasia Collaborative to establish consensus practices-defined as recommendations with at least 80% agreement-for infants with BPD being discharged from the hospital. Specifically, we evaluated recommendations for diagnostic tests to be completed around discharge, follow-up respiratory care, and family education. RESULTS: Thirty-one expert participants completed 3 rounds of surveys, with a 99% response rate (92 of 93). Consensus was established that infants with moderate-severe BPD (ie, those who remain on respiratory support at 36 weeks) and those discharged on oxygen should be targeted for in-person pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal follow-up is an alternative for infants with mild BPD. Infants with moderate or severe BPD should have an echocardiogram performed after 36 weeks to screen for pulmonary hypertension. Infants with BPD warrant additional evaluations if they have growth restriction or poor growth, pulmonary hypertension, or tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral feeds. CONCLUSIONS: This Delphi survey establishes expert consensus around best practices for follow-up respiratory management and routine evaluation for infants with BPD surrounding neonatal discharge. Areas of disagreement for which consensus was not established are discussed.

Exhaled Volatile Organic Compounds for Early Prediction of Bronchopulmonary Dysplasia in Infants Born Preterm.

OBJECTIVE(S): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS: Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion fragments detected by gas chromatography-mass spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks of postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS: Breath samples were collected from 117 infants (mean gestation 26.8 ± 1.5 weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% CI 0.80-0.97) and 0.92 (95% CI 0.84-0.99) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in noninvasively supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 vs 0.92, P value .04; day 7: c-statistic 0.82 vs 0.94, P value .03). CONCLUSIONS: This study showed that VOC profiles in exhaled breath of preterm infants on noninvasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.

Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants.

OBJECTIVE: To compare the discriminative performances of the 2018 National Institutes of Health (NIH) and the 2019 Jensen definitions of bronchopulmonary dysplasia (BPD) with the 2001 NIH definition on adverse neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age. STUDY DESIGN: In this single-center retrospective cohort study, outcomes of infants born at <30 weeks of gestational age were collected. The 3 definitions of BPD were compared by adding the different definitions to the National Institute of Child Health and Human Development's outcome prediction model for neurodevelopmental impairment (NDI) or death. Discriminative performance was compared for both outcomes at 2 years and 5 years corrected age by calculating the areas under the receiver operating characteristic curve and z-statistics. RESULTS: The presence of BPD and its severity were determined in 584 infants. There were considerable shifts in BPD grading among the different definitions. At both time points, all BPD definition models had comparable discriminating power for NDI and respiratory morbidity, with one exception. Compared with the 2001 NIH definition, the 2018 NIH definition had less predictive power for the neurologic outcome at 2 years corrected age. CONCLUSIONS: Our comparison of the 3 BPD definitions shows similar discriminative performance on long term neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age.

Leveraging transcriptomics to develop bronchopulmonary dysplasia endotypes: a concept paper.

IMPACT: Bronchopulmonary dysplasia has multiple definitions that are currently based on phenotypic characteristics. Using an unsupervised machine learning approach, we created BPD subclasses (e.g., endotypes) by clustering whole microarray data. T helper 17 cell differentiation was the most significant pathway differentiating the BPD endotypes. INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Discovery of BPD endotypes in an unbiased format, derived from the peripheral blood transcriptome, may uncover patterns underpinning this complex lung disease. METHODS: An unsupervised agglomerative hierarchical clustering approach applied to genome-wide expression of profiling from 62 children at day of life five was used to identify BPD endotypes. To identify which genes were differentially expressed across the BPD endotypes, we formulated a linear model based on least-squares minimization with empirical Bayes statistics. RESULTS: Four BPD endotypes (A, B,C,D) were identified using 7,319 differentially expressed genes. Across BPD endotypes, 5,850 genes had a p value < 0.05 after multiple comparison testing. Endotype A consisted of neonates with a higher gestational age and birthweight. Endotypes B-D included neonates between 25 and 26 weeks and a birthweight range of 640 to 940 g. Endotype D appeared to have a protective role against BPD compared to Endotypes B and C (36% vs. 62% vs. 60%, respectively). The most significant pathway focused on T helper 17 cell differentiation. CONCLUSION: Bioinformatic analyses can help identify BPD endotypes that associate with clinical definitions of BPD.

Microbial signatures in amniotic fluid at preterm birth and association with bronchopulmonary dysplasia.

BACKGROUND: Microbiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial disease with pre- and postnatal origins including intra-amniotic infection as main risk factor. Recently, postnatal pathologic lung microbiota colonization was associated with BPD. The objectives of this prospective observational cohort study were to describe differences in bacterial signatures in the amniotic fluid (AF) of intact pregnancies without clinical signs or risk of preterm delivery and AF samples obtained during preterm deliveries and their variations between different BPD disease severity stages. METHODS: AF samples were collected under sterile conditions during fetal intervention from intact pregnancies (n = 17) or immediately before preterm delivery < 32 weeks (n = 126). Metabarcoding based approaches were used for the molecular assessment of bacterial 16S rRNA genes to describe bacterial community structure. RESULTS: The absolute amount of 16S rRNA genes was significantly increased in AF of preterm deliveries and detailed profiling revealed a reduced alpha diversity and a significant change in beta diversity with a reduced relative abundance of 16S rRNA genes indicative for Lactobacillus and Acetobacter while Fusobacterium, Pseudomonas, Ureaplasma and Staphylococcus 16S rRNA gene prevailed. Although classification of BPD by disease severity revealed equivalent absolute 16S rRNA gene abundance and alpha and beta diversity in no, mild and moderate/severe BPD groups, for some 16S rRNA genes differences were observed in AF samples. Bacterial signatures of infants with moderate/severe BPD showed predominance of 16S rRNA genes belonging to the Escherichia-Shigella cluster while Ureaplasma and Enterococcus species were enriched in AF samples of infants with mild BPD. CONCLUSIONS: Our study identified distinct and diverse intrauterine 16S rRNA gene patterns in preterm infants immediately before birth, differing from the 16S rRNA gene signature of intact pregnancies. The distinct 16S rRNA gene signatures at birth derive from bacteria with varying pathogenicity to the immature lung and are suited to identify preterm infants at risk. Our results emphasize the prenatal impact to the origins of BPD.

Bronchopulmonary dysplasia prediction models: a systematic review and meta-analysis with validation.

Prediction models could identify infants at the greatest risk of bronchopulmonary dysplasia (BPD) and allow targeted preventative strategies. We performed a systematic review and meta-analysis with external validation of identified models. Studies using predictors available before day 14 of life to predict BPD in very preterm infants were included. Two reviewers assessed 7628 studies for eligibility. Meta-analysis of externally validated models was followed by validation using 62,864 very preterm infants in England and Wales. A total of 64 studies using 53 prediction models were included totalling 274,407 infants (range 32-156,587/study). In all, 35 (55%) studies predated 2010; 39 (61%) were single-centre studies. A total of 97% of studies had a high risk of bias, especially in the analysis domain. Following meta-analysis of 22 BPD and 11 BPD/death composite externally validated models, Laughon's day one model was the most promising in predicting BPD and death (C-statistic 0.76 (95% CI 0.70-0.81) and good calibration). Six models were externally validated in our cohort with C-statistics between 0.70 and 0.90 but with poor calibration. Few BPD prediction models were developed with contemporary populations, underwent external validation, or had calibration and impact analyses. Contemporary, validated, and dynamic prediction models are needed for targeted preventative strategies. IMPACT: This review aims to provide a comprehensive assessment of all BPD prediction models developed to address the uncertainty of which model is sufficiently valid and generalisable for use in clinical practice and research. Published BPD prediction models are mostly outdated, single centre and lack external validation. Laughon's 2011 model is the most promising but more robust models, using contemporary data with external validation are needed to support better treatments.

Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns.

BACKGROUND: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS: We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Oscillatory mechanics trajectory in very preterm infants: a cohort study.

BACKGROUND: The aim of this study was to describe the trajectory of oscillatory mechanics from the first week of life to term equivalent and evaluate whether oscillatory mechanics are associated with simultaneous lung disease in infants ≤32 weeks gestation. METHODS: In this observational, longitudinal study, we enrolled 66 infants. Forced oscillations were applied using a neonatal mechanical ventilator (Fabian HFOi) that superimposed oscillations (10 Hz, amplitude 2.5 cmH2O) on a positive end-expiratory pressure (PEEP). Measurements were performed at 5-7-9 cmH2O of PEEP or the clinical pressure ±2 cmH2O; they were repeated at 7, 14, 28 post-natal days, and 36 and 40 weeks post-menstrual age (PMA). RESULTS: The mean (range) gestational age of study participants was 29.2 (22.9-31.9) weeks. Nineteen infants (29%) developed bronchopulmonary dysplasia (BPD). Respiratory system reactance was significantly lower (lower compliance), and respiratory system resistance was significantly higher in infants with developing BPD from 7 post-natal days to 36 weeks PMA. All oscillatory mechanics parameters were significantly associated with the simultaneous respiratory severity score (p < 0.001 for all). CONCLUSIONS: Serial measurements of oscillatory mechanics allow differentiating lung function trajectory in infants with and without evolving BPD. Oscillatory mechanics significantly correlate with the severity of simultaneous lung disease. IMPACT: The results of the present study suggest that respiratory system reactance, as assessed by respiratory oscillometry, allows the longitudinal monitoring of the progression of lung disease in very premature infants. This paper describes for the first time the trajectory of oscillatory mechanics in very preterm infants with and without evolving bronchopulmonary dysplasia from the first week of life to term equivalent. Serial respiratory oscillometry measurements allow the identification of early markers of evolving bronchopulmonary dysplasia and may help personalizing the respiratory management strategy.

Prematurity and BPD: what general pediatricians should know.

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.

Diaphragmatic muscle function in term and preterm infants.

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 cmH2O; 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 cmH2O; 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.