Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: Basing Care on Physiology.

Bronchopulmonary dysplasia (BPD) is the heterogeneous chronic lung developmental disease of prematurity, which is often accompanied by multisystem comorbidities. Pulmonary vascular disease and pulmonary hypertension (PH) contribute significantly to the pathogenesis and pathophysiology of BPD and dramatically influence the outcomes of preterm infants with BPD. When caring for those patients, clinicians should consider the multitude of phenotypic presentations that fall under the "BPD-PH umbrella," reflecting the need for matching therapies to specific physiologies to improve short- and long-term outcomes. Individualized management based on the patient's prenatal and postnatal risk factors, clinical course, and cardiopulmonary phenotype needs to be identified and prioritized to provide optimal care for infants with BPD-PH.

Factors Associated with Neonatal Arterial Hypertension: Case and Control Study.

Background. Neonatal high blood pressure has been diagnosed more frequently in recent years, and its impact extends to adulthood. However, the knowledge gaps on associated factors, diagnosis, and treatment are challenging for medical personnel. The incidence of this condition varies depending on neonatal conditions. Patients in the Newborn Unit are at increased risk of developing high blood pressure. The persistence of this condition beyond the neonatal stage increases the risk of cardiovascular disease and chronic kidney disease in childhood and adulthood. Methodology. A case-control study was carried out. It included hospitalized patients with neonatal hypertension as cases. Three controls were randomly selected for each case and matched by gestational age. The variables were analyzed based on their nature. Multivariate analysis was performed using a multivariate conditional regression model to identify variables associated with the outcome. Finally, the model was adjusted for possible confounders. Results. 37 cases were obtained and matched with 111 controls. In the univariate analysis, heart disease (OR 2.86; 95% CI 1.22-6.71), kidney disease (OR 7.24; 95% CI 1.92-28.28), bronchopulmonary dysplasia (OR 6.62; 95% CI 1.42-50.82) and major surgical procedures (OR 3.71; 95% CI 1.64-8.39) had an association with neonatal arterial hypertension. Only the latter maintained this finding in the multivariate analysis (adjusted OR 2.88; 95% CI 1.14-7.30). A significant association of two or more comorbidities with neonatal arterial hypertension was also found (OR 3.81; 95% CI 1.53-9.49). Conclusions. The study analyzed the factors related to high blood pressure in hospitalized neonates, finding relevant associations in the said population. The importance of meticulous neonatal care and monitoring of risk factors such as birth weight and major surgeries is highlighted.

Delineating morbidity patterns in preterm infants at near-term age using a data-driven approach.

BACKGROUND: Long-term survival after premature birth is significantly determined by development of morbidities, primarily affecting the cardio-respiratory or central nervous system. Existing studies are limited to pairwise morbidity associations, thereby lacking a holistic understanding of morbidity co-occurrence and respective risk profiles. METHODS: Our study, for the first time, aimed at delineating and characterizing morbidity profiles at near-term age and investigated the most prevalent morbidities in preterm infants: bronchopulmonary dysplasia (BPD), pulmonary hypertension (PH), mild cardiac defects, perinatal brain pathology and retinopathy of prematurity (ROP). For analysis, we employed two independent, prospective cohorts, comprising a total of 530 very preterm infants: AIRR ("Attention to Infants at Respiratory Risks") and NEuroSIS ("Neonatal European Study of Inhaled Steroids"). Using a data-driven strategy, we successfully characterized morbidity profiles of preterm infants in a stepwise approach and (1) quantified pairwise morbidity correlations, (2) assessed the discriminatory power of BPD (complemented by imaging-based structural and functional lung phenotyping) in relation to these morbidities, (3) investigated collective co-occurrence patterns, and (4) identified infant subgroups who share similar morbidity profiles using machine learning techniques. RESULTS: First, we showed that, in line with pathophysiologic understanding, BPD and ROP have the highest pairwise correlation, followed by BPD and PH as well as BPD and mild cardiac defects. Second, we revealed that BPD exhibits only limited capacity in discriminating morbidity occurrence, despite its prevalence and clinical indication as a driver of comorbidities. Further, we demonstrated that structural and functional lung phenotyping did not exhibit higher association with morbidity severity than BPD. Lastly, we identified patient clusters that share similar morbidity patterns using machine learning in AIRR (n=6 clusters) and NEuroSIS (n=8 clusters). CONCLUSIONS: By capturing correlations as well as more complex morbidity relations, we provided a comprehensive characterization of morbidity profiles at discharge, linked to shared disease pathophysiology. Future studies could benefit from identifying risk profiles to thereby develop personalized monitoring strategies. TRIAL REGISTRATION: AIRR: DRKS.de, DRKS00004600, 28/01/2013. NEuroSIS: ClinicalTrials.gov, NCT01035190, 18/12/2009.

Long-term impact of late pulmonary hypertension requiring medication in extremely preterm infants with severe bronchopulmonary dysplasia.

This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.

Immediate postnatal prediction of death or bronchopulmonary dysplasia among very preterm and very low birth weight infants based on gradient boosting decision trees algorithm: A nationwide database study in Japan.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) poses a substantial global health burden. Individualized treatment strategies based on early prediction of the development of BPD can mitigate preterm birth complications; however, previously suggested predictive models lack early postnatal applicability. We aimed to develop predictive models for BPD and mortality based on immediate postnatal clinical data. METHODS: Clinical information on very preterm and very low birth weight infants born between 2008 and 2018 was extracted from a nationwide Japanese database. The gradient boosting decision trees (GBDT) algorithm was adopted to predict BPD and mortality, using predictors within the first 6 h postpartum. We assessed the temporal validity and evaluated model adequacy using Shapley additive explanations (SHAP) values. RESULTS: We developed three predictive models using data from 39,488, 39,096, and 40,291 infants to predict "death or BPD," "death or severe BPD," and "death before discharge," respectively. These well-calibrated models achieved areas under the receiver operating characteristic curve of 0.828 (95% CI: 0.828-0.828), 0.873 (0.873-0.873), and 0.887 (0.887-0.888), respectively, outperforming the multivariable logistic regression models. SHAP value analysis identified predictors of BPD, including gestational age, size at birth, male sex, and persistent pulmonary hypertension. In SHAP value-based case clustering, the "death or BPD" prediction model stratified infants by gestational age and persistent pulmonary hypertension, whereas the other models for "death or severe BPD" and "death before discharge" commonly formed clusters of low mortality, extreme prematurity, low Apgar scores, and persistent pulmonary hypertension of the newborn. CONCLUSIONS: GBDT models for predicting BPD and mortality, designed for use within 6 h postpartum, demonstrated superior prognostic performance. SHAP value-based clustering, a data-driven approach, formed clusters of clinical relevance. These findings suggest the efficacy of a GBDT algorithm for the early postnatal prediction of BPD.

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.

The relationship between severe hypertensive diseases of pregnancy and moderate-severe bronchopulmonary dysplasia.

OBJECTIVE: Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks' gestation). STUDY DESIGN: Preterm birth cohort study of 693 mother-infant dyads. Severe HDP was defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, per the NICHD Consensus statement. RESULTS: 225 (32%) mothers developed severe HDP and 234 (34%) infants had moderate-severe BPD. There was an interaction between severe HDP and gestational age (p = 0.03). Infants born at < 25 weeks gestation to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born > 28 weeks to mothers with severe HDP had decreased odds for the outcome, though not statistically significant. CONCLUSIONS: Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.

Effects of bradycardia, hypoxemia and early intubation on bronchopulmonary dysplasia in very preterm infants: An observational study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common pulmonary complication in preterm infants. OBJECTIVES: The study aimed to explore the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. METHODS: This is a prospective observational cohort study. Preterm infants with a mean gestational age of 28.67 weeks were recruited from two level III neonatal intensive care units (NICUs) in Taiwan. Continuous electrocardiography was used to monitor heart rates and oxygen saturation (SpO2). Infants were monitored for heart rates of <100 beats per minute and SpO2 levels of <90 % lasting for 30 s. Generalized estimating equations were used to analyze the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. Model fit was visually assessed using receiver operating characteristic curve analysis. RESULTS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among the preterm infants (N = 39) during NICU stay; the odds ratios for bradycardia, hypoxemia, and early intubation for BPD versus non-BPD were 1.058, 1.013, and 29.631, respectively (all p < 0.05). A model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development (area under the curve = 0.919). CONCLUSIONS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among very preterm infants during NICU stay. The model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development.

Active versus restrictive ligation strategy for patent ductus arteriosus - A retrospective two-center study of extremely preterm infants born between 22 + 0 and 25 + 6 weeks of gestational age.

BACKGROUND: Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable. AIMS: To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA. STUDY DESIGN: Retrospective, two-center, cohort study. SUBJECTS: Infants born at 22+0-25+6 weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220). MAIN OUTCOME MEASURES: Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP). RESULTS: Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort. CONCLUSION: Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age.

OBJECTIVE: To clarify the relationships of 3 definitions of severity of bronchopulmonary dysplasia (BPD) with adverse neurodevelopmental and respiratory outcomes at early school-age. STUDY DESIGN: Participants comprised 218 consecutive survivors to 7-8 years of age born either <28 weeks' gestation or weighing <1000 g in Victoria, Australia, in 2005. BPD was classified as none, grade 1 (mild), grade 2 (moderate), or grade 3 (severe), using 2 commonly accepted definitions: 1) Jobe2001, and 2) Higgins2018, and our own 3) Victorian Infant Collaborative Study (VICS) 2005, adapted from Jensen2019. Outcomes included major neurodevelopmental disability, low IQ and academic achievement, poor motor function, and poor respiratory function as assessed by spirometry. Outcomes for children with each grade of BPD were compared with children with no BPD. RESULTS: Of the 218 survivors, 132 (61%) had BPD on Jobe2001 criteria, and 113 (52%) had BPD on both Higgins2018 and VICS2005 criteria. Grade 1 on any criteria was not associated with any adverse neurodevelopmental outcomes. Grade 1 on both Higgins2018 and VICS2005 was associated with reduced spirometry, grade 2 on both Higgins2018 and VICS2005, and grade 3 on all criteria were associated with increased risk for both adverse neurodevelopmental and respiratory outcomes. CONCLUSIONS: Compared with no BPD, receiving additional oxygen up to 29% but no positive pressure support at 36 weeks' postmenstrual age increased the risk of abnormal respiratory function but not adverse neurodevelopment. Receiving ≥30% oxygen or any positive pressure support at 36 weeks increased the risk of both adverse outcomes.

Combined gestational age and serum fucose for early prediction of risk for bronchopulmonary dysplasia in premature infants.

OBJECTIVE: As the predominant complication in preterm infants, Bronchopulmonary Dysplasia (BPD) necessitates accurate identification of infants at risk and expedited therapeutic interventions for an improved prognosis. This study evaluates the potential of Monosaccharide Composite (MC) enriched with environmental information from circulating glycans as a diagnostic biomarker for early-onset BPD, and, concurrently, appraises BPD risk in premature neonates. MATERIALS AND METHODS: The study incorporated 234 neonates of ≤32 weeks gestational age. Clinical data and serum samples, collected one week post-birth, were meticulously assessed. The quantification of serum-free monosaccharides and their degraded counterparts was accomplished via High-performance Liquid Chromatography (HPLC). Logistic regression analysis facilitated the construction of models for early BPD diagnosis. The diagnostic potential of various monosaccharides for BPD was determined using Receiver Operating Characteristic (ROC) curves, integrating clinical data for enhanced diagnostic precision, and evaluated by the Area Under the Curve (AUC). RESULTS: Among the 234 neonates deemed eligible, BPD development was noted in 68 (29.06%), with 70.59% mild (48/68) and 29.41% moderate-severe (20/68) cases. Multivariate analysis delineated several significant risk factors for BPD, including gestational age, birth weight, duration of both invasive mechanical and non-invasive ventilation, Patent Ductus Arteriosus (PDA), pregnancy-induced hypertension, and concentrations of two free monosaccharides (Glc-F and Man-F) and five degraded monosaccharides (Fuc-D, GalN-D, Glc-D, and Man-D). Notably, the concentrations of Glc-D and Fuc-D in the moderate-to-severe BPD group were significantly diminished relative to the mild BPD group. A potent predictive capability for BPD development was exhibited by the conjunction of gestational age and Fuc-D, with an AUC of 0.96. CONCLUSION: A predictive model harnessing the power of gestational age and Fuc-D demonstrates promising efficacy in foretelling BPD development with high sensitivity (95.0%) and specificity (94.81%), potentially enabling timely intervention and improved neonatal outcomes.

[A retrospective cohort study on the correlation between early energy management and bronchopulmonary dysplasia in premature infants].

Objective: To investigate the correlation between early energy supplement and bronchopulmonary dysplasia (BPD) in very preterm and very low birth weight infants. Methods: A retrospective cohort study design was used. A total of 939 preterm infants who were admitted to the Department of Neonatology of the West China Second Hospital of Sichuan University within 24 h after birth from January 2019 to December 2021 were enrolled in the study. They were born with a gestational age of <32 weeks and (or) a birth weight of <1 500 g. Of them, 250 preterm infants who developed BPD were enrolled in the BPD group, and each of them was matched to a preterm infant who did not develop BPD (matched for gestational age and birth weight) in the order of priority after calculating propensity score. Their total energy, enteral energy, parenteral energy, total fluid intake and energy per unit of fluid per week were collected within the first 2 weeks of life. The independent sample t-test or Mann Whitney U test was used for continuous variables, and the χ2 test for between-group comparisons of categorical variables. Univariate and multivariate Logistic regression analyses were used to explore the association between total energy and total fluid and BPD incidence, respectively. The dose-response relationship between parenteral energy and BPD was investigated by a generalized additive model, and the threshold effect of parenteral energy on BPD used a two-piecewise linear regression model. Results: The gestational age was (28.4±1.9) weeks in the BPD group and (29.5±1.3) weeks in the control group; the birth weight was (1 107±258) g in the BPD group and (1 324±261) g in the control group; and there were 140 males (56.0%) and 131 males (52.4%) in each group, respectively. An increase in energy per unit of fluid in the second week of life was associated with a reduced risk of BPD (OR=0.32, 95%CI 0.12-0.84, P=0.021), and an increase in total energy in the second week of life was also associated with a reduced risk of BPD, with total energy of >418-502 kJ/(kg·d) was significantly lower than when total energy was ≤334 kJ/(kg·d) (OR=0.15, 95%CI 0.03-0.85, P=0.033). There was no association between the average total fluid intake and BPD incidence (both P>0.05) in the first and second week. The increase in the proportion of parenteral energy to total energy in the second week of life was associated with an increased incidence of BPD (OR=8.45, 95%CI 2.14-33.32, P=0.003); specifically, the risk of BPD significantly increased when the parenteral energy was ≥305 kJ/(kg·d) (OR=1.02, 95%CI 1.01-1.03, P=0.003). Conclusions: Maintaining a high total energy supply in the early postnatal period in preterm infants may reduce the risk of BPD, but continued reliance on high parenteral energy to meet total energy requirements increases the risk of BPD, so enteral feeds should be initiated as early as possible and maximized as tolerated.

Pulmonary Hypertension in Established Bronchopulmonary Dysplasia: Physiologic Approaches to Clinical Care.

Preterm infants with bronchopulmonary dysplasia (BPD) are prone to develop pulmonary hypertension (PH). Strong laboratory and clinical data suggest that antenatal factors, such as preeclampsia, chorioamnionitis, oligohydramnios, and placental dysfunction leading to fetal growth restriction, increase susceptibility for BPD-PH after premature birth. Echocardiogram metrics and serial assessments of NT-proBNP provide useful tools to diagnose and monitor clinical course during the management of BPD-PH, as well as monitoring for such complicating conditions as left ventricular diastolic dysfunction, shunt lesions, and pulmonary vein stenosis. Therapeutic strategies should include careful assessment and management of underlying airways and lung disease, cardiac performance, and systemic hemodynamics, prior to initiation of PH-targeted drug therapies.

Transpyloric feeding is associated with adverse in-hospital outcomes in infants with severe bronchopulmonary dysplasia.

OBJECTIVE: To estimate the association of transpyloric feeding (TPF) with the composite outcome of tracheostomy or death for patients with severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: Retrospective multi-center cohort study of preterm infants <32 weeks with sBPD receiving enteral feedings. We compared infants who received TPF at 36, 44, or 50 weeks post-menstrual age to those who did not receive TPF at any of those timepoints. Odds ratios were adjusted for gestational age, small for gestational age, male sex, and invasive ventilation and FiO2 at 36 weeks. RESULTS: Among 1039 patients, 129 (12%) received TPF. TPF was associated with an increased odds of tracheostomy or death (aOR 3.5, 95% CI 2.0-6.1) and prolonged length of stay or death (aOR 3.1, 95% CI 1.9-5.2). CONCLUSIONS: Use of TPF in sBPD after 36 weeks was infrequent and associated with worse in-hospital outcomes, even after adjusting for respiratory severity at 36 weeks.

Synergistic effects of achieving perinatal interventions on bronchopulmonary dysplasia in preterm infants.

To investigate the effect of perinatal interventions on the risk of severe BPD (sBPD) and death in extremely preterm infants (EPIs) and their synergistic effects. This was a secondary analysis of the prospective cohort Chinese Neonatal Network (CHNN). Infants with a birth weight of 500 to 1250 g or 24-28 weeks completed gestational age were recruited. The impacts and the synergistic effects of six evidence-based perinatal interventions on the primary outcomes of sBPD and death were assessed by univariate and multivariable logistic regression modeling. Totally, 6568 EPIs were finally enrolled. Antenatal corticosteroid (adjusted OR, aOR, 0.74; 95%CI, 0.65-083), birth in centers with tertiary NICU (aOR, 0.64; 95%CI, 0.57-0.72), preventing intubation in the delivery room (aOR, 0.65; 95%CI, 0.58-0.73), early caffeine therapy (aOR, 0.59; 95%CI, 0.52-0.66), and early extubating (aOR, 0.42; 95%CI 0.37-0.47), were strongly associated with a lower risk of sBPD and death while early surfactant administration was associated with a lower risk of death (aOR, 0.84; 95%CI, 0.72, 0.98). Compared with achieving 0/1 perinatal interventions, achieving more than one intervention was associated with decreased rates (46.6% in 0/1 groups while 38.5%, 29.6%, 22.2%, 16.2%, and 11.7% in 2/3/4/5/6-intervention groups respectively) and reduced risks of sBPD/death with aORs of 0.76(0.60, 0.96), 0.55(0.43, 0.69), 0.38(0.30, 0.48), 0.28(0.22, 0.36), and 0.20(0.15, 0.27) in 2, 3, 4, 5, and 6 intervention groups respectively. Subgroup analyses showed consistent results. CONCLUSION: Six perinatal interventions can effectively reduce the risk of sBPD and death in a synergistic form. WHAT IS KNOWN: • Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease associated with prematurity. The effective management of BPD requires a comprehensive set of interventions. However, the extent to which these interventions can mitigate the risk of severe outcomes, such as severe BPD or mortality, or if they possess synergistic effects remains unknown. WHAT IS NEW: • The implementation of various perinatal interventions, such as prenatal steroids, birth in centers with tertiary NICU, early non-Invasive respiratory support, surfactant administration within 2 hours after birth, early caffeine initiation within 3 days, and early extubation within 7 days after birth has shown promising results in the prevention of severe bronchopulmonary dysplasia (BPD) or mortality in extremely preterm infants. Moreover, these interventions have demonstrated synergistic effects when implemented in combination.

Echocardiography Assessment of Left Ventricular Function in Extremely Preterm Infants, Born at Less Than 28 Weeks' Gestation, With Bronchopulmonary Dysplasia and Systemic Hypertension.

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.

Clinical exome sequencing elucidates underlying cause of death in sudden unexpected death of infants: two case reports.

Sudden unexpected death in infants (SUDI) is a traumatic event for families, and unfortunately its occurrence remains high in many parts of the world. Whilst cause of death is resolved for most cases, others remain undetermined following postmortem investigations. There has been a recognition of the role of genetic testing in unexplained cases, where previous studies have demonstrated the resolution of cases through DNA analyses. Here we present two case reports of SUDI cases admitted to Salt River Mortuary, South Africa, and show that underlying causes of death were determined for both infants using clinical exome sequencing. The first infant was heterozygous for a variant (rs148175795) in COL6A3, which suggested a bronchopulmonary dysplasia phenotype. This hypothesis led to finding of a second candidate variant in DMP1 (rs142880465), which may contribute towards a digenic/polygenic mechanism of a more severe phenotype. Histological analysis of retained tissue sections showed an asphyxial mechanism of death, where bronchiolar muscle weakness from an underlying bronchopulmonary dysplasia may have contributed to the asphyxia by affecting respiration. In the second infant, a homozygous variant (rs201340753) was identified in MASP1, which was heterozygous in each parent, highlighting the value of including parental DNA in genetic studies. Whilst mannose-binding lectin deficiency could not be assessed, it is plausible that this variant may have acted in combination with other risk factors within the triple-risk model to result in sudden death. These results may have genetic implications for family members, and represent possible new candidate variants for molecular autopsies.

Ambient Air Pollution and Outpatient Morbidities in Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia (BPD) is the most common long-term complication of prematurity. Although socioeconomic status is associated with BPD morbidities, the drivers of this association are poorly understood. In the United States, ambient air pollution (AAP) exposure is linked to both race/ethnicity and socioeconomic status. Furthermore, AAP exposure is known to have a detrimental effect on respiratory health in children. Objectives: To assess if AAP exposure is linked to BPD morbidity in the outpatient setting. Methods: Participants with BPD were recruited from outpatient clinics at Johns Hopkins University and the Children's Hospital of Philadelphia between 2008 and 2021 (N = 800) and divided into low, moderate, and high AAP exposure groups, based on publicly available U.S. Environmental Protection Agency data. Clinical data were obtained by chart review and caregiver questionnaires. Results: Non-White race, home ventilator use, and lower median household income were associated with higher degrees of air pollution exposure. After adjustment for these factors, moderate and high air pollution exposure were associated with requiring systemic steroids (odds ratio, 1.78 and 2.17, respectively) compared with low air pollution. Similarly, high air pollution exposure was associated with emergency department visits (odds ratio, 1.59). Conclusions: This study demonstrates an association between AAP exposure and BPD morbidity after initial hospital discharge. AAP exposure was closely linked to race and median household income. As such, it supports the notion that AAP exposure may be contributing to health disparities in BPD outcomes. Further studies directly measuring exposure and establishing a link between biomarkers of exposure and outcomes are prerequisites to developing targeted interventions protecting this vulnerable population.

Number of children in the household influences respiratory morbidities in children with bronchopulmonary dysplasia in the outpatient setting.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of prematurity, is associated with outpatient morbidities, including respiratory exacerbations. Daycare attendance is associated with increased rates of acute and chronic morbidities in children with BPD. We sought to determine if additional children in the household conferred similar risks for children with BPD. METHODS: The number of children in the household and clinical outcomes were obtained via validated instruments for 933 subjects recruited from 13 BPD specialty clinics in the United States. Clustered logistic regression models were used to test for associations. RESULTS: The mean gestational age of the study population was 26.5 ± 2.2 weeks and most subjects (69.1%) had severe BPD. The mean number of children in households (including the subject) was 2.1 ± 1.3 children. Each additional child in the household was associated with a 13% increased risk for hospital admission, 13% increased risk for antibiotic use for respiratory illnesses, 10% increased risk for coughing/wheezing/shortness of breath, 14% increased risk for nighttime symptoms, and 18% increased risk for rescue medication use. Additional analyses found that the increased risks were most prominent when there were three or more other children in the household. CONCLUSIONS: We observed that additional children in the household were a risk factor for adverse respiratory outcomes. We speculate that secondary person-to-person transmission of respiratory viral infections drives this finding. While this risk factor is not easily modified, measures do exist to mitigate this disease burden. Further studies are needed to define best practices for mitigating this risk associated with household viral transmission.

Association of the respiratory severity score with bronchopulmonary dysplasia-associated pulmonary hypertension in infants born extremely preterm.

OBJECTIVE: To test the hypothesis that elevations in the respiratory severity score (RSS) are associated with increased probability of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). STUDY DESIGN: Retrospective cohort study of infants born extremely preterm admitted to a BPD center between 2010 and 2018. Echocardiograms obtained ≥ 36 weeks' post-menstrual age (PMA) were independently adjudicated by two blinded cardiologists to determine the presence/absence of BPD-PH. Multivariable logistic regression estimated the association between RSS and BPD-PH. RESULT: BPD-PH was observed in 68/223 (36%) of subjects. The median RSS at time of echocardiography was 3.04 (Range 0-18.3). A one-point increase in the RSS was associated with BPD-PH, aOR 1.3 (95% CI 1.2-1.4), after adjustment for gestational age and PMA at time of echocardiography. CONCLUSION: Elevations in the RSS were associated with a greater probability of BPD-PH. Prospective studies are needed to determine the validity and performance of RSS as a clinical susceptibility/risk biomarker for BPD-PH.