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Background: Cytokines and growth factors (GF) have been implicated in the development of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD). We hypothesize that even small coordinated changes in inflammatory proteins or GFs may reveal changes in underlying regulating mechanisms that do not induce obvious changes in concentration of individual proteins. We therefore applied correlation network analysis of serum factors to determine early characteristics of these conditions., Methods: Concentrations of 17 cytokines and five GFs were measured and analysed in blood samples from cord blood, on day one and during the following month in 72 extremely preterm infants. Spearman's correlation networks distinguishing BPD and severe ROP patients from non-affected were created., Results: Most cytokine concentrations correlated positively with each other and negatively with GFs. Very few individual cytokines differed between patients with and without ROP or BPD. However, networks of differently correlated serum factors were characteristic of the diseases and changed with time. In ROP networks, EPO, G-CSF and IL-8 (cord blood), BDNF and VEGF-A (first month) were prominent. In BPD networks, IL-1β, IGF-1 and IL-17 (day one) were noted., Conclusions: Network analysis identifies protein signatures related to ROP or BPD in extremely preterm infants. The identified interactions between serum factors are not evident from the analysis of their individual levels, but may reveal underlying pathophysiological mechanisms in the development of these diseases., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Regional Ethical Board, Gothenburg (Dnr 303–11) (Clinical trial NCT02760472). Children were enrolled in the study following parental written informed consent. Consent for publication Not applicable. Competing interests Ann Hellström holds stocks in Premalux AB, a company with financial interest in IGF-I treatment of preterm infants. In addition, Ann Hellström, has received consulting fees from Takeda., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This prospective study aimed to investigate whether lung ultrasound score (LUSs) can predict the patent ductus arteriosus (PDA) ligation., Methods: Preterm infants ≤25 weeks of gestational age (GA) were enrolled. A lung ultrasound was performed on the 14th day of life. Each lung zone was given a score between 0 and 4. A receiver-operating characteristic (ROC) curve was constructed to evaluate the ability of the LUSs for predicting ligation., Results: A total of 81 infants were eligible with a median GA and birth weight (BW) of 25 weeks (24.1-25.2) and 710 g (645-770), respectively. The median time from birth to ligation was 35 days (32-51). Those who underwent ligation had a longer time of mechanical ventilation (34 [26-39] vs. 19 [12-30], p < 0.001), shorter time of noninvasive respiratory support (39 [32-51] vs. 50 [41.5-57], p < 0.01), higher incidence of the bronchopulmonary dysplasia (BPD) (p < 0.01), and severe BPD (p < 0.001). The LUSs had an area under the ROC of 0.96 (95% confidence interval: 0.93-0.99) for the prediction of ligation. A LUSs cutoff of 36 has a sensitivity and specificity of 96% and 86% and positive and negative predictive values of 82% and 98%, respectively., Conclusions: LUSs at an early stage of life can predict PDA ligation in extremely preterm infants. It would be helpful to reduce morbidity by reducing the duration and magnitude of respiratory support., (© 2023 Wiley Periodicals LLC.)

Objective: To determine the trends in inhaled nitric oxide (iNO) utilization in the late phase of hospitalization in a large Japanese cohort of extremely preterm infants and evaluate its benefit on long-term outcomes., Study Design: This was a retrospective multicenter cohort study of 15 977 extremely preterm infants born at <28 weeks of gestational age between 2003 and 2016, in the Neonatal Research Network, Japan. Demographic characteristics, morbidity, and mortality were compared between extremely preterm infants with and without post-acute iNO therapy. Multivariable logistic analysis was performed to determine factors associated with post-acute iNO and its impact on neurodevelopmental outcomes at 3 years of age., Results: Post-acute iNO utilization rates increased from 0.3% in 2009 to 1.9% in 2016, even under strict insurance coverage rules starting in 2009. Gestational age (1-week increment; aOR 0.82, 95% CI 0.76-0.88), small for gestational age (1.47, 1.08-1.99), histologic chorioamnionitis (1.50, 1.21-1.86), 5-minute Apgar score <4 (1.51, 1.10-2.07), air leak (1.92, 1.30-2.83), and bubbly/cystic appearance on chest X-Ray (1.68, 1.37-2.06) were associated with post-acute iNO. Post-acute iNO was not associated with neurodevelopmental outcomes at 3 years of age., Conclusions: The increasing post-acute iNO utilization rate among extremely preterm infants has been concurrent with improved survival rates of extremely preterm infants in Japan. Infants treated with post-acute iNO had more severe disease and complications than the comparison group, but there were no differences in neurodevelopmental outcome at 3 years. This suggests post-acute iNO may benefit extremely preterm infants., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids., Study Design: Retrospective case-control study in infants born at a gestational age of &lt;29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression., Results: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected., Conclusion: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Rationale: Identifying neonatal and post-discharge exposures among extremely low gestational age newborns (ELGANs) that drive increased pulmonary morbidity and abnormal lung function at 1 year of age proves challenging., Objective: The NIH-sponsored Prematurity and Respiratory Outcomes Program (PROP), evaluated infant pulmonary function tests (iPFTs) at 1 year corrected age to determine which demographic and clinical factors are associated with abnormal lung function., Methods: iPFTs were performed on a PROP subcohort of 135 participants following Institutional Review Board (IRB)-approved written consent. Demographic data, Neonatal Intensive Care Unit (NICU) clinical care, and post-NICU exposures were analyzed for association with iPFTs., Main Results: A significant decrease in forced expiratory volume at 0.5 s (FEV 0.5 ) and/or forced expiratory flows at 75% of forced vital capacity (FEF 75 ), were associated with male sex and African American race. Clinical factors including longer duration of ventilatory support, exposure to systemic steroids, and weight less than the 10th percentile at 36 weeks postmenstrual age were also associated with airflow obstruction, whereas supplemental oxygen requirement and bronchopulmonary dysplasia were not. Additionally, the need for respiratory medications, technology, or hospitalizations during the first year, ascertained by a quarterly survey, were the only post-NICU factors associated with decreased FEV 0.5 and FEF 75 . Only 7% of infants had reversible airflow obstruction., Conclusions: Neonatal demographic factors, respiratory support in the NICU, and a history of greater post-NICU medical utilization for respiratory disease had the strongest association with lower lung function at 1 year in ELGANs., (© 2021 Wiley Periodicals LLC.)

Hydrocortisone is used in preterm infants. However, early disruption of growth velocities was observed in infants exposed to hydrocortisone. This retrospective study aimed to explore the postnatal brain growth of extremely preterm infants requiring hydrocortisone treatment as well as its association with perinatal factors. Extremely preterm infants exposed to hydrocortisone from 2011 to 2016 who survived up to 12 months were included. Each of them was matched with two infants not treated with hydrocortisone exhibiting similar gestational ages and nearly similar birth head circumferences. The outcome variables were brain tissue areas on MRIs performed at term-equivalent age and postnatal head circumference growth up to a corrected age of 12 months. Univariate and multiple regression analyses were performed. Infants treated with hydrocortisone (n=20) were matched with 40 infants not exposed to hydrocortisone. The infants exposed to hydrocortisone exhibited a lower birth weight (p=0.04) and a longer duration of mechanical ventilation (p<0.0001). Infants treated with hydrocortisone exhibited a smaller basal ganglia/thalamus area (p=0.04) at term-equivalent age and a smaller head circumference at a corrected age of 12 months (p=0.003). However, the basal ganglia/thalamus area and the postnatal brain growth were independently associated with the duration of mechanical ventilation and not with hydrocortisone. Interestingly, a significant interaction between hydrocortisone and sex was observed (p=0.04).Conclusion: This study supports previous data that indicated no obvious impact of hydrocortisone on brain growth and highlights the relationship between the severity of the neonatal course and postnatal brain growth in extremely preterm infants. What is Known: • Postnatal hydrocortisone disrupts transiently growth velocities including the head circumference growth. • Postnatal hydrocortisone has less impact on neurodevelopment than dexamethasone. What is New: • Hydrocortisone prescribed for infants in the most severe conditions did not show independent effect on brain growth up to the corrected age of 12 months. However, a different effect of hydrocortisone according to sex can't be excluded and needs further explorations. • Perinatal factors as birth weight and duration of mechanical ventilation were determinant for the subsequent brain growth., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To determine whether the duration of invasive ventilation predicted the development of bronchopulmonary dysplasia (BPD) and need for discharge home on supplementary oxygen in extremely preterm infants., Methods: Retrospective whole-population study of all infants <28 weeks of gestation admitted to a neonatal unit in England between 2014 and 2018. BPD development was defined as any respiratory support at 36 weeks postmenstrual age. The performance of the duration of mechanical ventilation to predict BPD or discharge home on oxygen was assessed by receiver operator characteristic curve analysis., Results: The 11,806 infants had a median (IQR) gestational age of 26.0(24.9-27.1) weeks and birthweight of 0.81(0.67-0.96) kg. At discharge from neonatal care, 9,415 infants (79.7%) were alive. The incidence of BPD was 57.5% and of home oxygen 29.4%. Mechanical ventilation duration had areas under the curve of 0.793 and 0.703 in predicting BPD and home oxygen, respectively. Mechanical ventilation for >8 days predicted BPD development with 71% sensitivity and 71% specificity and mechanical ventilation for >10 days predicted discharge on home oxygen with 66% sensitivity and 65% specificity., Conclusion: In extremely preterm infants, the duration of invasive support predicted BPD and need for home oxygen with moderate sensitivity and specificity., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: To compare the efficacy of intra-tracheal (IT) surfactant/budesonide (SB) with that of surfactant alone (S) in reducing the rate of bronchopulmonary dysplasia (BPD) at 36 weeks post-menstrual age (PMA), we included extremely preterm very low birth weight (VLBW) infants with severe respiratory distress syndrome (RDS) in our tertiary neonatal level of care unit (Padua, Italy)., Study Design: A retrospective chart review of two cohorts of extremely preterm VLBW neonates (<28 +0  gestation weeks, birth weight [BW] < 1500 g) born in two consequent epochs (2017-2018/2018-2019) were compared. The SB group received surfactant (200 mg/kg 1st dose) and budesonide (0.25 mg/kg), while the S group received surfactant alone., Results: Among 68 neonates with RDS Grades III-IV, FiO 2  ≥ 0.3 within 12 h of life, 18 were included in each group after matching for perinatal, clinical, and laboratory characteristics. IT SB did not affect the rate of BPD (Vermont Oxford Network, Jensen's, and National Institute of Child Health and Human Development BPD Workshop 2018 definitions), death, BPD, or death at 36 weeks PMA. Hypotension requiring inotropic support within the first 5 days was lower in those receiving the combined treatment (p = .03). The SB group had fewer admissions to pediatric ward due to respiratory causes up to 12 months of corrected age (p = .03)., Conclusion: The preliminary results of this retrospective study suggest that in extremely preterm VLBW infants, IT SB for severe RDS did not affect the incidence of BPD, death, and BPD or death at 36 weeks PMA, compared to surfactant alone. The combined therapy proved to be safe in this population. Further studies are warranted to explore the role of early IT steroids on respiratory morbidity in preterm infants., (© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Pulmonary hypertension (PH) is a frequent complication in extremely preterm born infants that seriously affects outcome. We aimed to describe the prevalence of PH in extremely preterm infants and the policy on screening and follow-up in the ten Dutch intensive care units (NICUs). We performed a retrospective cohort study at the University Medical Centre Groningen on infants with gestational age < 30 weeks and/or birthweight < 1000 g, born between 2012 and 2013. Additionally, we carried out a survey among the Dutch NICUs covering questions on the awareness of PH, the perceived prevalence, and policy regarding screening and following PH in extremely preterm infants. Prevalence of early-onset PH in our study was 26% and 5% for late-onset PH. PH was associated with poor survival and early-onset PH was associated with subsequent development of bronchopulmonary dysplasia (BPD). All the NICUs completed the questionnaire and we found that no standardized policy existed regarding screening and following PH in extremely preterm infants.Conclusion: Despite the frequent occurrence of PH and its clinically important consequences, (inter-)national standardized guidelines regarding screening and following of PH in extremely preterm infants are lacking. Standardizing screening and follow-up will enable early identification of infants with late-onset PH and allow for earlier treatment. Additionally, greater clarity is required regarding the prevalence of early PH as are new preventive treatment strategies to combat BPD. What is known? • Pulmonary hypertension (PH) substantially impairs the survival of extremely preterm infants. • PH is associated with bronchopulmonary dysplasia (BPD): Early-onset PH predicts the development of BPD. Late-onset PH is prevalent in infants with severe BPD. What is new? • Pulmonary hypertension (PH) is prevalent in preterm infants. Its consequences for morbidity and mortality justify a standardized policy aimed at early detection to improve prevention and treatment. • No structured policy exists in the Netherlands regarding screening/follow-up for PH in extremely preterm infants.

Background: Bronchopulmonary dysplasia (BPD) remains one of the most serious morbidities associated with preterm birth. Previous study reported that bubbly/cystic appearance on chest X-rays in the neonatal period is the strongest determinant of impaired lung function at school age in BPD patients., Aims: To determine perinatal risk factors for bubbly/cystic appearance on chest X-rays in extremely premature infants with BPD exposed to histological chorioamnionitis histological chorioamnionitis (hCAM)., Study Design: Multicenter retrospective cohort study., Subjects: We analyzed 1369 extremely premature infants with severe hCAM who were admitted to the neonatal intensive care units participating in the Neonatal Research Network, Japan (NRNJ) Neonatal research network Japan., Outcome Measures: Perinatal characteristics were compared and logistic regression analysis was performed for multivariate risk factor assessment., Result: Infants with bubbly/cystic appearance on chest X-rays underwent longer duration of invasive mechanical ventilation and required inhaled nitric oxide and home oxygen therapy more frequently. Low gestational age (odds ratio 1.244; 95% confidence interval 1.139-1.359) and preterm premature rupture of membranes (odds ratio 1.507; 95% confidence interval 1.200-1.893) were significant risk factors., Conclusion: Low gestational age and preterm premature rupture of membranes were independent risk factors for bubbly/cystic appearance in extremely premature infants with BPD following exposure to severe hCAM.

Introduction: Early prediction of survival without bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age remains challenging for infants born extremely preterm. We aimed to provide a new predictive model including variables available only at or soon after birth based on the literature and existing models., Methods: We conducted a systematic review to identify all variables considered to be significant predictors of BPD and survival at birth in extremely preterm infants. We then assessed the external validity of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network BPD estimator on the PREMILOC cohort, a recent French study with a large sample of extremely preterm infants and a vast number of variables at baseline. Finally, we attempted to improve this model by testing the added value of other early predictors reported in previous studies., Results: Restricted to baseline predictors, the NICHD Neonatal Research Network BPD estimator confirmed its calibration and fair discrimination (area under the receiver operating characteristic [auROC] [95% CI] = 0.73 [0.68-0.77] when used with a published model and auROC [95% CI] = 0.77 [0.73-0.81] when fitted to the PREMILOC dataset). We were able to improve the discriminatory power by adding candidate variables at birth associated with BPD in previous studies. The modified best predicting model included gestational age at birth, birthweight, respiratory support at baseline, gender, center effect, and multiple pregnancy as baseline predictors. This model showed significantly better discrimination (auROC [95% CI] = 0.85 [0.82-0.88]) and better confirmed calibration (Hosmer-Lemeshow test, p = 0.45)., Conclusion: This new model, based on 6 early predictors, appears to improve the prediction soon after birth of BPD-free survival in extremely preterm infants., (© 2021 S. Karger AG, Basel.)

Aim: More infants born extremely preterm (EPT) are surviving, but major neonatal morbidities are consistently high. This study examined the impact of bronchopulmonary dysplasia (BPD), brain injuries and severe retinopathy of prematurity (ROP) on adolescents who were born EPT., Methods: We focused on EPT infants born at 23-25 weeks at the Swedish university hospitals in Uppsala and Umeå from January 1992 to December 1998. The poor outcome data covered 140 of 142 who survived to 36 weeks, and the chronic conditions data reported by parents covered 132 of 134 still alive at 10-15 years., Results: Of the 140 survivors at 36 weeks, 29 (21%) had poor outcomes: eight of 140 (6%) died, and 21 of 132 (16%) adolescent survivors had severe neurodevelopmental disabilities (NDD). BPD, severe ROP and/or brain injuries correlated independently with poor outcome. Of those adolescents who were free from BPD, brain injury and severe ROP, 6% had a severe NDD. The corresponding rates with any one, any two or all three neonatal morbidities were 21, 33 and 67%, respectively. BPD and brain injuries were associated with high rates of chronic conditions at 10-15 years of age resulting in functional limitations., Conclusion: In adolescent EPT survivors, BPD and brain injuries were associated with high rates of chronic conditions and special healthcare needs., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

The focus of this paper is to describe the following: (1) the benefits of implementing feeding guidelines, (2) management practices associated with the prevention of BPD, and (3) management practices associated with prevention of nosocomial infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective To identify risk factors for moderate to severe bronchopulmonary dysplasia (BPD) in extremely preterm infants born at less than 32 weeks' gestational age and to develop an early predictive nomogram model. Methods A retrospective analysis was conducted on extremely preterm infants born between January 2019 and December 2020 at the Third Affiliated Hospital of Guangzhou Medical University who developed BPD. Perinatal data and clinical information during hospitalization were collected, and risk factors for moderate to severe BPD were identified using logistic regression analysis. Based on these findings, a nomogram prediction model was constructed and internally validated using the Bootstrap method. An external validation cohort was selected from infants born between January 2021 and June 2021 meeting the same inclusion and exclusion criteria. Both the training and validation groups were used to assess the model's discrimination and accuracy. Results A total of 266 extremely preterm infants with BPD were included in the model development cohort, comprising 189 cases of mild BPD (71.1%) and 77 cases of moderate to severe BPD (28.9%). Multivariate logistic regression analysis indicated that preeclampsia, pneumonia, duration of invasive ventilation, and hemodynamically significant patent ductus arteriosus (hsPDA) were significant risk factors for moderate to severe BPD (P<0.05). The nomogram model constructed using these four factors demonstrated an area under the curve (AUC) of 0.810 (95% CI: 0.750-0.870) in the model development cohort and 0. 900 (95% CI: 0.826-0.975) in the validation cohort, with calibration curves close to the ideal diagonal line, indicating good calibration. Conclusion Preeclampsia, pneumonia, duration of invasive ventilation, and hsPDA are independent risk factors for moderate to severe BPD in extremely preterm infants. The nomogram model combining these four indicators demonstrates good predictive value, aiding in early identification of infants at risk of moderate to severe BPD to improve prevention and management outcomes. [ABSTRACT FROM AUTHOR]

Importance: Objective measures of lung function are critical for assessing respiratory outcomes of prematurity. Among extremely low gestational age neonates (ELGANs) (< 29 weeks gestational age), high rates of neurodevelopmental impairment may interfere with lung function testing. Impulse oscillometry (IOS) is a noninvasive test of respiratory system mechanics not requiring forced expiration. Objective: To describe a multicenter study design for respiratory follow‐up testing in a cohort with a high rate of extreme prematurity. Methods: School‐age children enrolled in two prior trials of ELGANs and term controls were assessed by IOS at five centers. Groups consisted of children with prematurity with a high incidence of bronchopulmonary dysplasia, children with prematurity with no or minimal lung disease, and healthy term children. A rigorous centralized review process reviewed IOS studies for technical acceptability. Approach to design and implementation, rates of feasibility and success, and characteristics of participants are described. Results: A total of 243 children were recruited, of whom 239 (98%) attempted oscillometry. There were high rates of technical acceptability across all three cohorts (85%–90% of attempted tests), and across all five centers (80%–94% of attempted tests). Respiratory and neuromotor clinical factors associated with testing failure included a higher number of days on ventilation during neonatal intensive care, a history of intraventricular hemorrhage grade 3 or 4, and gross motor functional impairment. Interpretation: We report high rates of feasibility and success of oscillometry in a large multicenter ELGAN population, in whom neurological and developmental comorbidities likely play a confounding role. [ABSTRACT FROM AUTHOR]

ABSTRACT Importance Objective measures of lung function are critical for assessing respiratory outcomes of prematurity. Among extremely low gestational age neonates (ELGANs) (< 29 weeks gestational age), high rates of neurodevelopmental impairment may interfere with lung function testing. Impulse oscillometry (IOS) is a noninvasive test of respiratory system mechanics not requiring forced expiration. Objective To describe a multicenter study design for respiratory follow‐up testing in a cohort with a high rate of extreme prematurity. Methods School‐age children enrolled in two prior trials of ELGANs and term controls were assessed by IOS at five centers. Groups consisted of children with prematurity with a high incidence of bronchopulmonary dysplasia, children with prematurity with no or minimal lung disease, and healthy term children. A rigorous centralized review process reviewed IOS studies for technical acceptability. Approach to design and implementation, rates of feasibility and success, and characteristics of participants are described. Results A total of 243 children were recruited, of whom 239 (98%) attempted oscillometry. There were high rates of technical acceptability across all three cohorts (85%–90% of attempted tests), and across all five centers (80%–94% of attempted tests). Respiratory and neuromotor clinical factors associated with testing failure included a higher number of days on ventilation during neonatal intensive care, a history of intraventricular hemorrhage grade 3 or 4, and gross motor functional impairment. Interpretation We report high rates of feasibility and success of oscillometry in a large multicenter ELGAN population, in whom neurological and developmental comorbidities likely play a confounding role.

BackgroundSerum lactate levels are used as biomarkers for perinatal asphyxia, while their value for outcome prediction in preterm infants is uncertain. It was the aim of this observational study to determine the association of the first postnatal serum-lactate levels on day 1 of life and short-term outcome in preterm infants less than 29 gestational weeks.MethodsWe analysed data in a population-based cohort of German Neonatal Network (GNN) preterm infants with available first postnatal lactate levels enrolled at 22–28 weeks of gestational age (GA) between 1st of April 2009 and 31st December 2020. We hypothesized that high lactate levels as measured in mmol/L increase the risk of intraventricular haemorrhage (IVH) and bronchopulmonary dysplasia (BPD) in infants with VLBW regardless of small-for-gestational-age (SGA) status. Hypotheses were evaluated in univariate analyses and multiple logistic regression models.ResultsFirst postnatal lactate levels were available in 2499 infants. The study population had a median GA of 26.7 [IQR 25.2–27.9] weeks and birth weight of 840 g [IQR 665–995]. Infants with short-term complications such as IVH and BPD had higher initial lactate levels than non-affected infants. The positive predictive value of a lactate cut-off of 4 mmol/L was 0.28 for IVH and 0.30 for BPD. After adjustment for known confounding variables, each 1 mmol/L increase of day 1 lactate levels was associated with a modestly increased risk of IVH (OR 1.18; 95% CI 1.03–1.37; p = 0.002) and BPD (OR 1.23; 95% CI 1.06–1.43; p = 0.005) but not with sepsis or mortality. Notably, SGA was associated with lower risk of any grade and severe IVH (OR 0.70; 95% CI 0.54–0.85; p = 0.001).ConclusionsIn our observational cohort study higher initial lactate levels were associated with adverse outcome regardless of SGA status. However, the predictive value of lactate cut-off levels such as 4 mmol/L is low.

Data from the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) indicate that targeting a higher (91–95%) versus lower (85–89%) pulse oximeter saturation (SpO2) range may reduce mortality and necrotizing enterocolitis (NEC) and increase retinopathy of prematurity (ROP). Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data. We used Bayes factors (BFs) to evaluate the likelihood of the data under the combination of models assuming the presence vs. absence of effect, heterogeneity, and moderation by sex. The Bayesian reanalysis showed moderate evidence in favor of no differences between SpO2 targets (BF10 = 0.30) in death or major disability, but moderate evidence (BF10 = 3.60) in favor of a lower mortality in the higher SpO2 group. Evidence in favor of differences was observed for bronchopulmonary dysplasia (BPD) (BF10 = 14.44, lower rate with lower SpO2), severe NEC (BF10 = 9.94), and treated ROP (BF10 = 3.36). The only outcome with moderate evidence in favor of sex differences was BPD. This reanalysis of the NeOProM trials confirmed that exposure to a lower versus higher SpO2 range is associated with a higher mortality and risk of NEC, but a lower risk of ROP and BPD. The Bayesian approach can help in assessing the strength of evidence supporting clinical decisions. [ABSTRACT FROM AUTHOR]

Objective The study aimed to evaluate the association between bronchopulmonary dysplasia (BPD) development at 36 weeks' postmenstrual age (PMA) and Gram-negative bacteria in tracheal aspirate cultures among extremely preterm infants. Study Design This study has a retrospective cohort. Patients were 155 infants aged less than or equal to 26 gestational weeks who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital from 2009 to 2018. Primary outcome was respiratory outcomes expressed as BPD development. Multivariable logistic regression analysis was used to identify neonatal and bacterial factors associated with BPD. Results After adjusting for gestational age, birth weight, sex, chorioamnionitis, Gram-positive cocci (GPC) and Gram-negative rods (GNRs) in tracheal aspirate cultures within 28 days after birth, GNRs were significantly associated with BPD development (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.68–8.94). In contrast, GPCs were not associated with BPD development (OR: 0.47, 95% CI: 0.05–1.61). Conclusion Gram-negative bacteria in tracheal cultures within 28 days of birth are associated with BPD development in infants aged less than or equal to 26 gestational weeks. Key Points BPD is a factor for morbidity in extremely preterm infants. Respiratory infection is an adverse outcome of BPD. GNRs in tracheal cultures soon after birth disturb BPD development. GPC was not associated with BPD development. [ABSTRACT FROM AUTHOR]

Histidine-rich glycoprotein (HRG) has been reported to inhibit signaling leading to the release of high mobility group box 1 protein, a damage-associated molecular pattern. The present study aimed to determine the longitudinal change in HRG levels in extremely preterm infants and assess whether complications such as bronchopulmonary dysplasia (BPD) were associated with differences in HRG levels. In this multicenter, prospective, observational study, we measured serum HRG levels every 2 weeks from birth to 8 weeks of age. Serum HRG was measured using an enzyme-linked immunosorbent assay. We included 19 extremely preterm infants in the study and 74 samples were analyzed. The median gestational age was 26.0 weeks, and the median birth weight was 858 g. Serum HRG levels showed a significant upward trend after birth (p < 0.001); median HRG concentrations at birth and at 2, 4, 6, and 8 weeks of age were 1.07, 1.11, 2.86, 6.05, and 7.49 µg/mL, respectively. Onset of BPD was not associated with differences in serum HRG levels. Further, the serum HRG levels increased significantly after birth in extremely preterm infants. [ABSTRACT FROM AUTHOR]

BackgroundVitamin D (VitD) is involved in lung development but its influence on respiratory distress syndrome of extremely preterm (EPT) infants have been little investigated. In this study, we examined the influence of low vitamin D status at birth on early respiratory outcomes of this vulnerable infant population.MethodsCord blood 25(OH)D levels ≤ 75 nmol/L were considered as Low vitamin D levels. Stepwise logistic regression and classification regression-tree analyses were used and the primary outcome was the combined outcome of death or mechanical ventilation need by the end of the first week (death or MV DoL7) as a marker od RDS severity.ResultsThe mean (SD) GA and birth weight were 26 (1.4) weeks and 801 (212) gr, respectively; 81/109 (74%) infants had low 25(OH)D levels. Infants with low VitD levels had 25% higher initial FiO2 levels (p < 0.05) and were more likely to be mechanically ventilated on DoL7 (36 vs. 7%, p < 0.05). Adjusted for gestational age, they had 10-fold higher odds of death or MV DoL7 (p < 0.01). By regression tree analysis, the rate of death or MV DoL7 increased from 18 to 71% in infants with GA < 26 weeks and with cord blood 25(OH)D levels higher and lower than 74 nmol/L, respectively (p < 0.05).ConclusionLow vitamin D levels at birth are associated with early adverse respiratory outcomes in infants with GA less 29 weeks. Further largest studies are needed to confirm this association.

Histidine-rich glycoprotein (HRG) has been reported to inhibit signaling leading to the release of high mobility group box 1 protein, a damage-associated molecular pattern. The present study aimed to determine the longitudinal change in HRG levels in extremely preterm infants and assess whether complications such as bronchopulmonary dysplasia (BPD) were associated with differences in HRG levels. In this multicenter, prospective, observational study, we measured serum HRG levels every 2 weeks from birth to 8 weeks of age. Serum HRG was measured using an enzyme-linked immunosorbent assay. We included 19 extremely preterm infants in the study and 74 samples were analyzed. The median gestational age was 26.0 weeks, and the median birth weight was 858 g. Serum HRG levels showed a significant upward trend after birth (p < 0.001); median HRG concentrations at birth and at 2, 4, 6, and 8 weeks of age were 1.07, 1.11, 2.86, 6.05, and 7.49 µg/mL, respectively. Onset of BPD was not associated with differences in serum HRG levels. Further, the serum HRG levels increased significantly after birth in extremely preterm infants.

Background: Despite the rapid advance of neonatal care, bronchopulmonary dysplasia (BPD) remains a significant burden for the preterm population, and there is a lack of effective intervention. Stem cell depletion because of preterm birth is regarded as one of the underlying pathological mechanisms for the arrest of alveolar and vascular development. Preclinical and small-sample clinical studies have proven the efficacy and safety of stem cells in treating and preventing lung injury. However, there are currently no randomized clinical trials (RCTs) investigating the use of autologous cord blood mononuclear cells (ACBMNC) for the prevention of BPD in premature infants. The purpose of this study is to investigate the effects of infusion of ACBMNC for the prevention of BPD in preterm neonates

Background: Pulmonary hypertension complicates the clinical course of extremely preterm infants and is associated with bronchopulmonary dysplasia (BPD). However, prevalence, risk factors, and outcome of pulmonary hypertension in these infants are insufficiently known. This systematic review and meta-analysis aims to provide an up-to-date overview of available data on prevalence, risk factors, and outcome of pulmonary hypertension and to identify current knowledge gaps.Methods: Medline, EMBASE, and the Cochrane Library databases were searched in July 2017. Two authors reviewed titles/abstracts and full-texts. Eligible studies reported prevalence, patient characteristics or mortality of infants with/without pulmonary hypertension. Studies were excluded if they did not include extremely preterm infants. Only similar study samples (selected infants with BPD or infants both with/without BPD) were compared in the meta-analyses.Results: Of 1829 unique articles identified, 25 were eligible for inclusion. Pulmonary hypertension was observed in infants with BPD (20%, 95% confidence interval [CI] 14, 25), but also in those without BPD (2%, 95% CI 0, 8). Infants with severe BPD were most at risk of pulmonary hypertension (risk ratio [RR] 2.7, 95% CI 1.7, 4.2). Infants with pulmonary hypertension were more at risk of mortality (RR 4.7, 95% CI 2.7, 8.3).Conclusions: Pulmonary hypertension occurs in particularly in infants with severe BPD, and increases risk of mortality. Due to selected study populations, heterogeneous pulmonary hypertension-definitions and poorly reported timing of pulmonary hypertension assessments, however, data available in current reports are insufficient to allow accurate assessment of true prevalence, risk factors, and time-related outcome. Prospective studies, with standardised methodology and follow-up are needed to determine these factors. [ABSTRACT FROM AUTHOR]

Five randomized controlled trials comparing lower (85-89%) versus higher (91-95%) pulse oximeter saturation (SpO2) targets for extremely preterm infants have now been reported from the United States of America, Canada, the United Kingdom, Australia and New Zealand. These trials included more than 4,800 infants, and they provide robust evidence to permit comparison of these target ranges and consider the next steps for clinicians and researchers. The lower SpO2 range was associated with a significant increase in the risk of death. There was no significant difference between the two target ranges in the rate of disability at 18-24 months, including blindness. A significant difference between groups in the risk of the composite primary outcome of death or disability in favour of the higher SpO2 range was mainly attributable to the difference between groups in the risk of death. The lower target range did not reduce bronchopulmonary dysplasia or severe visual impairment, but it did increase the risk of necrotizing enterocolitis requiring surgery or causing death. The trials provide no reason to prefer SpO2 targets below 90% and indicate the importance of more trials to see if a further survival advantage can be identified. The safety of targets above 95% has not been evaluated. The five trials were designed to be similar to facilitate an individual patient data meta-analysis, and this Neonatal Oxygen Prospective Meta-Analysis (NeOProM) may provide further insights. [ABSTRACT FROM AUTHOR]

Background: The optimal timing of pharmacological treatment for patent ductus arteriosus (PDA) in extremely preterm infants is unknown. Objective: To investigate whether timing of pharmacological PDA treatment is associated with a risk of secondary PDA surgery or death before 3 months of age, or bronchopulmonary dysplasia (BPD) in extremely preterm infants. Methods: In this population-based cohort of infants born before 27 gestational weeks in Sweden in 2004-2007, 290/585 infants (50%) received pharmacological PDA treatment. Cox proportional hazards regression estimated the hazard ratio (HR, with 95% confidence interval, CI) of secondary PDA surgery or death as a composite outcome in relation to postnatal age at the start of pharmacological treatment: early (0-2 days); intermediate (3-6 days); late (≥7 days). Furthermore, the odds ratio (OR, with 95% CI) of BPD was estimated in relation to postnatal age at PDA treatment by conditional logistic regression. Results: The median postnatal age at the start of pharmacological PDA treatment was 4 days. 102 infants had secondary PDA surgery. Timing of PDA treatment was not associated with risk of PDA surgery or death; adjusted HRs were 0.89 (95% CI 0.57-1.39) after an intermediate start and 1.10 (95% CI 0.53-2.28) after a late start, compared to an early start of treatment. Compared to the early start of PDA treatment, the intermediate start was not associated with any risk of BPD, while late PDA treatment was associated with a lower BPD risk; adjusted ORs were 0.83 (95% CI 0.42-1.64) and 0.28 (95% CI 0.13-0.61), respectively. Conclusion: Timing of pharmacological PDA treatment after extremely preterm birth is not associated with the risk of secondary PDA surgery or death. Moreover, expectant PDA management is not associated with an increased risk of BPD. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective:Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment.Study Design:As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile.Result:Median cortisol value was 16.0 μg per 100 ml at baseline for all infants, and 13.1 μg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia.Conclusion:Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone. [ABSTRACT FROM AUTHOR]

OBJECTIVE. Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes. METHODS. Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile. RESULTS. Median cortisol values were 16.0 μg/dL at baseline and 13.1 μg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or day 5 to 7 were not associated with increased morbidity or mortality rates and were not predictive of open-label hydrocortisone use. In fact, vasopressor use was lower for infants with lower cortisol values at baseline. Severe intraventricular hemorrhage was more frequent in infants with cortisol levels in the upper quartile at baseline, and values of >90th percentile were significantly associated with higher rates of death, severe intraventricular hemorrhage, periventricular leukomalacia, gastrointestinal perforation, and severe retinopathy of prematurity. CONCLUSIONS. Low cortisol concentrations were not predictive of adverse short-term outcomes, but high cortisol concentrations were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death. Low cortisol concentrations alone at these 2 time points did not identify the infants at highest risk for adverse outcomes. In contrast, high cortisol values were associated with increased morbidity and mortality rates. [ABSTRACT FROM AUTHOR]

Aim: To evaluate if different resuscitation and ventilatory styles exist between two neonatal units, and if the less aggressive approach has a beneficiary effect on BPD outcome. Method: Inborn infants delivered at a gestational age <28 weeks were retrospectively studied (Boston = 70 and Stockholm = 102). Data were collected from birth to discharge or to 40 weeks. Results: The study groups were similar with regard to gestational age, birth weight, gender and CRIB score, whereas SNAPPE-II score was greater in Stockholm and prenatal steroids were given less frequently in Boston. In Stockholm, continuous positive airway pressure (CPAP) was applied in the delivery room for 56% of the infants and the prevalence of infants not requiring intubation or mechanical ventilation (MV) during the first week of life was 22%. In Boston all infants were initially intubated. Subsequently, CPAP was used less often, and higher mean airway pressures (MAWPs) were applied during the first 4 weeks of life. Mortality and moderate/severe BPD at 36 weeks were similar; however, at 40 weeks oxygen supplementation was more frequent in Boston. Site was a predictor for moderate/severe BPD or death at 40 weeks. Conclusion: Practice style differences exist and the less aggressive approach with more CPAP administration was successful. It did not decrease the risk for BPD at 36 weeks; however, at 40 weeks, fewer infants were on oxygen support, and a strong association was found between site, MAWP or MV with pulmonary morbidity indicating that CPAP could have a beneficiary role in outcome. [ABSTRACT FROM AUTHOR]

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks' gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for ≥228 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks' PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. Methods. Data from 4866 infants (birth weight ≤1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD. Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions. [ABSTRACT FROM AUTHOR]