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Abstract Rationale Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity. Objectives To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks’ postmenstrual age best predicts death or serious respiratory morbidity through 18–26 months’ corrected age. Methods We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Measurements and Main Results Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks’ postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n = 773); grade 1, nasal cannula ≤2 L/min (n = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure (n = 617); and grade 3, invasive mechanical ventilation (n = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33–79%) was observed for death or neurodevelopmental impairment. Conclusions The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks’ postmenstrual age, regardless of supplemental oxygen use.

Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants. Our current screening criteria have remained unchanged since their inception and lack the ability to identify those at greatest risk. We sought to comprehensively analyze numerous proposed maternal, infant, and environmental ROP risk variables in a robustly phenotyped population using logistic regression to determine the most predictive model for ROP development and severity. We further sought to determine the statistical interaction between significant ROP risk variables, which has not previously been done in the field of ROP. We hypothesize that our comprehensive analysis will allow for better identification of risk variables that independently correlate with ROP disease. Going forward, this may allow for improved infant risk stratification along a time continuum from prenatal to postnatal development, making prevention more feasible. We performed a retrospective cohort analysis of preterm infants referred for ROP screening in one neonatal intensive care unit from 2010-2015. The primary outcome measure was presence of ROP. Secondary outcome measures were ROP requiring treatment and severe ROP not clearly meeting current treatment criteria. Univariate, stepwise regression and statistical interaction analyses of 57 proposed ROP risk variables was performed to identify variables which were significantly associated with each outcome measure. We identified 457 infants meeting our inclusion criteria. Within this cohort, numerous factors showed a significant individual association with our ROP outcome measures; however, stepwise regression analysis found the most predictive model for overall ROP risk included estimated gestational age, birth weight, the need for any surgery, and maternal magnesium prophylaxis. The corresponding Area Under the Curve (AUC) for this model was 0.8641, while the traditional model of gestational age and birth weight predicted ROP disease less well with an AUC of 0.8489. Development of severe ROP was best predicted by estimated gestational age (week), the need for any surgery and increased probability of death or moderate-severe BPD at 7 days. Finally, the model most predictive for type 1 ROP included estimated gestational age (week) and the presence of severe chronic lung disease. No significant statistical interaction was found between variables. Our work is unique as we report comprehensive analysis of the greatest number of proposed ROP risk variables to date in a robustly phenotyped population. We describe novel risk models for our ROP outcome measures and demonstrate independence of these variables using statistical modeling not previously applied to ROP. This may better allow for individual infant risk stratification and importantly mitigation of future risk.

Abstract Rationale Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment. Objectives To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death. Methods We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004. Measurements and Main Results Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org. Conclusions The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

ObjectiveTo investigate the relationships between early blood pressure (BP) changes, receipt of antihypotensive therapy and 18–22 months’ corrected age (CA) outcomes for extremely preterm infants.DesignProspective observational study of infants 230/7–266/7 weeks’ gestational age (GA). Hourly BP values and antihypotensive therapy exposure in the first 24 h were recorded. Four groups were defined: infants who did or did not receive antihypotensive therapy in whom BP did or did not rise at the expected rate (defined as an increase in the mean arterial BP of ≥5 mm Hg/day). Random-intercept logistic modelling controlling for centre clustering, GA and illness severity was used to investigate the relationship between BP, antihypotensive therapies and infant outcomes.SettingSixteen academic centres of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.Main outcome measuresDeath or neurodevelopmental impairment/developmental delay (NIDD) at 18–22 months’ CA.ResultsOf 367 infants, 203 (55%) received an antihypotensive therapy, 272 (74%) survived to discharge and 331 (90%) had a known outcome at 18–22 months’ CA. With logistic regression, there was an increased risk of death/NIDD with antihypotensive therapy versus no treatment (OR 1.836, 95% CI 1.092 to 3.086), but not NIDD alone (OR 1.53, 95% CI 0.708 to 3.307).ConclusionsIndependent of early BP changes, antihypotensive therapy exposure was associated with an increased risk of death/NIDD at 18–22 months’ CA when controlling for risk factors known to affect survival and neurodevelopment.Clinical trial registration numberclinicaltrials.gov #NCT00874393.

Background Bronchopulmonary dysplasia (BPD) affects up to half of extremely preterm infants, and is associated with adverse long-term respiratory, neurodevelopmental, and educational sequelae and costly health service and family economic outcomes. The NICHD Neonatal Research Network Hydrocortisone for Bronchopulmonary Dysplasia (BPD) Trial evaluated the efficacy and safety of hydrocortisone treatment to prevent BPD in high-risk infants. The trial enrolled 800 very preterm infants with respiratory failure and followed the participants until 2 years corrected age to assess safety of the trial intervention. Longer-term impacts of hydrocortisone exposure and severity of BPD on functional outcomes of high-risk infants remain unknown. The HYdrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study extends follow-up of all surviving children enrolled in the Hydrocortisone for BPD Trial until early school age. It aims to characterize the childhood functional motor, cognitive, academic, and pulmonary outcomes of this large, well-phenotyped trial cohort. Methods Parents of surviving trial participants complete telephone questionnaires when their children are 3 and 4 years corrected age. A single in-person study visit takes place at early school age (5 years, 0 months to 7 years, 11 months corrected age). Children undergo a multidimensional assessment of functional outcomes and parents complete a battery of questionnaires. In 5 of 19 participating centers, respiratory mechanics are evaluated with impulse oscillometry. Discussion The HYBRiD Outcomes Study will be the largest and most comprehensive evaluation to date of the functional early school age outcomes of children with a history of severe neonatal lung disease and of children exposed to HC during infancy. This will substantially improve understanding of the longer-term implications of severe neonatal lung disease; provide data to facilitate the development of future randomized intervention trials in this population; and inform public policy by enhancing knowledge about school age resource requirements in children with a history of prematurity and lung disease. Trial registration clinicaltrials.gov ID NCT01353313. Primary trial registration 5/11/11 modified to include followup through school age 12/13/17. This manuscript reflects version 3 of the trial manuscript, dated 10/12/2020.

ObjectiveTo compare the PF-PCO2 equation—partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) minus partial pressure of carbon dioxide (PCO2)—to three other tools for postnatal prediction of survival in infants with congenital diaphragmatic hernia (CDH).Study designA retrospective analysis of 203 infants with CDH from 1 January 2003 to 30 June 2018. Area under the curve (AUC) analysis was performed for survival and secondary outcomes of survival without extracorporeal membrane oxygenation support (ECMO) and death despite ECMO. Predictive scores were calculated to determine cutoff for PF-PCO2 score.ResultsThe PF-PCO2 tool had the highest AUC (0.84 for survival, 0.92 for survival without ECMO, and 0.83 for death despite ECMO). PF-PCO2 best predicted survival when >−60 and survival without ECMO when >+80. There was no optimal cutoff score for death despite ECMO.ConclusionThe PF-PCO2 tool best predicted postnatal survival in infants with CDH.

Background Necrotizing enterocolitis (NEC) is a serious complication of prematurity. Our objective was to evaluate the impact of an umbilical cord milking protocol (UCM) and pasteurized donor human milk (PDHM) on NEC rates in infants less than 30 weeks gestational age from January 1, 2010 to September 30, 2016. We hypothesized an incremental decrease in NEC after each intervention. Methods We performed a retrospective review of 638 infants born less than 30 weeks gestational age. Infants were grouped into three epochs: pre-UCM/pre-PDHM (Epoch 1, n  = 159), post-UCM/pre-PDHM (Epoch 2, n  = 133), and post-UCM/post-PDHM (Epoch 3, n  = 252). The incidence of NEC, surgical NEC, and NEC/death were compared. Logistic regression was used to determine independent significance of time epoch, gestational age, birth weight, and patent ductus arteriosus for NEC, surgical NEC, and death/NEC. Results At birth, infants in Epoch 1 were younger than Epoch 2 and 3 (26.8 weeks versus 27.3 and 27.2, respectively, P  = 0.036) and smaller (910 g versus 1012 and 983, respectively, P  = 0.012). Across epochs, there was a significant correlation between patent ductus arteriosus treatment and NEC rate ( P  < 0.001, Cochran-Mantel-Haenszel). There was a significant decrease in rates of NEC, surgical NEC, and NEC/death between groups. Logistic regression showed this as significant for rates of NEC and surgical NEC between Epoch 1 and 3. Patent ductus arteriosus was a significant variable affecting the incidence of NEC, but not surgical NEC or death/NEC. Conclusions An umbilical cord milking protocol and pasteurized donor human milk availability was associated with decreased rates of NEC and surgical NEC. This suggests an additive effect of these interventions in preventing NEC.

BackgroundMortality and ECMO rates for congenital diaphragmatic hernia (CDH) remain ~30%. In 2016, we changed our CDH guidelines to minimize stimulation while relying on preductal oxygen saturation, lower mean airway pressures, stricter criteria for nitric oxide (iNO), and inotrope use. We compared rates of ECMO, survival, and survival without ECMO between the two epochs.Design/MethodsRetrospective review of left-sided CDH neonates at the University of Utah/Primary Children’s Hospital NICUs during pre (2003–2015, n = 163) and post (2016–2019, n = 53) epochs was conducted. Regression analysis controlled for defect size and intra-thoracic liver.ResultsFollowing guideline changes, we identified a decrease in ECMO (37 to 13%; p = 0.001) and an increase in survival without ECMO (53 to 79%, p = 0.0001). Overall survival increased from 74 to 89% (p = 0.035).Conclusion(s)CDH management guideline changes focusing on minimizing stimulation, using preductal saturation and less aggressive ventilator/inotrope support were associated with decreased ECMO use and improved survival.

In a randomized trial involving extremely-low-birth-weight infants eligible for noninvasive ventilation, the survival rate without bronchopulmonary dysplasia after nasal intermittent positive-pressure ventilation was similar to the rate after nasal continuous positive airway pressure. In extremely-low-birth-weight infants, bronchopulmonary dysplasia remains a leading cause of early death, 1 a strong predictor of later neurologic impairment, 2 and a major reason for resource use 3 and rehospitalization during the first year of life. 4 Improvements in survival rates among such infants have led to rates of bronchopulmonary dysplasia of up to 60% at the lowest gestational ages. 1 , 5 , 6 Tracheal intubation and mechanical ventilation are associated with ventilator-induced lung injury and airway inflammation, leading to bronchopulmonary dysplasia. 7 , 8 Prolonged duration of intubation and mechanical ventilation in extremely-low-birth-weight infants is associated with an increased risk of death or survival with neurologic . . .

ObjectiveThe gold standard for diagnosing metabolic bone disease in pediatrics is dual-energy x-ray absorptiometry (DXA). Bone quantitative ultrasound (QUS) has increasing applications. This study compared the relationship of DXA to QUS in preterm infants.DesignProspective observational study of preterm infants ≤32 weeks gestation or ≤1800 grams at birth. DXA scans measuring bone mineral content (BMC) and tibial QUS scans measuring bone speed of sound (SOS) were obtained near term gestation.Results41 infants had bone scans at mean corrected gestation 37.7 ± 2.1 weeks. BMC and SOS showed weak inverse correlation (R2 0.163, p < 0.01). BMC and SOS correlated with parameters at corrected gestational age at the time of the bone scans (p < 0.05–0.001). SOS correlated with birth gestational age (p < 0.001), not BMC.ConclusionsA statistically significant weak inverse correlation between DXA and QUS was observed. QUS may have advantages over DXA.