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A major barrier to therapeutic development in neonates is a lack of standardized drug response measures that can be used as clinical trial endpoints. The ability to quantify treatment response in a way that aligns with relevant downstream outcomes may be useful as a surrogate marker for new therapies, such as those for bronchopulmonary dysplasia (BPD).To construct a measure of clinical response to dexamethasone that was well aligned with the incidence of severe BPD or death at 36 weeks' postmenstrual age.Retrospective cohort study.Level IV Neonatal Intensive Care Unit.Infants treated with dexamethasone for developing BPD between 2010 and 2020.Two models were built based on demographics, changes in ventilatory support, and partial pressure of carbon dioxide (pCONinety-five infants were treated with dexamethasone before 36 weeks. Compared to the baseline support and demographic data at the time of treatment, changes in ventilatory support improved ordinal model sensitivity and specificity. For the binary classification, BPD incidence was well aligned with risk levels, increasing from 16% to 59%.Incorporation of response variables as measured by changes in ventilatory parameters and pCO

Objective To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population. Study design Data from the Children’s Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references. Results Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (

BACKGROUND The decision to pursue chronic mechanical ventilation involves a complex mix of clinical and social considerations. Understanding the medical indications to pursue tracheostomy would reduce the ambiguity for both providers and families and facilitate focus on appropriate clinical goals. OBJECTIVE To describe potential indications to pursue tracheostomy and chronic mechanical ventilation in infants with severe BPD (sBPD). STUDY DESIGN We surveyed centers participating in the Children's Hospitals Neonatal Consortium to describe their approach to proceed with tracheostomy in infants with sBPD. We requested a single representative response per institution. Question types were fixed form and free text responses. RESULTS The response rate was high (31/34, 91%). Tracheostomy was strongly considered when: airway malacia was present, PCO2 ≥ 76-85 mmHg, FiO2 ≥ 0.60, PEEP ≥ 9-11 cm H2O, respiratory rate ≥ 61-70 breaths/min, PMA ≥ 44 weeks, and weight

To describe characteristics, outcomes, and risk factors for death or tracheostomy with home mechanical ventilation in full-term infants with chronic lung disease (CLD) admitted to regional neonatal intensive care units.This was a multicenter, retrospective cohort study of infants born ≥37 weeks of gestation in the Children's Hospitals Neonatal Consortium.Out of 67,367 full-term infants admitted in 2010-2016, 4886 (7%) had CLD based on receiving respiratory support at either 28 days of life or discharge. 3286 (67%) were still hospitalized at 28 days receiving respiratory support, with higher mortality risk than those without CLD (10% vs. 2%, p 0.001). A higher proportion received tracheostomy (13% vs. 0.3% vs. 0.4%, p 0.001) and gastrostomy (30% vs. 1.7% vs. 3.7%, p 0.001) compared to infants with CLD discharged home before 28 days and infants without CLD, respectively. The diagnoses and surgical procedures differed significantly between the two CLD subgroups. Small for gestational age, congenital pulmonary, airway, and cardiac anomalies and bloodstream infections were more common among infants with CLD who died or required tracheostomy with home ventilation (p 0.001). Invasive ventilation at 28 days was independently associated with death or tracheostomy and home mechanical ventilation (odds ratio 7.6, 95% confidence interval 5.9-9.6, p 0.0001).Full-term infants with CLD are at increased risk for morbidity and mortality. We propose a severity-based classification for CLD in full-term infants. Future work to validate this classification and its association with early childhood outcomes is necessary.

Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown.We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age.We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups.In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Few medications are available and well tested to treat infants who already have developed or inevitably will develop severe bronchopulmonary dysplasia (sBPD). Infants who develop sBPD clearly have not benefited from decades of research efforts to identify clinically meaningful preventive therapies for very preterm infants in the first days and weeks of their postnatal lives. This review addresses challenges to individualized approaches to medication use for sBPD. Specific challenges include understanding the combination of an individual infant’s postmenstrual and postnatal age and the developmental status of drug-metabolizing enzymes and receptor expression. This review will also explore the reasons for the variable responsiveness of infants to specific therapies, based on current understanding of developmental pharmacology and pharmacogenetics. Data demonstrating the remarkable variability in the use of commonly prescribed drugs for sBPD are presented, and a discussion about the current use of some of these medications is provided. Finally, the potential use of antifibrotic medications in late-stage sBPD, which is characterized by a profibrotic state, is addressed.

OBJECTIVE: To determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18–22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage (adjusted relative risk [aRR] = 1.0; 95% confidence interval [CI]: 0.87–1.14). A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (p = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR=0.81; 95% CI: 0.64 to 1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference

A prospective cohort study was performed in preterm infants less than 32 weeks gestation at birth who were treated with dexamethasone for developing or established bronchopulmonary dysplasia (BPD). Respiratory phenotype (Respiratory Severity Score (RSS)), serum, and urine metabolomics were assessed before and after treatment. Ten infants provided nine matched serum and nine matched urine samples. There was a significant decrease in RSS with steroid treatment. Serum gluconic acid had the largest median fold change (140 times decreased, P = 0.008). In metabolite set enrichment analysis, in both serum and urine, the urea cycle, ammonia recycling, and malate‐aspartate shuttle pathways were most significantly enriched when comparing pretreatment and post‐treatment (P value

Objective: To describe effectiveness of repeat dexamethasone for bronchopulmonary dysplasia (BPD) and to evaluate adverse effects on growth. Study design: Retrospective study of infants treated with 1 or 2 courses of dexamethasone for BPD. Effectiveness was defined as successful step-down in respiratory support by end of treatment. Adverse effects on growth were analyzed and compared to untreated controls. Results: A total of 132 dexamethasone-treated infants were identified. In total, 52% (69/132) of infants treated with initial dexamethasone achieved step-down in respiratory support compared to 38% (20/52) of infants with repeat dexamethasone. Growth trajectory did not significantly differ among infants treated with 1 or 2 courses of dexamethasone compared with controls (weight: P = 0.23, length: P = 0.68, and head circumference: P = 0.77). Conclusions: Repeat dexamethasone for BPD was less effective in weaning respiratory support compared to initial course. Changes in growth parameters to discharge were comparable between controls and infants treated with 1 or 2 dexamethasone courses.

Objectives To determine whether the need for invasive mechanical ventilation (iMV) at 36 weeks PMA in patients with severe bronchopulmonary dysplasia (sBPD) identifies those patients at highest risk for tracheostomy or gastrostomy, and to compare sBPD with recent definitions of BPD. Study design Observational study from Jan 2015 to Sept 2019 using data from the BPD Collaborative Registry. Results Five hundred and sixty-four patients with sBPD of whom 24% were on iMV at 36 weeks PMA. Those on iMV had significantly (p p Conclusions Patients with sBPD who were on iMV at 36 weeks had a significantly greater risk of inhospital mortality and survivors had a significantly greater risk of undergoing tracheostomy and/or gastrostomy. The use of type 2 sBPD or Grade 3 BPD would enhance the ability to target future studies to those infants with sBPD at the highest risk of adverse long-term outcomes.

Objective To determine if multidisciplinary team-based care of severe BPD/CLD infants improve survival to discharge. Design/methods Retrospective review of severe BPD/CLD infants cared for by dedicated multidisciplinary CLD team using consensus-driven protocols and guidelines. Results Total of 267 patients. Median gestational age was 26 weeks (IQR 24, 32); median birth-weight was 0.85 (IQR 0.64, 1.5). Twenty-four percent were preterm with severe BPD, 46% had other primary respiratory diseases (none BPD diseases). Total number of patients, proportion of patients with tracheostomy, prematurity, and genetic diagnoses increased over time. 88.8% survived to discharge. Unadjusted logistic regression showed that tracheostomy was not associated with odds of death; secondary pulmonary hypertension was associated with odds of tracheostomy (OR = 1.795 p value = 0.0264), or death (OR = 8.587 p value =

Objective The aim of this study is to determine patterns of neurally adjusted ventilatory assist (NAVA) use in ventilator-dependent preterm infants with evolving or established severe bronchopulmonary dysplasia (sBPD) among centers of the BPD Collaborative, including indications for its initiation, discontinuation, and outcomes. Study Design Retrospective review of infants with developing or established sBPD who were placed on NAVA after ≥4 weeks of mechanical ventilation and were ≥ 30 weeks of postmenstrual age (PMA). Results Among the 13 sites of the BPD collaborative, only four centers (31%) used NAVA in the management of infants with evolving or established BPD. A total of 112 patients met inclusion criteria from these four centers. PMA, weight at the start of NAVA and median number of days on NAVA, were different among the four centers. The impact of NAVA therapy was assessed as being successful in 67% of infants, as defined by the ability to achieve respiratory stability at a lower level of ventilator support, including extubation to noninvasive positive pressure ventilation or support with a home ventilator. In total 87% (range: 78–100%) of patients survived until discharge. Conclusion We conclude that NAVA can be used safely and effectively in selective infants with sBPD. Indications and current strategies for the application of NAVA in infants with evolving or established BPD, however, are highly variable between centers. Although this pilot study suggests that NAVA may be successfully used for the management of infants with BPD, sufficient experience and well-designed clinical studies are needed to establish standards of care for defining the role of NAVA in the care of infants with sBPD.

BACKGROUND:Many premature infants with respiratory failure are deficient in surfactant, but the relationship to occurrence of bronchopulmonary dysplasia (BPD) is uncertain. METHODS:Tracheal aspirates were collected from 209 treated and control infants enrolled at 7-14 days in the Trial of Late Surfactant. The content of phospholipid, surfactant protein B, and total protein were determined in large aggregate (active) surfactant. RESULTS:At 24 h, surfactant treatment transiently increased surfactant protein B content (70%, p

Importance Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, setting, and participants This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main outcomes and measures The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and relevance Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial registration ClinicalTrials.gov Identifier: NCT01192776.

Examine respiratory severity scores (RSS) (mean airway pressure × fraction of inspired oxygen) and resting energy expenditure (REE) on neurally adjusted ventilatory assist (NAVA) compared with synchronized intermittent mandatory ventilation with pressure controlled and supported breath (SIMV (PC)PS). A randomized, crossover trial in a level IV neonatal intensive care unit. Twenty-four patients were ventilated with NAVA or SIMV (PC) PS for 12 h and then crossed over to the alternative mode for 12 h. The primary outcome (RSS) and additional secondary respiratory outcomes were analyzed. RSS and measured REE were not different between modes. On NAVA, peak inspiratory pressures were lower (17.8 vs 19.9 cmH2O (P

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

The objective of the study was to compare the effect of two different dexamethasone regimens on respiratory outcomes of ventilator-dependent preterm infants. Retrospective study of ventilated preterm infants

OBJECTIVE: To evaluate neurodevelopmental outcomes of preterm infants with need for Child Protective Services (CPS) supervision at hospital discharge compared with those discharged without CPS supervision. STUDY DESIGN: For infants born at

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Objective To determine the relationship between interventricular septal position (SP) and right ventricular systolic pressure (RVSP) and mortality in infants with severe BPD (sBPD). Study design Infants with sBPD in the Children’s Hospitals Neonatal Database who had echocardiograms 34–44 weeks’ postmenstrual age (PMA) were included. SP and RVSP were categorized normal, abnormal (flattened/bowed SP or RVSP > 40 mmHg) or missing. Results Of 1157 infants, 115 infants (10%) died. Abnormal SP or RVSP increased mortality (SP 19% vs. 8% normal/missing, RVSP 20% vs. 9% normal/missing, both p

Objective The goal was to determine if inhaled nitric oxide (iNO) for 3 weeks during neonatal care of high-risk preterm infants was associated with improved pulmonary function and exercise capacity or altered exhaled nitric oxide (FeNO) levels in later childhood. Study Design Thirty-four very preterm children previously enrolled in a randomized, neonatal trial of iNO to prevent chronic lung disease, were assessed in follow-up at 7 to 9 years of age, including pulmonary function testing (PFT), exercise testing, and measurement of FeNO. Results There were no differences in PFTs or exercise capacity between iNO treated and controls. FeNO levels showed large interpatient variability but tended to be lower in the iNO treated. Conclusion Findings indicate no overall differences in pulmonary function or exercise capacity for children who had neonatal iNO treatment compared with placebo.

OBJECTIVE To determine the association of timing of steroid therapy for bronchopulmonary dysplasia (BPD) and outcomes. METHODS Retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD. Infants treated with steroids at day of life (DOL) 14-28 (moderately late group) were compared to infants treated at DOL 29-42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge. RESULTS Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified. The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high frequency ventilation (96% vs 47%, P

Objective This article aimed to identify readmission risk factors through 2 years of life for infants with severe bronchopulmonary dysplasia (BPD) who do not require tracheostomy and ventilatory support after neonatal intensive care unit (NICU) discharge. It also aimed to identify if clinical differences exist between the subcategories of severe BPD. Study Design A retrospective chart review was performed on 182 infants with severe BPD born between 2010 and 2015. A total of 130 infants met the inclusion criteria and were stratified into three groups based on their respiratory status at 36 weeks of gestational age: group A—oxygen (O2), group B—assisted ventilation (AV), group C—both O2 and AV. NICU clinical risk factors for readmission were assessed at set time points (6/12/18/24 months). Reasons for readmission were assessed for the entire cohort and severe BPD subgroups. Conclusion An NICU diagnosis of neurologic abnormality, necrotizing enterocolitis, invasive NICU infection, dysphagia, and O2 at NICU discharge differed between the three subgroups of severe BPD. The most common cause of readmission was viral respiratory tract infection. Inhaled steroid use remained stable over time, while oxygen use and diuretic use declined over time. Risk factors for readmission in the entire cohort included g-tube, O2 use, and diuretic use at 12 months. There was no significant difference in readmission rates between the three BPD subgroups.

ObjectiveTo assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight.Study designThis trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight

Background Bronchopulmonary Dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. Clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD. Methods Pharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was change in Respiratory Severity Score (RSS, mean airway pressure × FiO2) at day 7 of corticosteroid treatment. Results rs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis p=2.8×10−4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e. less response to systemic corticosteroids. Conclusion Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk to benefit ratio for an individual child.

Objective To report on the population of infants receiving a tracheostomy, identify acute post-tracheostomy clinical decompensations, and seek predictive markers associated with acute complications following the placement of a tracheostomy. Study Design Retrospective deidentified clinical data was provided by the Infant Pulmonary Data Repository at Children's Mercy Hospital, Kansas City. Data from infants undergoing tracheostomy from January 1, 2008 through September 30, 2016 were divided into one of two study groups based on clinical correlations: (1) no acute decompensations within 72 hours post-tracheostomy or (2) acute clinical decompensation defined as sustained escalation of respiratory care within the 72 hours following tracheostomy. Results Thirty-four percent of infants undergoing tracheostomy during this period developed acute post-tracheostomy clinical decompensations. Elevated pre-tracheostomy positive end expiratory pressure, mean airway pressure, and echocardiogram findings suggestive of pulmonary hypertension (PH) or ventricular dysfunction were associated with acute post-tracheostomy clinical decompensations. Additionally acute post-tracheostomy clinical decompensation was associated with higher rate of death prior to discharge. Conclusion Infants requiring higher respiratory support and infants with PH or ventricular dysfunction are at risk of acute post-tracheostomy clinical decompensation, thus identifying these patients may lead to better pre-tracheostomy counseling and potentially targeted treatments to decrease this risk.

Importance Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age. Design, Setting, and Participants This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Objective To analyze reasons for low enrollment in an RCT of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late-preterm newborns. Study Design The original study was a multicenter RCT. Eligibility: ≥34 weeks’ gestation

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier:NCT00614744

Objective To assess the usefulness of a bronchopulmonary dysplasia (BPD) outcome estimator developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in identifying high-risk preterm infants treated with steroids. Study design This was a single-center retrospective study of infants born ≤30 weeks of gestational age. The NICHD BPD outcome estimator was used to retrospectively calculate BPD risk at various postnatal ages. The best combination of risk estimates for identifying steroid treatment was identified using stepwise model selection. A cut-off value with the best combination of sensitivity and specificity was identified using receiver operating characteristic analysis. Results A total of 165 infants born preterm (mean gestational age 26 ± 1.6 weeks, mean birth weight 837 ± 171 g) were included. Of these, 61 were treated with steroids for BPD and 104 were not. Risk estimates for BPD or death were significantly greater in infants treated with steroids compared with controls. Both combined risk for severe BPD or death and single risk of no BPD were identified as factors with the best predictive power for identifying treatment with steroids, with accurate prediction possible as early as the second week of life. A greater than 37% risk for severe BPD or death or a less than 3% risk of no BPD on day of life 14 had 84%-92% sensitivity and 77%-80% specificity for predicting steroid treatment. Conclusion The NICHD BPD outcome estimator can be a useful objective tool for identifying infants at high risk for BPD who may benefit from postnatal steroids.

Objective The objective of this study was to assess the outcomes of preterm infants who failed to extubate following initial treatment with steroids. Materials and Methods This is a retrospective cohort study of ventilator-dependent preterm infants treated with first course of systemic steroids to facilitate extubation. Outcomes of infants who successfully extubated were compared with infants who failed to extubate. Results In this study, 74 infants (mean gestation 25.4 ± 1.4 weeks and mean birth weight 764 ± 163 g) met inclusion criteria. Of these, 41 (55%) were successfully extubated and 33 (45%) were not. Baseline demographics were similar between the two groups. The primary outcome of severe bronchopulmonary dysplasia (BPD) or death at 36 weeks was higher among infants who failed to extubate (94 vs. 63%, p = 0.002). Severe BPD remained significantly higher even after adjustment for potential confounders (odds ratio: 12.2, 95% confidence interval: 2.1–70.5, p = 0.005). Extubation failure was also associated with substantially higher rate of tracheostomy (32 vs. 5%, p = 0.003) and gastrostomy tube placement (61 vs. 22%, p = 0.001), as well as longer days of hospitalization (179 ± 72 vs. 129 ± 44 days, p = 0.001) and mechanical ventilation (112 ± 89 vs. 52 ± 42 days, p Conclusion Failure to extubate after first course of systemic steroids for BPD is associated with poor prognostic implications.

Objectives To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes. Study design This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated. Results WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator. Conclusions Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor. Trial registration ClinicalTrials.gov : NCT00063063 .

To evaluate the temperature distribution among moderately preterm (MPT, 29-33 weeks) and extremely preterm (EPT,29 weeks) infants upon neonatal intensive care unit (NICU) admission in 2012-2013, the change in admission temperature distribution for EPT infants between 2002-2003 and 2012-2013, and associations between admission temperature and mortality and morbidity for both MPT and EPT infants.Prospectively collected data from 18 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were used to examine NICU admission temperature of inborn MPT and EPT infants. Associations between admission temperature and mortality and morbidity were determined by multivariable logistic regression. EPT infants from 2002-2003 and 2012-2013 were compared.MPT and EPT cohorts consisted of 5818 and 3213 infants, respectively. The distribution of admission temperatures differed between the MPT vs EPT (P .01), including the percentage36.5°C (38.6% vs 40.9%), 36.5°C-37.5°C (57.3% vs 52.9%), and37.5°C (4.2% vs 6.2%). For EPT infants in 2012-2013 compared with 2002-2003, the percentage of temperatures between 36.5°C and 37.5°C more than doubled and the percentage of temperatures37.5°C more than tripled. Admission temperature was inversely associated with in-hospital mortality.Low and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists.

BackgroundExtremely preterm infants (EPT

Objective To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). Study design Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). Results Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. Conclusion Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. Trial registration ClinicalTrials.gov : NCT01022580

To estimate the risk of death or tracheostomy placement (D/T) in infants with severe bronchopulmonary dysplasia (sBPD) born32 weeks' gestation referred to regional neonatal intensive care units.We conducted a retrospective cohort study in infants born32 weeks' gestation with sBPD in 2010-2011, using the Children's Hospital Neonatal Database. sBPD was defined as the need for FiO2 ⩾ 0.3, nasal cannula support2 l min(-1) or positive pressure at 36 weeks' post menstrual age. The primary outcome was D/T before discharge. Predictors associated with D/T in bivariable analyses (P0.2) were used to develop a multivariable logistic regression equation using 80% of the cohort. This equation was validated in the remaining 20% of infants.Of 793 eligible patients, the mean gestational age was 26 weeks' and the median age at referral was 6.4 weeks. D/T occurred in 20% of infants. Multivariable analysis showed that later gestational age at birth, later age at referral along with pulmonary management as the primary reason for referral, mechanical ventilation at the time of referral, clinically diagnosed pulmonary hypertension, systemic corticosteroids after referral and occurrence of a bloodstream infection after referral were each associated with D/T. The model performed well with validation (area under curve 0.86, goodness-of-fit χ(2), P = 0.66).Seven clinical variables predicted D/T in this large, contemporary cohort with sBPD. These results can be used to inform clinicians who counsel families of affected infants and to assist in the design of future prospective trials.

Objective: Assess the impact of intercurrent respiratory infections in infants

To assess pulmonary outcomes of infants

IMPORTANCE: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. OBJECTIVE: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks’ gestational age. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial included 638 infants younger than 28 weeks’ gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. INTERVENTIONS: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. MAIN OUTCOMES AND MEASURES: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. RESULTS: Among 638 infants (mean, 26 weeks’ gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). CONCLUSIONS AND RELEVANCE: Among premature infants younger than 28 weeks’ gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Background: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW). Methods: We randomized 85 preterm infants ventilated at 7–14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL). Results: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02). Conclusion: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

The purpose of comparative effectiveness research (CER) is to improve health outcomes by developing and disseminating evidence-based information about which currently available interventions and practices are most effective for patients. While Randomized Controlled Trials (RCT) are the hallmark of scientific proof, when they have been used to compare interventions used in variable ways by different clinicians (Comparative Effectiveness RCTs, CER RCTs) they have at times, generated controversy. Usually the background for the CER RCT is a range of ‘standard therapy’ or ‘standard of care’. This may have been adopted on observational data alone, pilot data. At times, such prior data may derive from populations that differ from the population in which the widely variable standard approach is being applied. We believe controversies related to these CER-RCTs result from confusing ‘accepted’ therapies and ‘rigorously evaluated therapies”. We first define evidence based medicine, and consider how well neonatology conforms to that definition. We then contrast the approach of testing new therapies and those already existing and widely adopted, as in CER-RCTs. We next examine a central challenge in incorporating the control arm within CER, and aspects of the ‘titrated’ trial. We finally briefly consider some ethical issues that have arisen, and briefly discuss the wide range of neonatology practices that could be subject to CER-RCTs or alternative CER-based strategies that might inform practice in the absence of RCTs. Throughout, we emphasize the lack of awareness of the lay community, and indeed many researchers or commentators, in appreciating the wide variation of standard of care. There is a corresponding need to identify the best uses of available resources that will lead to the best outcomes for our patients. We conclude that CER is an essential methodology in modern neonatology to address many unanswered questions and test unproven therapies in newborn care.

To estimate the presence and sources of inter-center variation (ICV) in the risk of death or tracheostomy placement (D/T) among infants with severe bronchopulmonary dysplasia (sBPD)Study design:We analyzed the Children's Hospitals Neonatal Database between 2010 and 2013 to identify referred infants born32 weeks' gestation with sBPD. The association between center and the primary outcome of D/T was analyzed by multivariable modeling. Hypothesized diagnoses/practices were included to determine if these explained any observed ICV in D/T.D/T occurred in 280 (20%) of 1383 eligible infants from 21 centers. ICV was significant for D/T (range 2-46% by center, P0.001) and tracheostomy placement (n=187, range 2-37%, P0.001), but not death (n=93, range 0-19%, P=0.08). This association persisted in multivariable analysis (adjusted center-specific odds ratios for D/T varied 5.5-fold, P=0.009).ICV in D/T is apparent among infants with sBPD. These results highlight that the indications for tracheostomy (and subsequent chronic ventilation) remain uncertain.

Impressive advances in neonatology have occurred over the 30 years of life of The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). However, substantial room for improvement remains in investigating and further developing the evidence base for improving outcomes among the extremely premature. We discuss some of the specific methodological challenges in the statistical design and analysis of randomized trials and observational studies in this population. Challenges faced by the NRN include designing trials for unusual or rare outcomes, accounting for and explaining center variations, identifying other subgroup differences, and balancing safety and efficacy concerns between short-term hospital outcomes and longer-term neurodevelopmental outcomes. In conclusion, the constellation of unique patient characteristics in neonates calls for broad understanding and careful consideration of the issues identified in this article for conducting rigorous studies in this population.

To assess the prognostic accuracy of early cumulative supplemental oxygen (CSO) exposure for prediction of bronchopulmonary dysplasia (BPD) or death, and to evaluate the independent association of CSO with BPD or death.We performed a secondary analysis of the Trial of Late Surfactant, which enrolled 511 infants born at ≤28 weeks gestational age who were mechanically ventilated at 7-14 days of life. Our primary outcome was BPD or death at 36 weeks postmenstrual age, as determined by a physiological oxygen/flow challenge. Average daily supplemental oxygen (fraction of inspired oxygen - 0.21) was calculated. CSO was calculated as the sum of the average daily supplemental oxygen over time periods of interest up to 28 days of age. Area under the receiver operating curve (AUROC) values were generated to evaluate the accuracy of CSO for prediction of BPD or death. The independent relationship between CSO and BPD or death was assessed in multivariate modeling, while adjusting for mean airway pressure.In the study infants, mean gestational age at birth was 25.2 ± 1.2 weeks and mean birth weight was 700 ± 165 g. The AUROC value for CSO at 14 days was significantly better than that at earlier time points for outcome prediction (OR, 0.70; 95% CI, 0.65-0.74); it did not increase with the addition of later data. In multivariate modeling, a CSO increase of 1 at 14 days increased the odds of BPD or death (OR, 1.7; 95% CI, 1.3-2.2; P .0001), which corresponds to a 7% higher daily supplemental oxygen value.In high-risk extremely low gestational age newborns, the predictive accuracy of CSO plateaus at 14 days. CSO is independently associated with BPD or death. This index may identify infants who could benefit from early intervention to prevent BPD.

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA

Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO2 × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

Objective To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. Study design We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. Results Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. Conclusions Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. Trial registration ClinicalTrials.gov : NCT01022580 .

Objectives To describe the frequency and extent of delivery room resuscitation and evaluate the association of delivery room resuscitation with neonatal outcomes in moderately preterm (MPT) infants. Study design This was an observational cohort study of MPT infants delivered at 290/7 to 336/7 weeks' gestational age (GA) enrolled in the Neonatal Research Network MPT registry. Infants were categorized into 5 groups based on the highest level of delivery room intervention: routine care, oxygen and/or continuous positive airway pressure, bag and mask ventilation, endotracheal intubation, and cardiopulmonary resuscitation including chest compressions and/or epinephrine use. The association of antepartum and intrapartum risk factors and discharge outcomes with the intensity of resuscitation was evaluated. Results Of 7014 included infants, 1684 (24.0%) received routine care and no additional resuscitation, 2279 (32.5%) received oxygen or continuous positive airway pressure, 1831 (26.1%) received bag and mask ventilation, 1034 (14.7%) underwent endotracheal intubation, and 186 (2.7%) received cardiopulmonary resuscitation. Among the antepartum and intrapartum factors, increasing GA, any exposure to antenatal steroids and prolonged rupture of membranes decreased the likelihood of receipt of all levels of resuscitation. Infants who were small for GA (SGA) had increased risk of delivery room resuscitation. Among the neonatal outcomes, respiratory support at 28 days, days to full oral feeds and length of stay were significantly associated with the intensity of delivery room resuscitation. Higher intensity of resuscitation was associated with increased risk of mortality. Conclusions The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.