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ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation,

OBJECTIVE: To investigate the relationship of cortisol concentrations during the first week of life to patent ductus arteriosus (PDA), markers of lung inflammation, and respiratory outcome in very low birth weight infants. METHODS: Newborns <1,500 g birth weight were prospectively enrolled at 2 centers. Serum cortisol was measured 3 times during days 2 to 7 of life. Tracheal lavage was performed on intubated infants and analyzed for interleukin-1beta, -6, and -8, and for total protein, albumin, and alpha-1 protease inhibitor. Infants receiving prenatal glucocorticoids were excluded. RESULTS: We obtained 337 cortisol values from 125 infants. Infants treated for PDA had lower cortisol values after day 2. One hundred thirty-three tracheal fluid samples were obtained on matching days from 71 intubated infants. Cortisol correlated inversely with tracheal interleukins and proteins. Lower cortisol values during the second half of the week correlated with longer duration of supplemental oxygen therapy and with subsequent development of chronic lung disease at 28 days and at 36 weeks. CONCLUSION: Infants with lower cortisol values in the first week of life had an increased incidence of PDA, increased lung inflammation, and an increased incidence of chronic lung disease. These findings suggest that early adrenal insufficiency may underlie the previously observed association of increased lung inflammation and PDA with adverse respiratory outcome in this population. [ABSTRACT FROM AUTHOR]

BACKGROUND. Many extremely low birth weight infants (<1000 g) show biochemical evidence of adrenal insufficiency in the first week of life, correlating with subsequent development of chronic lung disease (CLD). METHODS: We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by.5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD. RESULTS: Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 +/- 135 g versus 770 +/- 135 g and 25.2 +/- 1.3 weeks versus 25.4 +/- 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died. CONCLUSIONS: First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The development of bronchopulmonary dysplasia (BPD) often has been attributed to injury from mechanical ventilation and supplemental oxygen. Early lung inflammation in infants with BPD has been thought to be secondary to these factors. The purpose of this study was to evaluate whether preexisting (prenatal) inflammation may be a primary causative factor in the development of BPD. METHODS: Intubated newborns of less than 2,000 g birth weight were prospectively enrolled. The presence or absence of chorioamnionitis was documented. Lung inflammation was evaluated on days 1, 2, and 4 of intubation by assaying concentrations of interleukin 1 beta (IL-1 beta), thromboxane B2, leukotriene B4, and prostaglandin E2 in tracheal lavages. Infants in whom BPD developed were compared with those in whom it did not using these measures. RESULTS: Fifty-three infants were enrolled; 41 survived. Thirty-eight had respiratory distress syndrome; 15 were intubated for other diagnoses. Infants prenatally exposed to chorioamnionitis were less likely to present with respiratory distress syndrome; however, chorioamnionitis was significantly associated with both the presence of IL-1 beta from the first day of intubation and the development of BPD. Tracheal lavage concentrations of IL-1 beta were higher in infants in whom BPD developed. Thromboxane B2 concentrations were similar on day 1 but were higher on days 2 and 4 in infants in whom BPD developed. CONCLUSIONS: In this study, intubated infants weighing less than 2,000 g at birth in whom BPD developed had increased exposure to inflammation prenatally (chorioamnionitis) and evidence of increased lung inflammation from the first postnatal day. We speculate that chorioamnionitis may accelerate lung maturation but that it also causes lung inflammation and subsequent lung injury in intubated infants, fostering the development of BPD. [ABSTRACT FROM AUTHOR]

OBJECTIVES. To test the cortisol response to adrenocorticotrophic hormone (ACTH) in a population of very low birth weight newborns at the end of the first week of life, and to evaluate the relationship of this response to the subsequent development of bronchopulmonary dysplasia and to the total length of oxygen dependence. METHODS. Appropriate for gestational age newborns < 1500 g birth weight were enrolled prospectively. Response to ACTH stimulation was tested on days 5, 6, or 7. Baseline cortisol, stimulated cortisol, and magnitude of response were compared between babies who developed bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 28 days, and those who recovered without BPD. RESULTS. In this population, the cortisol response to ATCH increased with increasing birth weight (P < .001). Using birth weight as a cofactor, analysis of variance showed that patients who developed BPD (n = 34, BW 974 +/- 192 g, mean +/- S.D.) had significantly reduced responses to ACTH at 5 to 7 days of age compared to those who recovered (n = 25, BW 1251 +/- 194 g), P = .006. Additionally, 84% of patients who recovered without BPD, but only 26% of BPD patients, achieved a prospectively defined positive cortisol response to ACTH (> or = 9 micrograms/dL; P < .005). Supplemental oxygen was discontinued at a younger postconceptional age in babies with a positive cortisol response to ACTH (P < .01) and fewer of those babies were on supplemental oxygen at 36-week postconceptional age (P < .01). CONCLUSIONS. At the end of the first week of life, infants who subsequently developed BPD and prolonged oxygen dependence had significantly lower cortisol secretion in response to ACTH than infants who recovered without BPD. We speculate that these babies may be unable to secrete adequate amounts of cortisol in a setting of increased stress, leaving them vulnerable to continuing lung injury. [ABSTRACT FROM AUTHOR]

Objectives: To clarify if systemic hydrocortisone, in protocols allowing to start it before the 15th day of life, prevents bronchopulmonary dysplasia (BPD) or other adverse outcomes in very preterm neonates, and to identify any possible effect size modifiers., Study Design: Systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Additional analyses included meta-regressions and review of biological plausibility., Results: Seven trials were included, they were of general good quality and accounted for a total of 2193 infants. Hydrocortisone treatment did not reduce BPD (risk ratio (RR) 0.84 (95% CI 0.64 to 1.04)), but heterogeneity was evident (I 2 =51.6%). The effect size for BPD is greatest for 10-12 days duration of treatment (β=0.032 (0.01), p=0.007) and tended to be greater in patients with chorioamnionitis (β=-1.5 (0.841), p=0.07). Hydrocortisone treatment may significantly reduce mortality (RR 0.75 (95% CI 0.59 to 0.91)), there is no heterogeneity (I 2 =0) and the reduction tended to be greater in males (β=-0.06 (0.03), p=0.07). Hydrocortisone may significantly reduce necrotising enterocolitis (NEC; RR 0.72 (95% CI 0.53 to 0.92)); there is neither heterogeneity (I 2 =0%) nor any effect size modifiers. Hydrocortisone did not affect other adverse outcomes of prematurity., Conclusions: Systemic hydrocortisone may be considered, on a case-by-case evaluation, to reduce mortality and NEC, while it does not affect BPD. There are some potential effect size modifiers for mortality and BPD which should be addressed in future explanatory trials., Prospero Registration Number: CRD42023400520., Competing Interests: Competing interests: DDL served in the advisory board for Chiesi farmaceutici, Airway Therapeutics and Ophirex. He received research grants or assistance from Chiesi farmaceutici, Vyaire and Getinge. He received speaker fees from Chiesi farmaceutici, Getinge, Vyaire, AstraZeneca, Medtronic, Masimo and BD. All these were unrelated to the present work. The other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypothesis: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period., Study Design: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (22 0/7 -28 6/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9-30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI)., Results: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91)., Conclusions: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births., Gov Id: Generic Database: NCT00063063., (© 2024. The Author(s).)

Bronchopulmonary dysplasia (BPD) is a common, severe chronic respiratory disease that affects very preterm infants. In utero and postnatal exposure to proinflammatory stimuli contribute to the pathophysiology of BPD. Corticosteroids, because of their potent anti-inflammatory properties, may decrease respiratory morbidity and reduce the risk of BPD in very preterm infants. However, these medications can have adverse effects on the developing brain and other organ systems. This review examines current evidence on the risks and benefits of postnatal corticosteroids used to prevent BPD in preterm infants., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Severe retinopathy of prematurity (ROP) is associated with adverse outcomes. Relationships between milder ROP and outcomes have not been defined. We hypothesized that children with ROP stage ≤3 who did not receive ophthalmologic intervention would have worse motor, cognitive, and language skills and more vision abnormalities than children without ROP., Methods: This was a secondary analysis of a randomized trial evaluating the effects of myo-inositol on ROP in the NICHD Neonatal Research Network. Primary outcomes were Bayley Scales of Infant Development composite scores; secondary outcomes included behavioral difficulties and ophthalmologic measures. Outcomes were compared using adjusted linear or modified Poisson models., Results: Of 506 children, 173 (34%) had no ROP, 262 (52%) had ROP stage ≤3 without intervention, and 71 (14%) had ROP with intervention. There was no difference in motor, cognitive, or language scores between children with ROP stage ≤3 without intervention and children without ROP. Children with ROP stage ≤3 without intervention had a higher rate of strabismus compared to children without ROP (p = 0.040)., Conclusion: Children with ROP stage ≤3 without intervention did not have adverse neurodevelopmental outcomes at 2 years' corrected age compared to children without ROP but did have an increased incidence of strabismus., Impact: This study addresses a gap in the literature regarding the relationship between milder forms of retinopathy of prematurity (ROP) that regress without intervention and neurodevelopment and vision outcomes. Children with a history of ROP stage ≤3 without intervention have similar neurodevelopmental outcomes at 2 years' corrected age as children born extremely preterm without a history of ROP and better outcomes than children with a history of ROP with ophthalmologic intervention. Counseling about likely neurodevelopment and vision outcomes for children born extremely preterm with a history of ROP may be tailored based on the severity of ROP., Clinical Trial Registration: ClinicalTrials.gov ID: Inositol to Reduce Retinopathy of Prematurity Trial: NCT01954082., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital., Study Design: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age., Results: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics., Conclusion: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers., Gov Id: Term Reference (under the Generic Database Study): NCT00063063., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results., Study Design: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized., Results: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31])., Conclusion: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results., Trial Registration: ClinicalTrials.gov ID: NCT01029353., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes., Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age., Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022., Interventions: Near-infrared spectroscopy monitoring of Csat and Msat., Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment., Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03)., Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia., Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Objective: To compare death or severe neurodevelopmental impairment (NDI) at 22-26 months' corrected age (CA) among extremely preterm infants following exposure to different forms of umbilical cord management., Design: Retrospective study., Setting: Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry., Patients: Infants born <27 weeks' gestation in 2016-2018 without severe congenital anomalies who received active treatment after birth and underwent neurodevelopmental assessments between 22 and 26 months' CA., Exposures: Immediate cord clamping (ICC), delayed cord clamping (DCC) or umbilical cord milking (UCM)., Main Outcomes and Measure: Primary composite outcome of death or severe NDI at 22-26 months' CA, defined as severe cerebral palsy, Bayley-III cognitive/motor composite score <70, bilateral deafness or blindness; individual components were examined as secondary outcomes. Multivariable regression examined associations, adjusting for risk factors identified a priori and potential confounders. Mediation analysis explored the effect of severe intraventricular haemorrhage (IVH) on the exposure-outcome relationship., Results: Among 1900 infants, 64.1% were exposed to ICC, 27.8% to DCC and 8.1% to UCM. Compared with ICC-exposed infants, DCC-exposed infants had lower odds of death or severe NDI (adjusted OR 0.64, 95% CI 0.50 to 0.83). No statistically significant differences were observed when comparing UCM with either ICC or DCC, or between secondary outcomes across groups. Association between cord management and the primary outcome was not mediated by severe IVH., Conclusion: Compared with ICC, DCC exposure was associated with lower death or severe NDI at 22-26 months' CA among extremely preterm infants, which was not mediated by severe IVH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended., Objective: To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants., Design, Setting, and Participants: This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022., Exposure: Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth., Main Outcomes and Measures: The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age., Results: A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%)., Conclusions and Relevance: Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.

Background: Extremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children., Methods: This secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6-7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed., Results: Cortisol was measured in 110 EPT and 29 term-born 6-7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group (p < 0.05) only., Conclusions: Among children born EPT, we identified an association of blunted cortisol awakening response with memory and inattention problems. This may have implications related to stress reactivity and its relationship to learning problems in children born EPT., Gov Id: Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324., Impact: In children born EPT, stress reactivity may have a relationship to learning problems. Cortisol awakening response should be a component for follow-up in EPT born children. Components of executive function, such as memory and attention, are related to stress reactivity., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) has been a leader in neonatal research since 1986. In this chapter we review its history and achievements in (1) continuing observation of populations, treatments, short and longer-term outcomes, and trends over time; (2) "negative studies" (trials with non-significant primary outcomes) and trials stopped for futility or adverse events, which have influenced practice and subsequent trial design; and, (3) landmark trials that have changed neonatal care. Its consistent framework has enabled the NRN to be a pioneer in conducting longer-term, school-age follow-up. Leveraging its established infrastructure, the NRN has also partnered with other NIH institutes, governmental agencies, and industry to more effectively advance neonatal care. As current examples of its evolution with changing times, the Network has instituted a process to open specific network trials to external institutions and is adding a parent and participant component to future endeavors., Competing Interests: Conflicts of Interest The other authors have no conflicts to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite improvements in the care and outcomes of infants born extremely preterm, bronchopulmonary dysplasia (BPD) remains a common and frustrating complication of prematurity. This review summarizes the BPD-focused research conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). To improve disease classification and outcome prediction, the NRN developed new data-driven diagnostic criteria for BPD and web-based tools that allow clinicians and investigators to reliably estimate BPD risk in preterm infants. Randomized trials of intramuscular vitamin A and prophylactic nasal continuous positive airway pressure conducted by the NRN have contributed to our current use of these therapies as evidence-based approaches to reduce BPD risk. A recent large, randomized trial of hydrocortisone administered beginning between the 2 nd and 4 th postnatal weeks provided strong evidence that this therapy promotes successful extubation but does not lower BPD rates. Ongoing studies within the NRN will address important, unanswered questions on the risks and benefits of intratracheal surfactant/corticosteroid combinations and treatment versus expectant management of the patent ductus arteriosus to prevent BPD., Competing Interests: Disclosures The authors have no conflicts to disclose. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government., (Copyright © 2022. Published by Elsevier Inc.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.)., (Copyright © 2022 Massachusetts Medical Society.)

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.

Objective: To evaluate the effects of early treatment with continuous positive airway pressure (CPAP) on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants., Study Design: EPT infants (24 0/7 -27 6/7  weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks of postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks of PMA and follow-up outcomes at 18-22 months corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed., Results: Growth data were analyzed for 810 of 1316 infants enrolled in SUPPORT (414 in the intervention group, 396 in the control group). The median gestational age was 26 weeks, and the mean birth weight was 839 g. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between the 2 groups. In a regression model, growth rates between birth and 36 weeks of PMA, as well as growth rates during multiple intervals from birth to day 7, days 7-14, days 14-21, days 21-28, day 28 to 32 weeks PMA, and 32-36 weeks PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of having a Bayley-III cognitive score <85 at 18-22 months corrected age (P = .002)., Conclusions: EPT infants randomized to early CPAP did not have higher in-hospital growth rates than infants randomized to early intubation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was 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 to 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: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%., Conclusions: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment., Competing Interests: The authors report no conflict of interests., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial., Study Design: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed., Results: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40)., Conclusions: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: To compare in-hospital outcomes after umbilical cord milking vs delayed cord clamping among infants <29 weeks of gestation., Study Design: Multicenter retrospective study of infants born <29 weeks of gestation from 2016 to 2018 without congenital anomalies who received active treatment at delivery and were exposed to umbilical cord milking or delayed cord clamping. The primary outcome was mortality or severe (grade III or IV) intraventricular hemorrhage (IVH) by 36 weeks of postmenstrual age (PMA). Secondary outcomes assessed at 36 weeks of PMA were mortality, severe IVH, any IVH or mortality, and a composite of mortality or major morbidity. Outcomes were assessed using multivariable regression, incorporating mortality risk factors identified a priori, confounders, and center. A prespecified, exploratory analysis evaluated severe IVH in 2 gestational age strata, 22-24 6/7 and 25-28 6/7  weeks., Results: Among 1834 infants, 23.6% were exposed to umbilical cord milking and 76.4% to delayed cord clamping. The primary outcome, mortality or severe IVH, occurred in 21.1% of infants: 28.3% exposed to umbilical cord milking and 19.1% exposed to delayed cord clamping, with an aOR that was similar between groups (aOR 1.45, 95% CI 0.93, 2.26). Infants exposed to umbilical cord milking had higher odds of severe IVH (19.8% umbilical cord milking vs 11.8% delayed cord clamping, aOR 1.70 95% CI 1.20, 2.43), as did the 25-28 6/7  week stratum (14.8% umbilical cord milking vs 7.4% delayed cord clamping, aOR 1.89 95% CI 1.22, 2.95). Other secondary outcomes were similar between groups., Conclusions: This analysis of extremely preterm infants suggests that delayed cord clamping is the preferred practice for placental transfusion, as umbilical cord milking exposure was associated with an increase in the adverse outcome of severe IVH., Trial Registration: ClinicalTrials.gov: NCT00063063., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours., Study Design: Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age., Results: Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively., Conclusions: MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia., Trial Registration: Clinicaltrials.gov: NCT00614744., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To describe relationship between cord blood (representing fetal) myo-inositol concentrations and gestational age (GA) and to determine trends of blood concentrations in enterally and parenterally fed infants from birth to 70 days of age., Design/methods: Samples were collected in 281 fed or unfed infants born in 2005 and 2006. Myo-inositol concentrations were displayed in scatter plots and analyzed with linear regression models of natural log-transformed values., Results: In 441 samples obtained from 281 infants, myo-inositol concentrations varied from nondetectable to 1494 μmol/L. Cord myo-inositol concentrations decreased an estimated 11.9% per week increase in GA. Postnatal myo-inositol concentrations decreased an estimated 14.3% per week increase in postmenstrual age (PMA) and were higher for enterally fed infants compared to unfed infants (51% increase for fed vs. unfed infants)., Conclusions: Fetal myo-inositol concentrations decreased with increasing GA. Postnatal concentrations decreased with increasing PMA and were higher among enterally fed than unfed infants.

Objective: To compare short-term outcomes after placental transfusion (delayed cord clamping (DCC) or umbilical cord milking (UCM)) versus immediate cord clamping among extremely preterm infants., Design: Retrospective study., Setting: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network registry., Patients: Infants born <29 weeks' gestation in 2016 or 2017 without congenital anomalies who received active treatment after delivery., Intervention/exposure: DCC or UCM., Main Outcome Measures: Primary outcomes: (1) composite of mortality or major morbidity by 36 weeks' postmenstrual age (PMA); (2) mortality by 36 weeks PMA and (3) composite of major morbidities by 36 weeks' PMA. Secondary composite outcomes: (1) any grade intraventricular haemorrhage or mortality by 36 weeks' PMA and (2) hypotension treatment in the first 24 postnatal hours or mortality in the first 12 postnatal hours. Outcomes were assessed using multivariable regression, adjusting for mortality risk factors identified a priori, significant confounders and centre as a random effect., Results: Among 3116 infants, 40% were exposed to placental transfusion, which was not associated with the primary composite outcome of mortality or major morbidity by 36 weeks' PMA (adjusted OR (aOR) 1.26, 95% CI 0.95 to 1.66). However, exposure was associated with decreased mortality by 36 weeks' PMA (aOR 0.71, 95% CI 0.55 to 0.92) and decreased hypotension treatment in first 24 postnatal hours (aOR 0.66, 95% CI 0.53 to 0.82)., Conclusion: In this extremely preterm infant cohort, exposure to placental transfusion was not associated with the composite outcome of mortality or major morbidity, though there was a reduction in mortality by 36 weeks' PMA., Trial Registration Number: NCT00063063., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The study was designed to investigate whether attainment of object permanence, a measure of early working memory used at 18-22 months corrected age, was associated with executive function at 6-7 years in a cohort of children born extremely preterm., Study Design: Children enrolled in the Neuroimaging and Neurodevelopmental Outcome (NEURO) study, a secondary study to the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) of the NICHD NRN, were eligible for this longitudinal study. Testing completed at 18 to 22 months corrected age was compared to testing at school age with a specific focus on measures of executive function., Results: Children who had achieved object permanence mastery at a corrected age of 18-22 months had higher mean scores on the WISC-IV tests of verbal comprehension and processing speed at age 6-7 years. Regression models indicated that object permanence scores were significant predictors of both verbal comprehension and processing speeds scores, after controlling for other factors. When analyzed by subgroup for sex, these results were significant for girls but not for boys., Conclusions: This study found that an early mastery of object permanence was associated with higher scores in areas of verbal comprehension and processing speed in girls. These results have implications for potentially identifying young children born preterm that are at greater risk for difficulties with cognitive and working memory skills at school age., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies., Objective: To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants., Design, Setting, and Participants: This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020., Main Outcomes and Measures: Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death., Results: A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008)., Conclusions and Relevance: In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.

Objective: To explore the relationship between neonatal oxygen saturation and BP at age 6-7 years in a cohort of infants born extremely preterm., Study Design: Infants <28 weeks gestation were assigned to a higher or lower oxygen saturation target. Oximeter data were monitored throughout the neonatal period. A subset of survivors was seen at age 6. BP was measured and compared by group assignment, achieved saturations, and time spent in hypoxemia (saturations <80%)., Results: There was no difference in systolic or diastolic BP between assigned groups. Median achieved weekly oxygen saturation was not associated with BP. Longer duration of hypoxemia during the first week of age was associated with higher systolic BP., Conclusions: Neither target nor actual median oxygen saturations in this study was associated with BP at school age. Increased duration of hypoxemia in the first postnatal week was associated with higher systolic BP at 6-7 years of age.

Background: Low birth weight in term-born individuals correlates with adverse cardiometabolic outcomes; excess glucocorticoid exposure has been linked to these relationships. We hypothesized that cortisol and adrenal androgens would correlate inversely with birthweight and directly with markers of cardiometabolic risk in school-aged children born extremely preterm; further, preterm-born would have increased cortisol and adrenal androgens compared to term-born children., Methods: Saliva samples were obtained at age 6 from 219 preterm-born children followed since birth and 40 term-born children and analyzed for dehydroepiandrosterone (DHEA) and cortisol. Cortisol was also measured at home (awakening, 30' later, evening)., Results: For preterm-born children, cortisol and DHEA correlated inversely with weight and length Z-scores at 36 weeks PMA and positively with systolic BP. DHEA was higher in preterm-born than term-born children (boys p < 0.01; girls p = 0.04). Cortisol was similar between preterm-born and term-born at study visit; however, preterm-born children showed a blunted morning cortisol. In term-born children, DHEA correlated with BMI (p = 0.04), subscapular, and abdominal skinfold thicknesses (both p < 0.01)., Conclusion: Cortisol and DHEA correlated inversely with early postnatal growth and directly with systolic BP in extremely preterm-born children, suggesting perinatal programming. Blunted morning cortisol may reflect NICU stress, as seen after other adverse childhood experiences (ACEs).

Inflammation is a key contributor to the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants, and cortisol plays a central role in controlling inflammation. Insufficient cortisol limits the ability of the sick newborn to handle stress and inhibit pulmonary inflammation. Evidence of lower cortisol and lower response to adrenocorticotropic hormone in infants subsequently developing BPD led to studies of early low-dose hydrocortisone to prevent BPD. Based on four randomised clinical trials enrolling almost 1000 extremely preterm infants, prophylaxis of early adrenal insufficiency with low-dose hydrocortisone significantly decreased BPD and mortality, as well as medical treatment for a patent ductus arteriosus. An increase in late-onset sepsis reported in the most immature infants had no adverse effect on mortality or neurodevelopmental outcomes. There was no increase in gastrointestinal perforation in the absence of indomethacin. The demonstrated beneficial effects of early low-dose hydrocortisone make a strong case for its use in extremely preterm infants at high risk for BPD., (© 2019 Published by Elsevier Ltd.)

Objective: To assess the effect of prophylaxis for early adrenal insufficiency using low-dose hydrocortisone on survival without bronchopulmonary dysplasia (BPD) in very preterm infants using an individual patient data meta-analysis., Study Design: All existing randomized controlled trials testing the efficacy of the prophylaxis of early adrenal insufficiency using low-dose hydrocortisone on survival without BPD were considered for inclusion when data were available. The primary outcome was the binary variable survival without BPD at 36 weeks of postmenstrual age., Results: Among 5 eligible studies, 4 randomized controlled trials had individual patient data available (96% of participants identified; n = 982). Early low-dose hydrocortisone treatment for 10-15 days was associated with a significant increase in survival without BPD (OR, 1.45; 95% CI, 1.11-1.90; P = .007; I 2 = 0%), as well as with decreases in medical treatment for patent ductus arteriosus (OR, 0.72; 95% CI, 0.56-0.93; P = .01; I 2 = 0%) and death before discharge (OR, 0.70; 95% CI, 0.51-0.97; P = .03; I 2 = 0%). The therapy was associated with an increased risk of spontaneous gastrointestinal perforation (OR, 2.50; 95% CI, 1.33-4.69; P = .004; I 2 = 31.9%) when hydrocortisone was given in association with indomethacin exposure. The incidence of late-onset sepsis was increased in infants exposed to hydrocortisone (OR, 1.34; 95% CI, 1.02-1.75; P = .04; I 2 = 0%), but no adverse effects were reported for either death or 2-year neurodevelopmental outcomes as assessed in an aggregate meta-analysis., Conclusions: This individual patient data meta-analysis showed that early low-dose hydrocortisone therapy is beneficial for survival without BPD in very preterm infants., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the relationship of parent-reported child behaviors on the Child Behavior Checklist (CBCL) to cognition, language, and motor skills on the Bayley Scales of Infant and Toddler Development - III (Bayley-III) in toddlers born extremely preterm., Study Design: Toddlers born extremely preterm (gestational ages 22 0/7 to 26 6/7 weeks) were tested at 22-26 months corrected age with Bayley-III while parents completed the CBCL. Socio-demographic variables and medical history were recorded. Linear regression models were used to assess the relationship of Bayley-III cognitive, motor, and language scores with CBCL scores, adjusting for medical and socio-demographic factors., Results: Internalizing, affective, and pervasive development problem behavior scores on the CBCL correlated significantly with lower Bayley-III cognitive, language, and motor scores on unadjusted and adjusted analyses. Although externalizing and anxiety problems were significantly associated with cognitive and language scores on unadjusted analysis, the relationships were not significant after adjusting for socio-economic factors. CBCL scores were similar for boys and girls, with the exception of the pervasive developmental problem scale; boys had significantly more problems than girls (p = 0.02)., Conclusions: This study showed that parent reported behavior problems were related to lower cognitive, language, and motor development in toddlers born extremely preterm. Early findings of behavioral problems in toddlers born extremely premature may help identify children at greater risk for later learning difficulties. Adding a measure of behavior to the evaluation of these children may help better understand factors that can contribute to delays, especially in cognition and language., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

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.

BackgroundExtremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-33 6/7 weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.

Importance: Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high., Objective: To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy., Design, Setting, and Participants: Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016., Interventions: A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83)., Main Outcomes and Measures: The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification., Results: The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours., Conclusions and Relevance: Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C., Trial Registration: clinicaltrials.gov Identifier: NCT01192776.

Despite remarkable improvements in survival of extremely premature infants, the burden of BPD among survivors remains a frustrating problem for parents and caregivers. Advances, such as antenatal steroids and surfactant replacement, which have dramatically improved survival, have not reduced BPD among survivors. Other advances that have significantly improved the combined outcome of death or BPD, such as vitamin A and avoidance of mechanical ventilation, have had smaller magnitude effects on the outcome of BPD alone. Postnatal steroids have a clear beneficial effect on BPD, but the optimal preparation, dose, and timing for maximizing benefit and minimizing harm have yet to be determined. This persistent burden of BPD among the most immature survivors remains a challenge for the NRN and other researchers in neonatal medicine., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age., Study Design: We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression., Results: Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups., Conclusion: Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization., Methods: Infants ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored., Results: At 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so., Conclusion: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

Objective: To 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., Design: Prospective observational study of infants 23(0/7)-26(6/7) 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., Setting: Sixteen academic centres of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network., Main Outcome Measures: Death or neurodevelopmental impairment/developmental delay (NIDD) at 18-22 months' CA., Results: Of 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)., Conclusions: Independent 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 Number: clinicaltrials.gov #NCT00874393., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Importance: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality., Objective: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers., Design, Setting, Participants: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012., Exposures: Extremely preterm birth., Main Outcomes and Measures: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex., Results: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation., Conclusions and Relevance: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions., Trial Registration: clinicaltrials.gov Identifier: NCT00063063.

Background: We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants., Objective: This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death., Study Design: The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed., Results: All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death., Conclusions: The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: (1) Evaluate the effect of different medications on pain and stress in neonates during nonemergent endotracheal intubation; (2) determine whether gestational age affects medication use; (3) determine whether better sedation results in a decrease in the number of attempts and/or total time for the procedure., Study Design: Prospective observational study. Infant responses were measured using a clinical pain scale and blood glucose, a biochemical marker of acute stress., Result: A total of 166 infants were included, with adjusted gestational ages 24 to 44 weeks at the time of procedure. Premedication regimens included no medication ('none,' 27%), morphine (19%), morphine+midazolam (11%), fentanyl (14%), fentanyl+midazolam (19%) and midazolam alone (10%). Fentanyl+midazolam resulted in lower pain scores and less increase in blood glucose (both P<0.0001). No other regimen was different from 'none'. The most immature infants were less likely to receive premedication (P=0.023), although their pain scores and blood glucose responses were similar to more mature infants. None of the medication regimens reduced the total procedure time (P=0.55) or the number of attempts (P=0.145)., Conclusion: Only fentanyl+midazolam significantly attenuated both the clinical pain score and the increase in blood glucose. Less mature infants had responses similar to those of more mature infants, but were less likely to receive premedication. None of the regimens decreased the time or number of attempts required for successful intubation.

Importance: Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models., Objective: To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy., Design, Setting, and Participants: A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013., Interventions: Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours., Main Outcomes and Measures: The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes)., Results: The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%., Conclusions and Relevance: Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials., Trial Registration: clinicaltrials.gov Identifier: NCT01192776.

Objective: The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions., Study Design: Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP) < GA; (2) MAP < GA + signs of inadequate perfusion; (3) any therapy for CVI; or (4) inotropic therapy. Short-term outcomes included death, days on ventilation, oxygen, and to full feedings and discharge., Results: Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes, and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotropic therapy was associated with increased mortality (11.1 vs. 1.3%; p < 0.05)., Conclusion: More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)