Importance:Infants with neonatal opioid withdrawal syndrome (NOWS) who receive pharmacologic treatment are traditionally treated with a scheduled opioid taper. An alternate approach, symptom-based dosing, may better align treatment with withdrawal severity. Objective:To compare time from birth to medical readiness for discharge for infants with moderate to severe withdrawal treated with either a symptom-based dosing or scheduled opioid taper approach. Design, Setting, and Participants:In this cluster, crossover randomized clinical trial with run-in period, 23 US hospitals cared for infants using the Eat, Sleep, Console approach (ESC) or Finnegan-based care (a comprehensive scoring system to quantify severity of symptoms; 15 ESC and 8 Finnegan hospitals) and their preferred primary opioid. Opioid dosing was guided by study-approved, site-specific algorithms. Infants with NOWS with a gestational age at birth of at least 36 weeks and at risk for pharmacologic treatment were enrolled between March 25, 2024, and April 9, 2025, with the last 3-month assessment on July 15, 2025. Sample size analyses were conducted between August 1, 2024, and September 23, 2024. Intervention:Sites were randomized to 1 of 2 sequences: (1) symptom-based dosing followed by scheduled opioid taper or (2) scheduled opioid taper followed by symptom-based dosing. Main Outcome and Measure:Time from birth to medical readiness for discharge. Results:Of the 626 enrolled infants (mean [SD] gestational age, 38 [1] weeks; 49% male), 383 were cared for with ESC (primary outcome cohort). The mean time to medical readiness for discharge was significantly shorter in the symptom-based dosing group compared with the scheduled opioid taper group (9.18 vs 11.61 days; adjusted mean ratio [aMR], 0.79 [95% CI, 0.65-0.96]). There was no difference in the risk for initiation of pharmacologic treatment (0.4 vs 0.41; adjusted risk ratio, 0.99 [95% CI, 0.77-1.27]) or length of stay (10.91 vs 12.09 days; aMR, 0.9 [95% CI, 0.72-1.13]) between groups. For infants in the symptom-based group, 35% (95% CI, 25%-45%) required scheduled opioid dosing due to withdrawal severity that was not controlled with intermittent dosing. In the Finnegan cohort (n = 243; planned secondary outcome), there were no significant differences in time to medical readiness for discharge (15.99 vs 17.56 days; aMR, 0.91 [95% CI, 0.72-1.15]) or length of stay (17.38 vs 19.39 days; aMR, 0.9 [95% CI, 0.69-1.16]). The inpatient composite safety outcome occurred rarely (in the ESC cohort, 3 of 188 in the symptom-based dosing vs 2 of 195 in the scheduled opioid taper groups). Conclusions and Relevance:Symptom-based dosing decreased time to medical readiness for discharge compared with a scheduled opioid taper approach among infants cared for with ESC. Trial Registration:ClinicalTrials.gov Identifier: NCT05980260.

Importance Infants with neonatal opioid withdrawal syndrome (NOWS) who receive pharmacologic treatment are traditionally treated with a scheduled opioid taper. An alternate approach, symptom-based dosing, may better align treatment with withdrawal severity. Objective To compare time from birth to medical readiness for discharge for infants with moderate to severe withdrawal treated with either a symptom-based dosing or scheduled opioid taper approach. Design, Setting, and Participants In this cluster, crossover randomized clinical trial with run-in period, 23 US hospitals cared for infants using the Eat, Sleep, Console approach (ESC) or Finnegan-based care (a comprehensive scoring system to quantify severity of symptoms; 15 ESC and 8 Finnegan hospitals) and their preferred primary opioid. Opioid dosing was guided by study-approved, site-specific algorithms. Infants with NOWS with a gestational age at birth of at least 36 weeks and at risk for pharmacologic treatment were enrolled between March 25, 2024, and April 9, 2025, with the last 3-month assessment on July 15, 2025. Sample size analyses were conducted between August 1, 2024, and September 23, 2024. Intervention Sites were randomized to 1 of 2 sequences: (1) symptom-based dosing followed by scheduled opioid taper or (2) scheduled opioid taper followed by symptom-based dosing. Main Outcome and Measure Time from birth to medical readiness for discharge. Results Of the 626 enrolled infants (mean [SD] gestational age, 38 [1] weeks; 49% male), 383 were cared for with ESC (primary outcome cohort). The mean time to medical readiness for discharge was significantly shorter in the symptom-based dosing group compared with the scheduled opioid taper group (9.18 vs 11.61 days; adjusted mean ratio [aMR], 0.79 [95% CI, 0.65-0.96]). There was no difference in the risk for initiation of pharmacologic treatment (0.4 vs 0.41; adjusted risk ratio, 0.99 [95% CI, 0.77-1.27]) or length of stay (10.91 vs 12.09 days; aMR, 0.9 [95% CI, 0.72-1.13]) between groups. For infants in the symptom-based group, 35% (95% CI, 25%-45%) required scheduled opioid dosing due to withdrawal severity that was not controlled with intermittent dosing. In the Finnegan cohort (n = 243; planned secondary outcome), there were no significant differences in time to medical readiness for discharge (15.99 vs 17.56 days; aMR, 0.91 [95% CI, 0.72-1.15]) or length of stay (17.38 vs 19.39 days; aMR, 0.9 [95% CI, 0.69-1.16]). The inpatient composite safety outcome occurred rarely (in the ESC cohort, 3 of 188 in the symptom-based dosing vs 2 of 195 in the scheduled opioid taper groups). Conclusions and Relevance Symptom-based dosing decreased time to medical readiness for discharge compared with a scheduled opioid taper approach among infants cared for with ESC. Trial Registration ClinicalTrials.gov Identifier: NCT05980260

The NICHD Neonatal Research Network MILK Trial randomized infants born preterm to receive donor milk or preterm formula. We hypothesized that there would be no growth differences at follow-up by study diet. We conducted a secondary analysis of the double-blind trial of infants <29 weeks’ gestation or <1000 g at birth at 15 US centers (September 2012–March 2019). Infants were randomized to receive donor milk or preterm formula. The primary outcome was body mass index (BMI) Z-score at 22–26 months corrected age. Among 483 trial participants, 376 were seen at follow-up (181 donor milk, 195 formula). At 22–26 month follow-up, anthropometrics were similar for the two groups, including BMI Z-score (donor milk 0.21 ± 1.13, formula 0.23 ± 1.28, p = 0.67). There was a greater increase in weight Z-score between discharge and follow-up for children randomized to donor milk (donor milk 1.04 ± 1.28, formula 0.73 ± 1.30, p = 0.004). While BMI Z-scores were similar at 22–26 months corrected age, patterns of growth between discharge and follow-up differed by study diet. Children fed donor milk in early infancy showed a greater increase in weight Z-score between discharge and follow-up than children fed preterm formula in early infancy.

Importance The neonatal brain injury score on magnetic resonance imaging following moderate or severe hypoxic-ischemic encephalopathy developed by the National Institute of Child Health and Human Development Neonatal Research Network has been revised to separate watershed and basal ganglia or thalamic injury and their associated outcomes. Objective To evaluate the association of the injury score with outcomes of death or moderate or severe disability among all infants, and with neurodevelopment among survivors in a trial of deeper and longer cooling. Design, Setting, and Participants In this secondary analysis of a multicenter randomized clinical trial, brain imaging was obtained from infants between October 2010 and November 2013. Infants were followed up to 18 months of age, with follow-up completed in January 2016. Data analysis was performed from August 2021 to September 2024. Interventions Infants were assigned to 4 hypothermia groups based on depth and duration of cooling, stratified by center and level of encephalopathy in a 2 x 2 factorial design to cooling at 33.5 degrees C or 32.0 degrees C and to 72 or 120 hours. A 10-level brain injury score was examined. Main Outcomes and Measures The primary outcome was death or moderate or severe disability measured by the Bayley Scales of Infant and Toddler Development III, the Gross Motor Function Classification System level, vision, and hearing. Results This study included 298 infants who had magnetic resonance imaging (MRI) and primary outcome data among 364 infants of the initial cohort (mean [SD] age at MRI, 9.18 [4.49] days). Death or moderate or severe disability occurred in 72 of 298 infants (24%), and disability occurred in 52 of 278 surviving infants (19%). Death or disability occurred in 12 of 28 infants (43%) with any or predominant watershed injury and in 17 of 46 (37%) of those with any or predominant basal ganglia or thalamic injury. Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. Injury scores of increasing severity were associated with death or disability among all infants (odds ratio, 13.66 [95% CI, 7.47-24.95]; area under the curve, 0.84 [95% CI, 0.78-0.90]) and with disability among surviving infants (odds ratio, 10.52 [95% CI, 5.46-20.28]; area under the curve, 0.80 [95% CI, 0.73-0.88]). There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or longer duration. Conclusions Among infants with hypoxic-ischemic encephalopathy, outcomes were similar between infants with watershed and basal ganglia injury. Higher imaging scores were associated with risk of death or disability among all infants and with neurodevelopmental disability among surviving infants. Trial RegistrationClinicalTrials.gov Identifier: NCT01192776

OBJECTIVE:To examine the association of a numerical Sarnat score (NSS) and modified Sarnat staging among newborn infants with moderate/severe hypoxic-ischemic encephalopathy and their neurodevelopmental outcomes at 18-22 months. STUDY DESIGN:This secondary analysis included participants with gestational age ≥36 weeks and moderate/severe hypoxic-ischemic encephalopathy (HIE) from the Induced Hypothermia and Optimizing Cooling trials. Early (<6 hours age) neurologic examinations were performed by trained examiners to categorize HIE severity by modified Sarnat staging. The NSS was calculated by summing abnormal scores (2 for moderate, 3 for severe) in the 6 examination categories. The primary outcome was death or moderate/severe disability. Statistical analysis included logistic regression, adjusting for center, trial, and cooling group, and linear regression for continuous scales. RESULTS:The cohort (n = 528) included infants with 71% moderate and 29% severe HIE (37% Induced Hypothermia and 63% Optimizing Cooling participants). Median (IQR) NSS of infants with moderate and severe HIE were 11 (9-13) and 16 (16-17), respectively. There were significant associations among NSS, NSS tertiles, and modified Sarnat staging and death or disability, but there were no differences found in their area-under-the-curve estimates. Similar to modified Sarnat staging, NSS showed significant associations with Bayley-III cognitive, language, and motor scores and Bayley-II mental and psychomotor developmental indices. CONCLUSION:Among infants with moderate or severe HIE, the NSS did not improve the predictive accuracy for death or disability at 18-22 months of age, compared with modified Sarnat staging performed in the initial 6 hours after birth by trained examiners.

Importance The neonatal brain injury score on magnetic resonance imaging following moderate or severe hypoxic-ischemic encephalopathy developed by the National Institute of Child Health and Human Development Neonatal Research Network has been revised to separate watershed and basal ganglia or thalamic injury and their associated outcomes. Objective To evaluate the association of the injury score with outcomes of death or moderate or severe disability among all infants, and with neurodevelopment among survivors in a trial of deeper and longer cooling. Design, Setting, and Participants In this secondary analysis of a multicenter randomized clinical trial, brain imaging was obtained from infants between October 2010 and November 2013. Infants were followed up to 18 months of age, with follow-up completed in January 2016. Data analysis was performed from August 2021 to September 2024. Interventions Infants were assigned to 4 hypothermia groups based on depth and duration of cooling, stratified by center and level of encephalopathy in a 2 × 2 factorial design to cooling at 33.5 °C or 32.0 °C and to 72 or 120 hours. A 10-level brain injury score was examined. Main Outcomes and Measures The primary outcome was death or moderate or severe disability measured by the Bayley Scales of Infant and Toddler Development III, the Gross Motor Function Classification System level, vision, and hearing. Results This study included 298 infants who had magnetic resonance imaging (MRI) and primary outcome data among 364 infants of the initial cohort (mean [SD] age at MRI, 9.18 [4.49] days). Death or moderate or severe disability occurred in 72 of 298 infants (24%), and disability occurred in 52 of 278 surviving infants (19%). Death or disability occurred in 12 of 28 infants (43%) with any or predominant watershed injury and in 17 of 46 (37%) of those with any or predominant basal ganglia or thalamic injury. Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. Injury scores of increasing severity were associated with death or disability among all infants (odds ratio, 13.66 [95% CI, 7.47-24.95]; area under the curve, 0.84 [95% CI, 0.78-0.90]) and with disability among surviving infants (odds ratio, 10.52 [95% CI, 5.46-20.28]; area under the curve, 0.80 [95% CI, 0.73-0.88]). There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or longer duration. Conclusions Among infants with hypoxic-ischemic encephalopathy, outcomes were similar between infants with watershed and basal ganglia injury. Higher imaging scores were associated with risk of death or disability among all infants and with neurodevelopmental disability among surviving infants. Trial Registration ClinicalTrials.gov Identifier: NCT01192776

Objectives:To develop a data harmonization framework for neonatal hypoxic-ischemic encephalopathy (HIE) studies and demonstrate its suitability for prognostic biomarker development. Materials and Methods:Variables were first categorized by chronological stages and then by medical topics. We created a dictionary to harmonize variable names and value coding. We began by merging comprehensive data from 2 landmark nationwide therapeutic hypothermia for HIE trials (2008-2016, 21 sites) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). The 2 datasets differ in available variables, variable naming and coding, necessitating harmonization. To demonstrate the utility of this data harmonization framework, we computed the distributions of variables and ranked them by the strength of associations with 18- to 22-month outcomes. Associations were measured using Pearson's correlation analysis. Outcomes were defined as (a) a 5-class variable: survivors with normal, mild, moderate, severe disability, or death and (b) the Bayley-III Scales. Results:We created a dictionary of 1181 variables on 532 patients across 5 chronologic categories and 60 medical subcategories. The distribution of major predictive and outcome variables, and the variables strongly associated with neurodevelopmental outcomes at 18-22 months were presented. The modified Sarnat scores at the Post-intervention and NICU-discharge stage, and the NRN pattern of MRI injury score showed strong associations with outcome variables. Conclusion:We designed a data harmonization framework specifically for HIE. Our initial effort in merging 2 iconic clinical trials shows strong predictor-outcome associations, allowing subsequent development of advanced prognostic biomarkers of neonatal HIE.

ImportanceMaternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula.ObjectiveTo determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months’ corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk.Design, Setting, and ParticipantsDouble-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days’ gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019.InterventionPreterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge.Main Outcomes and MeasuresThe primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months’ corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months’ corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death.ResultsOf 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent’s race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months’ corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, −0.77 [95% CI, −3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, −1% [95% CI, −4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, −5% [95% CI, −9% to −2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]).Conclusions and RelevanceAmong extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months’ corrected age did not differ between infants fed donor milk or preterm formula.Trial RegistrationClinicalTrials.gov Identifier: NCT01534481

(Abstracted from J Pediatr 2024;268:113944) Cerebral palsy (CP) is a group of neurodevelopmental motor and coordination disorders that disproportionately affect preterm children. While some studies suggest a decline in CP diagnoses among preterm children born from the 1990s to the early 2010s, findings vary by gestational age and birth weight.

The multicenter Necrotizing Enterocolitis Surgery Trial compared initial peritoneal drainage with laparotomy among infants with extremely low birth weight and surgical necrotizing enterocolitis or intestinal perforation. In this post hoc analysis of trial data, initial drainage was associated with adverse respiratory outcomes, both in hospital and through 2 years corrected age.

ObjectiveTo evaluate changes in prevalence and severity of cerebral palsy (CP) among surviving children born at <27 weeks of gestation over time and to determine associations between CP and other developmental domains, functional impairment, medical morbidities, and resource use among 2-year-old children who were born extremely preterm.Study designRetrospective cohort study using prospective registry data, conducted at 25 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Participants were children born at <27 weeks of gestation and followed at 18 through 26 months of corrected age from 2008 through 2019. Outcomes of interest were changes in prevalence of any CP and severity of CP over time and associations between CP and other neurodevelopmental outcomes, functional impairment, and medical comorbidities. Adjusted logistic, linear, multinomial logistic, and robust Poisson regression evaluated the relationships between child characteristics, CP severity, and outcomes.ResultsAmong 6927 surviving children with complete follow-up data, 3717 (53.7%) had normal neurologic examinations, 1303 (18.8%) had CP, and the remainder had abnormal neurologic examinations not classified as CP. Adjusted rates of any CP increased each year of the study period (aOR 1.11 per year, 95% CI 1.08-1.14). Cognitive development was significantly associated with severity of CP. Children with CP were more likely to have multiple medical comorbidities, neurosensory problems, and poor growth at follow-up.ConclusionsThe rate of CP among surviving children who were born extremely preterm increased from 2008 through 2019. At 18 to 26 months of corrected age, neurodevelopmental and medical comorbidities are strongly associated with all severity levels of CP.

Objective This study investigates whether and to what extent cerebral injury is associated with bilateral blindness in extremely preterm infants, which has been attributed mainly to retinopathy of prematurity (ROP). Design Multicentre analysis of children born from 1994 to 2021 at gestational age 22 0/7 to 28 6/7 weeks with follow-up at 18-26 months. Logistic regression examined the adjusted association of bilateral blindness with severe ROP and/or cerebral injury among extremely preterm infants. Exposures Severe ROP and cerebral injury, the latter defined as any of the following on cranial imaging: ventriculomegaly; blood/increased echogenicity in the parenchyma; cystic periventricular leukomalacia. Main outcome measures Bilateral blindness, defined as a follow-up examination meeting criteria of 'blind-some functional vision' or 'blind-no useful vision' in both eyes. Results The 19 863 children included had a mean gestational age of 25.6 +/- 1.7 weeks, mean birth weight of 782 +/- 158 g and 213 (1%) had bilateral blindness. Multiplicative interaction between ROP and cerebral injury was statistically significant. For infants with only severe ROP (n=3130), odds of blindness were 8.14 times higher (95% CI 4.52 to 14.65), and for those with only cerebral injury (n=2836), odds were 8.38 times higher (95% CI 5.28 to 13.28), compared with the reference group without either condition. Risks were not synergistic for infants with both severe ROP and cerebral injury (n=1438, adjusted OR=28.7, 95% CI 16.0 to 51.7, p<0.0001). Conclusions In a group of extremely preterm infants, severe ROP and cerebral injury were equally important risk factors for blindness. Besides ROP, clinicians should consider cerebral injury as a cause of blindness in children born extremely preterm. Trial registration number NCT00063063.

Objectives To assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic encephalopathy (HIE) and seizures. Design Retrospective study of infants enrolled in three National Institute of Child Health and Human Development Neonatal Research Network Trials of therapeutic hypothermia. Setting 22 US centres. Patients Infants with HIE who survived to discharge and had clinical or electrographic seizures treated with ASM. Exposures ASM continued or discontinued at discharge. Outcomes Death or moderate-to-severe disability at 18–22 months, using trial definitions. Multivariable logistic regression evaluated the association between continuation of ASM at discharge and the primary outcome, adjusting for severity of HIE, hypothermia trial treatment arm, use of electroencephalogram, discharge on gavage feeds, Apgar Score at 5 min, birth year and centre. Results Of 302 infants included, 61% were continued on ASMs at discharge (range 13%–100% among 22 centres). Electroencephalogram use occurred in 92% of the cohort. Infants with severe HIE comprised 24% and 22% of those discharged with and without ASM, respectively. The risk of death or moderate-to-severe disability was greater for infants continued on ASM at discharge, compared with those infants discharged without ASM (44% vs 28%, adjusted OR 2.14; 95% CI 1.13 to 4.05). Conclusions In infants with HIE and seizures, continuation of ASM at discharge varies substantially among centres and may be associated with a higher risk of death or disability at 18–22 months of age.

BACKGROUND:Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. METHODS:We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. RESULTS:A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). CONCLUSION:We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. IMPACT:Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

Objective This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes. Study Design This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate–severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate–severe impairment defined by any of the following: intelligence quotient <70, moderate–severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy. Results Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13–0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42–9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment. Conclusion RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy. Key Points

Assess if maternal betamethasone administration at 34–35 weeks accelerated neonatal amplitude integrated EEG (aEEG) maturation. Nested, observational cohort in 7 centers participating in the Antenatal Late Preterm Steroid randomized trial. Up to 2 aEEGs were obtained in neonates born from 340–356 weeks gestation before 72 h (aEEG 1) and at 5–7 days (aEEG 2) if hospitalized. Personnel and aEEG central readers were masked to the intervention. The primary outcome was maturation reflected by cycle frequency; secondary outcomes were border voltage, span, and discontinuity. 58 neonates were enrolled (betamethasone, 28, placebo, 30). On aEEG 1, cycle frequency did not differ, but betamethasone exposed infants had a greater lower border voltage and a broader span. On aEEG 2, both groups displayed increases in lower border voltage. Betamethasone associated changes in lower border voltage support accelerated electrical activity. Further investigation is needed to understand the broader span.

Objective Develop an online estimator that accurately predicts bronchopulmonary dysplasia (BPD) severity or death using readily-available demographic and clinical data. Design Retrospective analysis of data entered into a prospective registry. Setting Infants cared for at centres of the United States Neonatal Research Network between 2011 and 2017. Patients Infants 501–1250 g birth weight and 23 0/7–28 6/7 weeks’ gestation. Interventions None. Main outcome measures Separate multinomial regression models for postnatal days 1, 3, 7, 14 and 28 were developed to estimate the individual probabilities of death or BPD severity (no BPD, grade 1 BPD, grade 2 BPD, grade 3 BPD) defined according to the mode of respiratory support administered at 36 weeks’ postmenstrual age. Results Among 9181 included infants, birth weight was most predictive of death or BPD severity on postnatal day 1, while mode of respiratory support was the most predictive factor on days 3, 7, 14 and 28. The predictive accuracy of the models increased at each time period from postnatal day 1 (C-statistic: 0.674) to postnatal day 28 (C-statistic 0.741). We used these results to develop a web-based model that provides predicted estimates for BPD by postnatal day. Conclusion The probability of BPD or death in extremely preterm infants can be estimated with reasonable accuracy using a limited amount of readily available clinical information. This tool may aid clinical prognostication, future research, and center-specific quality improvement surrounding BPD prevention. Trial registration number NCT00063063

Determine whether blanket temperatures during therapeutic hypothermia (TH) are associated with 18–22 month outcomes for infants with hypoxic ischemic encephalopathy (HIE). Retrospective cohort study of 181 infants with HIE who received TH in two randomized trials within the Neonatal Research Network. We defined summative blanket temperature constructs and evaluated for association with a primary composite outcome of death or moderate/ severe disability at 18–22 months. Each 0.5 °C above 33.5 °C in the mean of the highest quartile blanket temperature was associated with a 52% increase in the adjusted odds of death/ disability (aOR 1.52, 95% CI 1.09–2.11). Having >8 consecutive blanket temperatures above 33.5 °C rendered an aOR of death/disability of 5.04 in the first 24 h (95% CI 1.54–16.6) and 6.92 in the first 48 h (95% CI 2.20–21.8) of TH. Higher blanket temperature during TH may be an early, clinically useful biomarker of HIE outcome.

Key Points Question Are racial/ethnic disparities in care practices and major outcomes increasing or decreasing among extremely preterm infants in the US? Findings In this cohort study of 20 092 extremely preterm infants, racial/ethnic disparities in rates of antenatal corticosteroids and cesarean delivery decreased over time. Changes in rates of mortality and most major morbidities did not differ among white, black, and Hispanic infants, and while mortality decreased over time from 2002 to 2016, rates of moderate-severe neurodevelopmental impairment increased over time in all groups. Meaning Racial/ethnic disparities in rates of potentially life-saving care practices decreased over time in the US, with reductions in mortality but increases in neurodevelopmental impairment in all racial/ethnic groups.

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