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Background: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear. Methods: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 g birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 h after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/day with early feeding) compared to placebo plus routine dose (400 IU/day with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at 1 month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes), and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22–26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability. Discussion: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterm infants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results. Trial registration: ClinicalTrials.gov NCT05459298. Registered on July 14, 2022. [ABSTRACT FROM AUTHOR]

Background: Decisions to stop randomized trials are often based on traditional P value thresholds and are often unconvincing to clinicians. To familiarize clinical investigators with the application and advantages of Bayesian monitoring methods, we illustrate the steps of Bayesian interim analysis using a recent major trial that was stopped based on frequentist analysis of safety and futility.Methods: We conducted Bayesian reanalysis of a factorial trial in newborn infants with hypoxic-ischemic encephalopathy that was designed to investigate whether outcomes would be improved by deeper (32 °C) or longer cooling (120 h), as compared with those achieved by standard whole body cooling (33.5 °C for 72 h). Using prior trial data, we developed neutral and enthusiastic prior probabilities for the effect on predischarge mortality, defined stopping guidelines for a clinically meaningful effect, and derived posterior probabilities for predischarge mortality.Results: Bayesian relative risk estimates for predischarge mortality were closer to 1.0 than were frequentist estimates. Posterior probabilities suggested increased predischarge mortality (relative risk > 1.0) for the three intervention groups; two crossed the Bayesian futility threshold.Conclusions: Bayesian analysis incorporating previous trial results and different pre-existing opinions can help interpret accruing data and facilitate informed stopping decisions that are likely to be meaningful and convincing to clinicians, meta-analysts, and guideline developers.Trial Registration: ClinicalTrials.gov NCT01192776 . Registered on 31 August 2010. [ABSTRACT FROM AUTHOR]

Presents a study, the objectives of which are to assess risk factors affecting viability and analyze the effects of mechanical ventilation on neonatal outcome and resource use among extremely premature infants. Design; Setting; Participants; Main outcome measures; Results; Conclusions.

OBJECTIVE: The goal was to identify, among extremely low birth weight (⩽1000 g) live births, the proportion of infants who were unimpaired at 18 to 22 months of corrected age. METHODS: Unimpaired outcome was defined as Bayley Scales of Infant Development II scores of ⩾85, normal neurologic examination findings, and normal vision, hearing, swallowing, and walking. Outcomes were determined for 5250 (86%) of 6090 extremely low birth weight inborn infants. RESULTS: Of the 5250 infants whose outcomes were known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 (22%) had moderate/severe neurodevelopmental impairments, and 2100 (40%) had died. Unimpaired survival rates varied according to birth weight, from <1% for infants ⩽500 g to 24% for infants 901 to 1000 g. The regression model to predict unimpaired survival versus death or impairment for live births (N = 5250) indicated that 25.3% of the variance was derived from infant factors present at birth, including female gender, higher birth weight, singleton birth. The regression model to predict unimpaired survival for discharged infants indicated that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographic features (15.7%) and only 8.5% was derived from infant factors present at birth. CONCLUSIONS: Although <1% of live-born infants of ⩽500 g survive free of impairment at 18 months, this increases to almost 24% for infants of 901 to 1000 g. Female gender, singleton birth, higher birth weight, absence of neonatal morbidities, private health insurance, and white race increase the likelihood of unimpaired status. [ABSTRACT FROM AUTHOR]

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial., Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia., Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023., Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age., Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period., Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup)., Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit., Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Importance: Risk-adjusted neonatal intensive care unit (NICU) utilization and outcomes vary markedly across regions and hospitals. The causes of this variation are poorly understood., Objective: To assess the association of hospital-level NICU bed capacity with utilization and outcomes in newborn cohorts with differing levels of health risk., Design, Setting, and Participants: This population-based retrospective cohort study included all Medicaid-insured live births in Texas from 2010 to 2014 using linked vital records and maternal and newborn claims data. Participants were Medicaid-insured singleton live births (LBs) with birth weights of at least 400 g and gestational ages between 22 and 44 weeks. Newborns were grouped into 3 cohorts: very low birth weight (VLBW; <1500 g), late preterm (LPT; 34-36 weeks' gestation), and nonpreterm newborns (NPT; ≥37 weeks' gestation). Data analysis was conducted from January 2022 to October 2023., Exposure: Hospital NICU capacity measured as reported NICU beds/100 LBs, adjusted (ie, allocated) for transfers., Main Outcomes and Measures: NICU admissions and special care days; inpatient mortality and 30-day postdischarge adverse events (ie, mortality, emergency department visit, admission, observation stay)., Results: The overall cohort of 874 280 single LBs included 9938 VLBW (5054 [50.9%] female; mean [SD] birth weight, 1028.9 [289.6] g; mean [SD] gestational age, 27.6 [2.6] wk), 63 160 LPT (33 684 [53.3%] female; mean [SD] birth weight, 2664.0 [409.4] g; mean [SD] gestational age, 35.4 [0.8] wk), and 801 182 NPT (407 977 [50.9%] female; mean [SD] birth weight, 3318.7 [383.4] g; mean [SD] gestational age, 38.9 [1.0] wk) LBs. Median (IQR) NICU capacity was 0.84 (0.57-1.30) allocated beds/100 LB/year. For VLBW newborns, NICU capacity was not associated with the risk of NICU admission or number of special care days. For LPT newborns, birth in hospitals with the highest compared with the lowest category of capacity was associated with a 17% higher risk of NICU admission (adjusted risk ratio [aRR], 1.17; 95% CI, 1.01-1.33). For NPT newborns, risk of NICU admission was 55% higher (aRR, 1.55; 95% CI, 1.22-1.97) in the highest- vs the lowest-capacity hospitals. The number of special care days for LPT and NPT newborns was 21% (aRR, 1.21; 95% CI,1.08-1.36) and 37% (aRR, 1.37; 95% CI, 1.08-1.74) higher in the highest vs lowest capacity hospitals, respectively. Among LPT and NPT newborns, NICU capacity was associated with higher inpatient mortality and 30-day postdischarge adverse events., Conclusions and Relevance: In this cohort study of Medicaid-insured newborns in Texas, greater hospital NICU bed supply was associated with increased NICU utilization in newborns born LPT and NPT. Higher capacity was not associated with lower risk of adverse events. These findings raise important questions about how the NICU is used for newborns with lower risk.

Randomized controlled trials (RCTs) are challenging, but are the studies most likely to change practice and benefit patients. RCTs investigating neonatal surgical therapies are rare. The Necrotizing Enterocolitis Surgery Trial (NEST) was the first surgical RCT conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and multiple lessons were learned. NEST was conducted over a 7.25-year enrollment period and the primary outcome was death or neurodevelopmental impairment (NDI) at 18-22 months corrected age. Surgical investigators designing clinical trials involving neonatal surgical treatments have many considerations to include, including how to study eligible but non-randomized patients, heterogeneity of treatment effect, use of frequentist and Bayesian analyses, assessment of generalizability, and anticipating criticisms during peer review. Surgeons are encouraged to embrace these challenges and seek innovative methods to acquire evidence that will be used to improve patient outcomes., 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 Elsevier Inc. All rights reserved.)

The perinatal and neonatal periods are the periods of considerable organ development and maturation. Perinatal and neonatal illnesses can result in mortality and morbidities that burden families and the healthcare system. Outcome prediction is essential for informing perinatal and intensive care management, prognosis, and post-discharge interventions. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) research databases include hospital and neurodevelopment follow-up outcomes of infants with various underlying diseases and conditions receiving intensive care, providing a unique opportunity to assess outcome risk prediction. The NRN has developed outcome risk prediction tools for use in infants with various diseases and conditions that allow data-driven, transparent discussions to inform family-focused communications and clinical management. This review presents the published neonatal outcome risk prediction research from the NRN, their present clinical utility, and possible future directions for advanced individualized risk prediction., Competing Interests: Declaration of Competing Interest Waldemar A. Carlo, MD is on the board of directors of MEDNAX Services, Inc. All other authors have indicated that they have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk., Study Design: We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000 g and receiving respiratory support at 24 hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4 weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36 weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant., Results: As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P = .03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups., Conclusions: Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants., Trial Registration: ClinicalTrials.gov NCT01203488., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: Children with medical complexity (CMC) frequently experience fragmented care. We have demonstrated that outpatient comprehensive care (CC) reduces serious illnesses, hospitalizations, and costs for high-risk CMC. Yet continuity of care for CMC is often disrupted with emergency department (ED) visits and hospitalizations., Objective: To evaluate a hospital consultation (HC) service for CMC from their outpatient CC clinicians., Design, Setting, and Participants: Randomized quality improvement trial at the University of Texas Health Science Center at Houston with an outpatient CC clinic and tertiary pediatric hospital (Children's Memorial Hermann Hospital). Participants included high-risk CMC (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrolling in our clinic) receiving CC. Data were analyzed between January 11, 2018, and December 20, 2019., Interventions: The HC included serial discussions between CC clinicians, ED physicians, and hospitalists addressing need for admission, inpatient treatment, and transition back to outpatient care. Usual hospital care (UHC) involved routine pediatric hospitalist care., Main Outcomes and Measures: Total hospital days (primary outcome), PICU days, hospitalizations, and health system costs in skeptical bayesian analyses (using a prior probability assuming no benefit)., Results: From October 3, 2016, through October 2, 2017, 342 CMC were randomized to either HC (n = 167) or UHC (n = 175) before meeting the predefined bayesian stopping guideline (>80% probability of reduced hospital days). In intention-to-treat analyses, the probability that HC reduced total hospital days was 91% (2.72 vs 6.01 per child-year; bayesian rate ratio [RR], 0.61; 95% credible interval [CrI], 0.30-1.26). The probability of a reduction with HC vs UHC was 98% for hospitalizations (0.60 vs 0.93 per child-year; RR, 0.68; 95% CrI, 0.48-0.97), 89% for PICU days (0.77 vs 1.89 per child-year; RR, 0.59; 95% CrI, 0.26-1.38), and 94% for mean total health system costs ($24 928 vs $42 276 per child-year; cost ratio, 0.67; 95% CrI, 0.41-1.10). In secondary analysis using a bayesian prior centered at RR of 0.78, reflecting the opinion of 7 experts knowledgeable about CMC, the probability that HC reduced hospital days was 96%., Conclusions and Relevance: Among CMC receiving comprehensive outpatient care, an HC service from outpatient clinicians likely reduced total hospital days, hospitalizations, PICU days, other outcomes, and health system costs. Additional trials of an HC service from outpatient CC clinicians are needed for CMC in other centers., Trial Registration: ClinicalTrials.gov Identifier: NCT02870387.

Importance: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) extremely preterm birth outcome model is widely used for prognostication by practitioners caring for families expecting extremely preterm birth. The model provides information on mean outcomes from 1998 to 2003 and does not account for substantial variation in outcomes among US hospitals., Objective: To update and validate the NRN extremely preterm birth outcome model for most extremely preterm infants in the United States., Design, Setting, and Participants: This prognostic study included 3 observational cohorts from January 1, 2006, to December 31, 2016, at 19 US centers in the NRN (derivation cohort) and 637 US centers in Vermont Oxford Network (VON) (validation cohorts). Actively treated infants born at 22 weeks' 0 days' to 25 weeks' 6 days' gestation and weighing 401 to 1000 g, including 4176 in the NRN for 2006 to 2012, 45 179 in VON for 2006 to 2012, and 25 969 in VON for 2013 to 2016, were studied. VON cohorts comprised more than 85% of eligible US births. Data analysis was performed from May 1, 2017, to March 31, 2019., Exposures: Predictive variables used in the original model, including infant sex, birth weight, plurality, gestational age at birth, and exposure to antenatal corticosteroids., Main Outcomes and Measures: The main outcome was death before discharge. Secondary outcomes included neurodevelopmental impairment at 18 to 26 months' corrected age and measures of hospital resource use (days of hospitalization and ventilator use)., Results: Among 4176 actively treated infants in the NRN cohort (48% female; mean [SD] gestational age, 24.2 [0.8] weeks), survival was 63% vs 62% among 3702 infants in the era of the original model (47% female; mean [SD] gestational age, 24.2 [0.8] weeks). In the concurrent (2006-2012) VON cohort, survival was 66% among 45 179 actively treated infants (47% female; mean [SD] gestational age, 24.1 [0.8] weeks) and 70% among 25 969 infants from 2013 to 2016 (48% female; mean [SD] gestational age, 24.1 [0.8] weeks). Model C statistics were 0.74 in the 2006-2012 validation cohort and 0.73 in the 2013-2016 validation cohort. With the use of decision curve analysis to compare the model with a gestational age-only approach to prognostication, the updated model showed a predictive advantage. The birth hospital contributed equally as much to prediction of survival as gestational age (20%) but less than the other factors combined (60%)., Conclusions and Relevance: An updated model using well-known factors to predict survival for extremely preterm infants performed moderately well when applied to large US cohorts. Because survival rates change over time, the model requires periodic updating. The hospital of birth contributed substantially to outcome prediction.

Objective: To assess the contribution of maternal and newborn characteristics to variation in neonatal intensive care use across regions and hospitals., Study Design: This was a retrospective population-based live birth cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 2 subcohorts: very low birth weight (VLBW) singletons and late preterm singletons. Crude and risk-adjusted neonatal intensive care unit (NICU) admission rates, intensive and intermediate special care days, and imaging procedures were calculated across Neonatal Intensive Care Regions (n = 21) and hospitals (n = 100). Total Medicaid payments were calculated., Results: Overall, 11.5% of live born, 91.7% of VLBW, and 37.6% of infants born late preterm were admitted to a NICU, receiving an average of 2 days, 58 days, and 5 days of special care with payments per newborn inpatient episode of $5231, $128 075, and $10 837, respectively. There was little variation across regions and hospitals in VLBW NICU admissions but marked variation for NICU admissions in late preterm newborn infants and for special care days and imaging rates in all cohorts. The variation decreased slightly after health risk adjustment. There was moderate substitution of intermediate for intensive care days across hospitals (Pearson r VLBW -0.63 P < .001; late preterm newborn -0.53 P < .001)., Conclusions: Across all risk groups, the variation in NICU use was poorly explained by differences in newborn illness levels and is likely to indicate varying practice styles. Although the "right" rates are uncertain, it is unlikely that all of these use patterns represent effective and efficient care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Readmission reduction is linked to improved quality of care, saves cost, and is a desirable patient-centered outcome. Nationally representative readmission metrics for patients with stroke are unavailable to date. Such estimates are necessary for benchmarking performance., Objectives: To provide US nationwide estimates and a temporal trend for overall, planned, and potentially preventable 30-day hospital readmission among patients with ischemic and hemorrhagic stroke; to investigate the association between hospitals' stroke discharge volume, teaching status, and 30-day readmission; and to highlight reasons for 30-day readmission and explore the association of 30-day readmission in terms of mortality, length of stay, and cost of care among patients with stroke., Design, Setting, and Participants: Cohort, year-wise analysis of the Nationwide Readmissions Database between January 1, 2010, and September 30, 2015. The setting was a population-based cohort study providing national estimates of 30-day readmission. The database represents 50% of all US hospitalizations from 22 geographically dispersed states. Participants were adult (≥18 years) patients with a primary discharge diagnosis of intracerebral hemorrhage, acute ischemic stroke, or subarachnoid hemorrhage. Hospitals were categorized by their annual stroke discharge volume and were classified as teaching hospitals if they had an American Medical Association-approved residency program or had a ratio of full-time equivalent interns and residents to beds of 0.25 or higher., Main Outcomes and Measures: Readmission was defined as any admission within 30 days of index hospitalization discharge. Using Centers for Medicare & Medicaid Services-defined algorithms, events were classified as planned or unplanned and as potentially preventable., Results: Based on study criteria, 2 078 854 eligible patients were included (mean [SE] age, 70.02 [0.07] years; 51.9% female). Thirty-day readmission was highest for patients with intracerebral hemorrhage (13.70%; 95% CI, 13.40%-13.99%), followed by patients with acute ischemic stroke (12.44%; 95% CI, 12.33%-12.55%) and patients with subarachnoid hemorrhage (11.48%; 95% CI, 11.01%-11.96%). On average, there was a 3.3% annual decline in readmission between 2010 and 2014, which was statistically significant for the period of investigation (odds ratio, 0.96; 95% CI, 0.95-0.97). Patients discharged from nonteaching hospitals with high stroke discharge volume were at a significantly higher risk of 30-day readmission, and the top 2 reasons for readmission were acute cerebrovascular disease and septicemia., Conclusions and Relevance: This study suggests that nationally representative readmission metrics can be used to benchmark hospitals' performance, and a temporal trend of 3.3% may be used to evaluate the effectiveness of readmission reduction strategies.

Objective The objective of this study was to use data from the 20-center beneficial effect of antenatal magnesium sulfate (BEAM) trial to assess the external validity of the Neonatal Research Network (NRN) estimator, a widely employed web-based counseling tool to estimate the probability of an adverse outcome for periviable infants given intensive care. Study Design The probability of different adverse outcomes predicted from the NRN estimator was compared with observed rates at 18 to 22 months for ventilated, nonanomalous infants born at 23 to 25 weeks and assessed in BEAM as in the NRN. Results were assessed using rigorous validation methods for prediction models. Results Among 289 eligible infants, 26% died, 40% died or had profound neurodevelopmental impairment (PNDI), and 71% died or had NDI. The area under the receiver operating characteristic curve was 0.70 (95% confidence interval [CI], 0.63-0.78) for death, 0.64 (95% CI, 0.56-0.71) for death or NDI, and 0.71 (95% CI, 0.65-0.78) for death or PNDI. Observed and predicted rates were somewhat different for death or NDI but quite similar for death and for death or PNDI in different risk groups. Brier scores for accuracy were favorable (0.17-0.22) for all outcomes. Conclusion Our results provide external validation of the NRN estimator for assessing the probability of adverse outcomes at 18 to 22 months for periviable infants given intensive care., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants., Study Design: Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment., Results: Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02)., Conclusion: The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: The effect of birth location on hypothermia-related outcomes has not been rigorously examined in the literature. In this study, we determined whether birth location had an impact on the benefits of whole-body cooling to 33.5 °C for 72 h in term infants (n = 208) with hypoxic-ischemic encephalopathy (HIE) who participated in the Neonatal Research Network (NRN) randomized controlled trial., Methods: Heterogeneity by birth location was examined with respect to cooling treatment for the 18-mo primary outcomes (death, moderate disability, severe disability) and secondary outcomes (death, components of disability), and in-hospital organ dysfunction. Logistic regression models were used to generate adjusted odds ratios., Results: Infants born at a location other than an NRN center (outborn) (n = 93) experienced significant delays in initiation of therapy (mean (SD): 5.5 (1.1) vs. 4.4 (1.2) h), lower baseline temperatures (36.6 (1.2) vs. 37.1 (0.9) °C), and more severe HIE (43 vs. 29%) than infants born in an NRN center (inborn) (n = 115). Maternal education <12 y (50 vs. 14%) and African-American ethnicity (43 vs. 25%) were more common in the inborn group. When adjusted for NRN center and HIE severity, there were no significant differences in 18-mo outcomes or in-hospital organ dysfunction between inborn and outborn infants., Conclusion: Although limited by sample size and some differences in baseline characteristics, the study showed that birth location does not appear to modify the treatment effect of hypothermia after HIE.

Objective: To evaluate the association between early hypocarbia and 18- to 22-month outcome among neonates with hypoxic-ischemic encephalopathy., Study Design: Data from the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy were used for this secondary observational study. Infants (n = 204) had multiple blood gases recorded from birth to 12 hours of study intervention (hypothermia versus intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18 to 22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO(2) and cumulative exposure to PCO(2) <35 mm Hg. The relationship between cumulative PCO(2) <35 mm Hg (calculated as the difference between 35 mm Hg and the sampled PCO(2) multiplied by the duration of time spent <35 mm Hg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), and time to spontaneous respiration and ventilator days; results were expressed as odds ratios and 95% confidence intervals. Alternative models of CO(2) concentration were explored to account for fluctuations in CO(2)., Results: Both minimum PCO(2) and cumulative PCO(2) <35 mm Hg were associated with poor outcome (P < .05). Moreover, death/disability increased with greater cumulative exposure to PCO(2) <35 mm Hg., Conclusions: Hypocarbia is associated with poor outcome after hypoxic-ischemic encephalopathy., (Copyright © 2011 Mosby, Inc. All rights reserved.)

It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.

Objectives: To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers >or=4 0 years to the corresponding rates among infants of younger mothers., Study Design: Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome., Results: The sample consisted of 14 671 live ELBW births divided into maternal age groups: <20, 20 to 29, 30 to 39, and >or= 40 years. Of infants born to mothers >or= 40 years, 20% were multiples. Mothers >or= 40 years had high rates of obstetric interventions and medical morbidities compared with mothers <40 years. ELBW live births of mothers >or= 40 years were 22% more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared with mothers <20. Multiple birth, however, was associated with a 10% greater risk of neurodevelopmental impairment or death., Conclusion: Although mothers >or= 40 years had high pregnancy-related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.

Objective: To document the mortality and morbidity of infants weighing 501-1500 g at birth according to gestational age, birthweight, and sex., Study Design: Prospective collection of perinatal events and neonatal course to 120 days of life, discharge, or death from January 1990 through December 2002 for infants born at 16 participating centers of the National Institute of Child Health & Human Development Neonatal Research Network., Results: Compared with 1995-1996, for 1997-2002 the survival of infants with birthweight of 501-1500 g increased by 1 percentage point (from 84% to 85%). Survival without major neonatal morbidity remained static, at 70%; this includes bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Survival increased for multiple births (26%, up from 22%), antenatal corticosteroid use (79%, up from 71%), and maternal antibiotics (70%, up from 62%) (P < .05). From 1997 to 2002, birthweight-specific survival was 55% for infants weighing 501-750 g, 88% for 751-1000 g, 94% for 1001-1250 g, and 96% for 1251-1500 g. More females survived. The incidence of NEC (7%), severe IVH (12%), and late-onset septicemia (22%) remained essentially unchanged, but BPD decreased slightly, from 23% to 22%. The use of postnatal corticosteroids declined from 20% in 1997-2000 to 12% in 2001-2002. Growth failure (weight <10th percentile) at 36 weeks' postmenstrual age decreased from 97% in 1995-1996 to 91% in 1997-2002., Conclusion: There have been no significant increases in survival without neonatal and long-term morbidity among VLBW infants between 1997 and 2002. We speculate that to improve survival without morbidity requires determining, disseminating, and applying best practices using therapies currently available, and also identifying new strategies and interventions.

Objective: To compare duration of ventilation to mortality and adverse neurodevelopmental outcomes among extremely low birth weight (ELBW; 501-1000 g) infants., Study Design: Retrospective analysis of prospectively collected data from 5364 infants with a birthweight of 501 to 1000 g born at National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers from 1995 to 1998. The main outcome measures were: survival, duration of mechanical ventilation, and neurodevelopmental outcome., Results: Overall survival was 71%. The median duration of ventilation for survivors was 23 days; 75% were free of mechanical ventilation by 39 days, and 7% were ventilated for > or = 60 days. Of those ventilated for > or = 60 days, 24% survived without impairment. Of those ventilated for > or = 90 days, only 7% survived without impairment. Of those ventilated > or = 120 days, all survivors were impaired., Conclusions: The prognosis for ELBW with protracted ventilation remains grim. The cohort who remain intubated have diminished survival and high rates of impairment. Parents of these infants should be informed of changes in prognosis as the time of ventilation increases.

Background: It is unclear whether the protective benefits of regular physical activity on mortality extend to patients with end-stage renal disease (ESRD). We tested this hypothesis in a national cohort of new patients with ESRD in the United States., Methods: Data for a subset of patients (n = 2,507; 62%) from the Dialysis Morbidity and Mortality Wave 2 study were used to explore the associations of exercise and limitations in physical activity with mortality., Results: Overall, 56% of patients exercised less than once a week, whereas the remainder reported more frequent physical activity; 2 to 3 times/wk in 18%, 4 to 5 times/wk in 6%, and daily exercise in 20%. Severe limitations in vigorous and moderate physical activities were reported by 75% and 42%, respectively. Mortality risks were greatest for those with severe limitations in either moderate (relative risk [RR], 1.72; 95% confidence interval [CI], 1.44 to 2.05) or vigorous physical activities (RR, 1.51; 95% CI, 1.20 to 1.90) compared with those reporting minimal or no limitations. Conversely, mortality risks were lower for patients who exercised 2 to 3 (RR, 0.74; 95% CI, 0.58 to 0.95) or 4 to 5 times/wk (RR, 0.70; 95% CI, 0.47 to 1.07), whereas no advantage was associated with daily exercise (RR, 1.06; 95% CI, 0.86 to 1.30)., Conclusion: Although limitations in physical activity are common among new patients with ESRD in the United States and correlate highly with increased mortality risk, this study shows an association of frequent exercise of up to 4 to 5 times/wk with improved survival. The surprising lack of association of daily exercise with increased survival deserves additional study.

Objective: To survey the attitudes and practices among level III neonatal intensive care units in the United States regarding vitamin A supplementation for extremely-low-birth-weight (ELBW; birth weight < or =1000 g) infants. Study design A pretested questionnaire regarding vitamin A supplementation was distributed to all (n=102) neonatal-perinatal training program directors (TPD) and 105 randomly selected directors of level III neonatal intensive care units (nontraining program directors, NTPD)., Results: Ninety-nine percent of TPD and 94% of NTPD responded. In a minority of programs (20% TPD, 13% NTPD), >90% of eligible extremely-low-birth-weight neonates are supplemented with vitamin A, whereas in most programs (69% TPD, 82% NTPD), routine supplementation is not practiced. Most centers (91% TPD, 81% NTPD) supplementing vitamin A use a dose of 5000 IU IM 3 times per week for 4 weeks. The most common reason that TPD give for not supplementing vitamin A is the perceived small benefit, whereas the most common reason for NTPD is that they consider the intervention unproven., Conclusions: These findings indicate inconsistency in practicing evidence-based medicine in neonatal practice, where therapies are often administered on the basis of weaker evidence of safety and benefit than supports vitamin A supplementation. Educational interventions may be required to endorse the benefits and safety of vitamin A supplementation.

Objective: Previous multicenter studies have shown significant center differences in neonatal characteristics and morbidities. This study evaluated center differences in outcome at 18 to 22 months among extremely low birth weight (ELBW; 401-1000 g) infants after adjusting for demographics and antenatal interventions, and it identified neonatal interventions associated with outcome differences., Methods: We assessed the outcome of 2478 liveborn infants who were admitted in 1993 and 1994 to the 12 centers of the Neonatal Research Network of the National Institute of Child Health and Human Development; 1483 (60%) infants survived to 18 to 22 months, and 1151 (78%) had comprehensive evaluations. Logistic regression analyses were performed to identify center differences and the association of 4 neonatal interventions--active resuscitation, postnatal steroids, ventilator treatment for < or =27 days, and full enteral feedings < or =24 days--with adverse outcomes (cerebral palsy, low Bayley scores, and neurodevelopmental impairment [NDI]), after adjusting for demographics and antenatal interventions., Results: Using bivariate analyses, significant center differences were identified for mortality, antenatal and postnatal interventions, social and environmental variables, neonatal morbidities, and neurodevelopmental outcomes for the 12 centers. After adjustment for maternal and infant demographics and antenatal interventions, the percentage of ELBW infants who had died or had NDI at 18 to 22 months ranged from 52% to 85%. Active resuscitation and postnatal steroids were associated with increases of NDI of 11.8% and 19.3%, whereas shorter ventilation support and shorter time to achieve full enteral feeds were associated with decreases in NDI of 20.7% and 17.3%, respectively., Conclusion: There are large and disturbing differences among centers in outcomes at 18 to 22 months after adjusting for demographic and antenatal interventions. Center differences in postnatal interventions associated with differences in outcome can provide hypotheses for testing in clinical trials to improve outcome.

The reliability of classification of cerebral palsy (CP) in low-birthweight children was assessed by using clinical and research study records sampled from population-based cohort studies in the USA, The Netherlands, Canada, and Germany. Records of neurological examination findings and functional motor assessments were submitted to up to five pediatricians with expertise in CP diagnosis, who grouped children into categories referred to as 'disabling' CP, 'non-disabling' CP, and no CP. Each study provided between 31 and 51 records of children assessed between 2 and 8 years of age, approximately equally divided among the three groupings. The discrimination between 'any CP' and 'no CP' was only fair (mean Kappa coefficients 0.37 to 0.69). However, when more detailed information describing motor function was used, children with 'disabling' CP could be distinguished, on the basis of records, from those without CP or with 'non-disabling' CP with good to excellent reliability (mean Kappa coefficients 0.69 to 0.88). Because of the substantially higher agreement observed when these functional distinctions are made, we recommend that reports or comparisons of rates of CP should include levels of motor function of children with CP, and not simply total CP, among the outcomes of interest.

Objective: To determine whether minimal ventilation decreases death or bronchopulmonary dysplasia (BPD)., Study Design: Infants with birth weight 501 g to 1000 g and mechanically ventilated before 12 hours were randomly assigned to minimal ventilation (partial pressure of carbon dioxide [PCO(2)] target >52 mm Hg) or routine ventilation (PCO(2) target <48 mm Hg) and a tapered dexamethasone course or saline placebo for 10 days, using a 2 x 2 factorial design. The primary outcome was death or BPD at 36 weeks' postmenstrual age., Results: After enrollment of 220 patients, the trial was halted because of unanticipated nonrespiratory adverse events related to dexamethasone therapy. The relative risk for death or BPD at 36 weeks in the minimal versus routine ventilation groups was 0.93 (95% CI, 0.77-1.12; P =.43). Ventilator support at 36 weeks was 1% in the minimal versus 16% in the routine group (P <.01). Major morbidities and long-term outcome were comparable in both treatment groups., Conclusions: With the sample size studied, minimal ventilation did not reduce the incidence of death or BPD. The reduced ventilator support at 36 weeks in the minimal ventilation group warrants further study of this intervention.