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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.)

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.)

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 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.)

Objective: To assess the sustainability of the benefits relative to usual care of a medical home providing comprehensive care for high-risk children with medical complexity (≥2 hospitalizations or ≥1 pediatric intensive care unit [PICU] admission in the year before enrollment) after we made comprehensive care our standard practice and expanded the program., Study Design: We conducted pre-post comparisons of the rate of children with serious illness (death, PICU admission, or >7-day hospitalization) and health-system costs observed after program expansion (March 2014-June 2015) to those during the clinical trial (March 2011-August 2013) for each of the trial's treatment groups (usual care, n = 96, and comprehensive care, n = 105; primary analyses), and among all children given comprehensive care (n Post-trial = 233, including trial usual care children who transitioned to comprehensive care post-trial and newly enrolled medically complex children, and n Trial = 105; secondary analyses). We also analyzed the findings for the trial patients as a 2-phase stepped-wedge study., Results: In intent-to-treat analyses, rates of children with serious illness and costs were reduced or unchanged post-trial vs trial for the trial's usual care group (rate ratio [RR], 0.36; 95% CI, 0.20-0.64; cost ratio [CR], 0.68; 95% CI, 0.28-1.68), the trial's comprehensive care group (RR, 0.74; 95% CI, 0.39-1.41; CR, 0.67; 95% CI, 0.51-0.89), and among all children given comprehensive care (RR, 0.97; 95% CI, 0.61-1.52; CR, 0.75; 95% CI, 0.61-0.93). Conservative stepped-wedge analyses identified overall benefits with comprehensive care across both study periods (RR, 0.46; 95% CI, 0.30-0.72; CR, 0.64; 95% CI, 0.43-0.99)., Conclusions: Major benefits of comprehensive care did not diminish with post-trial program expansion., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To describe the frequency of postnatal discussions about withdrawal or withholding of life-sustaining therapy (WWLST), ensuing WWLST, and outcomes of infants surviving such discussions. We hypothesized that such survivors have poor outcomes., Study Design: This retrospective review included registry data from 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Infants born at 22-28 weeks of gestation who survived >12 hours during 2011-2013 were included. Regression analysis identified maternal and infant factors associated with WWLST discussions and factors predicting ensuing WWLST. In-hospital and 18- to 26-month outcomes were evaluated., Results: WWLST discussions occurred in 529 (15.4%) of 3434 infants. These were more frequent at 22-24 weeks (27.0%) compared with 27-28 weeks of gestation (5.6%). Factors associated with WWLST discussion were male sex, gestational age (GA) of ≤24 weeks, birth weight small for GA, congenital malformations or syndromes, early onset sepsis, severe brain injury, and necrotizing enterocolitis. Rates of WWLST discussion varied by center (6.4%-29.9%) as did WWLST (5.2%-20.7%). Ensuing WWLST occurred in 406 patients; of these, 5 survived to discharge. Of the 123 infants for whom intensive care was continued, 58 (47%) survived to discharge. Survival after WWLST discussion was associated with higher rates of neonatal morbidities and neurodevelopmental impairment compared with babies for whom WWLST discussions did not occur. Significant predictors of ensuing WWLST were maternal age >25 years, necrotizing enterocolitis, and days on a ventilator., Conclusions: Wide center variations in WWLST discussions occur, especially at ≤24 weeks GA. Outcomes of infants surviving after WWLST discussions are poor., Trial Registration: ClinicalTrials.gov: NCT00063063., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns., Study Design: We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD., Results: The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD., Conclusions: Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.)

Objective: To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (birth weight ≤1000 g) infants treated with 7 days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants., Study Design: A predetermined sample size of 64 extremely low birth weight infants, between 10-21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric magnetic resonance imaging was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and 9 structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at magnetic resonance imaging scan., Results: The study groups were similar at baseline and 8 infants died in each arm. Unadjusted total brain tissue volume (mean ± SD) in the hydrocortisone (N = 23) and placebo treated infants (N = 21) was 272 ± 40.3 cm(3) and 277.8 ± 59.1 cm(3), respectively (adjusted mean difference: 6.35 cm(3) (95% CI: (-20.8, 32.5); P = .64). Three of the 31 hydrocortisone treated infants and 5 of the 33 placebo treated infants survived without severe bronchopulmonary dysplasia (relative risk 0.62, 95% CI: 0.13, 2.66; P = .49). No significant differences were noted in prespecified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed., Conclusions: Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to neonatal intensive care unit discharge., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia., Study Design: Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models., Results: Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability., Conclusions: On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants., Study Design: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1β; IL-8; tumor necrosis factor-α; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants., Results: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-β, soluble IL rα, macrophage inflammatory protein 1β) were found to be altered on days 0-4 in infants who developed CP., Conclusions: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin., (Copyright © 2011 Mosby, Inc. All rights reserved.)

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.)

Objective: We explored whether gut inflammation, colonic fermentation, and/or an altered colonic flora could provide a pathophysiological mechanism for colic., Study Design: The study population consisted of 36 term infants ranging in age from 14 to 81 days. We measured fecal calprotectin (a marker of neutrophil infiltration) by ELISA; stool microorganisms by denaturing gradient gel electrophoresis, cloning, and sequencing; and breath hydrogen levels using gas chromatography., Results: During 24 hours, infants with colic (n = 19) cried and fussed for a mean of 314 +/- 36 (SEM) minutes, compared with control infants (n = 17, 103 +/- 17 minutes). Fecal calprotectin levels were 2-fold higher in infants with colic than in control infants (413 +/- 71 vs 197 +/- 46 microg/g, P = .042). Stools of infants with colic had fewer identifiable bands on denaturing gradient gel electrophoresis. Klebsiella species were detected in more colic patients than in control patients (8 vs 1, P = .02), whereas Enterobacter/Pantoea species were detected only in the control patients. These differences could not be attributed to differences in formula versus breast milk feeding, consumption of elemental formula, or exposure to antibiotics., Conclusions: Infants with colic, a condition previously believed to be nonorganic in nature, have evidence of intestinal neutrophilic infiltration and a less diverse fecal microflora.

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 assess the association between urinary lactate to creatinine ratio (ULCR) and neurodevelopmental outcome in term infants with hypoxic ischemic encephalopathy and examine the effect of hypothermia on the change in ULCR., Study Design: Spot urine samples were collected in 58 term infants (28 hypothermia, 30 control subjects) with hypoxic ischemic encephalopathy. Urinary lactate and creatinine were measured by using (1)H nuclear magnetic resonance spectroscopy and expressed as ULCR. Survivors were examined at 18 months of age., Results: The ULCR was significantly higher in infants who died or had moderate/severe neurodevelopmental disability. Logistic regression analysis controlling for hypothermia and severity of encephalopathy confirmed the association (adjusted odds ratio, 5.52; 95% CI, 1.36, 22.42; P < .02). Considerable overlap in ULCR was observed between infants with normal/mild disability and those who died or survived with moderate/severe disability. ULCR fell significantly between 6 and 24 hours and 48 and 72 hours of age for all infants. The magnitude of decline did not differ between hypothermia and control groups., Conclusions: High ULCR is associated with death or moderate/severe neurodevelopmental disability. Significant overlap in values between the normal/mild and moderate/severe disability groups limits predictive value of this measure. Whole-body hypothermia did not affect the decline in ULCR.

Objectives: We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group., Study Design: Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness., Results: Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43)., Conclusions: In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

Objective: To compare the incidence of apnea, bradycardia, or desaturation in a car seat with that in a car bed for preterm very low birth weight (< or = 1500 g) infants., Study Design: Infants were studied for 120 minutes in a car seat and in a car bed. Apnea (> 20 seconds), bradycardia (heart rate < 80/min for > 5 seconds), desaturation (SpO2 < 88% for > 10 seconds), and absent nasal flow were monitored., Results: We assessed 151 infants (median birth weight, 1120 g [range, 437 to 3105]; median birth gestational age, 29 weeks [24 to 34]) in both devices. Twenty-three infants (15%) had > or = 1 event in the car seat compared with 29 (19%) in the car bed (P = .4). Time to first event was similar in the car seat and car bed (mean, 54 to 55 minutes). In logistic regression analyses, bronchopulmonary dysplasia was a significant predictor for a car seat event and a lower gestational age at birth was a risk factor for a car bed event., Conclusions: We found no evidence that an event is less likely in a car bed than in a car seat. Whichever device is used, very low birth weight infants require observation during travel.

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.

Objective: Vitamin A supplementation reduces bronchopulmonary dysplasia (BPD)/death in extremely low birth weight neonates. It was hypothesized that compared with the standard regimen of 5000 IU 3 times per week for 4 weeks, (1) a higher dose (10,000 IU 3 x per week) would increase serum retinol and retinol binding protein (RBP) and lower relative dose responses (RDR), and (2) once-per-week dosing (15,000 IU once per week) would lead to equivalent levels, RBP, and RDR., Study Design: Extremely low birth weight neonates (n = 120) receiving O(2)/mechanical ventilation at 24 hours were randomly assigned to (1) standard, (2) higher dose, or (3) once-per-week regimens. Measures of vitamin A deficiency were serum retinol <20 microg/dL, RBP <2.5 mg/dL, and/or RDR >10% on day 28. BPD was defined as O(2)/mechanical ventilation at 36 weeks' postmenstrual age., Results: Groups were similar at enrollment (median gestational age, 25 weeks; birth weight, 689 g). Possible toxicity was seen in <5%. The higher dose regimen did not increase retinol or RBP, decrease RDR, or improve outcomes. Infants in the once-per-week regimen had lower retinol levels and higher RDR without an effect on outcomes., Conclusions: Compared with the standard regimen, once-per-week dosing worsened, and higher doses did not reduce, vitamin A deficiency. Therefore, the standard regimen is recommended.

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.

Objective: Ballard scores are commonly used to estimate gestational age (GA). The purpose of this study was to determine the accuracy of the New Ballard Score (NBS) for infants <28 weeks GA by accurate menstrual history and to evaluate NBS as an outcome predictor., Methods: Infants weighing 401 to 1500 g in 12 National Institute of Child Health and Human Development Neonatal Research Network centers had NBS performed before age 48 hours. Accuracy of NBS estimates of GA was assessed for infants with GA determined by accurate menstrual history. In a larger cohort of infants, NBS was included in regression models of the association of NBS and death, poor outcome, and duration of hospital stay., Results: At each week from 22 to 28 weeks GA by accurate menstrual history, NBS estimates exceeded GA by dates by 1.3 to 3.3 weeks, and estimates varied widely (range of widths of 95% CIs for the observations, 6.8 to 11.9 weeks). NBS did not contribute significantly to regression models of death, poor outcome, or duration of hospital stay., Conclusions: Inaccuracies in GA determined by the NBS should be considered when treating extremely premature infants, particularly in decisions to forego or administer intensive care. Refinement of GA scoring systems is needed to optimize clinical benefit.

Objective: The objective of this study was to assess a modified consent procedure allowed under federal regulations and developed for studies, particularly clinical trials, that are judged by the Institutional Review Board to reduce or have no effect on patient risk., Study Design: This was a randomized trial of a conventional consent procedure that required parental signature to give consent (opting in) after a comprehensive disclosure of the rights of participants in research versus a modified consent procedure that required parental signature to refuse consent (opting out) after specific disclosures appropriate when risk is not increased. Consent was sought for a trial of primary follow-up care for disadvantaged infants at high risk, a trial judged by our Institutional Review Board to increase access to care for both groups. A blinded assessor interviewed mothers within 24 hours of the consent decision., Results: Among the 44 mothers interviewed, the modified consent group scored higher than the conventional consent group in recall and understanding of study purpose and methods (47% vs 30%; p < 0.02). Other comparisons provided no evidence that the modified consent procedure was less desirable. Virtually all mothers reported satisfaction., Conclusions: The modified approach may improve communication and facilitate studies judged by the Institutional Review Board to be risk-neutral or risk-reducing. Further evaluation of a modified consent procedure for such studies is warranted.

Objective: Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 7861 VLBW (401 to 1500 gm) neonates admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991 to 1993)., Methods: The NICHD Neonatal Research Network maintains a prospectively collected registry of all VLBW neonates cared for at participating centers. Data from this registry were analyzed retrospectively., Results: Of 6911 infants who survived beyond 3 days, 1696 (25%) had one or more episodes of blood culture-proven sepsis. The vast majority of infection (73%) were caused by gram-positive organisms, with coagulase-negative staphylococci accounting for 55% of all infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of infection included intubation, respiratory distress syndrome, prolonged ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, and necrotizing enterocolitis. Among infants with bronchopulmonary dysplasia, those with late-onset sepsis had a significantly longer duration of mechanical ventilation (45 vs 33 days; p <0.01). Late-onset sepsis prolonged hospital stay: the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days, respectively (p <0.001). Even after adjustment for other complications of prematurity, including intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia, infants with late-onset sepsis had a significantly longer hospitalization (p <0.001). Moreover, neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected (17% vs 7%; p <0.000 1), especially if they were infected with gram-negative organisms (40%) or fungi (28%). Deaths attributed to infection increased with increasing chronologic age. Whereas only 4% of deaths in the first 3 days of life were attributed to infection, 45% of deaths after 2 weeks were related to infection., Conclusions: Late-onset sepsis is a frequent and important problem among VLBW preterm infants. Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates, shorten hospital stay, and reduce costs.

Objective: Early-onset sepsis (occurring within 72 hours of birth) is included in the differential diagnosis of most very low birth weight (VLBW) neonates. To determine the current incidence of early-onset sepsis, risk factors for disease, and the impact of early-onset sepsis on subsequent hospital course, we studied a cohort of 7861 VLBW neonates (401 to 1500 gm) admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991-1993)., Methods: The NICHD Neonatal Research Network maintains a prospectively collected registry on all VLBW neonates born or cared for at participating centers. Data from this registry were analyzed retrospectively., Results: Blood culture-proven early-onset sepsis was uncommon, occurring in only 1.9% of VLBW neonates. Group B streptococcus was the most frequent pathogen associated with early-onset sepsis (31%), followed by Escherichia coli (16%) and Haemophilus influenzae (12%). Decreasing gestational age was associated with increased rates of infection. Antibiotic therapy for suspected sepsis is frequently initiated at birth in VLBW neonates. Almost half of the infants in this cohort were considered to have clinical sepsis and continued to receive antibiotics for 5 or more days, despite a negative blood culture result in 98% of cases. These findings underscore the difficulty of ruling out sepsis in the symptomatic immature neonate and the special concern for culture-negative clinical sepsis in the face of maternal antibiotic use. Neonates with early-onset sepsis were significantly more likely to have subsequent comorbidities, including severe intraventricular hemorrhage, patent ductus arteriosus, and prolonged assisted ventilation. Although 26% of VLBW neonates with early-onset sepsis died, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For those infants discharged alive, early-onset sepsis was associated with a significantly prolonged hospital stay (86 vs 69 days; p <0.02)., Conclusions: Early-onset sepsis remains an important but uncommon problem among VLBW preterm infants. Improved diagnostic strategies are needed to enable the clinician to distinguish between the infected and the uninfected VLBW neonate with symptoms and to target continued antibiotic therapy to those who are truly infected.

To obtain growth data on a large sample of low birth weight preterm infants, we monitored 608 infants longitudinally in an eight-site collaborative program. Ninety-nine infants weighed less than or equal to 1250 gm at birth, 289 between 1250 and 2000 gm, and 220 infants between 2000 and 2500 gm. Thirty-four percent were white, 52% black, and 14% Hispanic. Weight, height, and head circumference were measured at birth and at 40 weeks and 4, 8, and 12 months of gestation-corrected age on at least 553 infants each time. Descriptive statistics for all growth variables and a body mass index (kilograms per square meter), plotted by sex and birth weight group, demonstrated growth patterns lower than published standards for term infants of the same age and sex. These patterns of growth differed by birth weight group. No catch-up growth was noted by the 12-month examination (gestation-corrected age) for any birth weight group. We conclude that low birth weight preterm infants have different patterns of growth than term infants during the first year of life, even with plotting corrected for gestational age.

This study describes an attempt to define intrauterine growth retardation low birth weight preterm infants by comparing reference standards for intrauterine growth in weight, length, and head circumference on their variability across ethnic groups and cities, and on their specificity in independently classifying infants as short, thin, or having small heads. The sample consisted of 985 inborn preterm low birth weight infants enrolled at eight participating sites in a randomized clinical trial using uniform sampling criteria. When gestational age was used as the reference standard, striking differences were found by ethnicity and site in the prevalence of low weight infants at birth. These differences, as well as the potentially false overlap of classification, were attenuated when the use of gestational age as a reference standard was used only for birth length, while length itself was used (as an alternative to gestational age) as the reference standard for birth weight, and weight was used as the reference standard for head circumference. These results raise questions about the use of gestational age as the primary or only reference standard in assessing weight and head circumference at bith.

Banked human milk has been widely used, although its composition and nutritional adequacy for preterm infants are uncertain. We randomized 76 healthy infants of less than or equal to 1500 gm birth weight to ad lib feedings of frozen BHM or a protein-mineral-calorie-enriched formula (Similac Special Care) designed to sustain intrauterine accretion rates; BHM contained 2.2 gm fat/100 ml and 60 kcal/100 ml (gross energy). Infants fed BHM ingested more milk (197 vs 165 ml/kg/day) but less gross energy (118 vs 143 kcal/kg/day); grew less rapidly in weight (15 vs 30 gm/day), length (0.7 vs 1.1 cm/wk), and head circumference (0.8 vs 1.2 cm/wk); and were discharged at a lower weight (2200 vs 2348 gm) and older age (61 vs 47 day) than infants fed formula (P less than 0.02). At 37 weeks' postmenstrual age, infants fed BHM were less responsive to Brazelton inanimate stimuli (mean total score 5.0 vs 7.5; P less than 0.02). With few exceptions, blood amino acids, pH, and serum electrolyte values were similar in both groups. The different caloric intake of our feeding groups may explain only part of the large difference in growth rate. Donor milk should not be fed to preterm infants unless it has been analyzed and the feedings shown to provide a nutrient intake considered appropriate to the needs of these infants.

The relative validities of three clinical assessment methods for estimating gestational age in newborn low birth weight infants were evaluated with reference to estimates based on the date of the mother's last menstrual period. For 1246 infants in eight diverse institutions, estimates based on physical criteria correlated more strongly with dates estimates, yielded estimates more similar on average to dates estimates, and yielded higher proportions of correct classifications of prematurity and small for gestational age than did estimates based on neurologic criteria or neurologic and physical criteria combined. These results support the use of physical criteria rather than neurologic or combined criteria for the clinical assessment of gestational age in low birth weight infants. In a subsample of 511 black and white infants, there were no ethnic differences in mean error of estimate for any of the three methods.