Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

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

Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.

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.

Survival, Morbidities, and Developmental Outcomes among Low Birth Weight Infants with Congenital Heart Defects.

OBJECTIVE: Prematurity and low birth weight (LBW) are risk factors for increased morbidity and mortality in infants with congenital heart defects (CHDs). We sought to describe survival, inhospital morbidities, and 2-year neurodevelopmental follow-up in LBW infants with CHD. STUDY DESIGN: We included infants with birth weight (BW) <2,500 g diagnosed with CHD (except isolated patent ductus arteriosus) admitted January 2013 to March 2016 to a single level-IV academic neonatal intensive care unit. We reported CHD prevalence by BW and gestational age; selected in-hospital morbidities and mortality by infant BW, CHD type, and surgical intervention; and developmental outcomes by Bayley's scales of infant and toddler development, third edition (BSID-III) scores at age 2 years. RESULTS: Among 420 infants with CHD, 28 (7%) underwent cardiac surgery. Median (25th and 75th percentiles) gestational age was 30 (range: 27-33) weeks and BW was 1,258 (range: 870-1,853) g. There were 134 of 420 (32%) extremely LBW (<1,000 g) infants, 82 of 420 (20%) were small for gestational age, and 51 of 420 (12%) multiples. Most common diagnosis: atrial septal defect (260/420, 62%), followed by congenital anomaly of the pulmonary valve (75/420, 18%). Most common surgical procedure: pulmonary artery banding (5/28, 18%), followed by the tetralogy of Fallot corrective repair (4/28, 14%). Survival to discharge was 88% overall and lower among extremely LBW (<1,000 g, 81%) infants and infants undergoing surgery (79%). Comorbidities were common (35%); retinopathy of prematurity and bronchopulmonary dysplasia were most prevalent. BSID-III scores were available on 148 of 176 (84%); any scores <85 were noted in 73 of 148 (49%), with language being most commonly affected. CONCLUSION: Among LBW infants with congenital heart disease, hospital mortality varied by BW and cardiac diagnosis. KEY POINTS: · In low birth weight infants with congenital heart disease, survival varied by birth weight and cardiac diagnosis.. · Overall survival was higher than previously reported.. · There were fewer morbidities than previously reported.. · Bayley's scale-III scores at 2 years of age were <85 for nearly half..

Survival and Neurodevelopmental Outcomes among Periviable Infants.

BACKGROUND: Data reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes. METHODS: We compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death. RESULTS: Data on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P<0.001). The percentage of infants who survived without neurodevelopmental impairment increased from 16% (217 of 1391) in epoch 1 to 20% (276 of 1348) in epoch 3 (P=0.001), whereas the percentage of infants who survived with neurodevelopmental impairment did not change significantly (15% [207 of 1391] in epoch 1 and 16% [211 of 1348] in epoch 3, P=0.29). After adjustment for changes in the baseline characteristics of the infants over time, both the rate of survival with neurodevelopmental impairment (as compared with death) and the rate of survival without neurodevelopmental impairment (as compared with death) increased over time (adjusted relative risks, 1.27 [95% confidence interval {CI}, 1.01 to 1.59] and 1.59 [95% CI, 1.28 to 1.99], respectively). CONCLUSIONS: The rate of survival without neurodevelopmental impairment increased between 2000 and 2011 in this large cohort of periviable infants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT00063063 and NCT00009633 .).

Gastrostomy Tube Feeding in Extremely Low Birthweight Infants: Frequency, Associated Comorbidities, and Long-term Outcomes.

OBJECTIVE: To assess the frequency of gastrostomy tube (GT) placement in extremely low birth weight (ELBW) infants, associated comorbidities, and long-term outcomes. STUDY DESIGN: Analysis of ELBW infants from 25 centers enrolled in the National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-up Registry from 2006 to 2012. Frequency of GT placement before 18-22 months, demographic and medical factors associated with GT placement, and associated long-term outcomes at 18-22 months of corrected age were described. Associations between GT placement and neonatal morbidities and long-term outcomes were assessed with logistic regression after adjustment for center and common co-variables. RESULTS: Of the 4549 ELBW infants included in these analyses, 333 (7.3%) underwent GT placement; 76% had the GT placed postdischarge. Of infants with GTs, 11% had birth weights small for gestational age, 77% had bronchopulmonary dysplasia, and 29% severe intraventricular hemorrhage or periventricular leukomalacia. At follow-up, 56% of infants with a GT had weight <10th percentile, 61% had neurodevelopmental impairment (NDI), and 55% had chronic breathing problems. After adjustment, small for gestational age, bronchopulmonary dysplasia, intraventricular hemorrhage/periventricular leukomalacia, poor growth, and NDI were associated with GT placement. Thirty-two percent of infants with GTs placed were taking full oral feeds at follow-up. CONCLUSIONS: GT placement is common in ELBW infants, particularly among those with severe neonatal morbidities. GT placement in this population was associated with poor growth, NDI, and chronic respiratory and feeding problems at follow-up. The frequency of GT placement postneonatal discharge indicates the need for close nutritional follow-up of ELBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063.

Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids are given primarily to induce fetal lung maturation but results from meta-analyses of randomized controlled trials have not shown mortality or pulmonary benefits for extremely preterm infants although these are the infants most at risk of mortality and pulmonary disease. OBJECTIVE: We sought to determine if exposure to antenatal corticosteroids is associated with a lower rate of death and pulmonary morbidities by 36 weeks' postmenstrual age. STUDY DESIGN: Prospectively collected data on 11,022 infants 22 0/7 to 28 6/7 weeks' gestational age with a birthweight of ≥401 g born from Jan. 1, 2006, through Dec. 31, 2014, were analyzed. The rate of death and the rate of physiologic bronchopulmonary dysplasia by 36 weeks' postmenstrual age were analyzed by level of exposure to antenatal corticosteroids using models adjusted for maternal variables, infant variables, center, and epoch. RESULTS: Infants exposed to any antenatal corticosteroids had a lower rate of death (2193/9670 [22.7%]) compared to infants without exposure (540/1302 [41.5%]) (adjusted relative risk, 0.71; 95% confidence interval, 0.65-0.76; P < .0001). Infants exposed to a partial course of antenatal corticosteroids also had a lower rate of death (654/2520 [26.0%]) compared to infants without exposure (540/1302 [41.5%]); (adjusted relative risk, 0.77; 95% confidence interval, 0.70-0.85; P < .0001). In an analysis by each week of gestation, infants exposed to a complete course of antenatal corticosteroids had lower mortality before discharge compared to infants without exposure at each week from 23-27 weeks' gestation and infants exposed to a partial course of antenatal corticosteroids had lower mortality at 23, 24, and 26 weeks' gestation. Rates of bronchopulmonary dysplasia in survivors did not differ by antenatal corticosteroid exposure. The rate of death due to respiratory distress syndrome, the rate of surfactant use, and the rate of mechanical ventilation were lower in infants exposed to any antenatal corticosteroids compared to infants without exposure. CONCLUSION: Among infants 22-28 weeks' gestational age, any or partial antenatal exposure to corticosteroids compared to no exposure is associated with a lower rate of death while the rate of bronchopulmonary dysplasia in survivors did not differ.

Markers of Successful Extubation in Extremely Preterm Infants, and Morbidity After Failed Extubation.

OBJECTIVES: To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. STUDY DESIGN: This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network's Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks' gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. RESULTS: Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/ bronchopulmonary dysplasia (OR 3.27). CONCLUSIONS: Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00233324.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

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

Blood Cytokine Profiles Associated with Distinct Patterns of Bronchopulmonary Dysplasia among Extremely Low Birth Weight Infants.

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.

Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model.

Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.

Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants.

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

Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy.

OBJECTIVE: To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to 4 doses adjusted for volume and red blood cell content, 1-5 × 10(7) cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post-infusion vital signs. As exploratory analyses, we compared cell recipients' hospital outcomes (mortality, oral feeds at discharge) and 1-year survival with Bayley Scales of Infant and Toddler Development, 3rd edition scores ≥85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells. RESULTS: Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1-year outcomes survived with scores >85. CONCLUSIONS: Collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.

Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy.

BACKGROUND: Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE). METHODS: We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-. RESULTS: A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. CONCLUSION: Disability was not associated with the APOE genotype in this cohort of HIE survivors.

Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants.

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

Decreasing Blood Transfusions in Premature Infants Through Quality Improvement.

BACKGROUND AND OBJECTIVES: Packed red blood cell transfusions (pRBCT) in preterm infants have been associated with significant morbidity. Although infants <26 weeks' gestational age typically require several pRBCT, preterm infants born between 26 and 34 weeks' gestational age may also require pRBCT during their hospitalization that are potentially preventable. We aimed to reduce pRBCT in this population by 20%. METHODS: This quality improvement project was conducted in the Duke University Hospital NICU between July 2018 and February 2023. Interventions included the implementation of evidence-based transfusion thresholds, supporting bone marrow erythropoiesis, and reducing laboratory specimen volumes by increasing capillary test panels. The rates per 1000 patient days for pRBCT (outcome measure), number of new patients initiated on erythropoietin (process measure), number of basic metabolic panels (process measure), and total capillary panels (process measure) were monitored during the project period. Statistical process control charts were used to observe trends over time. RESULTS: Among infants born between 26 0/7 and 34 6/7 weeks' gestational age, the rate of pRBCT decreased from an average of 23.8 to 12.7 transfusions per 1000 patient days, which is a 46.6% decrease. Increases in the use of erythropoietin and capillary panels were observed, along with a decrease in the use of basic metabolic panels. There was no change in mortality or the rate of necrotizing enterocolitis. Improvement was sustained for 24 months after implementation. CONCLUSIONS: pRBCT can be decreased in preterm infants born between 26 and 34 completed weeks' gestation through a combination of strategies utilizing quality improvement methodology.

Risk factors and epidemiology of spontaneous intestinal perforation among infants born at 22-24 weeks' gestational age.

OBJECTIVE: To describe the epidemiology, risk factors, and timing of spontaneous intestinal perforation (SIP) among infants born at 22-24 weeks' gestational age (GA). STUDY DESIGN: Observational cohort study among infants born at 22-24 weeks' GA in 446 neonatal intensive care units. RESULTS: We identified 9712 infants, of whom 379 (3.9%) developed SIP. SIP incidence increased with decreasing GA (P < 0.001). Antenatal magnesium (odds ratio (OR) 1.42; 95% confidence interval (CI), 1.09-1.85), antenatal indomethacin (OR 1.40; 95% CI, 1.06-1.85), postnatal indomethacin (OR 1.61; 95% CI, 1.23-2.11), and postnatal hydrocortisone exposure (OR 2.02; 95% CI 1.50-2.73) were associated with SIP. Infants who lost 15-20% (OR 1.77; 95% CI, 1.28-2.44) or >20% (OR 2.04; 95% CI, 1.46-2.85) of birth weight had higher odds of SIP than infants with weight loss <10%. CONCLUSIONS: Antenatal magnesium exposure, antenatal indomethacin exposure, postnatal hydrocortisone exposure, postnatal indomethacin exposure, and weight loss ≥15% were associated with SIP.

Early sepsis does not increase the risk of late sepsis in very low birth weight neonates.

OBJECTIVE: To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS). STUDY DESIGN: Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤ 72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for ≥ 5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates. RESULTS: Of 34,396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047]. CONCLUSIONS: Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

Neurodevelopmental outcome of extremely low birth weight infants with Candida infection.

OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.

Association between blood spot transforming growth factor-ß and patent ductus arteriosus in extremely low-birth weight infants.

Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-ß appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-ß on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-ß measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-ß on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642-1,896]; median 1,386 pg/ml [range 868-1,913]) compared with others without PDA (median 1,334 pg/ml [range 760-2,064]; median 1,712 pg/ml [range 1,014-2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-ß levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-ß was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83-1.17; day 7 OR 0.88, 95 % CI 0.74-1.04) on adjusted analyses. Our results suggest that blood spot TGF-ß alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.

20-αHydroxycholesterol, an oxysterol in human breast milk, reverses mouse neonatal white matter injury through Gli-dependent oligodendrogenesis.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.