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.).

Increasing Prevalence of Cerebral Palsy Among Two-Year-Old Children Born at <27 Weeks of Gestation: A Cohort Study.

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

Risk Factors for Admission Hyperthermia and Associated Outcomes in Infants Born Preterm.

Maternal, placental, and neonatal factors were compared between infants born at ≤29 weeks of gestational age with admission hyperthermia (>37.5○C) and euthermia (36.5-37.5○C). Admission hyperthermia was associated with longer duration of face-mask positive-pressure ventilation and infant's temperature ≥37.5○C in the delivery room. Infants born preterm with admission hyperthermia had greater odds of developing necrotizing enterocolitis and neurodevelopmental impairment.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

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

Persistent high blood pressure and renal dysfunction in preterm infants during childhood.

BACKGROUND: Infants born very preterm (≤32 weeks gestational age, GA) and very-low birth weight (≤1500 g; PT-VLBW) demonstrate high systolic blood pressure (SBP), renal dysfunction, and obesity at 6 months-3 years and in early adulthood. Their parallel measurement and progression during childhood is unclear. METHODS: We reenrolled 62/120 patients originally seen at 1-3 years at 10-13 years and remeasured anthropometric indices, SBP, and serum creatinine (Cr) and cystatin C (cysC) to determine estimated glomerular filtration rate (eGFR). We selected Term-matched Controls at 10-13 years from the 2015-2016 NHANES database at a ratio of 2 Controls:1 Case (124:62). RESULTS: Reenrolled patients were predominantly Hispanic, birth weight 1073 ± 251 g, and GA at birth 28 ± 2 weeks. At 10-13 years, 45% were classified overweight/obese, 48% had SBP ≥ 90th centile (77% considered hypertensive), and 34% had low eGFR (<90 mL min-1 [1.73 m2]-1). Notably, 57% of reenrolled PT-VLBW Cases had low eGFRcysC at both 1-3 and 10-13 years, P < 0.03. Compared to Controls, Cases had four times the adjusted odds for having an elevated SBP and low eGFRCr despite similar proportions with overweight/obesity among Cases and Controls. CONCLUSIONS: PT-VLBW infants seen at 1-3 years exhibit obesity, elevated SBP, and low eGFR in infancy and 10-13 years. Although the small sample size may limit conclusions, pediatricians should consider serial evaluations of PT-VLBW throughout childhood. IMPACT: The association between preterm birth and elevated blood pressure, renal dysfunction, and obesity in young adults begins as early as 1 year and persists at 10-13 years of age. This is the first study reporting serial measurements of blood pressure, renal function, and obesity from infancy to preadolescence in children born very preterm. Fifty-seven percent of preterm 1-3 year olds have persistent low estimated glomerular filtration rate associated with hypertension at 10-13 years. Clinicians should consider serial evaluations of blood pressure, renal function, and obesity throughout infancy and childhood in all preterm births.

Relationship between Ventricular Size on Latest Ultrasonogram and the Bayley Scores ≥ 18 Months in Extremely Low Gestational Age Neonates: A Retrospective Cohort Study.

OBJECTIVE: A ventricle-to-brain index (VBI) >0.35 is associated with low scores on the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) in preterm infants with birth weight <1,250 g. However, VBI obtained at the third ventricle has only moderate interobserver reliability. The objective of this study was to test (1) reliability of VBI measured at the foramen of Monro on the latest ultrasonogram (US) before discharge using the intraclass correlation coefficient (ICC) and (2) the relationship between VBI and BSID-III scores at ≥18 months corrected age. STUDY DESIGN: The present study is a single-center retrospective cohort study. RESULTS: The study included 270 preterm infants born at 230/7 to 286/7 weeks of gestational age. The ICC of VBI between independent measurements by two study radiologists on the first 50 patients was 0.934. Factors associated with the value of VBI included severe intraventricular hemorrhage, bronchopulmonary dysplasia, and systemic steroid administration for BPD but not postmenstrual age. In multivariate analysis, VBI was negatively and independently associated with cognitive (p = 0.002), language (p = 0.004), and motor (p < 0.001) BSID-III scores. The association between VBI and BSID-III scores was observed even in infants in whom the latest US was obtained before term equivalent age. The association between VBI and BSID-III scores was also observed after excluding those with severe intraventricular hemorrhage. CONCLUSION: In this very preterm cohort the measurement of VBI had excellent reliability. Moreover, VBI measurements were negatively associated with motor, language, and cognitive BSID-III scores. KEY POINTS: · Mean values of VBI are stable with postmenstrual age.. · Values at the foramen of Monro are reliable and reproducible.. · VBI is negatively associated with Bayley scores.. · The association is observed even before term age..

Role of zinc in neonatal growth and brain growth: review and scoping review.

This manuscript includes (1) a narrative review of Zinc as an essential nutrient for fetal and neonatal growth and brain growth and development and (2) a scoping review of studies assessing the effects of Zinc supplementation on survival, growth, brain growth, and neurodevelopment in neonates. Very preterm infants and small for gestational age infants are at risk for Zinc deficiency. Zinc deficiency can cause several complications including periorificial lesions, delayed wound healing, hair loss, diarrhea, immune deficiency, growth failure with stunting, and brain atrophy and dysfunction. Zinc is considered essential for oligodendrogenesis, neurogenesis, neuronal differentiation, white matter growth, and multiple biological and physiological roles in neurobiology. Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20-21-day pregnancy and extends during lactation and in human may start at 26 weeks of gestation and extend until at least 44 weeks of postmenstrual age. Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth, and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment. IMPACT: Zinc is essential for growth and brain growth and development. In the USA, very preterm small for gestational age infants are at risk for Zinc deficiency. Data support the possibility that the critical period of Zinc delivery for brain growth in the mouse starts at 18 days of a 20-21-day pregnancy and extends during lactation and in human may start at 26 weeks' gestation and extend until at least 44 weeks of postmenstrual age. Several randomized trials of Zinc supplementation in neonates have shown improvement in growth when using high enough dose, for long duration in patients likely to or proven to have a Zinc deficiency. Studies are needed to better elucidate Zinc requirement in extremely low gestational age neonates to minimize morbidity, optimize growth and brain growth, prevent periventricular leukomalacia and optimize neurodevelopment.

Autism spectrum disorders in extremely preterm infants and placental pathology findings: a matched case-control study.

BACKGROUND: The prevalence of autism spectrum disorders (ASD) is 5-fold higher in preterm (PT) infants born ≤28 weeks gestational age (GA) as compared to the general population. The relationship between placental pathologic lesions and ASD in PT infants has not been studied. OBJECTIVES: The objective of this study was to determine the association of placental pathology with the occurrence of ASD in PT infants born ≤28 weeks GA. STUDY DESIGN: A matched case-control study to identify confirmed ASD cases (n = 16) and matched controls (n = 48) born at Parkland Hospital between January 2012 and December 2015. Patients were matched using known variables associated with increased risk of ASD in PT infants. Placental histology from all births was reviewed. RESULTS: Children with ASD had 2-fold greater incidence of multiple placental pathologic lesions vs. matched controls [11/16 (69%) vs.16/48 (33%), respectively; P = 0.01]. In contrast, single placental pathologic lesions were not associated with ASD [5/16 (31%) vs. 21/48 (43%), respectively; P = 0.1]. CONCLUSIONS: In this study, we have demonstrated an association between the increasing complexity of histologic placental lesions and the later risk for ASD in infants born ≤28 weeks GA. Thus, placental pathology findings may be valuable in further understanding the prenatal pathologic processes underlying ASD in PT infants. IMPACT: PT infants with ASD have a 2-fold greater incidence of multiple placental pathologies. This is the first study to report an association between the complexity of histologic placental lesions and later risk of ASD in infant born extremely PT (i.e., ≤28 weeks GA). This study reiterates the importance of examining placental pathologic lesions, since placental evidence of antenatal insults correlates with postnatal morbidities and mortality in PT infants.

Impact of multiple placental pathologies on neonatal death, bronchopulmonary dysplasia, and neurodevelopmental impairment in preterm infants.

BACKGROUND: To determine the association of placental pathology, including multiple placental lesions, with the occurrence and severity of bronchopulmonary dysplasia (BPD), death, and neurodevelopmental impairment (NDI) in preterm infants. METHOD: A retrospective cohort study of neonates <29 weeks gestational age (GA) born at Parkland Hospital from 08/2009 to 08/2012. Infants were stratified as follows: Group 1: no significant placental pathology; Group 2: single significant placental lesion; and Group 3: ≥2 placental lesions (multiple lesions). Primary outcome was death and/or BPD. Two-year neurodevelopmental follow-up was compared. RESULTS: In all, 42% (100/241) of infants had one placental lesion, and 34% (82/241) ≥2 lesions. As the number of the pathologic lesions increased (no lesions vs. 1 vs. ≥2), the occurrence of death or BPD increased (25%, 37%, and 52%, respectively; P = 0.004). Moreover, infants with multiple pathologic lesions were more likely to have NDI (29%, 29%, and 46%, respectively; P = 0.03). After logistic regression, infants with multiple pathologic lesions were more likely to develop moderate-to-severe BPD [P < 0.01; OR 3.9 (1.5-10.1)] but not NDI. CONCLUSION(S): Neonates <29 weeks GA with multiple placental pathologic lesions have an increased risk for developing BPD, suggesting an interaction between placental inflammation and vascular pathology and the pathogenesis of BPD; however, the risk of NDI is not increased.

Structural network maturation of the preterm human brain.

During the 3rd trimester, large-scale neural circuits are formed in the human brain, resulting in a highly efficient and segregated connectome at birth. Despite recent findings identifying important preterm human brain network properties such as rich-club organization, how the structural network develops differentially across brain regions and among different types of connections in this period is not yet known. Here, using high resolution diffusion MRI of 77 preterm-born and full-term neonates scanned at 31.9-41.7 postmenstrual weeks (PMW), we constructed structural connectivity matrices and performed graph-theory-based analyses. Faster increases of nodal efficiency were mainly located at the brain hubs distributed in primary sensorimotor regions, superior-middle frontal, and precuneus regions during 31.9-41.7PMW. Higher rates of edge strength increases were found in the rich-club and within-module connections, compared to other connections. The edge strength of short-range connections increased faster than that of long-range connections. Nodal efficiencies of the hubs predicted individual postmenstrual ages more accurately than those of non-hubs. Collectively, these findings revealed more rapid efficiency increases of the hub and rich-club connections as well as higher developmental rates of edge strength in short-range and within-module connections. These jointly underlie network segregation and differentiated emergence of brain functions.

Age-specific gray and white matter DTI atlas for human brain at 33, 36 and 39 postmenstrual weeks.

During the 3rd trimester, dramatic structural changes take place in the human brain, underlying the neural circuit formation. The survival rate of premature infants has increased significantly in recent years. The large morphological differences of the preterm brain at 33 or 36 postmenstrual weeks (PMW) from the brain at 40PMW (full term) make it necessary to establish age-specific atlases for preterm brains. In this study, with high quality (1.5 × 1.5 × 1.6 mm3 imaging resolution) diffusion tensor imaging (DTI) data obtained from 84 healthy preterm and term-born neonates, we established age-specific preterm and term-born brain templates and atlases at 33, 36 and 39PMW. Age-specific DTI templates include a single-subject template, a population-averaged template with linear transformation and a population-averaged template with nonlinear transformation. Each of the age-specific DTI atlases includes comprehensive labeling of 126 major gray matter (GM) and white matter (WM) structures, specifically 52 cerebral cortical structures, 40 cerebral WM structures, 22 brainstem and cerebellar structures and 12 subcortical GM structures. From 33 to 39 PMW, dramatic morphological changes of delineated individual neural structures such as ganglionic eminence and uncinate fasciculus were revealed. The evaluation based on measurements of Dice ratio and L1 error suggested reliable and reproducible automated labels from the age-matched atlases compared to labels from manual delineation. Applying these atlases to automatically and effectively delineate microstructural changes of major WM tracts during the 3rd trimester was demonstrated. The established age-specific DTI templates and atlases of 33, 36 and 39 PMW brains may be used for not only understanding normal functional and structural maturational processes but also detecting biomarkers of neural disorders in the preterm brains.

Extreme Preterm Infant Rates of Overweight and Obesity at School Age in the SUPPORT Neuroimaging and Neurodevelopmental Outcomes Cohort.

OBJECTIVE: To identify rates of overweight (body mass index [BMI] ≥85th percentile) and obesity (BMI ≥95th percentile) at 6-7 years of age and associated risk factors among extremely preterm infants born at <28 weeks of gestation. STUDY DESIGN: Anthropometrics, blood pressure, and active and sedentary activity levels were prospectively assessed. Three groups were compared, those with a BMI ≥85th percentile (overweight or obese for age, height, and sex) and ≥95th percentile (obese) vs <85th percentile. Multiple regression analyses estimated the relative risks of BMI ≥85th percentile and ≥95th percentile associated with perinatal and early childhood factors. RESULTS: Of 388 children, 22% had a BMI of ≥85th percentile and 10% were obese. Children with obesity and overweight compared with normal weight children had higher body fat (subscapular skinfold and triceps skinfold >85th percentile), central fat (waist circumference >90th percentile), spent more time in sedentary activity (20.5 vs 18.2 vs 16.7 hours/week), and had either systolic and/or diastolic hypertension (24% vs 26% vs 14%), respectively. Postdischarge weight gain velocities from 36 weeks postmenstrual age to 18 months, and 18 months to 6-7 years were independently associated with a BMI of ≥85th percentile, whereas weight gain velocity from 18 months to 6-7 years was associated with obesity. CONCLUSIONS: One in 5 former extremely preterm infants is overweight or obese and has central obesity at early school age. Postdischarge weight gain velocities were associated with overweight and obesity. These findings suggest the obesity epidemic is spreading to the most extremely preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00063063 and NCT0000.

Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI.

The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results.

Impact of the Neonatal Resuscitation Program-Recommended Low Oxygen Strategy on Outcomes of Infants Born Preterm.

OBJECTIVE: To evaluate the impact of the Neonatal Resuscitation Program (NRP)-recommended low oxygen strategy (LOX) on neonatal morbidities, mortality, and neurodevelopmental outcomes in neonates born preterm. STUDY DESIGN: In March 2011, Parkland Hospital changed from a high oxygen strategy (HOX) of resuscitation with initial 100% oxygen and targeting 85%-94% oxygen saturation for delivery room resuscitation to a LOX with initial 21% oxygen and titrating oxygen to meet NRP-recommended transitional target saturations. Neonates ≤28 weeks' gestational age born between August 2009 and April 2012 were identified. In this retrospective, observational study, neonates exposed to LOX vs HOX were compared for short-term morbidity, mortality, and long-term neurodevelopmental outcomes. Regression analysis was performed to control for confounding variables. RESULTS: Of 199 neonates, 110 were resuscitated with HOX and 89 with LOX. Compared with HOX, neonates exposed to LOX had lower oxygen exposure in the delivery room (5.2 ± 1.5 vs 7.8 ± 2.8 [∑FiO2 × time min], P < .01), spent fewer days on oxygen (30 [5, 54] vs 46 [11, 82], P = .01), and had lower odds of developing bronchopulmonary dysplasia (aOR 0.4 [0.2, 0.9]). There was no difference in mortality (17 [20%] vs 20 [18%]), but neonates exposed to LOX had greater motor composite scores on Bayley Scales of Infant and Toddler Development-Third edition assessment (91 [85, 97] vs 88 [76, 94], P < .01). CONCLUSION: The NRP-recommended LOX strategy was associated with improved respiratory morbidities and neurodevelopmental outcomes with no increase in mortality. Prospective trials to confirm the optimal oxygen strategy for the resuscitation of neonates born preterm are needed.

Biomarkers of adiposity are elevated in preterm very-low-birth-weight infants at 1, 2, and 3 y of age.

BACKGROUND: Preterm, very-low-birth-weight (PT-VLBW) neonates are at-risk for metabolic syndrome later in life. At 1-3 y, they exhibit excessive weight-for-length z-scores (Wt-LZ) and elevated systolic blood pressures (SBP). Serum adipokines are biomarkers of adiposity, but expression in PT-VLBW infants is unclear. We examined the correlation between serum adipokine levels, anthropometric measures and SBP in PT-VLBW neonates at follow-up. METHODS: This was a cross-sectional cohort study of PT-VLBW infants at 1, 2, and 3 y of age (40/cohort). We measured SBP, abdominal circumference (AC) and anthropometrics; calculated age/gender-specific z-scores for Wt, L, Wt-L and subscapular skin fold (SSZ), and measured serum adipokines. RESULTS: Serum leptin was unaffected by chronologic age and gender, but was positively correlated with weight, Wt-LZ, AC, and SSZ at 1 and 3 y (P < 0.01). Female infants at 1 and 3 y had a more significant relationship than males between serum leptin and SSZ (P < 0.001, R = 0.75 and P < 0.001, R = 0.70, respectively). Adiponectin levels were 16-20% lower at 3 vs. 1-2 y (P = 0.02, ANOVA) and negatively correlated with SBP. CONCLUSION: Although serum leptin was unrelated to advancing age, gender, and SBP in PT-VLBW infants, levels correlated with measures of adiposity at 1 and 3 y, females > males, suggesting leptin resistance may occur in early infancy.

Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

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

Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial.

BACKGROUND: Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS: Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS: The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046). CONCLUSIONS: We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Childhood outcomes after hypothermia for neonatal encephalopathy.

BACKGROUND: We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available. METHODS: In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70. RESULTS: Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80). CONCLUSIONS: The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).