Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).METHODS-Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007. RESULTS-Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤ 12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.CONCLUSION-Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed. Keywordsextremely low gestation; very low birth weight; morbidity; death Over the previous 2 decades, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) has monitored trends in morbidity and mortality rates among very low birth weight (VLBW) infants born at the university centers that constitute the NRN. 1-6 Increased VLBW infant survival rates have paralleled improvements in prenatal, obstetric, and neonatal care.7 , 8 NRN data suggest that a plateau in VLBW infant survival rates might have been reached, despite increased use of prenatal corticosteroid treatment, prenatal antibiotic treatment, and early neonatal surfactant treatment. 6 Previous NRN reports presented patient characteristics, interventions, and outcomes according to birth weight (BW), with an upper limit of 1500 g. Such BW-specific data may be skewed by more-mature infants with growth restriction. The aim of this study was to evaluate management, hospital complications, and mortality rates among infants with gestational ages (GAs) of 22 to 28 weeks who were born at NRN centers between 2003 and 2007. METHODS Study Population and Clinical OutcomesInfants born alive at NRN centers in 2003-2007 with GAs of 22 0/7 to 28 6/7 weeks and BWs of 401 to 1500 g were studied, including those with congenital anomalies. These infants were part of the NRN VLBW registry. [1][2][3][4][5][6] Research personnel collected maternal pregnancy/delivery data soon after birth and inf...

Objective To test the hypothesis that heart rate characteristics (HRC) monitoring improves neonatal outcomes. Study design Two-group, parallel, individually randomized controlled clinical trial of 3003 very low birth weight infants in 9 NICUs. In one group, HRC monitoring was displayed; in the other, it was masked. The primary outcome was number of days alive and ventilator-free in the 120 days after randomization. Secondary outcomes were mortality, number of ventilator days, NICU stay and antibiotic use. Results Mortality was reduced in infants whose HRC monitoring was displayed, from 10.2% to 8.1% (HR = 0.78, 95% CI = 0.61 to 0.99, P = 0.04, number needed to monitor 48), and there was a trend toward increased days alive and ventilator-free (95.9 of 120 days compared to 93.6 in controls, P = 0.08). Mortality benefit was concentrated in infants with birth weight <1000g (HR=0.74, 95% CI 0.57 to 0.95, P=0.02, number needed to monitor 23). There were no significant differences in the other outcomes. Conclusion Heart rate characteristics monitoring can reduce mortality in very low birth weight infants.

IntroductionIn the late 1990's, we designed and laid the foundations for a study intended to advance our understanding of what contributes to brain damage in extremely low gestational age newborns (ELGANs). Our planning considered the following: A model of brain damage in the preterm newbornWe postulate that the preterm newborn is at very high risk of brain damage, for at least three reasons.First, the very processes that lead to preterm delivery can contribute to brain damage.(1-3) These processes, which are likely inflammatory, involve the fetus,(4) are complex,(5-10) probably persist for days if not weeks,(11) and need not be initiated by microorganisms. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interests:The authors declare that they have no conflicts of interests. NIH Public Access Author ManuscriptEarly Hum Dev. Author manuscript; available in PMC 2010 November 1. Published in final edited form as:Early Hum Dev. 2009 November ; 85(11): 719-725. doi:10.1016/j.earlhumdev.2009.060. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOriginally our focus was on inflammatory exposures associated with preterm labor and prelabor premature rupture of membranes, but has since been expanded to the processes that impair fetal growth as well.Second, the developmental processes during the 23 rd through 27 th weeks of gestation might be among the most vulnerable. The transformation of oligodendrocyte precursor to oligodendrocyte is one maturational process that appears particularly vulnerable. (13) Another is the migration of neuron precursors from the germinal plate to their final destination. (14,15) In addition, excitatory neurotransmitter pathways are up-regulated in the immature brain, apparently to faciliate neuronal migration, division, and organization, and the development of synapses and synaptic networks.(16) This heightened excitatory state enhances the vulnerability of the brain to excitotoxic injury from inflammatory or metabolic disorders.Third, ELGANs are born before they can synthesize adequate amounts of proteins normally provided by the placenta/mother. These proteins, many of which satisfy criteria for being called neurotrophins because they promote the differentiation/maturation of neurons and oligodendroglia, have the capacity to protect these cells against perturbation/adversity. (17,17,18) The combination of a potentially damaging exposure, easily disturbed developmental processes, and the lack of protection against the disturbances provoked by the damaging exposure are what we think make the developing brain so vulner...

Background-Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.Methods-We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.Results-The rates of severe retinopathy or death did not differ significantly between the loweroxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P = 0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.Conclusions-A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.) Retinopathy of prematurity is an important cause of blindness and other visual disabilities in preterm infants. The incidence of retinopathy of prematurity was increased with exposure to unrestricted oxygen supplementation in preterm infants in randomized, controlled trials NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript performed in the 1950s. 1 In the 1960s, this increase resulted in the practice of restricting the fraction of inspired oxygen (FiO 2 ) to no more than 0.50, which was estimated to result in an excess of 16 deaths per case of blindness prevented. 2 More recent data suggest that levels of oxygen saturation previously thought to be at the upper end of the normal range may increase the risk of retinopathy of prematurity as compared with levels at the lower end of the normal range. [3][4][5] Oxygen toxicity may also increase the risk of death, 6,7 bronchopulmonary dysplasia, 8-...

OBJECTIVE-Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low-birth-weight (<1000 g) infants. We quantify risk factors predicting infection in high-risk premature infants and compare clinical judgment with a prediction model of invasive candidiasis. METHODS-The study involved a prospective observational cohort of infants <1000 g birth weight at 19 centers of the NICHD Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: 1) potentially modifiable risk factors and 2) a clinical model at time of blood culture to predict candidiasis.RESULTS-Invasive candidiasis occurred in 137/1515 (9.0%) infants and was documented by positive culture from ≥ 1 of these sources: blood (n=96), cerebrospinal fluid (n=9), urine obtained by catheterization (n=52), or other sterile body fluid (n=10). Mortality was not different from infants who had positive blood culture compared to those with isolated positive urine culture. Incidence varied from 2-28% at the 13 centers enrolling ≥ 50 infants. Potentially modifiable risk factors (model 1) included central catheter, broad-spectrum antibiotics (e.g., third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model (model 2) had an area under the receiver operating characteristic curve of 0.79, and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. Performance of clinical judgment did not vary significantly with level of training. CONCLUSION-Priorantibiotics, presence of a central catheter, endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment. KeywordsCandidiasis; premature infant; risk factors In the extremely low-birth-weight (ELBW; <1000g) infant, invasive candidiasis is common, often fatal, and frequently leads to poor neurodevelopmental outcomes. 1,2 Invasive candidiasis (Candida infections of the blood and other sterile body fluids) is the second most common cause of infectious disease-related death in the extremely premature infant. Despite antifungal treatment, 20% of infants who develop invasive candidiasis die, and neurodevelopmental impairment occurs in nearly 60% of survivors. 1,2 Rates of invasive candidiasis vary 10-fold among similar academic tertiary care neonatal intensive care units (NICUs). 3 This variation among nurseries is found throughout the world 4-9 and has not been explained, but exposure to environmental risk factors (e.g., incubator humidity), third-generation cephalosporins, and foreign bodies such as catheters have all been associated with development of disease. 3,10,11 The high morbidity related to invasive candidiasis leads to the consideration of empirical anti...

Objective Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number infants with chronic lung disease (CLD). Historical neonatal exposures associated with CLD now less frequently precede the disease. There is now increasing interest in exposures and events before delivery that predict CLD. The objective of this study was to identify current antenatal predictors of CLD. Patients and Methods We collected data about antenatal, placental and neonatal characteristics of 1241 newborns delivered before completion of the 28th week of gestation who were enrolled in a 14-center, observational study conducted during the years 2002-2004. Associations between antenatal factors, microbiologic and histologic characteristics of the placenta, and selected neonatal characteristics and CLD risk were first evaluated in univariate analyses. Subsequent multivariate analyses investigated the contribution of antenatal factors, particularly fetal growth restriction (FGR), to CLD risk. Results Among the antenatal factors, birth weight Z-score, used as a marker of FGR, provided the most information about CLD risk. Indicators of placental inflammation and infection were not associated with increased risk of CLD. Within nearly all strata of antenatal, placental and neonatal variables, growth restricted infants were at increased CLD risk compared with infants who were not growth restricted. FGR was the only maternal or antenatal characteristic that was highly predictive of CLD after adjustment for other risk factors. Conclusions FGR is independently associated with the risk of CLD. Thus factors that control fetal somatic growth may have a significant impact on vulnerability to lung injury, and in this way increase CLD risk. Future investigations should focus on the impact of FGR on growth factors that modulate lung growth.

Background It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less). Methods We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments. Results Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g. Conclusions Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)

OBJECTIVES The goals of this study were to describe nutritional practices in the first month of life for a large cohort of extremely low gestational age newborns and to determine the impact of these nutritional practices on growth velocity over the same period. METHODS The sample included 1187 infants born at 23 weeks to 27 weeks of gestation, at 14 institutions, between 2002 and 2004. Inclusion criteria included survival until day 28 and weight information for both day 7 and day 28. Growth velocity, expressed as grams per kilogram per day (g/kg/day), was calculated for the interval between days 7 and 28. Nutritional practices during the first week and on days 14, 21, and 28 were compared to current nutritional guidelines in the literature. Multivariable logistic regression models estimated the contribution of limited nutrition to limited growth velocity. RESULTS Protein and fat delivery approximated current nutritional recommendations while carbohydrate and total caloric delivery did not. Despite this, growth velocity of our study infants exceeded the current guideline of 15 g/kg/day. Nevertheless, we found extrauterine growth restriction (i.e., weight for gestational age below the 10th centile) in 75% of infants at 28 days, as compared to only 18% at birth. A growth velocity of 20-30 g/kg/day was associated with infants' maintaining or exceeding their birth weight Z-score, with rates in the upper range for the gestationally youngest infants. Early (day 7) nutritional practices were positively associated with growth velocity measured between days 7 and 28. CONCLUSION The early provision of nutrients is an important determinant of postnatal growth. Extrauterine growth restriction remains high in extremely premature infants even when they achieve a growth velocity rate within current guidelines.