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Evaluate the spectrum of neurodevelopmental outcome in a contemporary cohort of extremely preterm infants. We hypothesize that the rate of severe neurodevelopmental impairment (NDI) decreases over time. Retrospective analysis of neurodevelopmental outcome of preterm infants ≤27 weeks' gestational age (GA) from a Neonatal Research Network center that completed neurodevelopmental follow-up assessments between April 1, 2011, and January 1, 2015. The Bayley Scales of Infant Development-III (BSID III) and a standardized neurosensory examination were performed between 18 and 26 months' adjusted age. Outcome measures were neurologic examination diagnoses, BSID III cognitive and motor scores, sensory impairment, and the composite outcome of NDI, based on the BSID III cognitive score (analyzed by using a cutoff of

OBJECTIVES. Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individual's risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis. METHODS. We studied a cohort of extremely low birth-weight infants who survived [greater than or equal to] 72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns. RESULTS. There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant. CONCLUSIONS. Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk. Key Words antibiotic use, bloodstream infection, candida, candidemia, LBW, extremely low birth weight Abbreviations ELBW--extremely low birth weight BSA-- broad-spectrum antibiotic NEC--necrotizing enterocolitis CC--correlation coefficient, NEONATAL CANDIDIASIS IS associated with high mortality and increased risk of neurodevelopmental impairment among survivors. (1-3) Investigators have identified multiple risk factors for individual infants to develop candidiasis (1,4-6) and [...]

OBJECTIVE. Antenatal dexamethasone and betamethasone may not be equally efficacious in the prevention of adverse neonatal outcomes. We compared the risks of periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and neonatal death among very low birth weight infants who were exposed to dexamethasone, betamethasone, or neither steroid. METHODS. Infants (401-1500 g) in the National Institute of Child Health and Human Development Neonatal Research Network were studied. Multivariate logistic regression analyses compared the 3 groups with regard to PVL, IVH, ROP, and neonatal death, adjusting for network center and selected covariates. RESULTS. A total of 3600 infants met entry criteria. Compared with no antenatal steroids, there were trends for a reduced risk for PVL associated with dexamethasone and betamethasone but no difference in risk between dexamethasone and betamethasone. Dexamethasone reduced the risk for IVH and severe IVH, compared with no antenatal steroid exposure. Betamethasone reduced the risk for IVH, severe IVH, and neonatal death, compared with no antenatal steroids. Compared with betamethasone, dexamethasone had a statistically significant increased risk for neonatal death. There were trends for greater risks associated with dexamethasone compared with betamethasone for IVH and severe ROP. CONCLUSIONS. Betamethasone was associated with a reduced risk for neonatal death, with trends of decreased risk for other adverse neonatal outcomes, compared with dexamethasone. It may be in the best interest of neonates to receive betamethasone rather than dexamethasone when available. Key Words antenatal glucocorticoids, dexamethasone, betamethasone, neonatal morbidity, neonatal mortality, Abbreviations IVH--intraventricular hemorrhage PVL--periventricular leukomalacia ROP--retinopathy of prematurity NICHD--National Institute of Child Health and Human Development VLBW--very low birth weight GA--gestational age OR--odds ratio O--confidence interval PROM--prolonged rupture of membranes [...]

BACKGROUND. Neonatal candidiasis is associated with substantial morbidity and mortality rates. Neurodevelopmental follow-up data for a large multicenter cohort have not been reported. METHODS. Data were collected prospectively for neonates born at RESULTS. The cohort consisted of 4579 infants; 320 of 4579 (7%) developed candidiasis; 307 of 320 had Candida isolated from blood, 27 of 320 had Candida isolated from cerebrospinal fluid, and 13 (48%) of 27 of those with meningitis had negative blood cultures. In multivariate analysis of risk factors on day of life 3, birth weight, cephalosporins, gender, and lack of enteral feeding were associated with development of candidiasis. After diagnosis, most neonates had multiple positive cultures despite antifungal therapy, and 10% of neonates had candidemia for [greater than or equal to] 14 days. Death or neurodevelopmental impairment (NDI) was observed for 73% of extremely low birth weight infants who developed candidiasis. Death and NDI rates were greater for infants who had delayed removal or replacement of central catheters (>1 day after initiation of antifungal therapy), compared with infants whose catheters were removed or replaced promptly. CONCLUSIONS. Blood cultures were negative for approximately one half of the infants with Candida meningitis. Persistent candidiasis was common. Delayed catheter removal was associated with increased death and NDI rates. www.pediatrics.org/cgi/doi/10.1542/ peds.2004-2292 doi:10.1542/peds.2004-2292 The authors had full access to all of the data. The listed authors contributed to generation of the hypotheses (all authors), data collection (B.J.S., A.A.F., W.O., S.D., and R.G.), data analysis (D.K.B., S.A.M., and K.P.), data interpretation (all authors), and writing of the report (all authors). The members of the National institute of Child Health and Human Development Neonatal Research Network contributed to the collection data. Key Words candidiasis, meningitis, sensitivity, specificity, culture, premature infant Abbreviations CSF--cerebrospinal fluid CI--confidence interval DOL--day of life EGA--estimated gestational age ELBW--extremely low birth weight IVH--intraventricular hemorrhage NDI--neurodevelopmental impairment MDI--Mental Developmental Index OR--odds ratio PDA--patent ductus arteriosus PDI--Psychomotor Developmental Index, NEONATAL CANDIDIASIS IS often fatal among premature infants. (1-4) Most reports of neonatal candidiasis are single-center investigations. (2,5-9) Because of the gravity of the condition, newer diagnostic and treatment strategies [...]

Objective. This study evaluated the impact of changes in perinatal management on neurodevelopmental impairment (NDI) at 18 to 22 months' corrected age of low gestation (22-26 weeks) and higher gestation (27-32 weeks) extremely low birth weight infants (401-1000 g birth weight) who were cared for in the National Institute of Child Health and Human Development Neonatal Research Network during 3 epochs (1993-1994, 1995-1996, and 1997-1998). It was hypothesized that outcomes would improve over the 3 epochs. Methods. A multicenter cohort study was conducted of the outcomes of 3785 infants with assessments at 18 to 22 months' corrected age. Regression analyses were completed to evaluate for epoch effects, gestational age effects, and time plus gestational age interaction. Regression analyses were also performed to identify the independent associations of epoch and 4 study perinatal interventions: antenatal steroids (yes, no), high-frequency ventilation (yes, no), number of days to regain birth weight as a marker of nutritional intake, and postnatal steroids for treatment of bronchopulmonary dysplasia (yes, no) with outcomes. Results. Survival improved for both the low (55%-61%) and higher (82%-86%) gestational age groups during the 3 epochs. Regression analyses indicated that the decreased risk for adverse outcome was significantly lower in epoch 2 compared with epoch 1 with decreased rates of low Bayley Mental Development Index (MDI) and neurodevelopmental impairment (NDI). Antenatal steroids were associated with decreased risk for moderate to severe cerebral palsy (CP) and low Bayley Psychomotor Development Index. High-frequency ventilation was associated with a low Bayley MDI and NDI, and postnatal steroids were associated with moderate to severe CP, any CP, low Bayley MDI, low Bayley Psychomotor Development Index, and increased NDI. Conclusion. Survival of extremely low birth weight infants improved between 1993 and 1998. Although some outcomes remained unchanged, the rates of low Bayley MDI scores and NDI improved. Antenatal steroid administration was the only study intervention associated with improved outcomes. Pediatrics 2005;116:635-643; extremely low birth weight, neurologic outcome, impairment, cerebral palsy, Bayley, antenatal steroids., ABBREVIATIONS. ELBW, extremely low birth weight; NICHD, National Institute of Child Health and Development; BPD; bronchopulmonary dysplasia; BSID-II, Bayley Scales of Infant Development II; MDI, Mental Development Index; PDI, Psychomotor [...]

Objective. The purpose of this study was to evaluate the relationship between cerebral palsy (CP) diagnoses as measured by the topographic distribution of the tone abnormality with level of function on the Gross Motor Function Classification System (GMFCS) and developmental performance on the Bayley Scales of Infant Development II (BSID-II). It was hypothesized that (1) the greater the number of limbs involved, the higher the GMFCS and the lower the BSID-II Motor Scores and (2) there would be a spectrum of function and skill achievement on the GMFCS and BSID-II Motor Scores for children in each of the CP categories. Methods. A multicenter, longitudinal cohort study was conducted of 1860 extremely low birth weight (ELBW) infants who were born between August 1, 1995 and February 1, 1998, and evaluated at 18 to 22 months' corrected age. Children were categorized into impairment groups on the basis of the typography of neurologic findings: spastic quadriplegia, triplegia, diplegia, hemiplegia, monoplegia, hypotonic and/or athetotic CP, other abnormal neurologic findings, and normal. The neurologic category then was compared with GMFCS level and BSID-II Motor Scores. Results. A total of 282 (15.2%) of the 1860 children evaluated had CP. Children with more limbs involved had more abnormal GMFCS levels and lower BSID-II scores, reflecting more severe functional limitations. However, for each CP diagnostic category, there was a spectrum of gross motor functional levels and BSID-II scores. Although more than 1 (26.6%) in 4 of the children with CP had moderate to severe gross motor functional impairment, 1 (27.6%) in 4 had motor functional skills that allowed for ambulation. Conclusions. Given the range of gross motor skill outcomes for specific types of CP, the GMFCS is a better indicator of gross motor functional impairment than the traditional categorization of CP that specifies the number of limbs with neurologic impairment. The neurodevelopmental assessment of young children is optimized by combining a standard neurologic examination with measures of gross and fine motor function (GMFCS and Bayley Psychomotor Developmental Index). Additional studies to examine longer term functional motor and adaptive-functional developmental skills are required to devise strategies that delineate therapies to optimize functional performance. Pediatrics 2005;116:123-129; extremely low birth weight, neurologic outcome, cerebral palsy, gross motor function, development, sequelae. ABBREVIATIONS. CP, cerebral palsy; ELBW, extremely low birth weight; GMFCS, Gross Motor Function Classification System; BSID-II, Bayley Scales of Infant Development II; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index., Cerebral palsy (CP) remains a major sequela in extremely low birth weight (ELBW) infants, affecting 9% to 17% of survivors. (1-8) The traditional categorization of CP is dependent on the [...]

Objective. Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. Methods. In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5[degrees]C for 72 hours followed by slow rewarming. Results. In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 [+ or -] 0.2[degrees]C (mean [+ or -] standard deviation) around the set point of 33.5[degrees]C were reduced to 0.7 [+ or -] 0.2[degrees]C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 [+ or -] 0.3[degrees]C). In the human investigation, the infants were randomized at 4.1 [+ or -] 1.3 hours (mean [+ or -] standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5[degrees]C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 [+ or -] 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups. Conclusions. Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at, ABBREVIATIONS. HIE, hypoxic-ischemic encephalopathy; bpm, beats per minute; MRI, magnetic resonance imaging; SD, standard deviation; aEEG, amplitude-integrated EEG. Hypoxic-ischemic encephalopathy (HIE) associated with acute perinatal asphyxia in the term or [...]

To the Editor.-- We read with interest the retrospective case-control study by Guillet et al, (1) who found that H2-blocker therapy increases the incidence of necrotizing enterocolitis (NEC) for very [...]

OBJECTIVE. Extremely low birth weight (ELBW; [less than or equal to] 1000 g) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) are treated surgically with either initial laparotomy or peritoneal drain placement. The only published data comparing these therapies are from small, retrospective, single-center studies that do not address outcomes beyond nursery discharge. The objective of this study was to conduct a prospective, multicenter, observational study to (1) develop a hypothesis about the relative effect of these 2 therapies on risk-adjusted outcomes through 18 to 22 months in ELBW infants and (2) to obtain data that would be useful in designing and conducting a successful trial of this hypothesis. METHODS. A prospective, cohort study was conducted at 16 clinical centers within the National Institute of Child Health and Human Development Neonatal Research Network. To assist in risk adjustment, the attending pediatric surgeon recorded the preoperative diagnosis and intraoperative diagnosis and identified infants who were considered to be too ill for laparotomy. Predefined measures of short- and longer-term outcome included (1) either predischarge death or prolonged parenteral nutrition (>85 days) after enrollment and (2) either death or neurodevelopmental impairment on a standardized examination at 18 to 22 months' adjusted age. RESULTS. Severe NEC or IP occurred in 156 (5.2 %) of 2987 ELBW infants; 80 were treated with initial drainage, and 76 were treated with initial laparotomy. By 18 to 22 months, 78 (50%) had died; 112 (72%) had died or were shown to be impaired. Outcome was worse in the subgroup with NEC. Laparotomy was never performed in 76% (28 of 36) of drain-treated survivors. CONCLUSIONS. Drainage was commonly used, and outcome was poor. Our findings, particularly the risk-adjusted odds ratio favoring laparotomy for death or impairment, indicate the need for a large, multicenter clinical trial to assess the effect of the initial surgical therapy on outcome at [greater than or equal to] 18 months. KEY WORDS. necrotizing enterocolitis, neonatal surgery, neurodevelopmental outcomes.

OBJECTIVE. We sought to determine if an association exists between the use of histamine-2 receptor (H2) blockers and the incidence of necrotizing enterocolitis (NEC) in infants of 401 to 1500 g in birth weight. STUDY DESIGN. Data from the National Institute of Child Health and Human Development Neonatal Research Network very low birth weight (401-1500 g) registry from September 1998 to December 2001 were analyzed. The relation between the diagnosis of NEC (Bell stage II or greater) and antecedent H2-blocker treatment was determined by using case-control methodology. Conditional logistic regression was implemented, controlling for gender, site of birth (outborn versus inborn), Apgar score of RESULTS. Of 11 072 infants who survived for at least 12 hours, 787 (7.1%) developed NEC (11.5% of infants 401-750 g, 9.1% of infants 751-1000 g, 6.0% of infants 1001-1250 g, and 3.9% of infants 1251-1500 g). Antecedent H2-blocker use was associated with an increased incidence of NEC (P < .0001). CONCLUSIONS. H2-blocker therapy was associated with higher rates of NEC, which is in agreement with a previous randomized trial of acidification of infant feeds that resulted in a decreased incidence of NEC. In combination, these data support the hypothesis that gastric pH level may be a factor in the pathogenesis of NEC. KEY WORDS. prematurity, cimetidine, ranitidine, famotidine, necrotizing enterocolitis, H2 blockers. PEDIATRICS 2006;117:e137-e142. URL: www.pediatrics.org/ccji/doi/10.1542/peds.2005-1543, Ronnie Guillet, MD, PhD, Barbara J. Stoll, MD, C. Michael Cotten, MD, Marie Gantz, PhD, Scott McDonald, BS, W. Kenneth Poole, PhD, Dale L. Phelps, MD, for members of the [...]

Objective: Extremely low birth weight infants often require rehospitalization during infancy. Our objective was to identify at the time of discharge which extremely low birth weight infants are at higher risk for rehospitalization., Methods: Data from extremely low birth weight infants in Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers from 2002-2005 were analyzed. The primary outcome was rehospitalization by the 18- to 22-month follow-up, and secondary outcome was rehospitalization for respiratory causes in the first year. Using variables and odds ratios identified by stepwise logistic regression, scoring systems were developed with scores proportional to odds ratios. Classification and regression-tree analysis was performed by recursive partitioning and automatic selection of optimal cutoff points of variables., Results: A total of 3787 infants were evaluated (mean ± SD birth weight: 787 ± 136 g; gestational age: 26 ± 2 weeks; 48% male, 42% black). Forty-five percent of the infants were rehospitalized by 18 to 22 months; 14.7% were rehospitalized for respiratory causes in the first year. Both regression models (area under the curve: 0.63) and classification and regression-tree models (mean misclassification rate: 40%-42%) were moderately accurate. Predictors for the primary outcome by regression were shunt surgery for hydrocephalus, hospital stay of >120 days for pulmonary reasons, necrotizing enterocolitis stage II or higher or spontaneous gastrointestinal perforation, higher fraction of inspired oxygen at 36 weeks, and male gender. By classification and regression-tree analysis, infants with hospital stays of >120 days for pulmonary reasons had a 66% rehospitalization rate compared with 42% without such a stay., Conclusions: The scoring systems and classification and regression-tree analysis models identified infants at higher risk of rehospitalization and might assist planning for care after discharge.

Objective: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia., Design: Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months., Results: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19)., Conclusions: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE., (Copyright © 2011 by the American Academy of Pediatrics.)

Background: Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial., Objective: Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age., Design/methods: A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups., Results: Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories., Conclusions: Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.