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1.  Vitamin A Supplementation in Extremely Low- Birth-Weight Infants: Subgroup Analysis in Small-for-Gestational-Age Infants 
American journal of perinatology  2013;30(9):771-780.
Objective
Preterm infants with intrauterine growth restriction are at increased risk of respiratory distress syndrome and bronchopulmonary dysplasia (BPD). A randomized clinical trial by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network demonstrated that vitamin A supplementation in extremely low-birth-weight (ELBW) preterm infants requiring early respiratory support decreased the risk of developing BPD.
Study Design
A subgroup analysis of small-for-gestational-age (SGA) infants from the original NICHD trial was performed to test the hypothesis that in infants requiring early respiratory support, vitamin A supplementation decreases the relative risk of BPD or death in premature SGA infants to a greater extent than in gestational age–equivalent vitamin A–treated appropriate-for-gestational-age (AGA) infants.
Results
Although vitamin A supplementation significantly increased serum retinol concentrations in AGA ELBW infants (median [5th percentile, 95th percentile]: 16.3 [−7.0, 68.8] versus 2.4 [−13.9, 55.1]; p < 0.001), no increases were noted in SGA ELBW infants.
Conclusions
Given the limited power of this analysis due to a low number of SGA infants, these data did not provide evidence to support the hypothesis that vitamin A supplementation in preterm SGA infants requiring early respiratory support decreases the relative risk of BPD or death as compared with preterm AGA infants.
doi:10.1055/s-0032-1333410
PMCID: PMC3923571  PMID: 23329565
vitamin A; IUGR–intrauterine growth restriction; BPD–bronchopulmonary dysplasia; SGA–small for gestational age; AGA–appropriate for gestational age
2.  Characteristics of extremely low birth weight infant survivors with unimpaired outcomes at 30 months of age 
Objective
To evaluate characteristics of unimpaired outcome in ELBW survivors.
Study Design
ELBW infants (n=714) with 30 months’ assessments were analyzed. Logistic regression was used to develop a model for the binary outcome of unimpaired versus impaired outcome.
Results
Thirty-three percent of infants had an unimpaired outcome. 17% of ELBW survivors had a Bayley II Mental Developmental Index score of ≥101 and 2% had a score of ≥116. Female gender, use of antenatal steroids, maternal education ≥ high school and absence of major neonatal morbidities were independent predictors of unimpaired outcome. The likelihood of an unimpaired outcome in presence of major neonatal morbidities was higher in infants exposed to antenatal steroids.
Conclusions
The majority of unimpaired ELBW survivors had cognitive scores shifted towards the lower end of the normal distribution. Exposure to antenatal steroids was associated with higher likelihood of an unimpaired outcome in infants with major neonatal morbidities.
doi:10.1038/jp.2013.71
PMCID: PMC3903461  PMID: 23807719
extremely low birth weight; unimpaired outcome; outcome; antenatal steroids; cerebral palsy
3.  Hypothermia: Novel Approaches for Premature Infants 
Early human development  2011;87(Suppl 1):S17-S18.
Hypothermia for hypoxic ischemic encephalopathy has recently permeated clinical practice for term infants. Speculation regarding a neuroprotective benefit of hypothermia for premature infants with HIE has been raised as a need for further research. Hypothermia for other indications including necrotizing enterocolitis with the hope of tissue preservation following injury is less well studied. A summary of evidence for hypothermia and premature infants is presented in this brief report.
doi:10.1016/j.earlhumdev.2011.01.004
PMCID: PMC3058821  PMID: 21277717
Infant; premature; hypoxic-ischemic encephalopathy; hypothermia; necrotizing enterocolitis
5.  Improving the Neonatal Research Network Annual Certification for Neurologic Examination of the 18–22 month Child 
The Journal of pediatrics  2012;161(6):1041-1046.e2.
Objective
To describe the Neonatal Research Network’s (NRN) efforts to improve the certification process for the Follow-up Study neurologic exam and to evaluate inter-rater agreement before and after two annual training workshops.
Study design
The NRN Follow-up Study is a multi-center observational study that has examined more than 11,500 infants from 1998–2010 and born ≤ 26 weeks gestational age at 18 – 22 months corrected age for neurodevelopmental outcome. The percentages of examiners who agreed with the Gold Standard examiner on four neurodevelopmental outcomes on the initial training video and a test video were calculated. Consistency among examiners was assessed with the first-order agreement coefficient (AC1) statistic.
Results
Improvements in agreement among examiners occurred between 2009 and 2010 and between initial training and test. Examiner agreement with the Gold Standard during the initial training was 83% – 91% in 2009 and 89% – 99% in 2010. Examiner agreement on the workshop test video increased from 2009 to 2010 with agreement reaching 100% for all four neurodevelopmental outcomes examined in 2010. AC1 values for the four neurodevelopmental outcomes on the training videos ranged from 0.64 – 0.82 in 2009 and 0.77 – 0.97 in 2010.
Conclusions
We demonstrate the importance of annual certification and the benefits of evaluation and revision of certification protocols to achieve high levels of confidence in neurodevelopmental study outcomes for multi-center networks.
doi:10.1016/j.jpeds.2012.05.048
PMCID: PMC3465479  PMID: 22748517
examiner training; neurodevelopmental outcome; inter-rater agreement
6.  Neurobehavioral Disinhibition Predicts Initiation of Substance Use in Children with Prenatal Cocaine Exposure 
Drug and alcohol dependence  2012;126(1-2):80-86.
Background
In previous work we (Fisher et al., 2011) examined the emergence of neurobehavioral disinhibition (ND) in adolescents with prenatal substance exposure. We computed ND factor scores at three age points (8/9, 11 and 13/14 years) and found that both prenatal substance exposure and early adversity predicted ND. The purpose of the current study was to determine the association between these ND scores and initiation of substance use between ages 8–16 in this cohort as early initiation of substance use has been related to later substance use disorders. Our hypothesis was that prenatal cocaine exposure predisposes the child to ND, which, in turn, is associated with initiation of substance use by age 16.
Methods
We studied 386 cocaine exposed and 517 unexposed children followed since birth in a longitudinal study. Five dichotomous variables were computed based on the subject’s report of substance use: alcohol only; tobacco only; marijuana only; illicit substances and any substance.
Results
Cox proportional hazard regression showed that the 8/9 year ND score was related to initiation of alcohol, tobacco, illicit and any substance use but not marijuana use. The trajectory of ND across the three age periods was related to substance use initiation in all five substance use categories. Prenatal cocaine exposure, although initially related to tobacco, marijuana and illicit substance initiation, was no longer significant with ND scores in the models.
Conclusion
Prenatal drug exposure appears to be a risk pathway to ND, which by 8/9 years portends substance use initiation.
doi:10.1016/j.drugalcdep.2012.04.014
PMCID: PMC3439586  PMID: 22608010
neurodevelopmental disinhibition; substance use initiation; prenatal cocaine exposure
7.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Objective
Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBW) with and without blood stream infection (BSI) during their birth hospitalization.
Patients and Methods
Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4, and 6 months after birth with blood drawn 4–6 weeks after 3rd dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with birth-weight groups and other confounding factors identified in the primary study.
Results
244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody ≥0.35μg/mL.
Conclusions
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
doi:10.1038/jp.2013.5
PMCID: PMC3722279  PMID: 23370608
VLBW; immune response; vaccine; sepsis; blood stream infection
8.  Executive Summary of the Workshop on Infection in the High Risk Infant 
For newborn infants in intensive care units, the morbidity and mortality from infection continues to be a major burden despite advances in neonatal care. Infants are at risk for early onset, late onset, as well as hospital acquired infections. Research studies are needed to optimize timely diagnosis and treatment, and develop patient-specific and system-wide strategies to prevent perinatal and neonatal infections. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) organized a workshop in August 2008. In this paper we provide a summary of the discussions, focusing on major knowledge gaps, and prioritized suggestions for research in this area.
doi:10.1038/jp.2009.199
PMCID: PMC3038782  PMID: 20072133
infant; infection; newborn; sepsis
9.  Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes 
The Journal of pediatrics  2012;161(2):222-8.e3.
Objectives
To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development’s Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006–2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008–2011 (period 2).
Study design
Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.
Results
Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).
Conclusion
Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.
doi:10.1016/j.jpeds.2012.01.057
PMCID: PMC3796892  PMID: 22421261
10.  Cytokines and Post-hemorrhagic Ventricular Dilation in Premature Infants 
American journal of perinatology  2012;29(9):731-740.
Objective
To determine in extremely low birth weight (ELBW) infants if elevated blood inteferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGFβ) are associated with need for shunt following severe intraventricular hemorrhage (IVH), or with ventricular dilation following milder grades /no IVH.
Study design
Whole blood cytokines were measured on postnatal days 1, 3, 7, 14, and 21. Maximum IVH grade in the first 28d, and shunt surgery or ventricular dilation on subsequent ultrasound (28d -36 w PMA) were determined.
Results
Of 902 infants in the NICHD NRN Cytokine study who survived to 36w/discharge, 3.1% had shunts. Of the 12% of infants with severe (Gr III–IV) IVH, 26% had a shunt associated with elevated TNF-α. None of the infants without IVH (69%) or with Gr I (12%) or II (7%) IVH received shunts, but 8.4% developed ventricular dilation, associated with lower IFN-γ and higher IL-18.
Conclusion
Statistically significant but clinically non-discriminatory alterations in blood cytokines were noted in infants with severe IVH who received shunts and in those without severe IVH who developed ventricular dilation. Blood cytokines are likely associated with brain injury but may not be clinically useful as biomarkers for white matter damage.
doi:10.1055/s-0032-1316443
PMCID: PMC3619127  PMID: 22773292
Infant; premature; Cytokines; Hydrocephalus; Intraventricular hemorrhage; Intracranial hemorrhage
11.  Hypothermia for Hypoxic Ischemic Encephalopathy in Infants ≥ 36 weeks 
Early human development  2009;85(10 Suppl):S49.
Hypoxic ischemic encephalopathy is a serious condition affecting infants which can result in death and disability. This is a summary of pathogenesis of HIE, animal studies of cooling for hypoxic and ischemic models, human hypothermia trials, and the American Academy of Pediatrics publication on hypothermia for HIE. Hypothermia for neonatal HIE is continuing to evolve as a therapy. Studies, gaps in knowledge and opportunities for research are presented herein.
doi:10.1016/j.earlhumdev.2009.08.015
PMCID: PMC2813680  PMID: 19762176
12.  Candida Virulence Properties and Adverse Clinical Outcomes in Neonatal Candidiasis 
The Journal of pediatrics  2012;161(3):441-447.e2.
Objective
To determine if premature infants with invasive Candida infection caused by strains with increased virulence properties have worse clinical outcomes than those infected with less virulent strains.
Study design
Clinical isolates were studied from 2 populations; premature infants colonized with Candida (commensal, n=27), and those with invasive candidiasis (n=81). Individual isolates of C. albicans and C. parapsilosis were tested for virulence in each of 3 assays: phenotypic switching, adhesion, and cytotoxicity. Invasive isolates were considered to have enhanced virulence if they measured more than 1 SD above the mean for the commensal isolates in at least 1 assay. Outcomes of patients with invasive isolates with enhanced virulence were compared with those with invasive isolates lacking enhanced virulence characteristics.
Results
61% of invasive isolates of C. albicans and 42% of invasive isolates of C. parapsilosis had enhanced virulence. All C. albicans cerebrospinal fluid (CSF) isolates (n=6) and 90% of urine isolates (n=10) had enhanced virulence, compared with 48% of blood isolates (n=40). Infants with more virulent isolates were younger at the time of positive culture and had higher serum creatinine.
Conclusions
Individual isolates of Candida species vary in their virulence properties. Strains with higher virulence are associated with certain clinical outcomes.
doi:10.1016/j.jpeds.2012.02.051
PMCID: PMC3419788  PMID: 22504098
C. albicans; C. parapsilosis; mortality; neurodevelopmental impairment; phenotypic switch; adhesion; cytotoxicity
13.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
Objective
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
Results
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Conclusions
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
doi:10.1016/j.jpeds.2012.01.053
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
14.  Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic–ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial 
Pediatric research  2012;72(4):414-419.
BACKGROUND
The effect of birth location on hypothermia-related outcomes has not been rigorously examined in the literature. In this study, we determined whether birth location had an impact on the benefits of whole-body cooling to 33.5 °C for 72 h in term infants (n = 208) with hypoxic–ischemic encephalopathy (HIE) who participated in the Neonatal Research Network (NRN) randomized controlled trial.
METHODS
Heterogeneity by birth location was examined with respect to cooling treatment for the 18-mo primary outcomes (death, moderate disability, severe disability) and secondary outcomes (death, components of disability), and in-hospital organ dysfunction. Logistic regression models were used to generate adjusted odds ratios.
RESULTS
Infants bom at a location other than an NRN center (outborn) (n = 93) experienced significant delays in initiation of therapy (mean (SD): 5.5 (1.1) vs. 4.4 (1.2) h), lower baseline temperatures (36.6 (1.2) vs. 37.1 (0.9) °C), and more severe HIE (43 vs. 29%) than infants born in an NRN center (inborn) (n = 115). Maternal education <12 y (50 vs. 14%) and African-American ethnicity (43 vs. 25%) were more common in the inborn group. When adjusted for NRN center and HIE severity, there were no significant differences in 18-mo outcomes or in-hospital organ dysfunction between inborn and outborn infants.
CONCLUSION
Although limited by sample size and some differences in baseline characteristics, the study showed that birth location does not appear to modify the treatment effect of hypothermia after HIE.
doi:10.1038/pr.2012.103
PMCID: PMC3730811  PMID: 22914450
15.  Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants 
The Journal of Pediatrics  2012;161(1):65-69.e1.
Objective
To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.
Study design
This was a prospective pilot RCT of infants 230/7 – 266/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
Results
Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. 161 (44%) infants were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study due to the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.
Conclusions
This pilot RCT was not feasible due to low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.
doi:10.1016/j.jpeds.2012.01.014
PMCID: PMC3357442  PMID: 22336574
Extremely preterm infant; hypotension; hydrocortisone; dopamine; informed consent
16.  Risk Factors for Post-NICU Discharge Mortality Among Extremely Low Birth Weight Infants 
The Journal of Pediatrics  2012;161(1):70-74.e2.
Objective
To evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among ELBW infants.
Study design
This is a retrospective analysis of extremely low birth weight (<1,000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network sites from January 2000 to June 2007. Infants were tracked until death or 18–22 months corrected age. Infants who died between NICU discharge and the 18–22 month follow-up visit were classified as post-NICU discharge mortality. Association of maternal and infant risk factors with post-NICU discharge mortality was determined using logistic regression analysis. A prediction model with six significant predictors was developed and validated.
Results
5,364 infants survived to NICU discharge. 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. Post-NICU discharge mortality rate was 22.3 per 1000 ELBW infants. In the prediction model, African-American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intra-partum antibiotics was associated with decreased risk of post-NICU discharge mortality.
Conclusion
We identified African-American race, unknown medical insurance and prolonged NICU stay as risk factors associated with post-NICU discharge mortality among ELBW infants.
doi:10.1016/j.jpeds.2011.12.038
PMCID: PMC3366175  PMID: 22325187
extremely preterm infants; discharge; mortality; predictive model
17.  Outcome Trajectories in Extremely Preterm Infants 
Pediatrics  2012;130(1):e115-e125.
OBJECTIVE:
Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization.
METHODS:
Data on infants with birth weight ≤1.0 kg admitted to 18 large academic tertiary NICUs during 1998–2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months.
RESULTS:
Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30.
CONCLUSIONS:
Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual “outcome trajectories” and evaluate impact of possible morbidities on outcome.
doi:10.1542/peds.2011-3693
PMCID: PMC3382921  PMID: 22689874
logistic models; premature infant; predictive value of tests; prognosis
18.  Outcomes of Extremely Low Birth Weight Infants with Bronchopulmonary Dysplasia: Impact of the Physiologic Definition 
Early human development  2012;88(7):509-515.
Aims
We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition.
Study Design
ELBW (birth weights <1000 grams) infants admitted to the Neonatal Research Network centers and hospitalized at 36 weeks postmenstrual age (n=1,189) were classified using the physiologic definition of BPD. Infants underwent Bayley III assessment at 18-22 months corrected age. Multivariable logistic regression was used to determine the association between physiologic BPD and cognitive impairment (score < 70).
Results
BPD by the physiologic definition was diagnosed in 603 (52%) infants, 537 of whom were mechanically ventilated or on FiO2 > 30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as “no BPD” (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores < 70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment.
Conclusions
Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention.
doi:10.1016/j.earlhumdev.2011.12.013
PMCID: PMC3686277  PMID: 22236557
Outcome; preterm; bronchopulmonary dysplasia; physiologic definition
19.  Long-Term Impact of Maternal Substance Use during Pregnancy and Extrauterine Environmental Adversity: Stress Hormone Levels of Preadolescent Children 
Pediatric research  2011;70(2):213-219.
Prenatal cocaine exposure (PCE) is associated with blunted stress responsivity within the extrauterine environment. This study investigated the association between PCE and diurnal salivary cortisol levels in preadolescent children characterized by high biological and/or social risk (N = 725). Saliva samples were collected at their home. Analyses revealed no group differences in basal evening or morning cortisol levels; however, children with higher degrees of PCE exhibited blunted overnight increases in cortisol, controlling for additional risk factors. Race and caregiver depression were also associated with diurnal cortisol patterns. While repeated PCE may contribute to alterations in the normal or expected stress response later in life, sociodemographic and environmental factors are likewise important in understanding hormone physiology, especially as more time elapses from the PCE. Anticipating the potential long-term medical, developmental, or behavioral effects of an altered ability to mount a normal protective cortisol stress response is essential in optimizing the outcomes of children with PCE.
doi:10.1203/PDR.0b013e3182291b13
PMCID: PMC3686483  PMID: 21546861
20.  Cytokine Profiles of Preterm Neonates with Fungal and Bacterial Sepsis 
Pediatric research  2012;72(2):212-220.
Background
Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight infants (ELBW), is lacking. We hypothesized that cytokine profiles in the 1st 21 days of life in ELBW with FS differ from those with bacterial sepsis (BS) or no sepsis (NS).
Methods
In a secondary analyses of the NICHD Cytokine study, three groups were defined - FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3±1, 7±2, 14±3, and 21±3 and sepsis group was explored.
Results
Of 1066 infants, 89 had FS and 368 had BS. Compared to BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (p<0.05). Analyses controlling for covariates showed significant group differences over time for IFN-γ, IL-10, IL-18, TGF-β and TNF-α (p<0.05).
Conclusion
Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β and TNF-α in FS, BS or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.
doi:10.1038/pr.2012.56
PMCID: PMC3629907  PMID: 22562288
21.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
Objective
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Study design
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Results
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
Conclusions
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
doi:10.1016/j.jpeds.2011.09.018
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
22.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
doi:10.1093/cid/cir800
PMCID: PMC3258271  PMID: 22144537
23.  Temperature Profile and Outcomes of Neonates Undergoing Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
BACKGROUND
Decreases below target temperature were noted among neonates undergoing cooling in the NICHD Neonatal Research Network Trial of whole body hypothermia for neonatal hypoxic-ischemic encephalopathy.
OBJECTIVE
To examine the temperature profile and impact on outcome among ≥ 36 week gestation neonates randomized at ≤ 6 hours of age targeting esophageal temperature of 33.5°C for 72 hours.
DESIGN/SETTING/PATIENTS
Infants with intermittent temperatures recorded < 32.0°C during induction and maintenance of cooling were compared to all other cooled infants and relationship with outcome at 18 months was evaluated.
RESULTS
There were no differences in stage of encephalopathy, acidosis, or 10 minute Apgar scores between infants with temperatures < 32.0°C during induction (n=33) or maintenance (n=10) and all other infants who were cooled (n=58); however birth weight was lower and need for blood pressure support higher among infants with temperatures < 32.0 °C compared to all other cooled infants. No increase in acute adverse events were noted among infants with temperatures < 32.0 °C and hours spent < 32°C were not associated with the primary outcome of death or moderate/severe disability or the Bayley II Mental Developmental Index at 18 months.
CONCLUSION
Term infants with a lower birth weight are at risk for decreasing temperatures < 32.0°C while undergoing body cooling using a servo controlled system. This information suggests extra caution during the application of hypothermia as these lower birth weight infants are at risk for overcooling. Our findings may assist in planning additional trials of lower target temperature for neonatal hypoxic-ischemic encephalopathy.
doi:10.1097/PCC.0b013e31821926bc
PMCID: PMC3161166  PMID: 21499182
temperature; hypothermia; newborn; hypoxia-ischemia; encephalopathy; whole-body cooling
24.  Bloodstream infections in very low birth weight infants with intestinal failure 
The Journal of pediatrics  2011;160(1):54-9.e2.
Objective
To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSI) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC).
Study design
Infants 401–1500 grams at birth who survived >72 hours and received care at NICHD Neonatal Research Network centers were studied. Frequency of culture positive BSI and pathogens were compared for infants with medical NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, duration of parenteral nutrition (PN) and other outcomes were evaluated.
Results
932 infants were studied (IF, n=78; surgical NEC without IF, n=452; medical NEC, n=402). The proportion with BSI after NEC diagnosis was higher in infants with IF than with surgical NEC (p=0.007) or medical NEC (p<0.001). Gram positive pathogens were most frequent. Among infants with IF, increased number of infections was associated with longer hospitalization and duration on PN (0, 1, ≥2 infections; median stay (days): 172, 188, 260, p=0.06; median days on PN: 90, 112, 115, p=0.003), and the proportion who achieved full feeds during hospitalization decreased (87%, 67%, 50%, p=0.03).
Conclusion
Recurrent BSIs are common in VLBW infants with IF. Gram positive bacteria were most commonly identified in these infants.
doi:10.1016/j.jpeds.2011.06.034
PMCID: PMC3419271  PMID: 21840538
Short bowel syndrome; Bloodstream infections; Late onset sepsis; Very low birth weight; Nutrition; Intestinal failure
25.  Phenobarbital and temperature profile during hypothermia for hypoxic-ischemic encephalopathy 
Journal of child neurology  2011;27(4):451-457.
Data from the whole body hypothermia trial was analyzed to examine the effects of phenobarbital administration prior to cooling (+PB) on the esophageal temperature (Te) profile, during the induction phase of hypothermia. A total of 98 infants were analyzed. At enrollment, +PB infants had a higher rate of severe HIE and clinical seizures and lower Te and cord pH than infants that have not received PB (−PB). There was a significant effect of PB itself and an interaction between PB and time in the Te profile. Mean Te in the +PB group was lower than in the −PB group and the differences decreased over time. In +PB infants the time to surpass target Te of 33.5°C and to reach the minimum Te during overshoot were shorter. In conclusion, the administration of PB prior to cooling was associated with changes that may reflect a reduced thermogenic response associated with barbiturates.
doi:10.1177/0883073811419317
PMCID: PMC3530920  PMID: 21960671
phenobarbital; hypoxic-ischemic encephalopathy; hypothermia; temperature control

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