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1.  A Data-Driven Algorithm Integrating Clinical and Laboratory Features for the Diagnosis and Prognosis of Necrotizing Enterocolitis 
PLoS ONE  2014;9(2):e89860.
Background
Necrotizing enterocolitis (NEC) is a major source of neonatal morbidity and mortality. Since there is no specific diagnostic test or risk of progression model available for NEC, the diagnosis and outcome prediction of NEC is made on clinical grounds. The objective in this study was to develop and validate new NEC scoring systems for automated staging and prognostic forecasting.
Study design
A six-center consortium of university based pediatric teaching hospitals prospectively collected data on infants under suspicion of having NEC over a 7-year period. A database comprised of 520 infants was utilized to develop the NEC diagnostic and prognostic models by dividing the entire dataset into training and testing cohorts of demographically matched subjects. Developed on the training cohort and validated on the blind testing cohort, our multivariate analyses led to NEC scoring metrics integrating clinical data.
Results
Machine learning using clinical and laboratory results at the time of clinical presentation led to two NEC models: (1) an automated diagnostic classification scheme; (2) a dynamic prognostic method for risk-stratifying patients into low, intermediate and high NEC scores to determine the risk for disease progression. We submit that dynamic risk stratification of infants with NEC will assist clinicians in determining the need for additional diagnostic testing and guide potential therapies in a dynamic manner.
Algorithm availability
http://translationalmedicine.stanford.edu/cgi-bin/NEC/index.pl and smartphone application upon request.
doi:10.1371/journal.pone.0089860
PMCID: PMC3938509  PMID: 24587080
2.  Systemic inflammation associated with mechanical ventilation among extremely preterm infants 
Cytokine  2012;61(1):315-322.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
doi:10.1016/j.cyto.2012.10.014
PMCID: PMC3518391  PMID: 23148992
inflammation; ventilation; preterm infant; cytokine; chemokine
3.  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
4.  Screening for Autism Spectrum Disorders in Extremely Preterm Infants 
Background
Extremely preterm (EP) infants screen positive for Autism Spectrum Disorders (ASD) at high rates. However it is not clear whether this is due to high rates of ASD in EPs or to high rates of false positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs.
Objectives
To determine rates of positive screen for ASD at 18–22months(m) in EPs using three screens; to determine factors associated with a positive screen.
Methods
554 infants born <27 weeks were screened at 18–22m using the Pervasive Developmental Disorders Screening Test, 2nd edition, Stage 2 (PDDST-II) and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness and blindness were excluded. Associations between positive screen and neonatal/infant characteristics were determined.
Results
113/554 (20 %) had ≥1 positive screen. 10% had a positive PDDST-II, 6% response to name, 9% response to joint attention; in only 1% were all 3 screens positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/language delay.
Conclusions
The use of three screens for ASD in EPs results in higher screen positive rates than use of one screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known.
doi:10.1097/DBP.0b013e31825fd0af
PMCID: PMC3434239  PMID: 22926660
Autism; Prematurity; Screening
5.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
Background
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
Aims
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
Results
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Conclusions
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
doi:10.1016/j.earlhumdev.2012.04.004
PMCID: PMC3694609  PMID: 22732241
6.  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
7.  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
8.  Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy 
Objective
The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia.
Design and patients
Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age.
Results
Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.
Conclusions
Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy.
doi:10.1136/archdischild-2011-301524
PMCID: PMC3722585  PMID: 23080477
9.  Association Between Blood Spot Transforming Growth Factor-β and Patent Ductus Arteriosus in Extremely Low-Birth Weight Infants 
Pediatric cardiology  2012;34(1):149-154.
Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.
doi:10.1007/s00246-012-0404-7
PMCID: PMC3704212  PMID: 22684193
Transforming growth factor; Patent ductus arteriosus; Preterm; Neonate
10.  Neutrophil Cd64 as a Diagnostic Marker in Neonatal Sepsis 
We assessed neutrophil CD64 as a diagnostic marker for neonatal sepsis. For early-onset sepsis, the CD64 index with a cut-point value of 2.38 had sensitivity, specificity and a negative predictive values of 100%, 68%, and 100%, respectively. For late-onset sepsis, the respective values were 3.62, 75%, 77%, and 96%. Neutrophil CD64 index can be incorporated as a valuable marker for excluding neonatal sepsis.
doi:10.1097/INF.0b013e318256fb07
PMCID: PMC3375383  PMID: 22481422
Sensitivity; specificity; infection; newborn; CD64; diagnosis of sepsis
11.  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
12.  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
13.  Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation 
Context
Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now.
Objective
To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks.
Design, Setting, Participants
Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables.
Main Outcome Measures
Mortality and neurodevelopmental impairment at 18–22 months corrected age
RESULTS
Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received antenatal corticosteroids but the only outcome significantly lower at 22 weeks was death/necrotizing enterocolitis (antenatal corticosteroids, 73.5% vs no antenatal corticosteroids, 84.5%; adjusted odds ratio 0.54; 95% CI, 0.30–0.97).
CONCLUSIONS
Among infants born at 23–25 weeks gestation, use of antenatal corticosteroids compared to non-use was associated with a lower rate of death or neurodevelopmental impairment at 18–22 months.
doi:10.1001/jama.2011.1752
PMCID: PMC3565238  PMID: 22147379
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
14.  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
15.  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
16.  Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2011;159(6):919-925.e3.
Objective
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Study design
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
Results
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
Conclusions
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
doi:10.1016/j.jpeds.2011.05.042
PMCID: PMC3215787  PMID: 21798559
17.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
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.)
doi:10.1056/NEJMoa1112066
PMCID: PMC3459579  PMID: 22646631
18.  Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials 
Pediatrics  2011;128(4):729-739.
BACKGROUND:
Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.
DESIGN/METHODS:
Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.
RESULTS:
Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92–1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98–1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74–0.98]) was found.
CONCLUSIONS:
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.
doi:10.1542/peds.2010-2725
PMCID: PMC3387905  PMID: 21930540
inhaled nitric oxide; chronic lung disease; respiratory disease; preterm infants; individual-patient data meta-analysis
19.  Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first two postnatal weeks 
Pediatric research  2011;70(3):292-296.
We examined the association between elevated concentrations of 25 blood proteins in blood spots collected on postnatal days 1, 7, and 14 from infants < 28 weeks gestation who survived to 24 months and the risk of two patterns of early lung disease i.e., early and persistent pulmonary dysfunction (EPPD), and normal early pulmonary function followed by pulmonary deterioration (PD). 38% (N=347) of our cohort had PD, and 43% (N=383) had EPPD. On postnatal day 14, elevated concentrations of two proteins (RANTES and VEGF) were associated with reduced risk of PD. Similarly, the risk of EPPD was also reduced if three proteins had elevated concentrations on postnatal day 14 (RANTES, MMP-1, and VEGF). In contrast, the risk of EPPD was increased if on day 14 two proteins had elevated concentrations (IL-8 and ICAM-1). Inflammation might influence the risk of EPPD and PD, or be a consequence of lung damage or therapies to minimize lung dysfunction.
doi:10.1203/PDR.0b013e3182274f35
PMCID: PMC3152639  PMID: 21646942
20.  Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination 
Pediatrics  2011;128(1):e112-e120.
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.
doi:10.1542/peds.2010-2036
PMCID: PMC3124102  PMID: 21669899
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
21.  Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants 
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
doi:10.1164/rccm.201101-0055OC
PMCID: PMC3136997  PMID: 21471086
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
22.  Early Nutrition Mediates the Influence of Severity of Illness on Extremely Low Birth Weight Infants 
Pediatric research  2011;69(6):522-529.
To evaluate whether differences in early nutritional support provided to extremely premature infants mediate the effect of critical illness on later outcomes, we examined whether nutritional support provided to “more critically ill” infants differs from that provided to “less critically ill” infants during the initial weeks of life, and if, after controlling for critical illness, that difference is associated with growth and rates of adverse outcomes. 1366 participants in the NICHD Neonatal Research Network parenteral glutamine supplementation randomized controlled trial who were alive on day of life 7 were stratified by whether they received mechanical ventilation for the first 7 days of life. Compared to more critically ill infants, less critically ill infants received significantly more total nutritional support during each of the first 3 weeks of life, had significantly faster growth velocities, less moderate/severe bronchopulmonary dysplasia, less late-onset sepsis, less death, shorter hospital stays, and better neurodevelopmental outcomes at 18–22 months corrected age. Rates of necrotizing enterocolitis were similar. Adjusted analyses using general linear and logistic regression modeling and a formal mediation framework demonstrated that the influence of critical illness on the risk of adverse outcomes was mediated by total daily energy intake during the first week of life.
doi:10.1203/PDR.0b013e318217f4f1
PMCID: PMC3090495  PMID: 21378596
23.  Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2010;158(5):752-758.e1.
Objective
To evaluate the association between early hypocarbia and 18-22 month outcome among neonates with hypoxic-ischemic encephalopathy (HIE).
Study design
Data from the NICHD NRN randomized controlled trial of whole body hypothermia for neonatal HIE were used for this secondary observational study. Infants (n=204) had multiple blood gases recorded from birth-12h of study intervention (hypothermia vs. intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18-22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO2 and cumulative exposure to PCO2 <35 mmHg. The relationship between cumulative PCO2 <35 mmHg (calculated as the difference between 35mmHg and the sampled PCO2 multiplied by the duration of time spent <35 mmHg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), time to spontaneous respiration and ventilator days; results were expressed as OR and 95% confidence intervals. Alternative models of CO2 concentration were explored to account for fluctuations in CO2.
Results
Both minimum PCO2 and cumulative PCO2 <35mmHg were associated with poor outcome (P<0.05). Moreover, death/disability increased with greater cumulative exposure to PCO2 <35mmHg.
Conclusion
Hypocarbia is associated with poor outcome following HIE.
doi:10.1016/j.jpeds.2010.10.019
PMCID: PMC3229432  PMID: 21146184
hypocarbia; hypoxic ischemic encephalopathy; whole body hypothermia; outcome; neurodevelopmental impairment
24.  Blood protein concentrations in the first two postnatal weeks that predict bronchopulmonary dysplasia among infants born before the 28th week of gestation 
Pediatric research  2011;69(4):347-353.
Lung inflammation contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) and may be accompanied by a systematic inflammatory response. The objective of this study was to investigate the role of systemic inflammation in the development of BPD in a cohort of extremely low gestational age newborns (ELGANs) by examining the relationships between inflammation-associated proteins in neonatal blood samples and pulmonary outcomes. Proteins were measured in blood specimens collected on postnatal days 1–3, 5–8 and 12–15 from 932 ELGANs. Increased risk of BPD was associated with elevated blood concentrations of a variety of pro-inflammatory cytokines, adhesion molecules and proteases. Reduced risk was prominently associated with increased concentrations of one chemokine, RANTES. Elevations of inflammatory proteins associated with BPD risk occurred during the first days following birth, and inflammation intensified thereafter. Therefore, exposures that promote inflammation after the first postnatal days may be more critical in the pathogenesis of BPD. Fetal growth restriction, a known BPD risk factor, was not accompanied by proteins elevations and therefore does not appear to be mediated by systemic inflammation. By contrast, mechanical ventilation altered protein levels and may be associated with systemic inflammation.
doi:10.1203/PDR.0b013e31820a58f3
PMCID: PMC3083822  PMID: 21150694
25.  Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial 
Journal of Child Neurology  2010;26(3):322-328.
It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.
doi:10.1177/0883073810380915
PMCID: PMC3290332  PMID: 20921569
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy

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