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1.  Hypoxic Episodes in Bronchopulmonary Dysplasia 
Clinics in perinatology  2015;42(4):825-838.
Hypoxic episodes are troublesome components of bronchopulmonary dysplasia in preterm infants. Immature respiratory control appears to be the major contributor, typically superimposed upon abnormal respiratory function. As a result, relatively short respiratory pauses may precipitate desaturation and accompanying bradycardia. As this population is predisposed to pulmonary hypertension, it is likely that pulmonary vasoconstriction may also play a role in hypoxic episodes. The natural history of intermittent hypoxic episodes has been well characterized in the preterm population at risk for BPD. However, the consequences of these episodes are less clear. Proposed associations of intermittent hypoxia include retinopathy of prematurity, sleep disordered breathing, and neurodevelopmental delay. Future study should address whether these associations are causal relationships.
doi:10.1016/j.clp.2015.08.009
PMCID: PMC4660265  PMID: 26593081
neonatal respiratory control; apnea of prematurity; desaturation episodes in preterm infants
2.  PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) 
Objective
To determine the association of PaCO2 with severe intraventricular hemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18–22 months in premature infants.
Design
Secondary exploratory data analysis of SUPPORT.
Setting
Multiple referral NICUs.
Patients
1316 infants 24 0/7 to 27 6/7 weeks gestation randomized to different oxygenation (SpO2 target 85–89% vs 91–95%) and ventilation strategies.
Main Outcome Measures
Blood gases from postnatal days 0–14 were analyzed. Five PaCO2 variables were defined: minimum [Min], maximum [Max], standard deviation, average (time-weighted), and a 4 level categorical variable (hypercapnic [highest quartile of Max PaCO2], hypocapnic [lowest quartile of Min PaCO2], fluctuators [both hypercapnia and hypocapnia], and normocapnic [middle two quartiles of Max and Min PaCO2]). PaCO2 variables were compared for infants with and without sIVH, BPD, and NDI (+/− death). Multivariable logistic regression models were developed for adjusted results.
Results
sIVH, BPD, and NDI (+/− death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (Per 10 mmHg increase: sIVH/death: OR 1.27 [1.13–1.41]; BPD/death: OR 1.27 [1.12–1.44]; NDI/death: OR 1.23 [1.10–1.38], Death: OR 1.27 [1.12–1.44], all p <0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death, or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) & ventilator days (rs0.61, p<0.0001).
Conclusions
Higher PaCO2 was an independent predictor of sIVH/death, BPD/death, and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high risk infants.
doi:10.1136/archdischild-2014-306802
PMCID: PMC4336211  PMID: 25425651
Infant; premature; Infant mortality; Infant; Premature; Diseases/epidemiology; Predictive value of tests; Prognosis; Intracranial hemorrhage; Blood Gas Analysis
3.  Early blood pressure, anti-hypotensive therapy and outcomes at 18 to 22 month corrected age in extremely preterm infants 
Objective
Investigate relationships between early blood pressure (BP) changes, receipt of anti-hypotensive therapy, and 18 – 22 month corrected age (CA) outcomes for extremely preterm infants.
Design
Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Hourly BP values and anti-hypotensive therapy exposure in the first 24 hours were recorded. Four groups were defined: infants who did or did not receive anti-hypotensive therapy in whom BP did or did not rise at the expected rate (defined as an increase in the mean arterial BP of ≥5 mmHg/day). Random-intercept logistic modeling controlling for center clustering, GA, and illness severity was used to investigate the relationship between BP, anti-hypotensive therapies, and infant outcomes.
Setting
Sixteen academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
Main Outcome Measures
Death or neurodevelopmental impairment / developmental delay (NIDD) at 18 – 22 months CA.
Results
Of 367 infants, 203 (55%) received an anti-hypotensive therapy, 272 (74%) survived to discharge, and 331 (90%) had a known outcome at 18 – 22 months CA. With logistic regression, there was an increased risk of death/NIDD with anti-hypotensive therapy versus no treatment (odds ratio: 1.836, 95% confidence interval: 1.092 – 3.086), but not NIDD alone (odds ratio: 1.53, 95% confidence interval: 0.708 – 3.307).
Conclusion
Independent of early BP changes, anti-hypotensive therapy exposure was associated with an increased risk of death/NIDD at 18 to 22 months CA when controlling for risk factors known to affect survival and neurodevelopment.
doi:10.1136/archdischild-2015-308899
PMCID: PMC4849123  PMID: 26567120
Extremely preterm infant; blood pressure; neurodevelopment; hypotension
4.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
Objectives
To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.
Study design
Retrospective cohort study from 16 centers of the NICHD Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N=8,683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI, a composite of one or more of: developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed impact of timing, by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.
Results
Tracheostomies were associated with all neonatal morbidities examined, and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without [odds ratio (OR) adjusted for center 7.0 (95%CI, 5.2-9.5)]. After adjustment for potential confounders, odds of death or NDI remained higher [OR 3.3 (95%CI, 2.4-4.6)], but odds of death alone were lower [OR 0.4 (95%CI, 0.3-0.7)], among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life [adjusted OR 0.5 (95%CI, 0.3-0.9)].
Conclusions
Tracheostomy in preterm infants is associated with adverse developmental outcomes, and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.
doi:10.1016/j.jpeds.2013.12.014
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
5.  Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012 
JAMA  2015;314(10):1039-1051.
Importance
Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.
Objective
To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.
Design, Setting, Participants
Prospective registry of 34,636 infants 22–28 weeks’ gestational age (GA) and 401–1500 gram birthweight born at 26 Network centers, 1993–2012.
Exposure
Extremely preterm birth.
Main Outcomes
Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were: severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes, adjusting for study center, race/ethnicity, GA, birthweight for GA, and sex.
Results
Use of antenatal corticosteroids increased from 1993 to 2012 (348/1431 [24%] to 1674/1919 [87%], p<0.001), as did cesarean delivery (625/1431 [44%] to 1227/1921 [64%], p<0.001). Delivery room intubation decreased from 1144/1433 (80%) in 1993 to 1253/1922 (65%) in 2012 (p<0.001). After increasing in the 1990s, postnatal steroid use declined to 141/1757 (8%) in 2004 (p<0.001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 120/1666 (7%) in 2002 to 190/1756 (11%) in 2012 (p<0.001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each GA (median GA 26 weeks, 109/296 [37%] to 85/320 [27%], adjusted relative risk [aRR]: 0.93 [95% CI, 0.92–0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants 26–27 weeks (26 weeks, 130/258 [50%] to 164/297 [55%], p<0.001). Survival increased between 2009 and 2012 for infants 23 weeks (41/152 [27%] to 50/150 [33%], aRR: 1.09 [95% CI, 1.05–1.14]) and 24 weeks (156/248 [63%] to 174/269 [65%], aRR: 1.05 [95% CI, 1.03–1.07]), with smaller relative increases for infants 25 and 27 weeks and no change for infants 22, 26 and 28 weeks. Survival without major morbidity increased approximately 2% per year for infants 25–28 weeks with no change for infants 22–24 weeks.
Conclusions and Relevance
Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks and survival without major morbidity increased for infants 25–28 weeks. These findings may be valuable in counselling families and developing novel interventions.
doi:10.1001/jama.2015.10244
PMCID: PMC4787615  PMID: 26348753
6.  Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants 
Pediatrics  2015;135(1):e32-e42.
BACKGROUND:
Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age.
METHODS:
Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks’ gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.
RESULTS:
Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.
CONCLUSIONS:
Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.
doi:10.1542/peds.2014-0898
PMCID: PMC4279063  PMID: 25554820
MRI; neurodevelopmental; neuroimaging; preterm infant; ultrasound
7.  Antenatal Magnesium Sulfate Exposure and Acute Cardiorespiratory Events in Preterm Infants 
Objective
Antenatal magnesium (anteMg) is used for tocolysis, pregnancy-induced hypertension (PIH) and neuroprotection for preterm birth. Infants exposed to anteMg are at risk for respiratory depression and resuscitation in the delivery room (DR). The study objective was to compare the risk of acute cardio-respiratory (CR) events among preterm infants exposed to anteMg and those unexposed (noMg).
Study Design
This was a retrospective analysis of prospective data collected in the NICHD Neonatal Research Network's Generic Database from 4/1/11 to 3/31/12. The primary outcome was DR intubation or mechanical ventilation (MV) at birth or on day 1 of life. Secondary outcomes were endotracheal MV (eMV), hypotension and other neonatal morbidities and mortality. Logistic regression analysis evaluated the risk of primary outcomes after adjustment for gestational age (GA), center, antenatal steroids (ANS) and PIH/eclampsia.
Results
We evaluated 1,544 infants <29 weeks GA (1,091 in anteMg group and 453 in noMg group). Mothers in the anteMg group were more likely to have higher education, PIH/eclampsia and ANS; while their infants were younger in gestation and weighed less (P<0.05). The primary outcome, mortality and neonatal morbidities were similar between groups; while eMV and hypotension were significantly less among the anteMg group compared to the noMg group. AnteMg exposure was significantly associated with decreased risk of hypotension on day 1 of life and eMV on day 3 of life in the regression analysis.
Conclusion
Preterm infants <29 weeks GA who were exposed to anteMg did not suffer worse CR outcomes compared to those without exposure.
doi:10.1016/j.ajog.2014.07.023
PMCID: PMC4275326  PMID: 25046806
antenatal magnesium; nasal CPAP; neonatal resuscitation; preterm infants
8.  Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants 
American journal of perinatology  2015;32(11):1024-1030.
Background
We previously reported on the overall incidence, management and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short term outcomes in term and late preterm newborn infants.
Objective
To evaluate how 4 definitions of CVI relate to short term outcomes and death.
Study Design
The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short term outcomes at discharge and 4 different definitions of CVI were further analyzed.
Results
All 4 definitions were associated with greater number of days on MV & days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days to full feeding, days in the NICU or death. The definition based on treatment of CVI was associated with all outcomes including death.
Conclusions
The definition using a threshold BP alone was not consistently associated with adverse short term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.
doi:10.1055/s-0035-1547321
PMCID: PMC4689139  PMID: 25825962
blood pressure; cardiovascular insufficiency; outcomes; newborn; infant
9.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
BACKGROUND
Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth.
METHODS
We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%).
RESULTS
Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation.
CONCLUSIONS
Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1410689
PMCID: PMC4465092  PMID: 25946279
10.  Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants 
Pediatrics  2014;134(5):e1369-e1377.
OBJECTIVE:
Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP.
METHODS:
This was a cohort study of 15 751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP.
RESULTS:
Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49–1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37–0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36–0.777, P = .0011).
CONCLUSIONS:
The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.
doi:10.1542/peds.2014-0183
PMCID: PMC4533280  PMID: 25349317
indomethacin; intestinal perforation; necrotizing enterocolitis; neonate
11.  Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants with Spontaneous Intestinal Perforation or Surgical Necrotizing Enterocolitis 
Objective
To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18–22 months corrected age compared to infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation.
Study Design
Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000–2005. The study infants were designated into 3 groups: 1) Spontaneous intestinal perforation without necrotizing enterocolitis; 2) Surgical necrotizing enterocolitis (Bell's stage III); and 3) Neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center.
Results
Infants with surgical necrotizing enterocolitis had the highest rate of death prior to hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared to infants in the spontaneous intestinal perforation group (39.1% and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1% and 53.3%; p<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted OR 2.21, 95% CI: 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9 respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4 respectively).
Conclusions
Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18–22 months corrected age.
doi:10.1038/jp.2013.128
PMCID: PMC3877158  PMID: 24135709
spontaneous intestinal perforation; necrotizing enterocolitis; extremely low birth weight; neurodevelopmental impairment
12.  A Multicenter Cohort Study of Treatments and Hospital Outcomes in Neonatal Abstinence Syndrome 
Pediatrics  2014;134(2):e527-e534.
OBJECTIVES:
To compare pharmacologic treatment strategies for neonatal abstinence syndrome (NAS) with respect to total duration of opioid treatment and length of inpatient hospital stay.
METHODS:
We conducted a cohort analysis of late preterm and term neonates who received inpatient pharmacologic treatment of NAS at one of 20 hospitals throughout 6 Ohio regions from January 2012 through July 2013. Physicians managed NAS using 1 of 6 regionally based strategies.
RESULTS:
Among 547 pharmacologically treated infants, we documented 417 infants managed using an established NAS weaning protocol and 130 patients managed without protocol-driven weaning. Regardless of the treatment opioid chosen, when we accounted for hospital variation, infants receiving protocol-based weans experienced a significantly shorter duration of opioid treatment (17.7 vs 32.1 days, P < .0001) and shorter hospital stay (22.7 vs 32.1 days, P = .004). Among infants receiving protocol-based weaning, there was no difference in the duration of opioid treatment or length of stay when we compared those treated with morphine with those treated with methadone. Additionally, infants treated with phenobarbital were treated with the drug for a longer duration among those following a morphine-based compared with methadone-based weaning protocol. (P ≤ .002).
CONCLUSIONS:
Use of a stringent protocol to treat NAS, regardless of the initial opioid chosen, reduces the duration of opioid exposure and length of hospital stay. Because the major driver of cost is length of hospitalization, the implications for a reduction in cost of care for NAS management could be substantial.
doi:10.1542/peds.2013-4036
PMCID: PMC4531273  PMID: 25070317
drug withdrawal; opioid; methadone; morphine; neonatal abstinence syndrome; treatment protocol
13.  Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial 
The Journal of pediatrics  2014;165(2):240-249.e4.
Objective
To explore the early childhood pulmonary outcomes of infants who participated in the NICHD SUPPORT Trial, using a factorial design that randomized extremely preterm infants to lower vs. higher oxygen saturation targets and delivery room CPAP vs. intubation/surfactant, found no significant difference in the primary composite outcome of death or BPD.
Study design
The Breathing Outcomes Study, a prospective secondary to SUPPORT, assessed respiratory morbidity at 6 month intervals from hospital discharge to 18–22 months corrected age (CA). Two pre-specified primary outcomes, wheezing more than twice per week during the worst 2 week period and cough longer than 3 days without a cold were compared between each randomized intervention.
Results
One or more interviews were completed for 918 of 922 eligible infants. The incidence of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between study arms of either randomized intervention. Infants randomized to lower vs. higher oxygen saturation targets had similar risks of death or respiratory morbidities (except for croup, treatment with oxygen or diuretics at home). Infants randomized to CPAP vs. intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs. 36.5%, p<0.05), respiratory illnesses diagnosed by a doctor (47.7% vs. 55.2%, p<0.05) and physician or emergency room visits for breathing problems (68.0% vs. 72.9%, p<0.05) by 18–22 months CA.
Conclusion
Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18–22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.
doi:10.1016/j.jpeds.2014.02.054
PMCID: PMC4111960  PMID: 24725582
Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Low Birth Weight; Infant, Extremely Low Birth Weight; Infant, Premature; Infant, Extremely Low Gestational Age; Infant mortality; Respiratory morbidity; Intensive care, neonatal; Hospital Readmission; Oximetry; Randomized controlled trial; Retinopathy of prematurity (ROP); Continuous Positive Airway Pressure; Intubation, endotracheal; Pulmonary surfactants/therapeutic use; Oxygen inhalation therapy/methods; Oxygen administration & dosage; Follow-up studies
14.  Causes and Timing of Death in Extremely Premature Infants from 2000 through 2011 
The New England journal of medicine  2015;372(4):331-340.
BACKGROUND
Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.
METHODS
We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.
RESULTS
The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008–2011 period (P = 0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008–2011 than in 2000–2003 and 2004–2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P = 0.002). Similarly, in 2008–2011, as compared with 2000–2003, there were decreases in deaths attributed to immaturity (P = 0.05) and deaths complicated by infection (P = 0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P = 0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.
CONCLUSIONS
We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis–related deaths increased. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1403489
PMCID: PMC4349362  PMID: 25607427
15.  Spontaneous Intestinal Perforation in Extremely Low Birth Weight Infants: Association with Indometacin Therapy and Effects on Neurodevelopmental Outcomes at 18-22 months Corrected Age 
Background
Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. We hypothesized: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for IVH (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age.
Design/Methods
We retrospectively identified ELBW infants with SIP in the Neonatal Research Network’s generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted odds ratio for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18 to 22 months corrected age.
Results
Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25,2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or NDI (adjusted OR−1.85; 95% CI 1.32,2.60) and NDI among survivors (adjusted OR−1.75, 95% CI 1.20,2.55).
Conclusion
Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes.
doi:10.1136/archdischild-2011-300659
PMCID: PMC3753803  PMID: 22684157
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
16.  The Effect of Red Blood Cell Transfusion on Intermittent Hypoxemia in ELBW Infants 
Objective
To test the hypothesis that the effect of red blood cell (RBC) transfusion on intermittent hypoxemia (IH) in extremely low birth weight (ELBW) infants is dependent on postnatal age.
Study Design
Oxygen saturation of 130 ELBW infants, who required transfusion, was monitored continuously for the first 8wks of life. We compared the characteristics of IH (SpO2 ≤ 80% for ≥4s and ≤3min), 24h before and both 24h and 24-48h after each RBC transfusion at three distinct time periods: Epoch 1, 1-7d; Epoch 2, 8-28d; and Epoch 3, >28d.
Results
In Epoch 1, the frequency and severity of IH events were not significantly different before and after transfusion. In both Epochs 2 and 3 there was a decrease in IH frequency and severity 24h after RBC transfusion that persisted for 48h. In addition, there was a decrease in the overall time spent with SpO2 ≤ 80% which persisted for 24h after transfusion in Epochs 1 and 3, and for 48h in Epoch 3.
Conclusion
The benefit of RBC transfusion on IH is age dependent as improvement in the frequency and severity of IH after transfusion only occurs beyond the first week of life. These observations will aid clinician’s decision making by clarifying the benefit of RBC transfusions on patterns of oxygenation in preterm infants.
doi:10.1038/jp.2014.115
PMCID: PMC4245392  PMID: 24921411
Red Blood Cell Transfusion; Intermittent Hypoxemia; Apnea of Prematurity; Oxygen Saturation
17.  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
18.  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
19.  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
20.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
IMPORTANCE
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
OBJECTIVE
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
DESIGN, SETTING, AND PARTICIPANTS
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
INTERVENTIONS
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
MAIN OUTCOMES AND MEASURES
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
RESULTS
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
CONCLUSIONS AND RELEVANCE
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
doi:10.1001/jama.2014.16058
PMCID: PMC4335311  PMID: 25536254
21.  Inhaled Nitric Oxide Usage in Preterm Infants in the NICHD Neonatal Research Network: Inter-site Variation and Propensity Evaluation 
Background
The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, an NIH consensus development conference cautioned against use of iNO in preterm infants.
Objective
1) To determine prevalence and variability in use of iNO in the NICHD Neonatal Research Network (NRN) before and after the consensus conference and 2) separately, to examine associations between iNO use and severe BPD or death.
Design/Methods
The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008–2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.
Results
A total of 4,885 infants were assessed between 2008–2011; 128 (2.6%) received iNO before Day 7, 140 (2.9%) between Day 7 and 28 and 47 (1.0%) at >28 days. Center-specific iNO use during 2008–2010 ranged from 21.9% to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6% to 1.6% (p<0.001) in 2011. Use of iNO started between Day 7 and Day 14 was more prevalent among younger infants with more severe courses in Week 1 and associated with increased risk of severe BPD or death (OR 2.24;95% CI 1.23–4.07).
Conclusions
The variability and total use of iNO decreased in 2011 compared to 2008–2010. iNO administration started at ≥Day 7 was associated with more severe outcomes compared to infants without iNO exposure.
doi:10.1038/jp.2014.105
PMCID: PMC4323079  PMID: 24901452
Inhaled nitric oxide; bronchopulmonary dysplasia; extremely premature infant
22.  Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 
Pediatrics  2014;133(2):226-235.
OBJECTIVE:
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.
METHODS:
Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.
RESULTS:
Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.
CONCLUSIONS:
In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.
doi:10.1542/peds.2013-1702
PMCID: PMC3904274  PMID: 24446439
trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm infants
23.  Chorioamnionitis and Early Childhood Outcomes among Extremely Low-Gestational-Age Neonates 
JAMA pediatrics  2014;168(2):137-147.
Importance
Chorioamnionitis is strongly linked to preterm birth and to neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18-22 month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.
Objective
To compare the neonatal and neurodevelopmental outcomes of three groups of extremely-low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.
Design
Longitudinal observational study.
Setting
Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
Participants
2390 extremely preterm infants born <27 weeks' gestational age between January 1, 2006 and December 31, 2008 with placental histopathology and 18-22 months' corrected age follow-up data were eligible.
Main exposure
Chorioamnionitis
Main Outcome Measures
Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant Development, 3rd-Edition) and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.
Results
Neonates exposed to chorioamnionitis had a lower gestational age (GA) and had higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of gestational age in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological+clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (Adjusted OR 2.4, [1.3- 4.3] without GA; Adjusted OR 2.0, [1.1-3.6] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological+clinical chorioamnionitis (Adjusted OR 0.68, [0.52-0.89] without GA; 0.66, [0.49-0.89] with GA). Risk of behavioral problems did not differ statistically between groups.
Conclusions and Relevance
Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.
doi:10.1001/jamapediatrics.2013.4248
PMCID: PMC4219500  PMID: 24378638
chorioamnionitis; preterm; neurodevelopmental impairment; outcome
24.  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
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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