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1.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998 and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index < 70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small for gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18–22 months’ corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20% of infants survived without NDI.
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
2.  Spontaneous Intestinal Perforation in Extremely Low Birth Weight Infants: Association with Indometacin Therapy and Effects on Neurodevelopmental Outcomes at 18-22 months Corrected Age 
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.
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.
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).
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.
PMCID: PMC3753803  PMID: 22684157
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
3.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
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).
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.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
4.  Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy 
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.
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.
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.
PMCID: PMC3722585  PMID: 23080477
5.  Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants 
The Journal of Pediatrics  2012;161(1):65-69.e1.
To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.
Study design
This was a prospective pilot RCT of infants 230/7 – 266/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. 161 (44%) infants were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study due to the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.
This pilot RCT was not feasible due to low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.
PMCID: PMC3357442  PMID: 22336574
Extremely preterm infant; hypotension; hydrocortisone; dopamine; informed consent
6.  Risk Factors for Post-NICU Discharge Mortality Among Extremely Low Birth Weight Infants 
The Journal of Pediatrics  2012;161(1):70-74.e2.
To evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among ELBW infants.
Study design
This is a retrospective analysis of extremely low birth weight (<1,000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network sites from January 2000 to June 2007. Infants were tracked until death or 18–22 months corrected age. Infants who died between NICU discharge and the 18–22 month follow-up visit were classified as post-NICU discharge mortality. Association of maternal and infant risk factors with post-NICU discharge mortality was determined using logistic regression analysis. A prediction model with six significant predictors was developed and validated.
5,364 infants survived to NICU discharge. 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. Post-NICU discharge mortality rate was 22.3 per 1000 ELBW infants. In the prediction model, African-American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intra-partum antibiotics was associated with decreased risk of post-NICU discharge mortality.
We identified African-American race, unknown medical insurance and prolonged NICU stay as risk factors associated with post-NICU discharge mortality among ELBW infants.
PMCID: PMC3366175  PMID: 22325187
extremely preterm infants; discharge; mortality; predictive model
7.  Outcome Trajectories in Extremely Preterm Infants 
Pediatrics  2012;130(1):e115-e125.
Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization.
Data on infants with birth weight ≤1.0 kg admitted to 18 large academic tertiary NICUs during 1998–2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months.
Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30.
Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual “outcome trajectories” and evaluate impact of possible morbidities on outcome.
PMCID: PMC3382921  PMID: 22689874
logistic models; premature infant; predictive value of tests; prognosis
8.  Outcomes of Extremely Low Birth Weight Infants with Bronchopulmonary Dysplasia: Impact of the Physiologic Definition 
Early human development  2012;88(7):509-515.
We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition.
Study Design
ELBW (birth weights <1000 grams) infants admitted to the Neonatal Research Network centers and hospitalized at 36 weeks postmenstrual age (n=1,189) were classified using the physiologic definition of BPD. Infants underwent Bayley III assessment at 18-22 months corrected age. Multivariable logistic regression was used to determine the association between physiologic BPD and cognitive impairment (score < 70).
BPD by the physiologic definition was diagnosed in 603 (52%) infants, 537 of whom were mechanically ventilated or on FiO2 > 30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as “no BPD” (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores < 70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment.
Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention.
PMCID: PMC3686277  PMID: 22236557
Outcome; preterm; bronchopulmonary dysplasia; physiologic definition
9.  Population Pharmacokinetics of Piperacillin Using Scavenged Samples from Preterm Infants 
Therapeutic Drug Monitoring  2012;34(3):312-319.
Piperacillin is often used in preterm infants for intra-abdominal infections; however, dosing has been derived from small single-center studies excluding extremely preterm infants at highest risk for these infections. We evaluated the population pharmacokinetics (PK) of piperacillin using targeted sparse sampling and scavenged samples obtained from preterm infants ≤32 weeks gestational age at birth and <120 postnatal days.
Materials and Methods
A 5-center study was performed. A population PK model using nonlinear mixed effect modeling was developed. Covariate effects were evaluated based on estimated precision and clinical significance.
Fifty-six preterm infants were evaluated and had a median (range) gestational age at birth of 25 (22–32) weeks, a postnatal age of 17 (1–77) days, a postmenstrual age of 29 (23–40) weeks, and a weight of 867 (400–2580) grams. The final PK data set contained 211 samples; 202/211 (96%) were scavenged from discarded clinical specimens. Piperacillin population PK was best described by a 1-compartment model. The population mean clearance (CL) was derived by the equation CL (liter/h)=0.479 x (weight)0.75 x 0.5/serum creatinine and using a volume of distribution (V) (liter) of 2.91 x (weight). The relative standard errors around parameter estimates ranged from 13.7–32.2%. A trend towards increased CL was observed with increasing gestational age at birth; infants with serum creatinine ≥1.2 mg/dL had a 60% reduction in piperacillin CL. The majority (>70%) of infants did not meet pre-defined pharmacodynamic efficacy targets.
Scavenged PK sampling is a minimal-risk approach that can provide meaningful information related to development of PK models but not dosing recommendations for piperacillin. The utility of scavenged sampling in providing definitive dosing recommendations may be drug-dependent and needs to be further explored.
PMCID: PMC3354042  PMID: 22569355
neonate; drug; pharmacokinetics; piperacillin
10.  Approach to Infants Born at 22 to 24 Weeks’ Gestation: Relationship to Outcomes of More-Mature Infants 
Pediatrics  2012;129(6):e1508-e1516.
We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation).
Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity.
Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants.
This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants.
PMCID: PMC3362905  PMID: 22641761
low-birth weight infant; NICUs; treatment; patient outcome assessment
11.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
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.
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.
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.
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
12.  Methicillin-Resistant and Susceptible Staphylococcus aureus Bacteremia and Meningitis in Preterm Infants 
Pediatrics  2012;129(4):e914-e922.
Data are limited on the impact of methicillin-resistant Staphylococcus aureus (MRSA) on morbidity and mortality among very low birth weight (VLBW) infants with S aureus (SA) bacteremia and/or meningitis (B/M).
Neonatal data for VLBW infants (birth weight 401–1500 g) born January 1, 2006, to December 31, 2008, who received care at centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were collected prospectively. Early-onset (≤72 hours after birth) and late-onset (>72 hours) infections were defined by blood or cerebrospinal fluid cultures and antibiotic treatment of ≥5 days (or death <5 days with intent to treat). Outcomes were compared for infants with MRSA versus methicillin-susceptible S aureus (MSSA) B/M.
Of 8444 infants who survived >3 days, 316 (3.7%) had SA B/M. Eighty-eight had MRSA (1% of all infants, 28% of infants with SA); 228 had MSSA (2.7% of all infants, 72% of infants with SA). No infant had both MRSA and MSSA B/M. Ninety-nine percent of MRSA infections were late-onset. The percent of infants with MRSA varied by center (P < .001) with 9 of 20 centers reporting no cases. Need for mechanical ventilation, diagnosis of respiratory distress syndrome, necrotizing enterocolitis, and other morbidities did not differ between infants with MRSA and MSSA. Mortality was high with both MRSA (23 of 88, 26%) and MSSA (55 of 228, 24%).
Few VLBW infants had SA B/M. The 1% with MRSA had morbidity and mortality rates similar to infants with MSSA. Practices should provide equal focus on prevention and management of both MRSA and MSSA infections among VLBW infants.
PMCID: PMC3313632  PMID: 22412036
Staphylococcus aureus; methicillin resistant; infant; newborn
13.  Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation 
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.
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
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).
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.
PMCID: PMC3565238  PMID: 22147379
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
14.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
PMCID: PMC3258271  PMID: 22144537
15.  Temperature Profile and Outcomes of Neonates Undergoing Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
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.
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.
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.
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.
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.
PMCID: PMC3161166  PMID: 21499182
temperature; hypothermia; newborn; hypoxia-ischemia; encephalopathy; whole-body cooling
16.  Bloodstream infections in very low birth weight infants with intestinal failure 
The Journal of pediatrics  2011;160(1):54-9.e2.
To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSI) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC).
Study design
Infants 401–1500 grams at birth who survived >72 hours and received care at NICHD Neonatal Research Network centers were studied. Frequency of culture positive BSI and pathogens were compared for infants with medical NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, duration of parenteral nutrition (PN) and other outcomes were evaluated.
932 infants were studied (IF, n=78; surgical NEC without IF, n=452; medical NEC, n=402). The proportion with BSI after NEC diagnosis was higher in infants with IF than with surgical NEC (p=0.007) or medical NEC (p<0.001). Gram positive pathogens were most frequent. Among infants with IF, increased number of infections was associated with longer hospitalization and duration on PN (0, 1, ≥2 infections; median stay (days): 172, 188, 260, p=0.06; median days on PN: 90, 112, 115, p=0.003), and the proportion who achieved full feeds during hospitalization decreased (87%, 67%, 50%, p=0.03).
Recurrent BSIs are common in VLBW infants with IF. Gram positive bacteria were most commonly identified in these infants.
PMCID: PMC3419271  PMID: 21840538
Short bowel syndrome; Bloodstream infections; Late onset sepsis; Very low birth weight; Nutrition; Intestinal failure
17.  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.
PMCID: PMC3530920  PMID: 21960671
phenobarbital; hypoxic-ischemic encephalopathy; hypothermia; temperature control
18.  Population Pharmacokinetics of Metronidazole Evaluated Using Scavenged Samples from Preterm Infants 
Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.
PMCID: PMC3318328  PMID: 22252819
19.  Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2010;158(5):752-758.e1.
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.
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.
Hypocarbia is associated with poor outcome following HIE.
PMCID: PMC3229432  PMID: 21146184
hypocarbia; hypoxic ischemic encephalopathy; whole body hypothermia; outcome; neurodevelopmental impairment
20.  Neurodevelopmental Outcomes of Triplets or Higher-Order Extremely Low Birth Weight Infants 
Pediatrics  2011;127(3):e654-e660.
Extremely low birth weight twins have a higher rate of death or neurodevelopmental impairment than singletons. Higher-order extremely low birth weight multiple births may have an even higher rate of death or neurodevelopmental impairment.
Extremely low birth weight (birth weight 401–1000 g) multiple births born in participating centers of the Neonatal Research Network between 1996 and 2005 were assessed for death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined by the presence of 1 or more of the following: moderate to severe cerebral palsy; mental developmental index score or psychomotor developmental index score less than 70; severe bilateral deafness; or blindness. Infants who died within 12 hours of birth were excluded. Maternal and infant demographic and clinical variables were compared among singleton, twin, and triplet or higher-order infants. Logistic regression analysis was performed to establish the association between singletons, twins, and triplet or higher-order multiples and death or neurodevelopmental impairment, controlling for confounding variables that may affect death or neurodevelopmental impairment.
Our cohort consisted of 8296 singleton, 2164 twin, and 521 triplet or higher-order infants. The risk of death or neurodevelopmental impairment was increased in triplets or higher-order multiples when compared with singletons (adjusted odds ratio: 1.7 [95% confidence interval: 1.29–2.24]), and there was a trend toward an increased risk when compared with twins (adjusted odds ratio: 1.27 [95% confidence: 0.95–1.71]).
Triplet or higher-order births are associated with an increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age when compared with extremely low birth weight singleton infants, and there was a trend toward an increased risk when compared with twins.
PMCID: PMC3304548  PMID: 21357334
extremely low birth weight; triplets; neurodevelopmental outcomes
21.  Survival and Morbidity Outcomes of Very Low Birth Weight Infants with Down Syndrome 
Pediatrics  2010;126(6):1132-1140.
Individuals with Down syndrome (DS) are at increased risk of several morbidities with lifelong health consequences. Little is known about mortality or morbidity risks in early infancy among very-low-birth-weight (VLBW) infants with DS. Our objective was to compare survival and neonatal morbidities between VLBW infants with DS and VLBW infants with other non-DS chromosomal anomalies, other non-chromosomal birth defects, and VLBW infants without major birth defects.
Data were collected prospectively for infants weighing 401-1500 grams born and/or cared for at one of the study centers participating in the NICHD Neonatal Research Network from 1994 through 2008. Risk of death and morbidities including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups.
Infants with DS were at increased risk of death (adjusted relative risk [RR] 2.47, 95% confidence interval [CI] 2.00-3.07), PDA, NEC, LOS, and BPD relative to infants with no birth defects. Decreased risk of death (RR 0.40, 95% CI 0.31-0.52) and increased risks of NEC and LOS were observed when comparing infants with DS to infants with other non-DS chromosomal anomalies. Relative to infants with non-chromosomal birth defects, infants with DS were at increased risk of PDA and NEC.
The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for caretakers in anticipating the need for enhanced surveillance for prevention of these morbidities.
PMCID: PMC3059605  PMID: 21098157
neonatal mortality; neonatal morbidity; preterm infants; Down syndrome; trisomy 21
22.  Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome 
The Journal of pediatrics  2010;157(5):720-725.e2.
To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
Study design
A total of 6499 ELBW infants (401–1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n=414) and without (n=6085) clinical seizures during the initial hospitalization. Multivariate logistic regression modeling examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.
Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio 3.15 [95% confidence interval 2.37–4.19]).
ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.
PMCID: PMC2939969  PMID: 20542294
preterm; neurodevelopmental impairment; electroencephalography
23.  Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment 
Pediatrics  2010;126(4):e865-e873.
Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low-birth-weight (<1000 g) infants. We quantify risk factors predicting infection in high-risk premature infants and compare clinical judgment with a prediction model of invasive candidiasis.
The study involved a prospective observational cohort of infants <1000 g birth weight at 19 centers of the NICHD Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: 1) potentially modifiable risk factors and 2) a clinical model at time of blood culture to predict candidiasis.
Invasive candidiasis occurred in 137/1515 (9.0%) infants and was documented by positive culture from ≥ 1 of these sources: blood (n=96), cerebrospinal fluid (n=9), urine obtained by catheterization (n=52), or other sterile body fluid (n=10). Mortality was not different from infants who had positive blood culture compared to those with isolated positive urine culture. Incidence varied from 2–28% at the 13 centers enrolling ≥ 50 infants. Potentially modifiable risk factors (model 1) included central catheter, broad-spectrum antibiotics (e.g., third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model (model 2) had an area under the receiver operating characteristic curve of 0.79, and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. Performance of clinical judgment did not vary significantly with level of training.
Prior antibiotics, presence of a central catheter, endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.
PMCID: PMC3045840  PMID: 20876174
Candidiasis; premature infant; risk factors
24.  Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcome of Small Preterm Infants 
Pediatrics  2010;126(2):222-231.
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
PMCID: PMC2924191  PMID: 20643715
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
25.  Two-Year Neurodevelopmental Outcomes of Ventilated Preterm Infants Treated with Inhaled Nitric Oxide 
The Journal of pediatrics  2010;156(4):556-561.e1.
In a randomized multi-center trial, we demonstrated that inhaled nitric oxide begun between 7 and 21 days and treated for 24 days significantly increased survival without bronchopulmonary dysplasia (BPD) in ventilated premature infants weighing < 1250 g. Since some preventative BPD treatments are associated with neurodevelopmental impairment, we designed a follow-up study to assess the safety of nitric oxide.
Study design
Our hypothesis was that inhaled nitric oxide will not increase neurodevelopmental impairment compared with placebo. We prospectively evaluated neurodevelopmental and growth outcomes at 24 months PMA in 477 (89%) of 535 surviving infants enrolled in the trial.
In the treated group, 109 of 243 children (45%) had neurodevelopmental impairment (moderate or severe cerebral palsy, bilateral blindness, bilateral hearing loss or score of less than 70 on the Bayley Scales II), compared with 114 of 234 (49%) in the placebo group (Relative Risk 0.92; 95% confidence interval, 0.75 to 1.12; p = 0.39). No differences on any subcomponent of neurodevelopmental impairment or growth variables were found between inhaled nitric oxide or placebo.
Inhaled nitric oxide improved survival free of bronchopulmonary dysplasia with no adverse neurodevelopmental effects at 2 years of age.
PMCID: PMC2843768  PMID: 20138299

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