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1.  Genes and Environment in Neonatal Intraventricular Hemorrhage 
Seminars in perinatology  2015;39(8):592-603.
Emerging data suggest intraventricular hemorrhage (IVH) of the preterm neonate is a complex disorder with contributions from both the environment and the genome. Environmental analyses suggest factors mediating both cerebral blood flow and angiogenesis contribute to IVH, while candidate gene studies report variants in angiogenesis, inflammation and vascular pathways. Gene-by-environment interactions demonstrate the interaction between the environment and the genome, and a non-replicated genome-wide association study suggests that both environmental and genetic factors contribute to the risk for severe IVH in very low birth weight preterm neonates.
PMCID: PMC4668116  PMID: 26516117
2.  Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants 
Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at under registration no. NCT01728363.)
PMCID: PMC4862454  PMID: 26926644
3.  Genomics in the Neonatal Nursery: Focus on ROP 
Seminars in perinatology  2015;39(8):604-610.
Retinopathy of prematurity (ROP) is a complex disease that is influenced by both genetic and environmental factors. Several small studies have found genetic variants in EPAS1, VEGF, SOD and members of the WNT family in association with ROP. Design in genetic studies is challenging because of changing recommendations for the management of prematurity and ROP, the fact ROP is rare, and that availability of resources for managing premature infants can vary throughout the world. In addition, there is a shortage of ophthalmologists with the ability to diagnose and characterize severe ROP. Careful determination of the degree of prematurity is important when evaluating genetic studies. Controlling for significant epidemiologic factors and multiple comparisons is also important to consider when evaluating genetic studies. One large candidate gene study controlled for degree of prematurity, significant epidemiologic factors, and multiple comparisons and found variants within the intron of BDNF associated with severe ROP. Future studies using unbiased techniques to assess genetic risk are important as are in-depth study of BDNF through deep sequencing and associated mechanistic studies using appropriate experimental models.
PMCID: PMC4644692  PMID: 26477493
4.  Thinner Retinal Nerve Fiber Layer in Very Preterm versus Term Infants and Relationship to Brain Anatomy and Neurodevelopment 
American journal of ophthalmology  2015;160(6):1296-1308.e2.
To assess retinal nerve fiber layer (RNFL) thickness at term-equivalent age in very preterm (<32 weeks gestational age) versus term-born infant cohorts, and compare very preterm infant RNFL thickness with brain anatomy and neurodevelopment.
Cohort study.
RNFL was semi-automatically segmented (one eye per infant) in 57 very preterm and 50 term infants with adequate images from bedside portable, handheld spectral domain optical coherence tomography (Bioptigen, Inc., Research Triangle Park, NC) imaging at 37-42 weeks postmenstrual age. Mean RNFL thickness was calculated for the papillomacular bundle (−15° to + 15°) and temporal quadrant (−45° to +45°) relative to the fovea-optic nerve axis. Brain magnetic resonance imaging (MRI) scans clinically obtained in 26 very preterm infants were scored for global structural abnormalities by an expert masked to data except for age. Cognitive, language, and motor skills were assessed with Bayley Scales of Infant and Toddler Development-III (Pearson, San Antonio, TX) in 33 of the very preterm infants at 18-24 months corrected age.
RNFL was thinner for very preterm versus term infants at the papillomacular bundle ([mean ± standard deviation] 61 ± 17 versus 72 ± 13 μm, p<0.001) and temporal quadrant (72 ± 21 versus 82 ± 16 μm, p=0.005). In very preterm infants, thinner papillomacular bundle RNFL correlated with higher global brain MRI lesion burden index (R2=0.35, p=0.001) and lower cognitive (R2=0.18, p=0.01) and motor (R2=0.17, p=0.02) scores. Relationships were similar for temporal quadrant.
Thinner RNFL in very preterm infants relative to term-born infants may relate to brain structure and neurodevelopment.
PMCID: PMC4651865  PMID: 26386157
5.  Right ventricular echocardiographic indices predict poor outcomes in infants with persistent pulmonary hypertension of the newborn 
Infants with persistent pulmonary hypertension of the newborn (PPHN) have elevated pulmonary vascular resistance that can lead to right ventricular (RV) failure and death. Clinicians must decide which infants will fail conventional therapy and require transfer to extra corporeal membrane oxygenation (ECMO) centres, but accurate echocardiographic predictors have not been identified. We assessed echocardiographic measurements of RV pressure and function in predicting progression to death or ECMO in infants with PPHN.
Methods and results
Echocardiograms for infants ≥35-week gestation with a clinical diagnosis of PPHN were retrospectively reviewed. Traditional and strain echocardiographic measures were compared for those with or without the primary outcome of ECMO/cardiovascular death. Receiver operator curves identified cut points for measures that were significantly different. Of the 86 subjects analysed, 25 (29%) of the patients had the primary outcome of ECMO/death. The ECMO/death group had diminished tricuspid annular plane systolic excursion (TAPSE; P = 0.002) and RV global longitudinal peak strain (GLPS; P = 0.03), a predominant right-to-left shunt across the patent ductus arteriosus (PDA; P = 0.05), and an elevated oxygenation index (OI; P < 0.001). Sensitivity/specificity for TAPSE <4 mm was 56 and 85%, and for GLPS greater than or equal to −9% was 52 and 77%.
TAPSE, GLPS, and right-to-left PDA shunting were associated with progression to death/ECMO. RV free wall strain was not associated with the outcome, suggesting that diminished global strain better reflects clinical outcomes in this group. These thresholds may assist in the decision-making to transfer high-risk infants to ECMO centres.
PMCID: PMC4609160  PMID: 25851325
persistent pulmonary hypertension; echocardiogram; mortality; ECMO; strain
6.  Association between positive urine cultures and necrotizing enterocolitis in a large cohort of hospitalized infants 
Early human development  2015;91(10):583-586.
We used a large research database to examine the association between urinary tract infections and necrotizing enterocolitis (NEC) in premature infants.
This retrospective data analysis included infants ≤32 weeks gestational age and ≤1500 g at birth who had urine cultures obtained at one of 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012. The primary outcome was a diagnosis of NEC within 7 days after urine culture. We used multivariable conditional logistic regression conditioned on postnatal age and controlling for gestational age, inotropic support on the day of culture, and mechanical ventilation on the day of culture to evaluate the association between urine culture result and NEC.
We identified 25,816 infants who had 43,556 urine cultures obtained; 6586 (15.1%) of the cultures were positive. A diagnosis of NEC within 7 days after culture was made in 334 (5.1%) of the 6586 positive cultures versus 1582 (4.3%) of the 36,970 negative cultures (p<0.01). On multivariable analysis, infants with any positive urine culture had increased risk of NEC (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02–1.31); the risk was higher when limited to Gram-negative organisms (OR 1.37, 95% CI 1.17–1.59). The risk of surgical NEC was increased in infants with any positive urine culture (OR 1.46, 95% CI 1.18–1.81) and was also higher when limited to Gram-negative organisms (OR 1.99, 95% CI 1.53–2.59).
Positive urine cultures were associated with increased risk of NEC within 7 days of culture.
PMCID: PMC4575648  PMID: 26226102
neonatal; necrotizing enterocolitis; urinary tract infection
7.  Functional Outcomes of Young Infants with and without Macular Edema 
Retina (Philadelphia, Pa.)  2015;35(10):2018-2027.
Summary Statement
Infants who showed age-appropriate retinal microanatomy on spectral domain optical coherence tomography imaging obtained in the nursery had age-appropriate visual acuities on follow-up as toddlers or school-aged children. By contrast, infants with macular edema on imaging, subsequently demonstrated suboptimal vision, sensorimotor deficits, brain abnormalities, and/or poor neurodevelopment.
We relate posterior segment microanatomy from perinatal spectral-domain optical coherence tomography (SDOCT) to visual acuity (VA), brain abnormalities, and neurodevelopment.
Thirteen infants (11 preterm, 2 term birth), imaged in the nursery with portable SDOCT, had VA and sensorimotor testing at age 9-15 months (grating acuity) or 4-5 years (optotype), and medical records reviewed for brain magnetic resonance imaging (MRI) reports and Bayley Scales testing at age 18-24 months.
Eight children with age-appropriate macular microanatomy without edema on perinatal SDOCT had optimal (>/= 20/40) or within normal limits (grating acuity) VA. Five children with perinatal macular edema had suboptimal VA (in 9/10 eyes) and either sensorimotor deficits, MRI abnormalities or poor neurodevelopment. Macular edema persisted in one infant through 9 months corrected age.
Maturation of the visual system and evolution of retinal anomalies can be monitored with posterior segment SDOCT. Retinal microanatomy observed in infancy might relate to subsequent vision as well as other central nervous system events, but additional studies are needed to determine the range of normal microanatomy in infants and how this relates to vision and neurodevelopment.
PMCID: PMC4581893  PMID: 25932550
Bayley scales; cystoid macular edema; development; macula; retinopathy of prematurity; infant; magnetic resonance imaging; optical coherence tomography; visual acuity; visual function
8.  Management Practice and Mortality for Infants with Congenital Diaphragmatic Hernia 
American journal of perinatology  2015;32(9):887-894.
Congenital diaphragmatic hernia (CDH) is fatal in 20–40% of cases, largely due to pulmonary dysmaturity, lung hypoplasia, and persistent pulmonary hypertension. Evidence for survival benefit of inhaled nitric oxide (iNO), extracorporeal membrane oxygenation (ECMO), and other medical interventions targeting pulmonary hypertension is lacking. We assessed medical interventions and mortality over time in a large multicenter cohort of infants with CDH.
Study Design
We identified all infants ≥34 weeks gestation with CDH discharged from 29 neonatal intensive care units between 1999 and 2012 with an average of ≥2 CDH admissions per year. We examined mortality and the proportion of infants exposed to medical interventions, comparing 4 periods of time: 1999–2001, 2002–2004, 2005–2007, and 2008–2012.
We identified 760 infants with CDH. From 1999–2001 to 2008–2012, use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0% to 14%, and milrinone use increased from 0% to 22% (p<0.001). Overall mortality (28%) did not significantly change over time compared with the earliest time period.
Despite changing use of iNO, sildenafil, and milrinone, CDH mortality has not significantly decreased in this population of infants.
PMCID: PMC4516623  PMID: 25715314
infants; congenital diaphragmatic hernia; lung dysmaturity; lung hypoplasia; pulmonary hypertension; respiratory management
9.  PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) 
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.
Secondary exploratory data analysis of SUPPORT.
Multiple referral NICUs.
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.
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).
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.
PMCID: PMC4336211  PMID: 25425651
Infant; premature; Infant mortality; Infant; Premature; Diseases/epidemiology; Predictive value of tests; Prognosis; Intracranial hemorrhage; Blood Gas Analysis
10.  Necrotizing Enterocolitis in Infants with Ductal-Dependent Congenital Heart Disease 
American journal of perinatology  2014;32(7):633-638.
Infants with congenital heart disease (CHD) receiving prostaglandins (PGE) may be at increased risk for necrotizing enterocolitis (NEC). Enteral feeding may further increase risk of NEC in these patients. We evaluated the incidence of NEC and its association with enteral feeding in infants with ductal-dependent CHD.
Study Design
We examined a cohort of infants with CHD receiving PGE in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. We used logistic regression to evaluate the association between NEC and enteral feeding, as well as other risk factors including antacid medications, inotropic and ventilator support, and anatomic characteristics, controlling for gestational age.
We identified 6710 infants with ductal-dependent CHD receiving PGE for 17,158 infant days. NEC occurred in 21 of 6710 (0.3%) infants, of whom 12/21(57%) were <37 weeks gestational age. The incidence of NEC was 1.2/1000 infant days while on enteral feeds versus 0.4/1000 infant days while not on enteral feeds (p=0.27). Enteral feeding was not associated with a statistically significant increased odds of NEC on the day of diagnosis (odds ratio [OR] 2.08; 95% confidence interval [CI] 0.38, 11.7). Risk factors associated with a significant increased odds of NEC included a diagnosis of single-ventricle heart defect (OR 2.82; 95% CI 1.23, 6.49), although the overall risk in this population remained low (8/1631, 0.5%).
The incidence of NEC in our cohort of infants with ductal-dependent CHD on PGE therapy was low and did not increase with enteral feeding.
PMCID: PMC4449801  PMID: 25486286
single-ventricle anomaly; neonatal intensive care; prostaglandin E1; NPO
11.  Antibiotic Stewardship: Reassessment of Guidelines for Management of Neonatal Sepsis 
Clinics in perinatology  2014;42(1):195-x.
Since publication of the first Guidelines to Prevent Perinatal Group B Strep (GBS) disease in 1996, the incidence and mortality from early onset sepsis (EOS), and particularly GBS, the leading cause of EOS, has drastically decreased. In 2010, the Centers for Disease Control (CDC) provided updated Guidelines for the prevention of perinatal Group B streptococcal disease. In 2012, the AAP Committee on Fetus and Newborn (COFN) provided a Clinical Report that provided a thorough review of EOS and voiced overall support of the 2010 CDC Guidelines. In addition, the COFN authors suggested an approach different from the 2010 CDC Guidelines for at-risk asymptomatic infants. The COFN also ventured into the uncertain territory of recommending longer duration of empirical antibiotic treatment for asymptomatic infants with negative cultures, but abnormal CBC and/or CRP values. With the current focus on antibiotic stewardship, the 2012 COFN Clinical Report algorithms evoked questions from the Neonatology community. The COFN has recently responded with modified recommendations for empirical antibiotic duration and explanations for the recommendations for use of antibiotics in subgroups of infants for whom the CDC did not recommend starting antibiotics. Our goal in this article is to review the 2010 CDC and 2012 COFN guidelines and COFN's recently published guideline modifications and discuss mechanisms that may reduce the number of term and near term infants to be started on antibiotics.
PMCID: PMC4888789  PMID: 25678005
12.  Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012 
JAMA  2015;314(10):1039-1051.
Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.
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.
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.
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.
PMCID: PMC4787615  PMID: 26348753
13.  Poorer Neurodevelopmental Outcomes Associated with Cystoid Macular Edema Identified in Preterm Infants in the Intensive Care Nursery 
Ophthalmology  2014;122(3):610-619.
To evaluate the association between cystoid macular edema (CME) observed in very preterm infants and developmental outcomes at 18 to 24 months corrected age.
Cohort study.
Infants born at or less than 1500 g or at or less than 30 weeks postmenstrual age who underwent screening for retinopathy of prematurity (ROP) in an intensive care nursery.
Bedside handheld spectral-domain optical coherence tomography (SD OCT; Envisu, Bioptigen, Inc, Research Triangle Park, NC) imaging was obtained from preterm infants who were being screened for ROP and graded for presence of CME, central foveal thickness (CFT), inner nuclear layer thickness, and foveal-to-parafoveal thickness ratio. At 18 to 24 months corrected age, the children were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition.
Main Outcome Measures
Scores on the Bayley cognitive, language, and motor subscales.
Among 77 children with SD OCT imaging, 53 were evaluated with the Bayley Scales. Compared with children who did not have CME as infants (n = 22), the mean score for children who had CME (n = 31) was 7.3 points (95% confidence interval [CI], −15.5 to 0.9; P = 0.08) lower on the cognitive subscale, 14.1 points (95% CI, −22.7 to −5.5; P = 0.002) lower for the language subscale, and 11.5 points (95% CI, −21.6 to −1.3; P = 0.03) lower for the motor subscale. Differences were maintained after adjusting for gestational age and birth weight. Severity of CME, as assessed by foveal-to-parafoveal thickness ratio, within the CME group correlated with poorer cognitive (R2 = 0.16, P = 0.03) and motor (R2 = 0.15, P = 0.03) development.
Cystoid macular edema observed on SD OCT in very preterm infants screened for ROP is associated with poorer language and motor skills at 18 to 24 months corrected age. Evaluation of the retina with SD-OCT may serve as an indicator of neurodevelopmental health for very preterm infants in the intensive care nursery.
PMCID: PMC4339440  PMID: 25439600
14.  Integrated Genomic Analyses in Bronchopulmonary Dysplasia 
The Journal of pediatrics  2014;166(3):531-537.e13.
To identify single nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks’ post-menstrual age risk is strongly influenced by heritable factors.
Study design
A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated using gene expression in BPD lung tissue and in mouse models.
Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (p<10−8) although multiple SNPs in adenosine deaminase (ADARB2), CD44, and other genes were just below p<10−6. Of approximately 8000 pathways, 75 were significant at False Discovery Rate (FDR) <0.1 and p<0.001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (p=1.41E-08, FDR 9.5E-05) for BPD/death and Phosphorous Oxygen Lyase Activity (includes adenylate and guanylate cyclases) for both severe BPD/death (p=5.68E-08, FDR 0.00019) and severe BPD in survivors (p=3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD.
Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, Phosphorus Oxygen Lyase Activity) and indicated novel molecules and pathways (ADARB2, Targets of miR-219) involved in genetic predisposition to BPD.
PMCID: PMC4344889  PMID: 25449221
Bronchopulmonary dysplasia; Infant; premature; Infant mortality; Single nucleotide polymorphisms
15.  Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants 
Pediatrics  2015;135(1):e117-e125.
To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.
We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.
A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).
Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.
PMCID: PMC4279070  PMID: 25511117
necrotizing enterocolitis; very low birth weight infants; anaerobes; antibiotics; mortality; intestinal strictures
16.  Feasibility of Autologous Cord Blood Cells for Infants with Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2013;164(5):973-979.e1.
To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE).
Study design
We enrolled infants in the Intensive Care Nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to four doses adjusted for volume and RBC content,1 – 5 × 107cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post- infusion vital signs. As exploratory analyses we compared cell recipients’ hospital outcomes (mortality, oral feeds at discharge) and one year survival with Bayley III scores ≥ 85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells.
Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 milliliters. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1 year outcomes survived with scores ≥ 85.
Collection, preparation and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.
PMCID: PMC3992180  PMID: 24388332
Asphyxia; Neonatal encephalopathy; Umbilical cord blood; Neonate
17.  Feeding Practices and Other Risk Factors for Developing Transfusion-Associated Necrotizing Enterocolitis 
Early human development  2014;90(5):237-240.
Determine the incidence of and risk factors for necrotizing enterocolitis (NEC) and transfusion-associated NEC (TANEC) in very-low-birth-weight (VLBW) infants pre/post implementation of a peri-transfusion feeding protocol.
Study Design
A retrospective cohort study was conducted including all inborn VLBW infants admitted to the Duke intensive care nursery from 2002–10. We defined NEC using Bell’s modified criteria IIA and higher and TANEC as NEC occurring within 48 hours of a packed red blood cell (pRBC) transfusion. We compared demographic and laboratory data for TANEC vs. other NEC infants and the incidence of TANEC pre/post implementation of our peri-transfusion feeding protocol. We also assessed the relationship between pre-transfusion hematocrit and pRBC unit age with TANEC.
A total of 148/1380 (10.7%) infants developed NEC. Incidence of NEC decreased after initiating our peri-transfusion feeding protocol: 126/939 (12%) to 22/293 (7%), P=0.01. The proportion of TANEC did not change: 51/126 (41%) vs. 9/22 (41%), P>0.99. TANEC infants were smaller, more likely to develop surgical NEC, and had lower mean pre-transfusion hematocrits prior to their TANEC transfusions compared with all other transfusions before their NEC episode: 28% vs. 33%, P<0.001. Risk of TANEC was inversely related to pre-transfusion hematocrit: odds ratio 0.87 (0.79–0.95).
Pre-transfusion hematocrit is inversely related to risk of TANEC, which suggests that temporally maintaining a higher baseline hemoglobin in infants most at risk of NEC may be protective. The lack of difference in TANEC pre-/post-implementation of our peri-transfusion feeding protocol, despite an overall temporal decrease in NEC, suggests other unmeasured interventions may account for the observed decreased incidence of NEC.
PMCID: PMC4050434  PMID: 24598173
18.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
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.
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%).
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.
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.)
PMCID: PMC4465092  PMID: 25946279
19.  Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia 
Therapeutic drug monitoring  2014;36(5):584-589.
Population pharmacokinetic (popPK) models derived from small PK studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.
A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (UCSF) dataset. The predictive performance of this model was evaluated in an external retrospective dataset from UCSF (Validation A) and another from Duke University (Validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.
41 neonates (18 Validation A, 23 Validation B) with median (range) gestational age of 40wks (33–42) and birth weight of 3.3kg (1.9–4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36h post dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (Validation A; median average fold error [AFE]=1.1 and numerical prediction distribution error [NPDE] p-value>0.05) but under-predicted concentrations from the outside institution (Validation B; median AFE=0.6 and NPDE p-value<0.05).
The model demonstrated adequate predictive performance for an external dataset in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.
PMCID: PMC4166612  PMID: 25225917
gentamicin; hypothermia; hypoxic ischemic encephalopathy; model validation
20.  Apolipoprotein E (APOE) Genotype and Outcome in Infants with Hypoxic-Ischemic Encephalopathy (HIE) 
Pediatric research  2013;75(3):424-430.
Adults with the apolipoprotein E gene (APOE) alleles e4 and e2 are at high risk of poor neurologic outcome after brain injury. The e4 allele has been associated with cerebral palsy and the e2 allele has been associated with worse neurologic outcome with congenital heart disease. This study was done to test the hypothesis that APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).
We conducted a cohort study of infants who survived HIE and had 18 – 22 month standardized neurodevelopmental evaluations to assess associations between disability and APOE genotypes e3/e3, e4/-, and e2/-
139 survivors were genotyped. 86 (62%) were e3/e3, 41 (29%) were e4/-, and 14 (10%) were e2/-. 129 infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30% and 19% among those with and without e3/e3 genotype, 25% and 26% among those with and without the e2 allele, and 18% and 29% among those with and without the e4 allele. None of the differences were statistically significant. Cerebral palsy prevalence was also similar among genotype groups.
Disability was not associated with APOE genotype in this cohort of HIE survivors.
PMCID: PMC4095992  PMID: 24322171
21.  Impact of a Palliative Care Program on End-of-life Care in a Neonatal Intensive Care Unit 
Evaluate changes in end-of-life care following initiation of a Palliative Care Program in a neonatal intensive care unit.
Study Design
Retrospective study comparing infant deaths before and after implementation of a Palliative Care Program comprised of medication guidelines, an individualized order set, a nursing care plan, and staff education.
82 infants died before (Era 1) and 68 infants died after implementation of the program (Era 2). Morphine use was similar [88% vs. 81%; p=0.17], while benzodiazepines use increased in Era 2 [26% vs. 43%; p=0.03]. Withdrawal of life support (73% vs. 63%; p=0.17) and do-not-resuscitate orders (46% vs. 53%; p=0.42) were similar. Do-not-resuscitate orders and family meetings were more frequent among Era 2 infants with activated palliative care orders (n=21) compared to infants without activated orders (n=47).
End-of-life family meetings and benzodiazepine use increased following implementation of our program, likely reflecting adherence to guidelines and improved communication.
PMCID: PMC4491914  PMID: 25341195
22.  Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates 
Determine effects of low-dose dopamine on urine output in very low birth weight premature neonates.
Study Design
Retrospective cohort study of all low-dose (3-5 μg/kg/min) dopamine infusions >24 hours duration in neonates ≤1500 g and ≤32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on urine output.
We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased urine output occurred with 64% of episodes. Low-dose dopamine use was associated with a 0.6 mL/kg/hr increase in urine output (p<0.001) and a 1.3 mL/kg/hr increase when baseline urine output was <1.5 mL/kg/hr (p<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake.
Low-dose dopamine use was associated with increased urine output in very low birth weight neonates.
PMCID: PMC4028044  PMID: 23448938
renal dose; dopamine; urine output
23.  Duration of empirical antibiotic therapy for infants suspected of early-onset sepsis 
Current opinion in pediatrics  2013;25(2):167-171.
Purpose of review
Clinicians’ adherence to AAP and CDC Guidelines to prevent Group B Streptococcal (GBS) early onset sepsis (EOS) have reduced GBS EOS. While evidence-based testing and empirical antibiotic initiation is likely saving lives, clinicians have less compelling data to guide duration of empirically initiated antibiotics when cultures remain sterile and clinical signs resolve quickly. Our purpose is to review current opinions and evidence influencing clinicians’ choices for duration of empirically initiated antibiotics in newborns with sterile cultures.
Recent findings
Retrospective cohort studies indicate potential for harm with longer duration of empirical antibiotics for EOS when cultures are sterile. Cohort studies indicate timing of widely used tests used to estimate EOS risk affects their predictive value, and tests acquired 24 – 48 hours postnatally may provide reassurance for safe discontinuation.
Every day clinicians caring for thousands of neonates in the US stop antibiotics which were started empirically to treat EOS on the first postnatal day. Evidence is lacking to support a universal approach to decisions on duration of empirical antibiotics when cultures remain sterile. Reviewing predictive value relative to timing of laboratory testing can help clinicians develop locally appropriate antimicrobial duration decision-making guidelines.
PMCID: PMC3596444  PMID: 23407181
empirical antibiotics; early onset sepsis
24.  Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants 
To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants.
Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis.
Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10−5) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10−7).
Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.
Two variants in the gene encoding brain-derived neurotrophic factor were significantly associated with severe ROP in the largest candidate gene study of extremely low birth weight US infants.
PMCID: PMC4188045  PMID: 25118269
retinopathy of prematurity; extremely low birth weight; brain-derived neurotrophic factor; genetic associations; neurovascular
25.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBW) with and without blood stream infection (BSI) during their birth hospitalization.
Patients and Methods
Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4, and 6 months after birth with blood drawn 4–6 weeks after 3rd dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with birth-weight groups and other confounding factors identified in the primary study.
244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody ≥0.35μg/mL.
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
PMCID: PMC3722279  PMID: 23370608
VLBW; immune response; vaccine; sepsis; blood stream infection

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