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1.  Postnatal Weight Gain in Preterm Infants with Severe Bronchopulmonary Dysplasia 
American journal of perinatology  2013;31(3):223-230.
To characterize postnatal growth failure (PGF), defined as weight < 10th percentile for postmenstrual age (PMA) in preterm (≤27 weeks’ gestation) infants with severe bronchopulmonary dysplasia (sBPD) at specified time points during hospitalization, and to compare these in subgroups of infants who died/underwent tracheostomy and others.
Study Design
Retrospective review of data from the multicenter Children’s Hospital Neonatal Database (CHND).
Our cohort (n = 375) had a mean ± standard deviation gestation of 25 ± 1.2 weeks and birth weight of 744 ± 196 g. At birth, 20% of infants were small for gestational age (SGA); age at referral to the CHND neonatal intensive care unit (NICU) was 46 ± 50 days. PGF rates at admission and at 36, 40, 44, and 48 weeks’ PMA were 33, 53, 67, 66, and 79% of infants, respectively. Tube feedings were administered to > 70% and parenteral nutrition to a third of infants between 36 and 44 weeks’ PMA. At discharge, 34% of infants required tube feedings and 50% had PGF. A significantly greater (38 versus 17%) proportion of infants who died/underwent tracheostomy (n = 69) were SGA, compared with those who did not (n = 306; p < 0.01).
Infants with sBPD commonly had progressive PGF during their NICU hospitalization. Fetal growth restriction may be a marker of adverse outcomes in this population.
PMCID: PMC4451086  PMID: 23690052
nutrition; tracheostomy; growth; bronchopulmonary dysplasia
2.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
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.
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)].
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.
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
3.  Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: A randomized clinical trial 
Invasive candidiasis in premature infants causes mortality and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole is unknown.
To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants.
This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013.
Fluconazole (6 mg/kg of body weight) or placebo.
The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes—defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18–22-months corrected age.
Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio 0.73 [95% CI 0.43–1.23]; P=.24; treatment difference −5% [95% CI, −13%–3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%] vs the placebo group (9% [95% CI, 5%–14%]; P=.02; treatment difference −6% [95% CI, −11%–−1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole 31% [95% CI, 21–41%] vs placebo, 27% [95% CI, 18–37%]; P=.60; treatment difference 4% [95% CI, −10–17%]).
Among infants with a birth weight of less 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely-low-birth-weight infants.
PMCID: PMC4110724  PMID: 24794367
4.  Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy 
In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years.
Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy.
Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years.
Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability.
PMCID: PMC4324462  PMID: 24957482
5.  Apgar scores at 10 min and outcomes at 6–7 years following hypoxic-ischaemic encephalopathy 
To determine the association between 10 min Apgar scores and 6–7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT).
Evaluations at 6–7 years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre.
In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0–3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10 min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10 min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0–3; there was no significant interaction between cooling and Apgar scores (p=0.26).
Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration.
PMCID: PMC4166405  PMID: 23896791
6.  Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic–ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial 
Pediatric research  2012;72(4):414-419.
The effect of birth location on hypothermia-related outcomes has not been rigorously examined in the literature. In this study, we determined whether birth location had an impact on the benefits of whole-body cooling to 33.5 °C for 72 h in term infants (n = 208) with hypoxic–ischemic encephalopathy (HIE) who participated in the Neonatal Research Network (NRN) randomized controlled trial.
Heterogeneity by birth location was examined with respect to cooling treatment for the 18-mo primary outcomes (death, moderate disability, severe disability) and secondary outcomes (death, components of disability), and in-hospital organ dysfunction. Logistic regression models were used to generate adjusted odds ratios.
Infants bom at a location other than an NRN center (outborn) (n = 93) experienced significant delays in initiation of therapy (mean (SD): 5.5 (1.1) vs. 4.4 (1.2) h), lower baseline temperatures (36.6 (1.2) vs. 37.1 (0.9) °C), and more severe HIE (43 vs. 29%) than infants born in an NRN center (inborn) (n = 115). Maternal education <12 y (50 vs. 14%) and African-American ethnicity (43 vs. 25%) were more common in the inborn group. When adjusted for NRN center and HIE severity, there were no significant differences in 18-mo outcomes or in-hospital organ dysfunction between inborn and outborn infants.
Although limited by sample size and some differences in baseline characteristics, the study showed that birth location does not appear to modify the treatment effect of hypothermia after HIE.
PMCID: PMC3730811  PMID: 22914450
7.  Association Between Blood Spot Transforming Growth Factor-β and Patent Ductus Arteriosus in Extremely Low-Birth Weight Infants 
Pediatric cardiology  2012;34(1):149-154.
Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.
PMCID: PMC3704212  PMID: 22684193
Transforming growth factor; Patent ductus arteriosus; Preterm; Neonate
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.  Circulating β chemokine and MMP 9 as markers of oxidative injury in extremely low birth weight infants 
Pediatric research  2010;67(1):77-82.
Matrix metalloproteinases (MMP) and chemokines appear to be induced by hyperoxia in preclinical studies. We hypothesized that O2 exposure immediately after birth is associated with altered blood spot MMP 9 and β chemokine concentrations. The following analytes were measured on blood spots on days 1 and 3 of life, using luminex technology in 1059 infants (birth weights < 1000 grams) in the NICHD Neonatal Research Network: MMP 9, monocyte chemoattractant protein 1 (MCP 1), macrophage inflammatory proteins (MIP 1α and β), and Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES). Infants administered O2 continually from 6 to 24 hours of life (n=729), when compared to those with < 6 hours exposure (n=330), had significantly lower mean birth weight and higher rate of respiratory distress syndrome (p≤ 0.002). On day 3, MCP 1 was higher and RANTES lower among infants with early prolonged O2 exposure. After adjusting for covariates, prolonged early O2 exposure retained a statistically significant association with higher MCP 1 on day 3 (p=0.003). The consistent association between O2 exposure and MCP 1 among extremely preterm infants suggests that further investigation of its role in oxidative injury is warranted.
PMCID: PMC2831535  PMID: 19755933
10.  Real-Time Polymerase Chain Reaction for the Rapid Detection of Group B Streptococcal Colonization in Neonates 
Pediatrics  2006;118(1):14-22.
Group B streptococcal (GBS) infection remains a leading cause of neonatal sepsis. Currently, the management guidelines of neonates born to women with unknown GBS status at delivery are unclear. In this cohort, who undergo at least a 48-hour observation, a rapid method of detection of GBS colonization would allow targeted evaluation and treatment, as well as prevent delayed discharge.
The goal of this research was to evaluate the validity of rapid fluorescent real-time polymerase chain reaction in comparison with standard culture to detect GBS colonization in infants born to women whose GBS status is unknown at delivery.
Neonates at > 32 weeks’ gestation born to women whose GBS status was unknown at delivery were included. Samples were obtained from the ear, nose, rectum, and gastric aspirate for immediate culture and real-time polymerase chain reaction after DNA extraction using the LightCycler. Melting point curves were generated, and confirmatory agar gel electrophoresis was performed.
The study population (n = 94) had a mean ± SD gestational age of 38 ± 2 weeks and birth weight of 3002 ± 548 g. The rates of GBS colonization by culture were 17% and 51% by real-time polymerase chain reaction. The 4 surface sites had comparable rates of GBS. The overall sensitivities, specificities, and positive and negative predictive values of real-time polymerase chain reaction were: 90%, 80.3%, 28%, and 98.9%.
Real-time polymerase chain reaction resulted in a threefold higher rate of detection of GBS colonization and had an excellent negative predictive value in a cohort of neonates with unknown maternal GBS status at delivery. Thus, real-time polymerase chain reaction would be a useful clinical tool in the management of those infants potentially at risk for invasive GBS infection and would allow earlier discharge for those found to be not at risk.
PMCID: PMC1513630  PMID: 16818544
group B streptococcus; rapid diagnostic tests; polymerase chain reaction; newborn; GBS—group B streptococcus; PCR—polymerase chain reaction; CI— confidence interval

Results 1-10 (10)