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1.  The renin–angiotensin–aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia 
Preeclampsia is associated with alterations in the maternal renin–angiotensin–aldosterone system (RAAS), increased blood pressure (BP), and cardiovascular risk in the offspring. We hypothesized that preeclampsia is associated with alterations in the RAAS in the offspring that persist into adolescence.
Materials and methods
We compared components of the circulating (n = 111) and renal (n = 160) RAAS in adolescents born prematurely with very low birth weight (VLBW) of preeclamptic (PreE) and normotensive (NoHTN) pregnancies. Multivariable linear regression was used to evaluate potential confounding and intermediate variables. Analyses were stratified by sex.
Adjusting for race and antenatal steroid exposure, male offspring of PreE mothers had higher circulating aldosterone than those of NoHTN mothers (adjusted mean difference = 109; 95% confidence limits: −9, 227 pmol/L). Further adjustment for current BMI attenuated this difference (adjusted mean difference: 93; 95% confidence limits: −30, 215 pmol/L).
Among male preterm VLBW infants, maternal preeclampsia is associated with increased circulating aldosterone level in adolescence, which appears to be mediated in part by higher BMI.
PMCID: PMC4278943  PMID: 24737639
Very low birth weight; prematurity; preterm birth; fetal programming; sex differences
2.  Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial 
The Journal of pediatrics  2014;165(2):240-249.e4.
To explore the early childhood pulmonary outcomes of infants who participated in the NICHD SUPPORT Trial, using a factorial design that randomized extremely preterm infants to lower vs. higher oxygen saturation targets and delivery room CPAP vs. intubation/surfactant, found no significant difference in the primary composite outcome of death or BPD.
Study design
The Breathing Outcomes Study, a prospective secondary to SUPPORT, assessed respiratory morbidity at 6 month intervals from hospital discharge to 18–22 months corrected age (CA). Two pre-specified primary outcomes, wheezing more than twice per week during the worst 2 week period and cough longer than 3 days without a cold were compared between each randomized intervention.
One or more interviews were completed for 918 of 922 eligible infants. The incidence of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between study arms of either randomized intervention. Infants randomized to lower vs. higher oxygen saturation targets had similar risks of death or respiratory morbidities (except for croup, treatment with oxygen or diuretics at home). Infants randomized to CPAP vs. intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs. 36.5%, p<0.05), respiratory illnesses diagnosed by a doctor (47.7% vs. 55.2%, p<0.05) and physician or emergency room visits for breathing problems (68.0% vs. 72.9%, p<0.05) by 18–22 months CA.
Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18–22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.
PMCID: PMC4111960  PMID: 24725582
Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Low Birth Weight; Infant, Extremely Low Birth Weight; Infant, Premature; Infant, Extremely Low Gestational Age; Infant mortality; Respiratory morbidity; Intensive care, neonatal; Hospital Readmission; Oximetry; Randomized controlled trial; Retinopathy of prematurity (ROP); Continuous Positive Airway Pressure; Intubation, endotracheal; Pulmonary surfactants/therapeutic use; Oxygen inhalation therapy/methods; Oxygen administration & dosage; Follow-up studies
3.  A novel long non-coding natural antisense RNA is a negative regulator of Nos1 gene expression 
Scientific Reports  2015;5:11815.
Long non-coding natural antisense transcripts (NATs) are widespread in eukaryotic species. Although recent studies indicate that long NATs are engaged in the regulation of gene expression, the precise functional roles of the vast majority of them are unknown. Here we report that a long NAT (Mm-antiNos1 RNA) complementary to mRNA encoding the neuronal isoform of nitric oxide synthase (Nos1) is expressed in the mouse brain and is transcribed from the non-template strand of the Nos1 locus. Nos1 produces nitric oxide (NO), a major signaling molecule in the CNS implicated in many important functions including neuronal differentiation and memory formation. We show that the newly discovered NAT negatively regulates Nos1 gene expression. Moreover, our quantitative studies of the temporal expression profiles of Mm-antiNos1 RNA in the mouse brain during embryonic development and postnatal life indicate that it may be involved in the regulation of NO-dependent neurogenesis.
PMCID: PMC4495418  PMID: 26154151
4.  Impaired visual fixation at age 2 years in children born before the 28th week of gestation. Antecedents and correlates in the multi-center ELGAN Study 
Pediatric neurology  2014;51(1):36-42.
Very little is known about the prevalence, antecedents and correlates of impaired visual fixation in former very preterm newborns.
In the multi-center ELGAN Study sample of 1057 infants born before the 28th week of gestation who had a developmental assessment at 2 years corrected age, we identified 73 who were unable to follow an object across the midline. We compared them to the 984 infants who could follow an object across the midline.
In this sample of very preterm newborns, those who had impaired visual fixation were much more likely than those without impaired visual fixation to have been born after the shortest of gestations (odds ratio = 3.2; 99% confidence interval =1.4, 7.5) and exposed to maternal aspirin (OR: 5.2; 99% CI: 2.2, 12). They were also more likely than their peers to have had prethreshold ROP (OR: 4.1; 99% CI: 1.8, 9.0). At age 2 years, the children with impaired fixation were more likely than others to be unable to walk (even with assistance) (OR: 7.5; 99% CI: 2.2, 26) and have a Mental Development Index more than 3 standard deviations below the mean of a normative sample (OR:3.6; 99% CI: 1.4, 8.2).
Risk factors for brain and retinal damage, such as very low gestational age, appear to be risk factors for impaired visual fixation. This inference is further supported by the co-occurrence at age 2 years of impaired visual fixation, inability to walk, and a very low Mental Development Index
PMCID: PMC4062923  PMID: 24938138
Retinopathy of prematurity; preterm newborn; brain; developmental disabilities
5.  Retinopathy of prematurity and brain damage in the very preterm newborn 
To explain why very preterm newborns who develop retinopathy of prematurity (ROP) appear to be at increased risk of abnormalities of both brain structure and function.
A total of 1,085 children born at <28 weeks’ gestation had clinically indicated retinal examinations and had a developmental assessment at 2 years corrected age. Relationships between ROP categories and brain abnormalities were explored using logistic regression models with adjustment for potential confounders.
The 173 children who had severe ROP, defined as prethreshold ROP (n = 146) or worse (n = 27) were somewhat more likely than their peers without ROP to have brain ultrasound lesions or cerebral palsy. They were approximately twice as likely to have very low Bayley Scales scores. After adjusting for risk factors common to both ROP and brain disorders, infants who developed severe ROP were at increased risk of low Bayley Scales only. Among children with prethreshold ROP, exposure to anesthesia was not associated with low Bayley Scales.
Some but not all of the association of ROP with brain disorders can be explained by common risk factors. Most of the increased risks of very low Bayley Scales associated with ROP are probably not a consequence of exposure to anesthetic agents.
PMCID: PMC4057649  PMID: 24924276
6.  Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 months in extremely preterm infants 
Pediatric research  2014;75(6):781-787.
Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 years.
In a cohort of 600 children born before 28 weeks gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5–5 (CBCL/1.5-5) at two years of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least two days approximately one week apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93rd percentile.
A single-day elevation of ICAM-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of MPO, IL-6, TNF-RI, IL-8, ICAM-3, VEGF-R1, and VEGF-R2. These associations persisted among infants without white matter injury and cognitive impairment.
Among children born extremely prematurely, recurrent or persistent elevations of inflammation-related proteins in blood during in the first two postnatal weeks are associated with an attention problem at age 2 years.
PMCID: PMC4429865  PMID: 24614800
7.  Maternal race, demography and health care disparities impact risk for IVH in preterm neonates 
The Journal of pediatrics  2014;164(5):1005-1011.e3.
To determine whether risk factors associated with Grade (Gr) 2–4 intraventricular hemorrhage (IVH) differs between African ancestry and white subjects.
Study design
Inborn, appropriate for gestational age (GA) infants with birth weights (BW) 500–1250 grams and exposed to >1 dose of antenatal steroids were enrolled in 24 neonatal intensive care units. Cases had Gr 2–4 IVH and controls matched for site, race and BW range had 2 normal ultrasounds read centrally. Multivariate logistic regression modeling identified factors associated with IVH across African ancestry and white race.
Subjects included 579 African ancestry or white race infants with Gr 2–4 IVH and 532 controls. Mothers of African ancestry children were less educated, and white case mothers were more likely to have > 1 prenatal visit and have a multiple gestation (P ≤.01 for all). Increasing GA (P =.01), preeclampsia (P < .001), complete antenatal steroid exposure (P = .02), cesarean delivery (P < .001) and white race (P = .01) were associated with decreased risk for IVH. Chorioamnionitis (P = .01), Apgar< 3 at 5 min (P < .004), surfactant (P < .001) and high frequency ventilation (P < .001) were associated with increased risk for IVH. Among African ancestry infants, having >1 prenatal visit was associated with decreased risk (P = .02). Among white infants, multiple gestation was associated with increased risk (P < .001) and higher maternal education with decreased IVH risk (P < .05).
Risk for IVH differs between African ancestry and white infants and may be attributable to both race and health care disparities.
PMCID: PMC4095864  PMID: 24589078
preterm infant; intraventricular hemorrhage; race; multiple gestation; prenatal care
8.  Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates 
PLoS ONE  2015;10(3):e0115083.
We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI).
Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age.
Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI.
hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.
PMCID: PMC4368546  PMID: 25793991
9.  Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage? 
We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage.
We measured the concentrations of TSH on day 14, and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on two separate days a week apart during the first two postnatal weeks. We first assessed the risk of brain damage indicators comparing 1) neonates who had HTT to those without (regardless of ISSI), and 2) neonates with HTT only, ISSI only, or HTT+ ISSI, to those who were exposed to neither HTT nor ISSI. HTT was defined as a TSH concentration in the highest quartile for gestational age on postnatal day 14.
In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI, to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (OR) ranged from 2–6], while those with HTT only were at significantly reduced risk of a hypoechoic lesion [ORs ranged from 0.2–0.4]. Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis [ORs ranged from 1.6–2.4]. Elevated risk of a very low mental development score was associated with both ISSI only and with HTT+ISSI while a very low motor development score and microcephaly were associated with HTT+ISSI.
The association of HTT with increased or decreased risk of indicators of brain damage depends upon the presence or absence of ISSI.
PMCID: PMC4317282  PMID: 24897395
thyroid stimulating hormone; inflammation; cerebral palsy; microcephaly
10.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
11.  Systemic inflammation, intraventricular hemorrhage, and white matter injury 
Journal of child neurology  2012;28(12):1637-1645.
To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage (IVH) without white matter injury (WMI) differed from that of 68 peers who had both IVH and WMI, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had IVH and WMI were more likely than others to have elevated concentrations of CRP and IL-8 on days 1, 7, and 14, and elevated concentrations of SAA and TNF-alpha on 2 of these days. IVH should probably be viewed as two entities, IVH unaccompanied by WMI, and IVH accompanied by WMI. Each entity is associated with inflammation, but IVH accompanied by WMI has a stronger inflammatory signal than IVH unaccompanied by WMI.
PMCID: PMC4166653  PMID: 23112243
Infant; premature; hemorrhage; brain injuries; acute; inflammation
12.  An Empirical Comparison of Tree-Based Methods for Propensity Score Estimation 
Health Services Research  2013;48(5):1798-1817.
To illustrate the use of ensemble tree-based methods (random forest classification [RFC] and bagging) for propensity score estimation and to compare these methods with logistic regression, in the context of evaluating the effect of physical and occupational therapy on preschool motor ability among very low birth weight (VLBW) children.
Data Source
We used secondary data from the Early Childhood Longitudinal Study Birth Cohort (ECLS-B) between 2001 and 2006.
Study Design
We estimated the predicted probability of treatment using tree-based methods and logistic regression (LR). We then modeled the exposure-outcome relation using weighted LR models while considering covariate balance and precision for each propensity score estimation method.
Principal Findings
Among approximately 500 VLBW children, therapy receipt was associated with moderately improved preschool motor ability. Overall, ensemble methods produced the best covariate balance (Mean Squared Difference: 0.03–0.07) and the most precise effect estimates compared to LR (Mean Squared Difference: 0.11). The overall magnitude of the effect estimates was similar between RFC and LR estimation methods.
Propensity score estimation using RFC and bagging produced better covariate balance with increased precision compared to LR. Ensemble methods are a useful alterative to logistic regression to control confounding in observational studies.
PMCID: PMC3796115  PMID: 23701015
Propensity scores; tree-based methods; ensemble methods
13.  Interneuronal Mechanism for Tinbergen’s Hierarchical Model of Behavioral Choice 
Current Biology  2014;24(17):2018-2024.
Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks [1]. We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors. We provide evidence for this by investigating the interneuronal mechanisms mediating behavioral choice between two autonomous circuits that underlie whole-body withdrawal [4, 5] and feeding [6] in the pond snail Lymnaea. Whole-body withdrawal is a defensive reflex that is initiated by tactile contact with predators. As predicted by the hierarchical model, tactile stimuli that evoke whole-body withdrawal responses also inhibit ongoing feeding in the presence of feeding stimuli. By recording neurons from the feeding and withdrawal networks, we found no direct synaptic connections between the interneuronal and motoneuronal elements that generate the two behaviors. Instead, we discovered that behavioral choice depends on the interaction between two unique types of interneurons with asymmetrical synaptic connectivity that allows withdrawal to override feeding. One type of interneuron, the Pleuro-Buccal (PlB), is an extrinsic modulatory neuron of the feeding network that completely inhibits feeding when excited by touch-induced monosynaptic input from the second type of interneuron, Pedal-Dorsal12 (PeD12). PeD12 plays a critical role in behavioral choice by providing a synaptic pathway joining the two behavioral networks that underlies the competitive dominance of whole-body withdrawal over feeding.
Graphical Abstract
•Behavioral choice between mutually exclusive behaviors is hierarchically organized•Touch-induced whole-body withdrawal inhibits sucrose-driven feeding rhythms•Two interneurons with asymmetrical connectivity allow withdrawal to override feeding•Suppression of feeding is due to the enhancement of tonic inhibition
A current model of behavioral choice depends on the reconfiguration of shared interneuronal networks. Pirger et al. provide evidence for the alternative Tinbergen model, which depends on a hierarchically based competition between autonomous networks. An asymmetrical inhibitory interneuronal pathway allows one behavior to dominate the other.
PMCID: PMC4159561  PMID: 25155505
14.  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
15.  Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial 
The New England journal of medicine  2012;367(26):2495-2504.
Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.
Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.
The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046).
We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT number, NCT00233324.)
PMCID: PMC4140695  PMID: 23268664
16.  Antenatal Steroid Exposure and Pulmonary Outcomes in Adolescents Born With Very Low Birth Weight 
To compare asthma history and pulmonary function in adolescents born prematurely with very low birth weight with and without antenatal steroid exposure.
Study Design
We studied 188 fourteen-year-olds (94 exposed, 84 male). We used parent report to ascertain asthma and asthma-related symptoms and spirometry to assess pulmonary function. Steroid-exposed and unexposed groups were compared using Mann-Whitney U tests (continuous variables), chi-square analysis (categorical variables), and logistic regression (multivariate analyses).
The steroid-exposed group had greater prevalence of larger airway obstruction (35%v. 21%), and steroid-exposed adolescents with birth weights < 1000 grams had 4.5-fold higher odds of larger airway obstruction. Wheezing in the last 12 months was twice as prevalent in steroid-exposed adolescents with birth weights between 1000–1500 g.
Antenatal steroid exposure does not provide long-term benefits for pulmonary outcomes in adolescents born prematurely with very low birth weight in the era of surfactant therapy.
PMCID: PMC4077331  PMID: 23788368
Corticosteroids; Prematurity; Lung Function; Asthma
17.  Pharmacokinetics and Safety of a Single Intravenous Dose of myo-Inositol in Preterm Infants of 23 to 29 weeks 
Pediatric research  2013;74(6):721-729.
Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials.
Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed effects approach. Safety outcomes were recorded.
A 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 5.22 h when modeled without the covariates. During the first 12 h renal inositol excretion quadrupled in the 120 mg/kg group, returning to near baseline after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05).
A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol.
PMCID: PMC3962781  PMID: 24067395
18.  Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial 
Pediatric research  2013;74(5):570-575.
Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality.
This is a secondary analysis of clinical and HRC data from 2989 VLBW infants enrolled in a randomized controlled trial of HRC monitoring in 9 NICUs from 2004–2010.
LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and non-display groups. Mortality within 30 days of LOS was lower in the HRC display compared to the non-display group (11.8% vs 19.6%, RR 0.61, 95% CI 0.43, 0.87, p<0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed.
Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.
PMCID: PMC4026205  PMID: 23942558
19.  Adiposity in Adolescent Offspring Born Prematurely to Mothers with Preeclampsia 
The Journal of pediatrics  2012;162(5):912-7.e1.
To evaluate the relationship between maternal preeclampsia resulting in premature delivery and adiposity in the offspring during adolescence.
Study design
The 172 study participants were 14 years old and had very low birth weight. We compared height, weight, body mass index (BMI), percent fat, waist circumference, and triceps and subscapular skin fold thicknesses between those born prematurely secondary to preeclampsia (n = 51; 22 male) and those born prematurely after nor-motensive pregnancies (n = 121; 55 male). Multiple linear regression analysis was used to adjust for potential con-founders (maternal BMI, antenatal steroid exposure, and race) and to evaluate potential explanatory variables (fetal, infancy, and childhood weight gain, and caloric intake, level of fitness, and physical activity at 14 years).
When adjusted for potential prenatal confounders (antenatal steroid exposure and race), adolescent male offspring of preeclamptic pregnancies had higher BMI (4.0 kg/m2 [1.5, 6.6]) (mean difference [95% CI]), waist circumference (11.8 cm [3.8, 19.7]), triceps (4.6 mm [0.6, 8.6]) and subscapular skinfold thicknesses (6.2 mm [1.5, 10.9]), and percent body fat (4.1% [−0.1, 8.3]). Adjusting for infancy and childhood weight gain attenuated these group differences. There were no group differences among females.
Male adolescent offspring born prematurely of women with preeclampsia have higher measures of adiposity than those born prematurely of normotensive pregnancies. (J Pediatr 2012; ■:■-■).
PMCID: PMC3785107  PMID: 23211927
20.  Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants 
Brain, behavior, and immunity  2013;29:104-112.
Neonatal inflammation is associated with perinatal brain damage. We evaluated to what extent elevated blood levels of inflammation-related proteins supplement information about the risk of impaired early cognitive function provided by inflammation-related illnesses. From 800 infants born before the 28th week of gestation, we collected blood spots on days 1, 7 and 14, for analysis of 25 inflammation-related proteins, and data about culture-positive bacteremia, necrotizing enterocolitis (Bell stage IIIb), and isolated perforation of the intestine, during the first two weeks, and whether they were ventilated on postnatal day 14. We considered a protein to be persistently or recurrently elevated if its concentration was in the top quartile (for gestational age and day blood was collected) on two separate days one week apart. We assessed the children at 2 years of age with the Bayley Mental Development Index (MDI). The combinations of NEC and ventilation on day 14, and of bacteremia and ventilation on day 14 consistently provided information about elevated risk of MDI <55, regardless of whether or not a variable for an elevated protein concentration was included in the model. A variable for a persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1. We conclude that elevated blood concentrations of inflammation-related proteins provide information about the risk of impaired cognitive function at age 2 years that supplements information provided by inflammation-associated illnesses.
PMCID: PMC3582030  PMID: 23295265
cognitive impairment; necrotizing enterocolitis; extreme prematurity; systemic inflammatory response; neonatal chronic lung disease; neonatal sepsis
21.  Systemic inflammation associated with mechanical ventilation among extremely preterm infants 
Cytokine  2012;61(1):315-322.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
PMCID: PMC3518391  PMID: 23148992
inflammation; ventilation; preterm infant; cytokine; chemokine
22.  Brain damage in preterm newborns and maternal medication: The ELGAN Study 
To evaluate the association between maternal medication use during pregnancy and cerebral white matter damage and cerebral palsy (CP) among very preterm infants.
Study Design
This analysis of data from the ELGAN Study included 877 infants born <28 weeks gestation. Mothers were interviewed, charts reviewed, placentas were cultured and assessed histologically, and children evaluated at 24 months corrected age. A diagnostic algorithm classified neurologic findings as quadriparetic CP, diparetic CP, hemiparetic CP, or no CP.
After adjustment for the potential confounding of disorders for which medications might have been indicated, the risk of quadraparetic CP remained elevated among the infants of mothers who consumed aspirin (OR=3.0, 95% CI 1.3,6.9) and non-steroidal anti-inflammatory medications (NSAIDs) (OR=2.4, 95% CI 1.04,5.8). The risk of diparetic CP was also associated with maternal consumption of an NSAID, but only if the consumption was not approved by a physician (OR=3.5, 95% CI 1.1,11.0)
The possibility that aspirin and NSAID use in pregnancy could lead to perinatal brain damage cannot be excluded.
PMCID: PMC3432943  PMID: 22939723
Cerebral palsy; cerebral white matter damage; preterm
23.  Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation 
Pediatric research  2012;73(3):362-370.
We sought to disentangle the contributions of perinatal systemic inflammation and small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at age 2 years.
We measured the concentration of 25 inflammation-related proteins in blood obtained during the first 2 postnatal weeks from 805 infants who were born before the 28th week of gestation and who had MDI measurements at age 2 years and were able to walk independently.
SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on 2 days a week apart) were at greater risk of an MDI < 55, but not 55–69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of IL-1beta, TNF-alpha, or IL-8 during the first two postnatal weeks were at even higher risk of an MDI < 55 than their SGA peers without systemic inflammation and of their non-SGA peers with systemic inflammation.
SGA appears to place very preterm newborns at increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk.
PMCID: PMC3642985  PMID: 23364171
24.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
PMCID: PMC3694609  PMID: 22732241
25.  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

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