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1.  Association of Chorioamnionitis with Aberrant Neonatal Gut Colonization and Adverse Clinical Outcomes 
PLoS ONE  2016;11(9):e0162734.
Objective
Chorioamnionitis (inflammation of the placenta and fetal membranes) and abnormal gastrointestinal colonization have been associated with an increased risk of sepsis and death in preterm infants, but whether chorioamnionitis causes abnormal pioneering gastrointestinal colonization in infants is not known. We determined the relationship between chorioamnionitis, altered infant fecal microbiome indicating abnormal gastrointestinal colonization, and adverse outcomes.
Study Design
Preterm infants ≤ 28 weeks at birth were enrolled from 3 level III NICUs in Cincinnati, Ohio and Birmingham, Alabama. Sequencing for 16S microbial gene was performed on stool samples in the first 3 weeks of life. Chorioamnionitis was diagnosed by placental histology. Late onset sepsis and death outcomes were analyzed in relation to fecal microbiota and chorioamnionitis with or without funisitis (inflammation of the umbilical cord).
Results
Of the 106 enrolled infants, 48 infants had no chorioamnionitis, 32 infants had chorioamnionitis but no funisitis (AC), and 26 infants had chorioamnionitis with funisitis (ACF). The fecal samples from ACF infants collected by day of life 7 had higher relative abundance of family Mycoplasmataceae (phylum Tenericutes), genus Prevotella (phylum Bacteroidetes) and genus Sneathia (phylum Fusobacteria). Further, AC and ACF infants had higher incidence of late-onset sepsis/death as a combined outcome. Presence of specific clades in fecal samples, specifically, order Fusobacteria, genus Sneathia or family Mycoplasmataceae, were significantly associated with higher risk of sepsis or death.
Conclusion
The results support the hypothesis that specific alterations in the pioneering infant gastrointestinal microbiota induced by chorioamnionitis predispose to neonatal sepsis or death.
doi:10.1371/journal.pone.0162734
PMCID: PMC5033323  PMID: 27658190
2.  Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter 
The Journal of pediatrics  2014;165(1):23-29.
Objectives
To determine the impact of empiric ampicillin and gentamicin use in the first week of life on microbial colonization and diversity in preterm infants.
Study design
16s rDNA community profiling was used to compare the microbiota of 74 infants born ≤32 weeks gestational age by degree of antibiotic use in the first week of life. The degree of antibiotic use was classified as 0 days, 1-4 days and 5-7 days of antibiotic administration. . All of the antibiotic use was empiric, defined as treatment based solely on clinical suspicion of infection without a positive culture result.
Results
Infants who received 5-7 days of empiric antimicrobial agents in the first week had increased relative abundance of Enterobacter (p=0.016) and lower bacterial diversity in the second and third weeks of life. Infants receiving early antibiotics also experienced more cases of NEC, sepsis or death than those not exposed to antibiotics.
Conclusions
Early empiric antibiotics have sustained effects on the intestinal microbiota of preterm infants. Intestinal dysbiosis in this population has been found to be associated with elevated risk of necrotizing enterocolitis, sepsis, or death.
doi:10.1016/j.jpeds.2014.01.010
PMCID: PMC4074569  PMID: 24529620
diversity; empiric antibiotics; microbiome; necrotizing enterocolitis; preterm infant
3.  Metagenomic Sequencing with Strain-Level Resolution Implicates Uropathogenic E. coli in Necrotizing Enterocolitis and Mortality in Preterm Infants 
Cell reports  2016;14(12):2912-2924.
SUMMARY
Necrotizing enterocolitis (NEC) afflicts approximately 10% of extremely preterm infants with high fatality. Inappropriate bacterial colonization with Enterobacteriaceae is implicated, but no specific pathogen has been identified. We identify uropathogenic E. coli (UPEC) colonization as a significant risk factor for the development of NEC and subsequent mortality. We describe a large-scale deep shotgun metagenomic sequence analysis of the early intestinal microbiome of 144 preterm and 22 term infants. Using a pan-genomic approach to functionally subtype the E. coli, we identify genes associated with NEC and mortality that indicate colonization by UPEC. Metagenomic multilocus sequence typing analysis further defined NEC-associated strains as sequence types often associated with urinary tract infections, including ST69, ST73, ST95, ST127, ST131, and ST144. Although other factors associated with prematurity may also contribute, this report suggests a link between UPEC and NEC and indicates that further attention to these sequence types as potential causal agents is needed.
Graphical abstract
doi:10.1016/j.celrep.2016.03.015
PMCID: PMC4819403  PMID: 26997279
4.  Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants 
The Journal of pediatrics  2011;159(5):720-725.
Objective
To investigate the outcomes following prolonged empirical antibiotic administration to premature infants in the first week of life, concluding subsequent late onset sepsis (LOS), necrotizing enterocolitis (NEC), and death.
Study design
Study infants were ≤32 weeks gestational age and ≤ 1500 grams birth weight who survived free of sepsis and NEC for 7 days. Multivariable logistic regression was conducted to determine independent relationships between prolonged initial empirical antibiotic therapy (≥ 5 days) and study outcomes controlling for birth weight, gestational age, race, prolonged premature rupture of membranes, days on high frequency ventilation in 7 days, and the amount of breast milk received in the first 14 days of life.
Results
Of the 365 premature infants surviving 7 days free of sepsis or NEC, 36% received prolonged initial empirical antibiotics, which was independently associated with subsequent outcomes: LOS (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.28–4.67) and the combination of LOS, NEC, or death (OR 2.66, 95% CI 1.12–6.3).
Conclusions
Prolonged administration of empirical antibiotics to premature infants with sterile cultures in the first week of life is associated with subsequent severe outcomes. Judicious restriction of antibiotic use should be investigated as a strategy to reduce severe outcomes for premature infants.
doi:10.1016/j.jpeds.2011.05.033
PMCID: PMC3193552  PMID: 21784435
prolonged antibiotic treatment; death; human milk; late-onset sepsis; necrotizing enterocolitis; premature infant
5.  Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants 
PLoS ONE  2015;10(6):e0130604.
Objective
Late onset sepsis (LOS) contributes to mortality and morbidity in preterm infants. We tested the hypotheses that microbes causing LOS originate from the gut, and that distortions in the gut microbial community increases subsequent risk of LOS.
Study Design
We examined the gut microbial community in prospectively collected stool samples from preterm infants with LOS and an equal number of age-matched controls at two sites (Cincinnati, OH and Birmingham, AL), by sequencing the bacterial 16S rDNA. We confirmed our findings in a subset of infants by whole genome shotgun sequencing, and analyzed the data using R and LEfSe.
Results
Infants with LOS in Cincinnati, as compared to controls, had less abundant Actinobacteria in the first samples after birth (median 18 days before sepsis onset), and less abundant Pseudomonadales in the last samples collected prior to LOS (median 8 days before sepsis onset). Infants with LOS in Birmingham, as compared to controls, had no differences identified in the first sample microbial communities, but Lactobacillales was less abundant in the last samples prior to LOS (median 4 days before sepsis onset). Sequencing identified detectable levels of the sepsis-causative organism in stool samples prior to disease onset for 82% of LOS cases.
Conclusions
Translocation of gut microbes may account for the majority of LOS cases. Distortions in the fecal microbiota occur prior to LOS, but the form of distortion depends on timing and site. The microbial composition of fecal samples does not predict LOS onset in a generalizable fashion.
doi:10.1371/journal.pone.0130604
PMCID: PMC4482142  PMID: 26110908
6.  Intestinal microbiota of preterm infants differ over time and between hospitals 
Microbiome  2014;2:36.
Background
Intestinal microbiota are implicated in risk of necrotizing enterocolitis (NEC) and sepsis, major diseases of preterm infants in neonatal intensive care units (NICUs). Rates of these diseases vary over time and between NICUs, but time and NICU comparisons of the intestinal microbiota of preterm infants are lacking.
Methods
We included 66 singleton infants <29 weeks gestational age with stool samples collected between postnatal days 3 to 21 of life who survived free of NEC and sepsis. Infants were enrolled during 2010 and 2011. Twenty-six infants were enrolled at hospital 1 in Cincinnati, OH, and 40 infants were enrolled at hospital 2 in Birmingham, AL. Samples collected from days 3–9 (“week 1”) and days 10–16 (“week 2”) were compared between years and hospitals. Microbial succession was compared between hospitals in 28 infants with samples from the first 3 weeks of life. DNA extracted from stool was used to sequence the 16S rRNA gene by Illumina MiSeq using universal primers. Resulting operational taxonomic unit tables were analyzed for differences between years and hospitals using linear discriminant analysis effect size algorithm (LEfSe; significance, p < 0.05).
Results
Significant variation was observed in infant microbiota by year and hospital. Among hospital 1 infants, week 1 samples had more phylum Firmicutes (class Bacilli, families Clostridiaceae and Enterococcaceae) in 2010 and more phylum Proteobacteria (family Enterobacteriaceae) in 2011; week 2 samples did not significantly vary over time. However, among hospital 2 infants, the week 1 shift was nearly opposite, with more Proteobacteria (Enterobacteriaceae) in 2010 and more Firmicutes (Bacilli) in 2011; week 2 samples exhibited the same pattern. Regression analysis of clinical covariates found that antibiotic use had an important influence but did not explain these observed shifts in microbiota over time and between hospitals. Microbial succession also differed by hospital, with greater change in microbiota in hospital 1 than hospital 2 infants (p < 0.01, Jaccard distance).
Conclusion
Colonizing microbiota differ over time and between NICUs in ways that could be relevant to disease. Multi-site, longitudinal studies are needed to reliably define the impact of intestinal microbiota on adverse outcomes of preterm infants.
doi:10.1186/2049-2618-2-36
PMCID: PMC4203463  PMID: 25332767
Infants; Premature; Microbiome; Geo-temporal analysis; Microbial succession
7.  A Potential Biomarker for Acute Kidney Injury in Preterm Infants from Metabolic Profiling 
Background
Currently used biomarkers for acute kidney injury (AKI), namely Ngal, SCr, and BUN, are inadequate for timely detection of AKI in preterm infants.
Methods
Nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was conducted on urines from 20 preterm infants to determine if novel metabolic biomarkers could be identified for early detection of AKI. Urines were collected from every patient each day for the first 14 days of life. NMR spectra were measured for all urines and metabolic profiling analysis conducted.
Results
One metabolite, carnitine, increased significantly in urines of three extremely low birth weight (ELBW) infants starting on day five of life. The three affected infants either received prolonged antibiotic treatment, extended treatment with indomethacin, or both. One ELBW patient who received both treatments and reached the highest urinary carnitine level died on day 10 of life due to localized gut perforation complicated by suspected AKI.
Conclusions
It was concluded that carnitine increased in the three neonates in part due to antibiotic- and/or indomethacin-induced AKI. It is hypothesized that combined antibiotic and indomethacin treatment promoted AKI resulting in reduced proximal renal tubule reabsorption of carnitine and that β-lactam antibiotics blocked renal carnitine uptake by human organic cation transporter, hOCTN2.
doi:10.4172/2155-9929.S3-001
PMCID: PMC4096988  PMID: 25035813
Acute kidney injury; Preterm infant; Necrotizing enterocolitis; NMR; Metabonomics; Neutrophil gelatinase-associated lipocalin (Ngal); Carnitine; Blood Urea Nitrogen (BUN)
8.  Pharmacokinetics of Levetiracetam in Neonates with Seizures 
The Journal of pediatrics  2011;159(1):152-154.e3.
The pharmacokinetics of levetiracetam were determined prospectively in 18 neonates with seizures. Neonates were found to have lower clearance, higher volume of distribution, and a longer half-life as compared with older children and adults. Mild somnolence was the only adverse effect.
doi:10.1016/j.jpeds.2011.03.057
PMCID: PMC3789844  PMID: 21592494
9.  Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants 
Microbiome  2013;1:13.
Background
Necrotizing enterocolitis (NEC) is a devastating intestinal disease that afflicts 10% of extremely preterm infants. The contribution of early intestinal colonization to NEC onset is not understood, and predictive biomarkers to guide prevention are lacking. We analyzed banked stool and urine samples collected prior to disease onset from infants <29 weeks gestational age, including 11 infants who developed NEC and 21 matched controls who survived free of NEC. Stool bacterial communities were profiled by 16S rRNA gene sequencing. Urinary metabolomic profiles were assessed by NMR.
Results
During postnatal days 4 to 9, samples from infants who later developed NEC tended towards lower alpha diversity (Chao1 index, P = 0.086) and lacked Propionibacterium (P = 0.009) compared to controls. Furthermore, NEC was preceded by distinct forms of dysbiosis. During days 4 to 9, samples from four NEC cases were dominated by members of the Firmicutes (median relative abundance >99% versus <17% in the remaining NEC and controls, P < 0.001). During postnatal days 10 to 16, samples from the remaining NEC cases were dominated by Proteobacteria, specifically Enterobacteriaceae (median relative abundance >99% versus 38% in the other NEC cases and 84% in controls, P = 0.01). NEC preceded by Firmicutes dysbiosis occurred earlier (onset, days 7 to 21) than NEC preceded by Proteobacteria dysbiosis (onset, days 19 to 39). All NEC cases lacked Propionibacterium and were preceded by either Firmicutes (≥98% relative abundance, days 4 to 9) or Proteobacteria (≥90% relative abundance, days 10 to 16) dysbiosis, while only 25% of controls had this phenotype (predictive value 88%, P = 0.001). Analysis of days 4 to 9 urine samples found no metabolites associated with all NEC cases, but alanine was positively associated with NEC cases that were preceded by Firmicutes dysbiosis (P < 0.001) and histidine was inversely associated with NEC cases preceded by Proteobacteria dysbiosis (P = 0.013). A high urinary alanine:histidine ratio was associated with microbial characteristics (P < 0.001) and provided good prediction of overall NEC (predictive value 78%, P = 0.007).
Conclusions
Early dysbiosis is strongly involved in the pathobiology of NEC. These striking findings require validation in larger studies but indicate that early microbial and metabolomic signatures may provide highly predictive biomarkers of NEC.
doi:10.1186/2049-2618-1-13
PMCID: PMC3971624  PMID: 24450576
Microbiome; Premature infants; Necrotizing enterocolitis; Dysbiosis
10.  Grade and Laterality of Intraventricular Hemorrhage to Predict 18–22 Month Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
Aims
To determine whether extremely low birth weight (ELBW) infants with bilateral compared to unilateral intraventricular hemorrhage (IVH) have worse neurodevelopmental outcomes at 18–22 months.
Methods
166 ELBW infants (<1000 g) admitted to a Cincinnati NICU from 1998–2005 with a head ultrasound showing Grade I–IV IVH and neurodevelopmental assessment at 18–22 months corrected age were included. Multivariable linear and logistic regression models were developed to determine the impact of laterality and grade of IVH and other clinical variables to predict scores on the Bayley Scales of Infant Development, Second Edition, Mental Development Index (MDI) and Psychomotor Development Index (PDI) and the combined outcome of neurodevelopmental impairment (NDI).
Results
Infants with bilateral grade IV IVH had lower adjusted mean Bayley scores compared with infants with unilateral grade IV IVH. For grades I, II, and III IVH, bilaterality of IVH was not associated with lower mean Bayley scores. Infants with grade IV IVH had the highest odds of NDI. The probability of NDI increased with sepsis and postnatal steroid use.
Conclusions
ELBW infants with bilateral compared to those with unilateral grade IV IVH had worse neurodevelopmental outcomes. Infants with grades I–III IVH had similar outcomes whether they had unilateral or bilateral IVH.
doi:10.1111/j.1651-2227.2011.02584.x
PMCID: PMC3475499  PMID: 22220735
premature; sepsis; steroids; Bayley; cognitive; motor
11.  Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants 
The Journal of pediatrics  2011;158(5):745-751.
Objective
To investigate secretor gene fucosyltransferase2 (FUT2) polymorphism and secretor phenotype in relation to outcomes of prematurity.
Study design
Study infants were ≤32 weeks gestational age. Secretor genotype was determined from salivary DNA. Secretor phenotype was measured by H antigen, the carbohydrate produced by secretor gene enzymes, in saliva samples collected on day 9±5. The optimal predictive cut-point in salivary H values was identified by Classification and Regression Tree analysis. Study outcomes were death, necrotizing enterocolitis (NEC, Bell’s stage II/III), and confirmed sepsis.
Results
There were 410 study infants, 26 deaths, 30 cases of NEC, and 96 cases of sepsis. Analyzed by genotype, 13% of 95 non-secretors, 5% of 203 heterozygotes, and 2% of 96 infants who were secretor dominant died (p=0.01). Analyzed by phenotype, 15% of 135 infants with low secretor phenotype died, compared with 2% of 248 infants with high secretor phenotype (predictive value=76%, p<0.001). Low secretor phenotype was associated (P<.05) with NEC, and non-secretor genotype was associated (P=.05) with gram negative sepsis. Secretor status remained significant after controlling for multiple clinical factors.
Conclusions
Secretor genotype and phenotype may provide strong predictive biomarkers of adverse outcomes in premature infants.
doi:10.1016/j.jpeds.2010.10.043
PMCID: PMC3412418  PMID: 21256510
12.  Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants 
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
doi:10.1164/rccm.201101-0055OC
PMCID: PMC3136997  PMID: 21471086
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
13.  Use of a body proportionality index for growth assessment of preterm infants 
The Journal of pediatrics  2008;154(4):486-491.
Objective
We evaluated the utility of weight-for-length (defined as gm/cm3, “ponderal index”) as a complementary measure of growth in infants in neonatal intensive care units (NICUs).
Study design
Secondary analysis of infants (n=1214) 26-29 weeks at birth, included in a registry database (1991-2003), who had growth data at birth and discharge. Weight-for-age and weight-for-length were categorized as small (<10th percentile), appropriate or large (>90th percentile).
Results
Statistical agreement between the weight-for-age and weight-for-length measures was poor (kappa=0.02 at birth, 0.10 at discharge, Bowker test for symmetry p<0.0001). From birth to discharge, the percent of small-for-age infants increased from 12% to 21%, and the percent of small-for-length infants decreased from 10% to 4%; the percent of large-for-age infants remained similar (<1%), and the percent of large-for-length infants increased from 5% to 17%. At discharge, 92% of small-for-age infants were appropriate or large-for-length, and 19% of appropriate-for-age infants were large-for-length.
Conclusions
Weight-for-age and weight-for-length are complementary measures. Weight-for-length or other measure of body proportionality should be considered for inclusion in routine growth monitoring of infants in the NICU.
doi:10.1016/j.jpeds.2008.10.012
PMCID: PMC2745983  PMID: 19041096
Growth status; growth; weight-for-age; weight/length3; ponderal index; weight/length ratio; obesity; overweight; underweight; small-for-gestational age; nutrition

Results 1-13 (13)