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1.  Lactobacillus reuteri DSM 17938 Changes the Frequency of Foxp3+ Regulatory T Cells in the Intestine and Mesenteric Lymph Node in Experimental Necrotizing Enterocolitis 
PLoS ONE  2013;8(2):e56547.
Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine in premature infants. Lactobacillus reuteri DSM 17938 improves survival and reduces the incidence and severity of NEC in a rodent model. Foxp3+ regulatory T cells (Tregs) maintain intestinal homeostasis by controlling inflammation and inducing tolerance. To determine whether there are insufficient numbers of Tregs to control inflammation in NEC and to determine if LR17938 increases the frequency of Tregs, we studied selected groups of newborn Sprague-Dawley rats according to feeding plan: dam±LR17938, formula±LR17938, and NEC±LR17938. NEC was induced by gavage feeding with special formula and exposure to hypoxic conditions. Lymphocytes isolated from ileum, mesenteric lymph nodes (MLN), spleen and thymus were labeled for T cell surface markers (CD3, CD4, CD8) and intracellular Foxp3; and labeled cells were analyzed by flow cytometry. The percentage of CD3+ T cells and Foxp3+ Tregs in the ileum significantly decreased in pups with NEC, compared to normal controls. Feeding LR17938 to neonatal rats with NEC increased the % of Foxp3+ T cells in the ileum while decreasing the percentage of cells in the MLN. Administration of LR17938 to dam-fed rats significantly increased Foxp3+Tregs in the ileum as early as day of life (DOL)1 but did not produce an increase in Tregs in formula-fed rats on DOL1. These results suggest that factors in breast milk may enhance the early immunomodulatory effects of LR17938. An anti-inflammatory effect of LR17938 in NEC was associated with the modulation of immune responses and induction and what appears to be migration of Foxp3+ Tregs to the diseased gut. Probiotic-facilitated development of Tregs might play an important role in the prevention of NEC.
PMCID: PMC3577854  PMID: 23437165
2.  Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis 
(1) To characterise neurodevelopmental outcome of neonates with necrotizing enterocolitis (NEC); (2) to define whether NEC increases risk of neurodevelopmental impairment in very low birth weight neonates; (3) to investigate whether stage of disease or need for surgery increase risk of poor outcome.
A systematic review was performed. Searches identified 182 relevant papers. Ten studies compared extremely low birthweight neonates with NEC to infants of similar age and gestation who did not develop NEC. Data are reported as OR (95% CIs, p values for test for overall effect) and compared by χ2.
7843 children (821 with NEC) were included in the meta‐analysis. Median follow‐up was 20 months (range 12 to 156). Overall, 45% of children who had neonatal NEC were neurodevelopmentally impaired. Infants with NEC were significantly more likely than infants of similar age and gestation who did not develop NEC to be neurodevelopmentally impaired (1.6 (1.3 to 2.0), p = 0.0001) including a higher risk of cerebral palsy (1.5 (1.2 to 2.0), p = 0.001), visual (2.3 (1.0 to 5.1), p = 0.04), cognitive (1.7 (1.4 to 2.2), p<0.0001) and psychomotor impairment (1.7 (1.3 to 2.2), p<0.0001). The odds ratio of neurodevelopmental impairment was also 2.3 times higher in neonates with Bell's stage III disease or requiring surgery ((1.5 to 3.6), p = 0.0001).
NEC is associated with significantly worse neurodevelopmental outcome than prematurity alone. Presence of advanced NEC and need for surgery increase the risk of neurological impairment.
PMCID: PMC2675329  PMID: 16984980
3.  Epidemiology of Necrotizing Enterocolitis Temporal Clustering in Two Neonatology Practices 
The Journal of pediatrics  2008;154(5):656-661.
To develop a statistical method for defining clusters of necrotizing enterocolitis (NEC) cases in the neonatal intensive care unit (NICU).
Study design
2782 infants, between 1996–2004, weighing 401–1500 grams at birth were included. NEC was defined as Bell stage II or III. Two statistical methods used to define “disease clusters” were: (1) modified scan test; (2) comparison of observed and expected incidence density rates (IDR) of NEC at each NICU.
The proportion of infants with NEC was similar between NICUs (7.1% vs. 7.7%; p=0.6) as was the expected IDR of NEC (1.39/1000 patient-days vs. 1.32/1000 patient-days, p=0.72). Twelve temporal clusters of NEC were identified in the NICUs combined, comprising 18% of 203 total NEC cases during the study period. No seasonal/secular trends were noted for NEC rates or identified clusters. Potential NEC clusters of ≥3 cases at either NICU had >75% chance of being a true NEC cluster.
No operational definition of NEC cluster exists. This study introduced methods to be employed for prospective surveillance and guide studies to investigate etiologic relevance. Utilizing the proposed methods, statistically significant clusters (potential outbreaks) of NEC within NICUs can be identified early, providing early opportunity to implement cluster investigation protocols.
PMCID: PMC2700364  PMID: 19111317
disease clusters; outbreaks; neonatal intensive care unit; very low birth weight infants
4.  Bloodstream infections in very low birth weight infants with intestinal failure 
The Journal of pediatrics  2011;160(1):54-9.e2.
To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSI) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC).
Study design
Infants 401–1500 grams at birth who survived >72 hours and received care at NICHD Neonatal Research Network centers were studied. Frequency of culture positive BSI and pathogens were compared for infants with medical NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, duration of parenteral nutrition (PN) and other outcomes were evaluated.
932 infants were studied (IF, n=78; surgical NEC without IF, n=452; medical NEC, n=402). The proportion with BSI after NEC diagnosis was higher in infants with IF than with surgical NEC (p=0.007) or medical NEC (p<0.001). Gram positive pathogens were most frequent. Among infants with IF, increased number of infections was associated with longer hospitalization and duration on PN (0, 1, ≥2 infections; median stay (days): 172, 188, 260, p=0.06; median days on PN: 90, 112, 115, p=0.003), and the proportion who achieved full feeds during hospitalization decreased (87%, 67%, 50%, p=0.03).
Recurrent BSIs are common in VLBW infants with IF. Gram positive bacteria were most commonly identified in these infants.
PMCID: PMC3419271  PMID: 21840538
Short bowel syndrome; Bloodstream infections; Late onset sepsis; Very low birth weight; Nutrition; Intestinal failure
5.  Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation 
We sought to determine the incidence of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) in surviving extremely low-birth-weight (ELBW, <1000 g birth weight) infants and to establish the impact of NEC on outcomes by hospital discharge and at 18 to 22 months adjusted age in a large, contemporary, population-based practice.
Study Design
Hospital outcome data for all ELBW infants born in the greater Cincinnati region from 1998 to 2009 were extracted from the National Institute of Child Health Neonatal Research Network Database. Neurodevelopmental outcome at 18 to 22 months was assessed using Bayley Scales of Infant Development-II scores for Mental Developmental Index and Psychomotor Developmental Index. Multivariable logistic regression was used and adjusted odds ratios reported to control for confounders.
From 1998 to 2009, ELBW infants accounted for 0.5% of the 352 176 live-born infants in greater Cincinnati. The incidence of NEC was 12%, with a 50% case-fatality rate. Death before discharge, morbid complications of prematurity and neurodevelopmental impairment were all increased among infants diagnosed with NEC. Infants with surgical NEC and SIP had a higher incidence of death, but long-term neurodevelopmental outcomes were not different comparing surviving ELBW infants with medical NEC, surgical NEC and SIP.
Although ELBW infants comprise a very small proportion of live-born infants, those who develop NEC and SIP are at an increased risk for death, morbid complications of prematurity and neurodevelopmental impairment. No significant differences in neurodevelopmental outcomes were observed between the medical and surgical NEC and SIP groups.
PMCID: PMC3496418  PMID: 22157625
necrotizing enterocolitis; extremely low-birth-weight; neurodevelopmental outcome; Bayley scales of infant development
6.  An update on necrotizing enterocolitis: pathogenesis and preventive strategies 
Korean Journal of Pediatrics  2011;54(9):368-372.
Necrotizing enterocolitis (NEC) is one of the most critical morbidities in preterm infants. The incidence of NEC is 7% in very-low-birth-weight infants, and its mortality is 15 to 30%. Infants who survive NEC have various complications, such as nosocomial infection, malnutrition, growth failure, bronchopulmonary dysplasia, retinopathy of prematurity, and neurodevelopmental delays. The most important etiology in the pathogenesis of NEC is structural and immunological intestinal immaturity. In preterm infants with immature gastrointestinal tracts, development of NEC may be associated with a variety of factors, such as colonization with pathogenic bacteria, secondary ischemia, genetic polymorphisms conferring NEC susceptibility, anemia with red blood cell transfusion, and sensitization to cow milk proteins. To date, a variety of preventive strategies has been accepted or attempted in clinical practice with regard to the pathogenesis of NEC. These strategies include the use of breast feeding, various feeding strategies, probiotics, prebiotics, glutamine and arginine, and lactoferrin. There is substantial evidence for the efficacy of breast feeding and the use of probiotics in infants with birth weights above 1,000 g, and these strategies are commonly used in clinical practice. Other preventive strategies, however, require further research to establish their effect on NEC.
PMCID: PMC3250602  PMID: 22232629
Necrotizing enterocolitis; Infant; Premature; Pathogenesis; Prevention
7.  Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid 
BMC Pediatrics  2013;13:127.
Infants who survive advanced necrotizing enterocolitis (NEC) at the time of birth are at increased risk of having poor long term physiological and neurodevelopmental growth. The economic implications of the long term morbidity in these children have not been studied to date. This paper compares the long term healthcare costs beyond the initial hospitalization period incurred by medical and surgical NEC survivors with that of matched controls without a diagnosis of NEC during birth hospitalization.
The longitudinal healthcare utilization claim files of infants born between January 2002 and December 2003 and enrolled in the Texas Medicaid fee-for-service program were used for this research. Propensity scoring was used to match infants diagnosed with NEC during birth hospitalization to infants without a diagnosis of NEC on the basis of gender, race, prematurity, extremely low birth weight status and presence of any major birth defects. The Medicaid paid all-inclusive healthcare costs for the period from 6 months to 3 years of age among children in the medical NEC, surgical NEC and matched control groups were evaluated descriptively, and in a generalized linear regression framework in order to model the impact of NEC over time and by birth weight.
Two hundred fifty NEC survivors (73 with surgical NEC) and 2,909 matched controls were available for follow-up. Medical NEC infants incurred significantly higher healthcare costs than matched controls between 6–12 months of age (mean incremental cost = US$ 5,112 per infant). No significant difference in healthcare costs between medical NEC infants and matched controls was seen after 12 months. Surgical NEC survivors incurred healthcare costs that were consistently higher than that of matched controls through 36 months of age. The mean incremental healthcare costs of surgical NEC infants compared to matched controls between 6–12, 12–24 and 24–36 months of age were US$ 18,274, 14,067 (p < 0.01) and 8,501 (p = 0.06) per infant per six month period, respectively. These incremental costs were found to vary between sub-groups of infants born with birth weight < 1,000g versus ≥ 1,000g (p < 0.05).
The all-inclusive healthcare costs of surgical NEC survivors continued to be substantially higher than that of matched controls through the early childhood development period. These results can have important treatment and policy implications. Further research in this topic is needed.
PMCID: PMC3765805  PMID: 23962093
8.  The importance of pro-inflammatory signaling in neonatal NEC 
Seminars in perinatology  2008;32(2):100-106.
Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in neonatal intensive care units, affecting 10 percent of premature neonates born weighing less than 1500 grams. Although many advances have been made in the understanding of this disease, the etiology and pathophysiology remain incompletely understood, and treatment is limited to supportive care. In recent years, studies have focused on the role of the inflammatory cascade and its’ impact on the disease process, and investigators are evaluating strategies to attenuate inflammatory signaling that might prevent and/or ameliorate neonatal NEC. In this review, we examine the key points in the signaling pathways involved in NEC, and potential strategies for prevention and treatment of this dreaded disease.
PMCID: PMC2362144  PMID: 18346533
9.  Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death 
To determine the association between human milk (HM) intake and risk of necrotizing enterocolitis (NEC) or death among infants 401 to 1000 g birth weight.
Study Design
Analysis of 1272 infants in the National Institute of Child Health and Human Development Neonatal Network Glutamine Trial was performed to determine if increasing HM intake was associated with decreased risk of NEC or death. HM intake was defined as the proportion of HM to total intake, to enteral intake and total volume over the first 14 days. Known NEC risk factors were included as covariates in Cox proportional hazard analyses for duration of survival time free of NEC.
Among study infants, 13.6% died or developed NEC after 14 days. The likelihood of NEC or death after 14 days was decreased by a factor of 0.83 (95% confidence interval, CI 0.72, 0.96) for each 10% increase in the proportion of total intake as HM. Each 100 ml kg–1 increase in HM intake during the first 14 days was associated with decreased risk of NEC or death (hazard ratio, HR 0.87 (95% CI 0.77, 0.97)). There appeared to be a trend towards a decreased risk of NEC or death among infants who received 100% HM as a proportion to total enteral intake (HM plus formula), although this finding was not statistically significant (HR 0.85 (95% CI 0.60, 1.19)).
These data suggest a dose-related association of HM feeding with a reduction of risk of NEC or death after the first 2 weeks of life among extremely low birth weight infants.
PMCID: PMC2801431  PMID: 18716628
necrotizing enterocolitis; human milk; enteral feeding; extremely premature infants
To examine 5 infant characteristics and health factors that might be risk factors for necrotizing enterocolitis (NEC) in preterm infants.
134 preterm infants at high risk for NEC due to either having a birthweight of <1500 grams or requiring mechanical ventilation at birth.
Descriptive secondary analysis using data from a larger longitudinal study.
Weekly review of infant’s medical record until discharge. Demographic questionnaire completed by mothers at time of enrollment. Data analysis done with logistic regression, Fischer’s exact tests and correlations.
Outcome Measures
Total number of days infant required mechanical ventilation, birthweight in grams, number of infections prior to NEC diagnosis, maternal race (Black, White or Asian), and infant gender were used to predict the development of NEC.
Maximum likelihood estimates indicated that mechanical ventilation had a positive relationship with developing NEC, such that as the number of days of mechanical ventilation increased so did the risk of developing NEC. There was also a very strong positive relationship between the number of nosocomial infections and NEC indicating that as the number of infections increased the likelihood of developing NEC increased. Although the relationship between race and NEC was not significant in the logistic regression, a Fisher’s exact test showed that Black preterm infants had increased incidence of NEC as compared to other races. This relationship was not due to correlations between race and mechanical ventilation or infections. No relationship between gender on NEC was noted. Birthweight was not significantly associated with NEC in the logistic regression but was correlated with NEC, probably because of its correlation with mechanical ventilation and number of infections.
In this sample, number of infections and length of mechanical ventilation were the primary predictors of NEC in preterm infants. In addition, the frequency that Black infants are diagnosed with NEC is significantly higher than that of other races. Knowledge of risk factors for NEC can allow healthcare providers to evaluate and adjust care practices for preterm infants who present with higher risk for NEC based on empirical data.
PMCID: PMC2677063  PMID: 18827518
premature infant; necrotizing enterocolitis; risk factors; race; gender
11.  Analysis of the association between necrotizing enterocolitis and transfusion of red blood cell in very low birth weight preterm infants 
Korean Journal of Pediatrics  2013;56(3):112-115.
To investigate the association between necrotizing enterocolitis (NEC) and red blood cell transfusions in very low birth weight (VLBW) preterm infants.
We studied were 180 VLBW preterm infants who were admitted to the neonatal intensive care unit of CHA Gangnam Hospital from January of 2006 to December of 2009. The subjects were divided into 2 groups: an NEC group (greater than stage II on the modified Bell's criteria) and a control group (less than stage II on the modified Bell's critieria). We defined red blood cell transfusion before NEC diagnosis as the frequency of transfusion until NEC diagnosis (mean day at NEC diagnosis, day 18) in the NEC group and the frequency of transfusion until 18 days after birth in the control group.
Of the 180 subjects, 18 (10%) belonged to the NEC group, and 14 (78%) of these 18 patients had a history of transfusion before NEC diagnosis. The NEC group received 3.1±2.9 transfusions, and the control group received 1.0±1.1 transfusions before the NEC diagnosis (P=0.005). In a multivariate logistic regression corrected for gestational age, Apgar score at 1 minute, the presence of respiratory distress syndrome, patent ductus arteriosus, premature rupture of membrane, disseminated intravascular coagulopathy and death were confounding factors. The risk of NEC increased 1.63 times (95% confidence interval, 1.145 to 2.305; P=0.007) with transfusion before the NEC diagnosis.
The risk for NEC increased significantly with increased transfusion frequency before the NEC diagnosis.
PMCID: PMC3611044  PMID: 23559972
Necrotizing enterocolitis; Very low birth weight infants; Red blood cell transfusion
12.  Duodenal Microflora in Very-Low-Birth-Weight Neonates and Relation to Necrotizing Enterocolitis 
Journal of Clinical Microbiology  2000;38(12):4539-4547.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in the neonatal period. Small-bowel overgrowth with aerobic gram-negative bacteria has previously been implicated in the development of NEC. This prospective study performed quantitative bacteriology on 422 duodenal aspirates collected from 122 very-low-birth-weight (<1,500-g) newborns, at the time of routine changing of nasogastric tubes. Isolates of Enterobacteriaceae were typed by repetitive extragenic, palindromic PCR and pulsed-field gel electrophoresis. One or more samples from 50% of these infants yielded gram-negative bacteria, predominantly Escherichia coli, Klebsiella spp., and Enterobacter spp., with counts up to 108 CFU/g. The proportion of samples with gram-negative bacteria increased with postnatal age, while the percentage of sterile samples declined. Molecular typing revealed marked temporal clustering of indistinguishable strains. All infants had been fed prior to isolation of gram-negative organisms. Antibiotic use had no obvious effect on colonization with Enterobacteriaceae. There were 15 episodes of suspected NEC (stage I) and 8 confirmed cases of NEC (2 stage II and 6 stage III) during the study period. Duodenal aspirates were collected prior to clinical onset in 13 episodes of NEC. Seven of these yielded Enterobacteriaceae, of which five strains were also isolated from infants without NEC. Very-low-birth-weight infants have high levels of duodenal colonization with Enterobacteriaceae, with evidence of considerable cross-colonization with indistinguishable strains. There was no association between duodenal colonization with particular strains of Enterobacteriaceae and development of NEC.
PMCID: PMC87634  PMID: 11101593
13.  Probiotics and Necrotizing Enterocolitis: Finding the Missing Pieces of the Probiotic Puzzle 
Necrotizing enterocolitis (NEC) is one of the leading causes of death in the neonatal intensive care unit. Morbidity and mortality rates significantly increase with decreases in gestational age and birth weight. Strong evidence suggests probiotic prophylaxis may significantly decrease the incidence of NEC and should therefore be incorporated into the standard of care for preterm infants. However, debate still remains because of limitations of completed studies. The purpose of this review was to provide an overview of the controversies regarding probiotic use in preterm infants and to shed light on the practical considerations for implementation of probiotic supplementation.
PMCID: PMC3567885  PMID: 23412969
necrotizing enterocolitis; premature infant; probiotics
14.  Necrotizing Enterocolitis (NEC) and the Risk of Intestinal Stricture: The Value of C-Reactive Protein 
PLoS ONE  2013;8(10):e76858.
Necrotizing enterocolitis (NEC) is a severe complication frequently seen during the neonatal period associated with high mortality rate and severe and prolonged morbidity including Post-NEC intestinal stricture. The aim of this study is to define the incidence and risk factors of these post-NEC strictures, in order to better orient their medicosurgical care. Sixty cases of NEC were retrospectively reviewed from a single tertiary center with identical treatment protocols throughout the period under study, including systematic X-ray contrast study. This study reports a high rate of post-NEC intestinal stricture (n = 27/48; 57% of survivors), either in cases treated surgically (91%) and after the medical treatment of NEC (47%). A colonic localization of the strictures was more frequent in medically-treated patients than in those with NEC treated surgically (87% vs. 50%). The length of the strictures was significantly shorter in case of NEC treated medically. No deaths were attributable to the presence of post-NEC stricture. The mean hospitalization time in NICU and the median age at discontinuation of parenteral nutrition were longer in the group with stricture, but this difference was not significant. The median age at discharge was significantly higher in the group with stricture (p = 0.02). The occurrence of post-NEC stricture was significantly associated with the presence of parietal signs of inflammation and thrombopenia (<100 000 platelets/mm3). The mean maximum CRP concentration during acute phase was significantly higher in infants who developed stricture (p<0.001), as was the mean duration of the elevation of CRP levels (p<0.001). The negative predictive value of CRP levels continually <10 mg/dL for the appearance of stricture was 100% in our study. In conclusion, this retrospective and monocentric study demonstrates the correlation between the intensity of the inflammatory syndrome and the risk of secondary intestinal stricture, when systematic contrast study is performed following NEC.
PMCID: PMC3795640  PMID: 24146936
15.  New Concepts of Microbial Translocation in the Neonatal Intestine: Mechanisms and Prevention 
Clinics in perinatology  2010;37(3):565-579.
In very-low-birth weight (VLBW, <1500 gram) infants, late-onset neonatal sepsis and necrotizing enterocolitis prolong the hospital stay, increase the cost of care, and place the infant at greater risk for morbidity and mortality (1). Long-term follow-up studies have demonstrated that these infections significantly increase the risk of neurological disabilities (2). With incidences of ~20% and 5–10% respectively, late-onset sepsis [LOS] and necrotizing enterocolitis [NEC] in VLBW infants need new preventive approaches. A long-held belief is that LOS and NEC result from bacterial translocation [BT]. Bacterial translocation is defined as invasion of indigenous intestinal bacteria through the mucosa into normally sterile tissue (3). This definition has been extended to include bacterial toxins or antigens, which damage intestinal epithelia and enter the circulation resulting in a systemic inflammatory response (4). Local BT through the intestinal mucosa, or toxin-related injury of intestinal epithelia, is associated with NEC (5), while BT beyond the intestine causes sepsis and multi-organ failure (6,7). This chapter describes: 1) development of the intestinal microbiota, 2) how immaturity of the nascent epithelial lining of the gastrointestinal [GI] tract and its sub-mucosal tissues mediate BT, 3) strategies to accelerate barrier functions in the immature GI tract and 4) the effects of nutrition and colonization by commensal bacteria on the susceptibility of the immature intestine to BT.
PMCID: PMC2933426  PMID: 20813271
intestinal microbiota; gut epithelia; enterocytes; goblet cells; Paneth cells; human milk; lactoferrin; probiotics; prebiotics
16.  Necrotising Enterocolitis in Preterm Infants: Epidemiology and Antibiotic Consumption in the Polish Neonatology Network Neonatal Intensive Care Units in 2009 
PLoS ONE  2014;9(3):e92865.
The aim of this study was to describe the epidemiology of necrotising enterocolitis (NEC), antibiotic consumption and the usefulness of microbiological tests in very low birth weight (VLBW) Polish newborns.
Prospective surveillance was performed in the year 2009 by local infection control teams. The study covered 910 infants hospitalized in six Polish neonatal intensive care units. Two kinds of indicators were used for the description of antibiotic usage: the duration of treatment (days of treatment, DOTs) and the defined daily dose (DDD).
NEC incidence was 8.7% and fatality rate was 19%. Chorioamnionitis, late gestational age and low birth weight were identified as risk factors for NEC. Catheterization, mechanical ventilation and other selected procedures were used considerably longer in newborns with NEC than in the remaining neonates. Total usage of antibiotics reached 2.9 DDDs or 1.437 days; the average use of drugs per case of NEC amounted to 0.47 DDD or 23.2 DOTs. The level of antibiotic usage was analysed with correlation to microbiological tests performed and it was non-significantly greater in the group of children with NEC in whom the tests were performed.
A high risk of developing NEC is closely associated with VLBW and with inflammation of the amnion during labour. We observed no relationship between the consumption of antibiotics in neonates with NEC and positive results of microbiological testing indicating sepsis accompanying NEC or gut colonization with pathogens.
PMCID: PMC3962467  PMID: 24658445
17.  Survival and Morbidity Outcomes of Very Low Birth Weight Infants with Down Syndrome 
Pediatrics  2010;126(6):1132-1140.
Individuals with Down syndrome (DS) are at increased risk of several morbidities with lifelong health consequences. Little is known about mortality or morbidity risks in early infancy among very-low-birth-weight (VLBW) infants with DS. Our objective was to compare survival and neonatal morbidities between VLBW infants with DS and VLBW infants with other non-DS chromosomal anomalies, other non-chromosomal birth defects, and VLBW infants without major birth defects.
Data were collected prospectively for infants weighing 401-1500 grams born and/or cared for at one of the study centers participating in the NICHD Neonatal Research Network from 1994 through 2008. Risk of death and morbidities including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups.
Infants with DS were at increased risk of death (adjusted relative risk [RR] 2.47, 95% confidence interval [CI] 2.00-3.07), PDA, NEC, LOS, and BPD relative to infants with no birth defects. Decreased risk of death (RR 0.40, 95% CI 0.31-0.52) and increased risks of NEC and LOS were observed when comparing infants with DS to infants with other non-DS chromosomal anomalies. Relative to infants with non-chromosomal birth defects, infants with DS were at increased risk of PDA and NEC.
The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for caretakers in anticipating the need for enhanced surveillance for prevention of these morbidities.
PMCID: PMC3059605  PMID: 21098157
neonatal mortality; neonatal morbidity; preterm infants; Down syndrome; trisomy 21
18.  Non-Invasive Serum Amyloid A (SAA) Measurement and Plasma Platelets for Accurate Prediction of Surgical Intervention in Severe Necrotizing Enterocolitis (NEC) 
PLoS ONE  2014;9(3):e90834.
To evaluate the value of biomarkers to detect severe NEC.
Summary Background Data
The time point of surgery in necrotizing enterocolitis (NEC) is critical. Therefore, there is a need for markers that detect severe NEC, because clinical signs of severe NEC often develop late. This study evaluated the value of biomarkers reflecting intestinal cell damage and inflammation to detect severe NEC.
29 neonates with NEC were included. Two definitions of moderate versus severe NEC were analyzed: medical NEC (n = 12) versus surgical or fatal NEC (n = 17); and Bell stage II NEC (n = 13) versus stage III NEC (n = 16). Urinary intestinal fatty acid binding protein (I-FABP), serum amyloid A (SAA), C3a and C5a, and fecal calprotectin were measured. C-reactive protein (CRP), white blood cell count (WBC) and platelet count data were measured in blood.
In both definitions of moderate versus severe NEC, urinary SAA levels were significantly higher in severe NEC. A cut-off value of 34.4 ng/ml was found in surgical NEC versus medical NEC (sensitivity, 83%; specificity, 83%; LR+, 4.88 (95% CI, 1.37–17.0); LR−, 0.20 (95% CI, 0.07–0.60)) at diagnosis of NEC and at one day prior to surgery in neonates who were operated later on. Combination of urinary SAA and platelet count increased the accuracy, with a sensitivity, 94%; specificity, 83%; LR+, 5.53 (95% CI, 1.57–20.0); and LR−, 0.07 (95% CI, 0.01–0.48).
Urinary SAA is an accurate marker in differentiating severe NEC from moderate NEC; particularly if combined with serum platelet count.
PMCID: PMC3946234  PMID: 24603723
19.  Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero 
Necrotizing enterocolitis (NEC) is an acute neonatal inflammatory disease that affects the intestine and may result in necrosis, systemic sepsis and multisystem organ failure. NEC affects 5–10% of all infants with birth weight ≤ 1500 g or gestational age less than 30 weeks. Chorioamnionitis (CA) is the main manifestation of pathological inflammation in the fetus and is strong associated with NEC. CA affects 20% of full-term pregnancies and upto 60% of preterm pregnancies and, notably, is often an occult finding. Intrauterine exposure to inflammatory stimuli may switch innate immunity cells such as macrophages to a reactive phenotype (“priming”). Confronted with renewed inflammatory stimuli during labour or postnatally, such sensitized cells can sustain a chronic or exaggerated production of proinflammatory cytokines associated with NEC (two-hit hypothesis). Via the cholinergic anti-inflammatory pathway, a neurally mediated innate anti-inflammatory mechanism, higher levels of vagal activity are associated with lower systemic levels of proinflammatory cytokines. This effect is mediated by the α7 subunit nicotinic acetylcholine receptor (α7nAChR) on macrophages. The gut is the most extensive organ innervated by the vagus nerve; it is also the primary site of innate immunity in the newborn. Here we review the mechanisms of possible neuroimmunological brain-gut interactions involved in the induction and control of antenatal intestinal inflammatory response and priming. We propose a neuroimmunological framework to (1) study the long-term effects of perinatal intestinal response to infection and (2) to uncover new targets for preventive and therapeutic intervention.
PMCID: PMC3737662  PMID: 23964209
necrotizing enterocolitis; chorioamnionitis; preterm birth; inflammation; neuroimmunology; vagus nerve; intestines; prevention
20.  Necrotizing Enterocolitis Risk 
Advances in Neonatal Care  2012;12(2):77-89.
Necrotizing enterocolitis (NEC) is the most common cause of gastrointestinal-related morbidity and mortality in the neonatal intensive care unit (NICU). Its onset is sudden and the smallest, most premature infants are the most vulnerable. Necrotizing enterocolitis is a costly disease, accounting for nearly 20% of NICU costs annually. Necrotizing enterocolitis survivors requiring surgery often stay in the NICU more than 90 days and are among those most likely to stay more than 6 months. Significant variations exist in the incidence across regions and units. Although the only consistent independent predictors for NEC remain prematurity and formula feeding, others exist that could increase risk when combined. Awareness of NEC risk factors and adopting practices to reduce NEC risk, including human milk feeding, the use of feeding guidelines, and probiotics, have been shown to reduce the incidence of NEC. The purpose of this review is to examine the state of the science on NEC risk factors and make recommendations for practice and research.
PMCID: PMC3357630  PMID: 22469959
necrotizing enterocolitis; neonatal; nursing; risk assessment; risk profile
21.  Therapeutic Use of Prebiotics, Probiotics, and Postbiotics to Prevent Necrotizing Enterocolitis: What is the Current Evidence? 
Clinics in perinatology  2013;40(1):11-25.
Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality and preventative therapies that are both effective and safe are urgently needed. Current evidence from therapeutic trials suggests that probiotics are effective in decreasing NEC in preterm infants and probiotics are currently the most promising therapy on the horizon for this devastating disease. However, concerns regarding safety and optimal dosing have limited the widespread adoption of routine clinical use of probiotics in preterm infants. In addition, prebiotics and postbiotics may be potential alternatives or adjunctive therapies to the administration of live microorganisms, although studies demonstrating their clinical efficacy in preventing NEC are lacking. This review summarizes the current evidence regarding the use of probiotics, prebiotics and postbiotics in the preterm infant, including its therapeutic role in preventing NEC.
PMCID: PMC3575601  PMID: 23415261
Necrotizing Enterocolitis; Probiotic Bacteria; Premature Infants; Very Low Birth Weight
22.  Antibiotic Exposure in the Newborn Intensive Care Unit and the Risk of Necrotizing Enterocolitis 
The Journal of pediatrics  2011;159(3):392-397.
To determine if duration of antibiotic exposure is an independent risk factor for necrotizing enterocolitis (NEC)
Study design
A retrospective, 2:1 control-case analysis was conducted comparing neonates with NEC to those without from 2000 through 2008. Controls were matched on gestational age, birth weight, and birth year. In each matched triad, demographic and risk factor data were collected from birth until the diagnosis of NEC in the case subject. Bivariate and multivariate analyses were utilized to assess associations between risk factors and NEC.
124 cases of NEC were matched with 248 controls. Cases were less likely to have respiratory distress syndrome (p=0.018) and more likely to reach full enteral feeding (p=0.028) than controls. Cases were more likely to have culture-proven sepsis (p<0.0001). Given the association between sepsis and antibiotic use, we tested for and found a significant interaction between the two variables (p=0.001). When neonates with sepsis were removed from the cohort, the risk of NEC increased significantly with duration of antibiotic exposure. Exposure for >10 days resulted in a nearly three-fold increase in the risk of developing NEC
Duration of antibiotic exposure is associated with an increased risk of NEC among neonates without prior sepsis.
PMCID: PMC3137655  PMID: 21489560
sepsis; antimicrobials; prematurity; neonates
23.  Synergistic Protection of Combined Probiotic Conditioned Media against Neonatal Necrotizing Enterocolitis-Like Intestinal Injury 
PLoS ONE  2013;8(5):e65108.
Balance among the complex interactions of the gut microbial community is important for intestinal health. Probiotic bacteria can improve bacterial balance and have been used to treat gastrointestinal diseases. Neonatal necrotizing enterocolitis (NEC) is a life-threatening inflammatory bowel disorder primarily affecting premature infants. NEC is associated with extensive inflammatory NF-κB signaling activation as well as intestinal barrier disruption. Clinical studies have shown that probiotic administration may protect against NEC, however there are safety concerns associated with the ingestion of large bacterial loads in preterm infants. Bacteria-free conditioned media (CM) from certain probiotic organisms have been shown to retain bioactivity including anti-inflammatory and cytoprotective properties without the risks of live organisms. We hypothesized that the CM from Lactobacillus acidophilus (La), Bifidobacterium infantis (Bi), and Lactobacillus plantarum (Lp), used separately or together would protect against NEC. A rodent model with intestinal injury similar to NEC was used to study the effect of CM from Lp, La/Bi, and La/Bi/Lp on the pathophysiology of NEC. All the CM suppressed NF-κB activation via preserved IκBα expression and this protected IκBα was associated with decreased liver activity of the proteasome, which is the degrading machinery for IκBα. These CM effects also caused decreases in intestinal production of the pro-inflammatory cytokine TNF-α, a downstream target of the NF-κB pathway. Combined La/Bi and La/Bi/Lp CM in addition protected intestinal barrier function by maintaining tight junction protein ZO-1 levels and localization at the tight junction. Double combined La/Bi CM significantly reduced intestinal injury incidence from 43% to 28% and triple combined La/Bi/Lp CM further reduced intestinal injury incidence to 20%. Thus, this study demonstrates different protective mechanisms and synergistic bioactivity of the CM from different organisms in ameliorating NEC-like intestinal injury in an animal model.
PMCID: PMC3663790  PMID: 23717690
24.  Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants 
The Journal of pediatrics  2011;159(5):720-725.
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.
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).
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.
PMCID: PMC3193552  PMID: 21784435
prolonged antibiotic treatment; death; human milk; late-onset sepsis; necrotizing enterocolitis; premature infant
25.  Serum Cytosolic β-Glucosidase Levels In Neonatal Necrotizing Enterocolitis 
Iranian Journal of Pediatrics  2012;22(4):452-456.
This study was conducted to compare serum Cytosolic β-Glucosidase (CBG) levels of age-matched control patients with those of infants with neonatal necrotizing enterocolitis (NEC), to determine eventual association between Serum Cytosolic β-Glucosidase levels with intensity of the disease in NEC infants.
82 neonates were divided into controls (group I, n=41), feeding intolerance (group II, n=15), and NEC (group III, n=26). Serum Cytosolic β-Glucosidase was measured at the onset of feeding intolerance or NEC and at weeks 2–3 in control infants (Group I) by ELISA. Data were analyzed using descriptive statistics, non-parametric tests and Student t-test.
Median birth weights in three groups were 1761.3, 1951.9, 1893.7 g, median gestational ages were 33.6, 35.0 and 34.5 weeks and ages of sampling were 15.3, 14.7 and 15.1 days, respectively. The differences between NEC group, feeding intolerance group and the control group were not statistically significant (P>0.05). There was a trend toward an increase in Serum CBG levels (group I 36.5 nmmol/L), group II (112.4 nmmol/L) vs. group III (693.0 nmmol/L), (χ2=43.296, P<0.01). Infants in group III had highest CBG levels, compared with group II and I.
Serum CBG is elevated in NEC, maybe NEC is the reason of high level of Serum CBG. In addition, the serum CBG may have utility as an early marker of ischemia in patients at risk for NEC in future studies.
PMCID: PMC3533143  PMID: 23429454
Newborn; Cytosolic β-Glucosidase; Necrotizing Enterocolitis

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