Incidence Of Necrotizing Enterocolitis Research Articles

Recombinant human soluble thrombomodulin reduces the severity and incidence of necrotizing enterocolitis in a newborn rat model.

Necrotizing enterocolitis (NEC) remains the leading cause of death in preterm infants. Recombinant human soluble thrombomodulin (rTM) has been reported to have anti-inflammatory effects as well as antithrombogenic effects. The aim of this study was to evaluate the effect of rTM in a rat NEC model. NEC was induced by enteral feeding with hyperosmolar formula, gavage administration of lipopolysaccharide and asphyxia stress. Controls were fed by their mother ad libitum. In the treatment group, rTM was administered subcutaneously twice (once each on the first and second day). All animals surviving beyond 96h or that developed signs of distress were euthanized. The ileum was harvested for a histological evaluation and the measurement of the mRNA and protein expression. The rate of NEC-like intestinal injury in the treatment group (9/25, 36%) was significantly lower than in the NEC group (25/34, 73.5%). Tissue levels of TNF-α, IL-6 and HMGB1 were significantly elevated in the NEC group, whereas those in the treatment group were decreased to similar values as in the control group. Our experimental study showed that rTM is able to reduce the severity and incidence of NEC. It may be an alternative option for the treatment of NEC.

Probiotics may not prevent the deterioration of necrotizing enterocolitis from stage I to II/III

BackgroundProbiotic therapy can reduce the incidence of NEC. Therapeutic use of probiotics after NEC diagnosis reduces the severity of NEC in preterm infants or full-term infants is unclear. To evaluate the effect of probiotics on preventing the deterioration of necrotizing enterocolitis (NEC) from stage I to II/III.MethodsA retrospective matched cohort study was performed. Included patients were ultimately divided into two groups: the probiotic treatment group (probiotics were used ≥4 days) and the no probiotic treatment group. The differences in deterioration trends between the two groups were compared. Additionally, the risk factors associated with the deterioration of NEC were further analyzed with a case-control study.ResultsA total of 231 infants met the inclusion criteria. Eighty-one pairs were matched according to similar gestational age and birth weight. Before matching, we found that the rate of deterioration of NEC from stage I to II/III in the group with probiotic treatment was similar to that in the group without probiotic treatment (23.1% [25/108] vs 26.0% [32/123], P = 0.614). After matching, the rate of deterioration of NEC between the two groups still had no significant difference (21.0% [17/81] vs 27.2% [22/81], P = 0.358). Logistic regression analysis showed that sepsis after NEC was an independent risk factor for NEC deteriorating from stage I to II/III (OR 2.378, 95% CI 1.005–5.628, P = 0.049).ConclusionProbiotics may not prevent the deterioration of NEC from stage I to II/III in infants, but this conclusion should be treated with caution.

Prenatal inflammation impairs intestinal microvascular development through a TNF-dependent mechanism and predisposes newborn mice to necrotizing enterocolitis.

Prenatal inflammation is a risk factor for necrotizing enterocolitis (NEC), and it increases intestinal injury in a rat NEC model. We previously showed that maldevelopment of the intestinal microvasculature and lack of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) signaling play a role in experimental NEC. However, whether prenatal inflammation affects the intestinal microvasculature remains unknown. In this study, mouse dams were injected intraperitoneally with lipopolysaccharide (LPS) or saline at embryonic day 17. Neonatal intestinal microvasculature density, endothelial cell proliferation, and intestinal VEGF-A and VEGFR2 proteins were assessed in vivo. Maternal and fetal serum TNF concentrations were measured by ELISA. The impact of TNF on the neonatal intestinal microvasculature was examined in vitro and in vivo, and we determined whether prenatal LPS injection exacerbates experimental NEC via TNF. Here we found that prenatal LPS injection significantly decreased intestinal microvascular density, endothelial cell proliferation, and VEGF and VEGFR2 protein expression in neonatal mice. Prenatal LPS injection increased maternal and fetal serum levels of TNF. TNF decreased VEGFR2 protein in vitro in neonatal endothelial cells. Postnatal TNF administration in vivo decreased intestinal microvasculature density, endothelial cell proliferation, and VEGF and VEGFR2 protein expression and increased the incidence of severe NEC. These effects were ameliorated by stabilizing hypoxia-inducible factor-1α, the master regulator of VEGF. Furthermore, prenatal LPS injection significantly increased the incidence of severe NEC in our model, and the effect was dependent on endogenous TNF. Our study suggests that prenatal inflammation increases the susceptibility to NEC, downregulates intestinal VEGFR2 signaling, and affects perinatal intestinal microvascular development via a TNF mechanism. NEW & NOTEWORTHY This report provides new evidence that maternal inflammation decreases neonatal intestinal VEGF receptor 2 signaling and endothelial cell proliferation, impairs intestinal microvascular development, and predisposes neonatal mouse pups to necrotizing enterocolitis (NEC) through inflammatory cytokines such as TNF. Our data suggest that alteration of intestinal microvascular development may be a key mechanism by which premature infants exposed to prenatal inflammation are at risk for NEC and preserving the VEGF/VEGF receptor 2 signaling pathway may help prevent NEC development.

Role of Oropharyngeal Administration of Colostrum in Very Low Birth Weight Infants for Reducing Necrotizing Enterocolitis: A Randomized Controlled Trial.

This study aimed to study the role of oropharyngeal administration of colostrum (OAC) in very-low-birth-weight infants for reducing necrotizing enterocolitis (NEC). In this randomized controlled trial, 117 infants were enrolled, 59 were randomized to OAC group and 58 to routine care group. Infants with birth weight ≤ 1,250 g and/or gestational age ≤ 30 weeks were enrolled. Infants in OAC group received maternal colostrum (0.2 mL), 0.1 mL on either side, after 24 hours of postnatal life and were given every 2 hour for the next 72 hours irrespective of the enteral feeding status of the neonate. The primary outcome of the study was the incidence of NEC (stage 2 or 3). Baseline characteristics were comparable between the two groups. There was no significant reduction in the incidence of NEC in OAC group (0 [0%] vs. 3 [7.1%]; p = 0.11). There was significant reduction of 7 days of hospital stay in OAC group (34.2 ± 5.7 vs. 41.5 ± 6.7 days; p = 0.04).The incidence of early-onset sepsis, late-onset sepsis, blood culture positive sepsis, and ventilator-associated pneumonia were comparable between the two groups. OAC is safe and reduces the duration of hospital stay.

Maternal Immunoglobulin A protects against the development of necrotizing enterocolitis in preterm infants

Abstract Neonates are particularly susceptible to infection by colonizing microbes, and mammals protect their offspring via antibodies secreted into breast milk. Necrotizing Enterocolitis(NEC) is a disease of preterm infants characterized by intestinal epithelial damage and inflammation associated with the microbiota. The incidence of NEC is significantly lower in infants fed with maternal milk, though the mechanisms underlying this protective benefit are not clear. Here, we show that maternal Immunoglobulin A (IgA) is an important factor in protection against NEC. Analysis of IgA-binding within fecal samples from preterm infants indicated that breast milk was the predominant source of IgA in the first month of life and that a relative decrease in the fraction of bacteria bound by IgA is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that NEC was associated with increasing domination of the IgA unbound microbiota by Enterobacteriaceae, prior to disease onset. Further, we confirmed that IgA is critical in preventing NEC in a murine model, where we demonstrate that pups reared by IgA deficient mothers are susceptible to disease despite exposure to maternal milk. This study illustrates the importance of maternal IgA in shaping the host-microbiota relationship of preterm neonates and provides evidence that IgA is a critical factor in maternal milk necessary for the prevention of NEC.

Clinical and microbiological pathogenetic parallels with necrotizing enterocolitis in preterm infants Evidence-based prevention opportunities

There are summarized data of domestic and foreign publications on the issue of necrotizing enterocolitis (NEC) in children born prematurely. There is presented the trend of the prevalence of this pathology in the last decade, especially epidemiology and significance of NEC in the structure of perinatal morbidity and mortality. There were analyzed new concepts on etiology and pathogenesis of the disease. In recent years, there was descripted the key role of some risk factors for the development of NEC - immatureness of intestinal barrier functions, local and systemic immunity, reduced tolerance to enteral nutrition (especially in the absence of breast-feeding), inadequate microbial colonization of the immature gastrointestinal tract. Modern research methods allow us to decipher subtle mechanisms of activation of the cascade of the intestinal inflammation and breakdown of the immune defense mechanisms. There are established cellular and humoral compartments of the immune response in NEC; there were revealed typical deviations in intestinal microbiota. The investigation of etiopathogenetical NEC factors is the basis for the development of targeted methods of the prevention and treatment of this severe disease in premature infants, including with the use of probiotics. There are presented data that the use of probiotics significantly reduces the incidence of severe NEC and mortality risk from NEC.

Erythropoietin Protects Very Preterm Infants Against Necrotizing Enterocolitis and Potential Mechanisms: A Randomized Clinical Trial

Background: To determine whether recombinant human erythropoietin (rhEPO) protects against necrotizing enterocolitis (NEC) and the potential mechanisms in very preterm infants. Methods: The study was a prospective randomized clinical trial performed among 4 NICU centers. Preterm infants with gestational age ≤32 weeks were randomized to rhEPO (500 IU/kg, intravenously every other day for 2 weeks) or control group (the same volume of saline). Primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. Secondary outcomes were growth and neurodevelopment at 18 months of corrected age in very preterm infants with NEC. Meanwhile, peripheral blood of preterm infants after EPO treatment was collected and the transcriptome was assayed by RNA sequencing. Findings: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC, 84 died (6.5%) and 1030 (80.2%) completed the study at 18 months corrected age. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of NEC in gestational age of <28 weeks (OR = 0.178, 95% CI [0.037-0.865], p = 0.019). And transcriptome analysis showed that rhEPO treatment reduced intestinal inflammation signaling pathway. Interpretation: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial Registration Number: The trial was registered at ClinicalTrials.gov (NCT02036073). Funding Statement: This study was supported by the national Key Research and Development Program of China (2018YFC1004604), the Department of Science and Technology of Henan Province (134200510023), the Swedish Research Council (2015-02845). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was approved by the Life Science Ethics Committee of Zhengzhou University and Henan Medical Academy (201201002) in accordance with the Helsinki Declaration. Written informed consent was obtained from the parents of all included infants.

Prevention of necrotizing enterocolitis in premature infants - an updated review.

Necrotizing enterocolitis (NEC) is among the most common and devastating diseases encountered in premature infants, yet the true etiology continues to be poorly understood despite decades of research. Recently, gut bacterial dysbiosis has been proposed as a risk factor for the development of NEC. Based on this theory, several best clinical practices designed to reduce the risk of NEC have been proposed and/or implemented. This review summarizes the results of recent clinical trials and meta-analyses that support some of the existing clinical practices for reducing the risk of NEC in premature infants. It is evident that human milk feeding can reduce the incidence of NEC. While most of the studies demonstrated that probiotic supplementation can significantly reduce the incidence of NEC in premature infants, there are still some concerns regarding the quality, safety, optimal dosage, and treatment duration of probiotic preparations. Antibiotic prophylaxis does not reduce the incidence of NEC, and prolonged initial empirical use of antibiotics might in fact increase the risk of NEC for high-risk premature infants. Lastly, standardized feeding protocols are strongly recommended, both for prevention of postnatal growth restriction and NEC.

Are antibiotics a risk factor for the development of necrotizing enterocolitis-case-control retrospective study.

Previous studies have identified numerous risk factors associated with necrotizing enterocolitis (NEC) in very low birth weight (VLBW; birth weight less than 1500g) infants. One of the potential pathophysiological contributors could be antibiotic therapy. Our aim was to explore the association between antibiotic exposure and NEC in VLBW infants. We designed a retrospective 1:2 case-control cohort study in a level III neonatal intensive care unit. Our study group composed of VLBW infants born between January 2012 and December 2014 with a diagnosis of NEC stage IIA or greater (Bell's modified criteria). Our intent was to match every case in the study group to two controls. Our primary outcome was an association between antibiotic exposure and NEC. Twenty-two cases of NEC were matched to 32 controls. The infants who developed NEC were exposed to a statistically significantly more frequent number of antibiotic courses and to more days on any antibiotic prior to the development of NEC. There were significant differences between cases and controls with respect to the duration of exposure to gentamicin and meropenem specifically.Conclusion: The data from our study demonstrate that prolonged exposure to antibiotic therapy is associated with an increased risk of NEC among VLBW infants. Furthermore, gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC. What is known: • Early antibiotic exposure is a risk factor for the development of necrotising enterocolitis (NEC) in very low birth weight infants • Prolonged initial empirical antibiotic course for ≥ 5 days, despite sterile blood culture, is associated with an increased risk of developing NEC What is new: • The cumulative total number of days of antibiotic exposure is associated with an increased risk of developing NEC • Gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC in our study.

IGF1 is Developmentally Regulated in the Neonatal Intestine and Protects Neonatal Mice against Necrotizing Enterocolitis by Preserving the VEGF/VEGFR2 Signaling Pathway in an Animal Model

Necrotizing enterocolitis (NEC) is a common gastrointestinal disease affecting premature infants and associated with high morbidity and mortality. Its pathogenesis remains poorly understood. Decreased levels of serum IGF1 has been shown to be associated with a higher incidence of NEC in premature infants. We previously found that neonatal pups are most susceptible to NEC in the first few days of life. Here we hypothesize that IGF‐1 levels are low during the first days of life, and that exogenous IGF1 is protective against NEC via promoting intestinal VEGF/VEGFR2 signaling. To test our hypotheses, we first assessed the developmental expression of IGF1 in the serum and the intestinal tissues in neonatal mice during the first 3 weeks of life, and determined whether exposure to a NEC protocol affects serum and intestinal IGF1 levels. Secondly, we examined whether exogenous IGF1 protects against NEC and affects intestinal VEGF production both in vivo and in vitro. We found that: Serum IGF1 level is low during the first 2 days of life, and gradually increases over 3 weeks. In contrast, IGF1 expression in the intestinal tissue is low at birth, peaks between 3 days and 2 weeks of age, before decreasing to low level by 3 weeks. In pups exposed to a NEC protocol compared to DF controls, serum IGF1concentration was significantly decreased at 12 hours and 24 hours (by 35%, p&lt;0.05; and 59%, p&lt;0.0001 respectively ). Intestinal tissue IGF1 expression decreased as early as 6 hours into NEC, which occurred before the decrease in serum IGF1. Exogenous IGF1 treatment decreased mortality in pups exposed to NEC protocol (41% vs. 68%, p&lt;0.05), decreased the incidence of severe NEC (histological score ≥ 2) (χ2=4.03, p&lt;0.05) and increased intestinal VEGF/VEGFR2 protein expression. Neonatal intestinal endothelial cells treated with IGF1 in vitro had increased VEGF mRNA transcription and protein expression (p&lt;0.05 for both). We conclude that the beneficial effect of IGF1 on experimental NEC may be due to protection of small intestinal microvasculature development through preserving VEGF/VEGFR2 signaling pathway.Support or Funding InformationShireThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Improved feeding tolerance and growth are linked to increased gut microbial community diversity in very-low-birth-weight infants fed mother's own milk compared with donor breast milk

ABSTRACTBackgroundMother's own milk (MOM) is protective against gut microbiota alterations associated with necrotizing enterocolitis (NEC) and feeding intolerance among preterm infants. It is unclear whether this benefit is preserved with donor milk (DM) feeding.ObjectiveWe aimed to compare microbiota development, growth, and feeding tolerance in very-low-birth-weight (VLBW) infants fed an exclusively human milk diet of primarily MOM or DM.MethodsOne hundred and twenty-five VLBW infants born at Texas Children's Hospital were enrolled and grouped into cohorts based on percentage of MOM and DM in enteral feeds. Feeds were fortified with DM-derived fortifier per unit protocol. Weekly stool samples were collected for 6 wk for microbiota analysis [16S ribosomal RNA (rRNA) sequencing]. A research nurse obtained weekly anthropometrics. Clinical outcomes were compared via Wilcoxon's rank-sum test and Fisher's exact test, as well as multivariate analysis.ResultsThe DM cohort (n = 43) received on average 14% mothers’ milk compared with 91% for the MOM cohort (n = 74). Diversity of gut microbiota across all time points (n = 546) combined was increased in MOM infants (P < 0.001). By 4 and 6 wk of life, microbiota in MOM infants contained increased abundance of Bifidobacterium (P = 0.02) and Bacteroides (P = 0.04), whereas DM-fed infants had increased abundance of Staphylococcus (P = 0.02). MOM-fed infants experienced a 60% reduction in feeding intolerance (P = 0.03 by multivariate analysis) compared with DM-fed infants. MOM-fed infants had greater weight gain than DM-fed infants.ConclusionsCompared with DM-fed infants, MOM-fed infants have increased gut microbial community diversity at the phylum and genus levels by 4 and 6 wk of life, as well as better feeding tolerance. MOM-fed infants had superior growth. The incidence of NEC and other gastrointestinal morbidity is low among VLBW infants fed an exclusively human milk diet including DM-derived fortifier. This trial was registered at clinicaltrials.gov as NCT02573779.

Arguments against routine administration of probiotics for NEC prevention.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature neonates. Although randomized trials have shown that probiotics may be efficacious in the prevention of NEC, their use has not been universally adopted in the neonatal intensive care unit (NICU). Caveats regarding routine probiotic supplementation for the prevention of NEC are summarized in this review. Accumulating evidence indicates that prophylactic probiotic supplementation in preterm infants can reduce the incidence of NEC. However, substantial knowledge gaps, regulatory issues, and implementation challenges should be addressed before probiotics are introduced as standard of care for all preterm neonates. Limitations of published trial data have made it challenging to define regimens that optimize efficacy and safety in specific patient subgroups. Moreover, the current probiotic market lacks rigorous regulatory oversight, which could raise concerns about the quality and safety of probiotic products. Finally, implementation pitfalls include risks of cross-colonization and resource requirements to monitor and mitigate potential adverse events. Probiotics have shown promise in the prevention of NEC. However, there is insufficient evidence to guide the selection of optimal regimens. Furthermore, issues related to regulatory and institutional oversight should be addressed before supplementation is routinely implemented in NICUs.

Meconium-stained amniotic fluid as a risk factor for necrotizing enterocolitis in very low-birth weight preterm infants: a retrospective cohort study

Objective: To evaluate whether meconium-stained amniotic fluid (MSAF) is a risk factor for necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants.Materials and methods: The retrospective study was conducted at the Neonatal Diagnosis and Treatment Center of the Children’s Hospital of Chongqing Medical University from January 2010 to October 2016. The maternal and neonatal characteristics in cases of very low-birth weight infants born prior to 34 weeks of gestation were collected and compared between the MSAF and non-MSAF groups.Results: In the present study, 461 medical records of very low-birth-weight preterm infants were reviewed. A total of 41 (8.9%) infants were born to mothers with MSAF; in all, 180 infants were included in the study. Demographic characteristics and neonatal complications in the MSAF (n = 30) and non-MSAF groups (n = 150) were compared. A higher incidence of NEC (26.7% versus 10%, χ2 = 4.825, p = .028) was found in the MSAF group than in the non-MSAF group. Logistic regression analysis showed that MSAF (OR = 3.385, 95% CI: 1.349–8.492, p = .009) and sepsis (OR = 3.538, 95% CI: 1.442–8.679, p = .006) were independent risk factors for NEC.Conclusions: MSAF might be a risk factor for NEC in very-low-birth-weight infants. MSAF and sepsis contribute to the development of NEC.

Metabolism of Milk Oligosaccharides in Preterm Pigs Sensitive to Necrotizing Enterocolitis.

Human milk oligosaccharides (HMO) are major components of breast milk that may have local effects in the gastrointestinal tract and systemic functions after being absorbed, both depending on their metabolism. Using preterm pigs, we investigated the metabolic fate of HMO in three experiments with two different HMO blends. In addition, we examined effects on the colonic microbiota in the presence or absence of necrotizing enterocolitis (NEC). Thus, preterm pigs (n = 112) were fed formula without or with HMO supplementation (5–10) g/L of a mixture of 4 (4-HMO) or >25 HMO (25-HMO) for 5 (Experiment 1 and 2) or 11 days (Experiment 3). Individual HMO were quantified in colon contents and urine using MALDI-TOF-MS (matrix-assisted laser desorption ionization mass spectrometry) and HPAEC-PAD (high-performance anion-exchange chromatography with pulsed amperometric detection). Microbial colonization was analyzed by sequencing of 16S rRNA gene tags. Intestinal permeability was measured by lactulose to mannitol ratio in urine. HMO supplemented to formula were detected in urine and colon contents in preterm piglets after 5 and 11 days in all three experiments. The amount of HMO excreted via the gut or the kidneys showed large individual variations. Microbial diversity in the colon changed from high levels of Firmicutes (dominated by Clostridium) at day 5 (Exp 2) to high levels of Proteobacteria dominated by Helicobacter and Campylobacter at day 11 (Exp 3). Colonic microbiota composition as well as HMO excretion pattern varied greatly among piglets. Interestingly, the 5-day supplementation of the complex 25-HMO blend led to low concentrations of 3-fucosyllactose (FL) and lacto-N-fucopentaose (LNFP) I in colonic contents, indicating a preferred utilization of these two HMO. Although the interpretation of the data from our piglet study is difficult due to the large individual variation, the presence of Bifidobacteria, although low in total numbers, was correlated with total HMO contents, and specifically with 2′FL levels in colonic content. However, early supplementation of formula with HMO did not affect NEC incidence.

Single strain versus multispecies probiotic on necrotizing enterocolitis and faecal IgA levels in very low birth weight preterm neonates: A randomized clinical trial

According to the literature, probiotics are an attractive alternative to prevent necrotizing enterocolitis (NEC). However, due to differences in probiotic composition, randomized controlled trials are necessary to compare different probiotic mixtures. The objective of this study was to compare single strain (Lactobacillus acidophilus boucardii) versus multispecies probiotics on NEC incidence and faecal secretory Immunoglobulin A (sIgA) levels in very low preterm newborns. We performed a double-blind randomized trial in 90 newborns. L. acidophilus boucardii strain or multispecies probiotics were randomly assigned to preterm newborns. As the primary outcome, we evaluated NEC incidence on the total length of neonatal intensive care unit (NICU) stay. As the secondary outcome, we measured the change in faecal sIgA levels from baseline to 3 weeks following the use of probiotics. NEC incidence was similar between groups (0% vs. 2.2% for the single strain and multispecies probiotic, respectively). Faecal sIgA levels increased significantly (p<0.001) within groups (31% for single strain and 47% for multispecies probiotic), but this increase was not different between groups. Neonates with a faecal sIgA level increment >0.45mg/dl showed higher gestational age, birth weight, and weight at the second and third weeks of follow up than neonates with a faecal sIgA level increment ≤0.45mg/dl. No adverse effects were found after probiotics use. No difference between strains of probiotics used was found on NEC incidence or in the increase of faecal sIgA levels. Faecal sIgA levels were positively related to gestational age and body weight in very low preterm infants. ClinicalTrials.gov/NCT02245815.

Risk of Necrotizing Enterocolitis Following Packed Red Blood Cell Transfusion in Very Low Birth Weight Infants.

To evaluate the association between red blood cell (RBC) transfusion leading to necrotizing enterocolitis (NEC) within 48h, known as transfusion-associated necrotizing enterocolitis (TANEC). A nested case-control study using historical data was conducted in the neonatal intensive care unit of Songklanagarind Hospital, Thailand. All very low birth weight (VLBW) infants delivered between November 2009 and July 2016 were enrolled. The infants were identified as RBC transfusion received and NEC developed. Logistic regression was used to evaluate risk factors for transfusion and the association between RBC transfusion and NEC. Four hundred and forty-four VLBW infants were enrolled in the study. The median (interquartile range) gestational age was 29 (27, 31) wk. The overall incidence of NEC was 13%. Three (5.2%) of the NEC infants had TANEC. The infants who received RBC transfusion had a lower gestational age [odds ratio, OR 0.64; 95% confidence interval (95%CI) 0.57, 0.73, p <0.001] and were more likely to have pneumonia (OR 9.86; 95%CI 5.02, 19.35, p < 0.001) or to have received H2 blocker (OR 2.92; 95%CI 1.73, 4.93, p <0.001). The ORs (95% CI) after adjusting for confounders, the association between RBC transfusion and NEC for transfusions ≤2 d, >2 to 4 d, and > 4 to 6 d prior to NEC were 1.83 (0.41, 8.16; p = 0.43), 1.7 (0.26, 11.16; p =0.58) and 1.19 (0.31, 4.62; p = 0.80) respectively. After controlling of confounders, no evidence of association was found between RBC transfusion and TANEC.

Abdominal Ultrasound and Abdominal Radiograph to Diagnose Necrotizing Enterocolitis in Extremely Preterm Infants

Necrotizing enterocolitis (NEC) is an important contributor towardmortality in extremely premature infants and Very Low Birth Weight(VLBW) infants. The incidence of NEC was 9% in VLBW infants(birth weight 401 to 1,500 grams) in the Vermont Oxford Network(VON, 2006 to 2010, n = 188,703).1 The incidence of NEC was 7%in 1993, increased to 13% in 2008, and decreased to 9% in extremelypreterm infants (22 to 28 weeks gestation) in the Neonatal ResearchNetwork Centers (1993 to 2012).2 The incidence of surgically treatedNEC varies from 28 to 50% in all infants who develop NEC.3 SurgicalNEC occurred in 52% in the VON cohort.1 In this cohort, the odds ofsurgery decreased by 5% for each 100 gram increase in birth.The incidence of surgical NEC has not decreased in the pastdecade.4 The mortality from NEC is significantly higher in infantswho need surgery compared to those who did not (35% versus 21%).1The case fatality rate among patients with NEC is higher in thosesurgically treated (23 to 36%) compared to those medically treated (5to 24%).3 In addition to surgery, NEC mortality rates are influencedby gestational age, birth weight,1,2,5 assisted ventilation on the day ofdiagnosis of NEC, treatment with vasopressors at diagnosis of NEC,and black race.6,7Extremely preterm infants who survive NEC are at risk for severeneurodevelopmental disability and those with surgical NEC have asignificantly higher risk of such delays (38% surgical NEC versus 24%medical NEC).8 Diagnosis of necrotizing enterocolitis is challengingand it is usually suspected based on non-specific clinical signs. Bell’scriteria and Vermont-Oxford Network criteria help in the diagnosisof NEC.Bell’s criteria, commonly used for diagnosis, staging, and planningtreatment of NEC, were described in 1978 and modified in 1986.9,10Bell’s stage I signs are non-specific: temperature instability, lethargy,decreased perfusion, emesis or regurgitation of food, abdominal distension,recurrent apnea, and on occasion, increased support withmechanical ventilation. Abdominal distension and emesis are morecommon than bloody stools in very preterm infants compared to terminfants.7 Abdominal radiographic findings are an integral part of Bell’scriteria. Identification of Bell’s stage I NEC (early NEC) with abdominalradiograph is challenging, as the features on abdominal radiograph(normal gas pattern or mild ileus) are non-specific. With progressionof NEC to Bell Stage IIA, the symptoms (grossly bloody stools,prominent abdominal distension, absent bowel sounds) and featureson abdominal radiographs (one or more dilated loops and focal pneumatosis)are more specific.On the other hand, the Vermont Oxford Network criteria for NECconsist of at least one physical finding (bilious gastric aspirate oremesis, abdominal distension or occult/gross blood in the stool inthe absence of anal fissure) and at least one feature on abdominalradiograph (pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum).1 These features correspond to Bell Stage IIA or StageIIB and are not features of early NEC. Thus relying solely on abdominalradiograph for diagnosis of early NEC, as is practiced currently,has significant drawbacks especially in extremely premature infants.7Ultrasound has been suggested to improve the percentage of infantsdiagnosed with early NEC.11 However, this imaging modality is notused routinely in the diagnosis or management of NEC.As the incidence of surgical NEC and mortality from NEC continuesto be high, the literature to demonstrate the shortcomings ofabdominal radiographs and promise of abdominal ultrasound in diagnosisof NEC is reviewed.

Testing the feasibility and safety of feeding preterm infants fresh mother\u2019s own milk in the NICU: A pilot study

Necrotizing enterocolitis (NEC) is the leading cause of death among infants born at <30 weeks’ gestation, but donor human milk can reduce the incidence of NEC. Unfortunately, freezing or pasteurizing human milk deactivates beneficial bioactive components. We evaluated the feasibility, safety, and impact of feeding very preterm infants fresh (unprocessed) mother’s own milk within 4 hours of expression. In our multicentre prospective cohort analytic study, we fed 109 control and 98 intervention infants previously frozen donor or mother’s own milk; only the intervention group was fed fresh mother’s own milk once daily from enrollment until 32 weeks’ corrected age. Control group mothers could not commit to provide fresh milk daily and were less likely receive antenatal corticosteroids than mothers in the intervention group. In the intervention group, 87.5% (98/112) of mothers were able to provide at least one feed of fresh milk a day. No critical incidents or non-compliance with the protocol were reported. The duration of mechanical ventilation and total parenteral nutrition use were shorter in the intervention group than controls (P < 0.01) but the length of hospital stay was similar (P = 0.57). Although the study might be underpowered, the intervention group had lower unadjusted rates of the composite outcome NEC ≥ stage 2 or mortality (8% vs 20%, P = 0.04), sepsis (22% vs 38%, P = 0.02), retinopathy of prematurity (17% vs 39%, P < 0.01) and bronchopulmonary dysplasia (32% vs 47%, P < 0.01) than the control. These results indicated that feeding fresh mother’s own milk once daily was safe, feasible, and may reduce morbidity.

Probiotics for preterm infants - time to end all controversies.

SummaryMortality, necrotising enterocolitis (NEC), late onset sepsis (LOS) and feeding intolerance are significant issues for very preterm (< 32 weeks) and extremely preterm (< 28 weeks) infants. The complications of ≥ Stage II NEC [e.g. Resection of the gangrenous gut, survival with intestinal failure, recurrent infections, prolonged hospital stay, and long‐term neurodevelopmental impairment (NDI)] impose a significant health burden. LOS also carries significant burden including long‐term NDI due to adverse effects of inflammation on the preterm brain during the critical phase of development. Frequent stopping of feeds due to feeding intolerance is a significant iatrogenic contributor to postnatal growth failure in extremely preterm infants. Over 25 systematic reviews and meta‐analyses of RCTs (~12 000 participants) have reported that probiotics significantly reduce the risk of all‐cause mortality, NEC ≥ Stage II, LOS and feeding intolerance in preterm infants. Systematic reviews and meta‐analysis of non‐RCTs have also shown that the benefits after adopting probiotics as a standard prophylaxis for preterm infants are similar to those reported in RCTs. No intervention comes close to probiotics when it comes to significant reduction in death, NEC, LOS and feeding intolerance at a cost of less than a dollar a day irrespective of the setting and baseline incidence of NEC. The common controversies that are preventing the rapid uptake of probiotics for preterm infants are addressed in this paper.

Milk Fat Globule Membrane Ameliorates Necrotizing Enterocolitis in Neonatal Rats and Suppresses Lipopolysaccharide-Induced Inflammatory Response in IEC-6 Enterocytes.

Evidence has provided support for the beneficial effects of milk fat globule membrane (MFGM) on inflammation in the intestinal tract. The objective of this study was to investigate the effects of MFGM on a rat model of necrotizing enterocolitis (NEC) and its potential mechanism of action. Sixty-two newborn Sprague Dawley rats were randomly divided into 4 experimental groups: Breast-fed normal, formula fed (FF), FF + 6 g/L MFGM, and FF + 12 g/L MFGM. The FF rats and the FF rats supplemented with MFGM were exposed to asphyxia/cold stress to induce NEC. Body weight, histological score, survival time, oxidative stress injury, enterocyte proliferation/apoptosis, and inflammatory response were assessed. Meanwhile, lipopolysaccharide (LPS)-stimulated IEC-6 enterocytes were used as a model to test the anti-inflammatory effects of MFGM. Supplementation with 12 g/L MFGM alleviated body weight loss, reduced the incidence of NEC, increased the survival rate, and attenuated the severity of bowel damage in the NEC rat model. Furthermore, 12 g/L MFGM administration inhibited the protein expression of toll-like receptor 4 (TLR4) in the animal model. In IEC-6 enterocytes, the upregulation of TLR4, myeloid differentiation primary response gene 88 (MyD88), phosphorylated nuclear factor-κB (NF-κB) p65 subunit, and the nuclear translocation of NF-κBp65 induced by LPS was partially inhibited by MFGM pretreatment. Our findings suggested that MFGM has beneficial effects on neonatal rats with NEC by suppressing inflammation via the TLR4/MyD88/NF-κB pathway.