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Human Milk Growth Factors and Their Role in NEC Prevention: A Narrative Review.
York, DJ, Smazal, AL, Robinson, DT, De Plaen, IG
Nutrients. 2021;(11)
Abstract
Growing evidence demonstrates human milk's protective effect against necrotizing enterocolitis (NEC). Human milk derives these properties from biologically active compounds that influence intestinal growth, barrier function, microvascular development, and immunological maturation. Among these protective compounds are growth factors that are secreted into milk with relatively high concentrations during the early postnatal period, when newborns are most susceptible to NEC. This paper reviews the current knowledge on human milk growth factors and their mechanisms of action relevant to NEC prevention. It will also discuss the stability of these growth factors with human milk pasteurization and their potential for use as supplements to infant formulas with the goal of preventing NEC.
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Prenatal Immunity and Influences on Necrotizing Enterocolitis and Associated Neonatal Disorders.
Sampah, MES, Hackam, DJ
Frontiers in immunology. 2021;:650709
Abstract
Prior to birth, the neonate has limited exposure to pathogens. The transition from the intra-uterine to the postnatal environment initiates a series of complex interactions between the newborn host and a variety of potential pathogens that persist over the first few weeks of life. This transition is particularly complex in the case of the premature and very low birth weight infant, who may be susceptible to many disorders as a result of an immature and underdeveloped immune system. Chief amongst these disorders is necrotizing enterocolitis (NEC), an acute inflammatory disorder that leads to necrosis of the intestine, and which can affect multiple systems and have the potential to result in long term effects if the infant is to survive. Here, we examine what is known about the interplay of the immune system with the maternal uterine environment, microbes, nutritional and other factors in the pathogenesis of neonatal pathologies such as NEC, while also taking into consideration the effects on the long-term health of affected children.
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Transfusion-related Gut Injury and Necrotizing Enterocolitis.
Rose, AT, Saroha, V, Patel, RM
Clinics in perinatology. 2020;(2):399-412
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Necrotizing enterocolitis (NEC) accounts for 10% of deaths in neonatal intensive care units. Several causal mechanisms are likely to lead to a final common disease phenotype. This article summarizes recent data on NEC following red blood cell (RBC) transfusion, with a focus on the most recent literature and ongoing trials. It highlights potential mechanisms from preclinical and human physiologic studies. It also discusses the role of feeding during RBC transfusion and the risk of NEC. Ongoing randomized trials will provide important data on how liberal or conservative approaches to RBC transfusion influence the risk of NEC.
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Protective effects of different doses of human milk on neonatal necrotizing enterocolitis.
Zhang, B, Xiu, W, Dai, Y, Yang, C
Medicine. 2020;(37):e22166
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Abstract
We aim to summarize the evidence focusing on the effects of various doses of human milk on the risk of neonatal necrotizing enterocolitis (NEC). The eligible articles in the study were those investigating the association between human milk and NEC published before June 26, 2019, in the PubMed, EMBASE, the Cochrane Library, VIP database, CNKI database, and Wangfang database. The included criteria were as follows: premature infants of <37 weeks; randomly controlled trials (RCTs); those fed by mother's own milk or donor human milk; studies focused on the comparison of human milk and formula milk, involving various breast milk doses; and NEC-related studies. Compared with the exclusive formula, the incidence of NEC in the infants fed by exclusive human milk was significantly lower. The incidence of NEC in the infants fed by exclusive human milk was significantly lower than that of partial human milk [risk ratio (RR) = 0.54, 95% confidence interval (95% CI): 0.36-0.79, P < .05]. The incidence of NEC in the infants fed mainly by human milk was significantly lower than that of mainly fed by formula. Incidence of NEC in the infants fed by exclusive human milk was significantly lower than that of any formula (RR = 0.49, 95% CI: 0.34-0.71, P < .05). In summary, this meta-analysis was based on the RCTs involving the prevention of NEC using human milk. Exclusive human milk and partial human milk reduced the incidence of NEC in premature infants, especially in the those fed by high proportion of human milk. In addition, more RCTs are needed to further validate such conclusion.
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Necrotizing Enterocolitis Pathophysiology: How Microbiome Data Alter Our Understanding.
Kim, CS, Claud, EC
Clinics in perinatology. 2019;(1):29-38
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Necrotizing enterocolitis is a major cause of mortality and morbidity in the preterm infant population. The gut microbiome is of particular interest in research surrounding necrotizing enterocolitis, because variations in the intestinal microbiota seem to correlate with the risk of inflammation and disease. Recent advances in non-culture-based genomic sequencing have also allowed for more intricate analyses of the intestinal microbiome. Its evolution seems to be influenced by intrauterine and extrauterine factors, ranging from antenatal antibiotic exposure to type of enteral feeds. Ultimately, these alterations in the gut microbiome have the potential to result in devastating diseases like necrotizing enterocolitis.
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A Review of the Immunomodulating Components of Maternal Breast Milk and Protection Against Necrotizing Enterocolitis.
Nolan, LS, Parks, OB, Good, M
Nutrients. 2019;(1)
Abstract
Breast milk contains immunomodulating components that are beneficial to newborns during maturation of their immune system. Human breast milk composition is influenced by an infant's gestational and chronological age, lactation stage, and the mother and infant's health status. Major immunologic components in human milk, such as secretory immunoglobulin A (IgA) and growth factors, have a known role in regulating gut barrier integrity and microbial colonization, which therefore protect against the development of a life-threatening gastrointestinal illness affecting newborn infants called necrotizing enterocolitis (NEC). Breast milk is a known protective factor in the prevention of NEC when compared with feeding with commercial formula. Breast milk supplements infants with human milk oligosaccharides, leukocytes, cytokines, nitric oxide, and growth factors that attenuate inflammatory responses and provide immunological defenses to reduce the incidence of NEC. This article aims to review the variety of immunomodulating components in breast milk that protect the infant from the development of NEC.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Withholding Feeds and Transfusion-Associated Necrotizing Enterocolitis in Preterm Infants: A Systematic Review.
Jasani, B, Rao, S, Patole, S
Advances in nutrition (Bethesda, Md.). 2017;(5):764-769
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Limited evidence exists to support the withholding of feeds during packed red blood cell (PRBC) transfusion to reduce the incidence of transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants. The aim of the manuscript was to systematically review studies reporting the effect of implementing a policy of withholding feeds on the incidence of TANEC in preterm infants. The following databases were searched for relevant studies published between the databases' inception and December 2016: PubMed, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index of Nursing and Allied Health Literature, and Pediatric Academic Societies Abstract Archive. Other relevant sources were also searched. There were no restrictions on study design. Studies reporting on the incidence of TANEC (stage ≥2 necrotizing enterocolitis within 48-72 h) after implementation of a policy of withholding feeds in the peritransfusion period in preterm infants were included. This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. There were no randomized controlled trials (RCTs). Pooled results from 7 non-RCTs (n = 7492) showed that withholding feeds during PRBC transfusion significantly reduced the incidence of TANEC (RR: 0.47; 95% CI: 0.28, 0.80; P = 0.005; I2 = 11%). The overall quality of evidence was moderate on GRADE analysis. These findings suggest that withholding feeds during the peritransfusion period may reduce the risk of TANEC in preterm infants. Adequately powered RCTs are needed to confirm these findings.
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Benefits of probiotics in preterm neonates in low-income and medium-income countries: a systematic review of randomised controlled trials.
Deshpande, G, Jape, G, Rao, S, Patole, S
BMJ open. 2017;(12):e017638
Abstract
OBJECTIVE Although there is an overall reduction in underfive mortality rate, the progress in reducing neonatal mortality rate has been very slow. Over the last 20 years, preterm births have steadily increased in low-income and medium-income countries (LMICs) particularly in sub-Saharan Africa and South Asia. Preterm birth is associated with increased mortality and morbidity, particularly in LMICs. Based on systematic reviews of randomised controlled trials (RCTs), many neonatal units in high-income countries have adopted probiotics as standard of care for preterm neonates. We aimed to systematically review the safety and efficacy of probiotics in reducing mortality and morbidity in preterm neonates in LMICs. DESIGN Systematic review and meta-analysis of RCTs. DATA SOURCES Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and E-abstracts from Pediatric Academic Society meetings and other paediatric and neonatal conference proceedings were searched in January 2017. ELIGIBILITY CRITERIA RCTs comparing probiotics versus placebo/no probiotic in preterm neonates (gestation<37 weeks) conducted in LMICs. RESULTS Total 23 (n=4783) RCTs from 4 continents and 10 LMICs were eligible for inclusion in the meta-analysis using fixed effect model. The risk of necrotising enterocolitis (NEC greater than or equal to stage II) (risk ratio (RR) 0.46 (95% CI 0.34 to 0.61), P<0.00001, numbers needed to treat (NNT) 25 (95% CI 20 to 50)), late-onset sepsis (LOS) (RR 0.80 (95% CI 0.71 to 0.91), P=0.0009, NNT 25 (95% CI 17 to 100)) and all-cause mortality (RR 0.73 (95% CI 0.59 to 0.90), P=0.003, NNT 50 (95% CI 25 to 100)) were significantly lower in probiotic supplemented neonates. The results were significant on random effects model analysis and after excluding studies with high risk of bias. No significant adverse effects were reported. CONCLUSION Probiotics have significant potential to reduce mortality and morbidity (eg, NEC, LOS) in preterm neonates in LMICs.
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Necrotizing enterocolitis and preterm infant gut bacteria.
Warner, BB, Tarr, PI
Seminars in fetal & neonatal medicine. 2016;(6):394-399
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Necrotizing enterocolitis remains an intractable consequence of preterm birth. Gut microbial communities, especially bacterial communities, have long been suspected to play a role in the development of necrotizing enterocolitis. Direct-from-stool nucleic acid sequencing technology now offers insights into the make-up of these communities. Data are now converging on the roles of Gram-negative bacteria as causative agents, despite the dynamic nature of bacterial populations, the varying technologies and sampling strategies, and the overall small sample sizes in these case-control studies. Bacteria that confer protection from necrotizing enterocolitis have not been identified across studies. The beneficial effect of probiotics is not apparent in infants with birth weights <1000 g (these infants are at greatest risk of, and have the highest case fatality rate from, necrotizing enterocolitis). Further work should be directed to the modulating gut microbes, or the products they produce, to prevent this devastating complication of preterm birth.