Search

Objective: Caffeine is widely used in preterm infants to prevent or treat apnoea of prematurity. Adverse gastrointestinal effects of caffeine have not been thoroughly researched in preterm infants. With this systematic review and meta-analysis, we aim to summarise the results of trials on the gastrointestinal effects of caffeine in preterm infants., Design: We searched MEDLINE, Web of Science, Scopus and ClinicalTrials.gov up to 21 April 2023. We included randomised controlled trials assessing caffeine versus placebo in preterm neonates and reporting gastrointestinal side effects. Risk of bias was assessed using the Cochrane Risk of Bias tool. A Bayesian meta-analysis was performed to estimate the pooled OR of gastrointestinal side effects., Results: Nine trials involving 2746 preterm infants were analysed. Seven trials assessing necrotising enterocolitis and four trials assessing feeding intolerance in our meta-analysis found no differences between caffeine and placebo (OR=1.007 (95% credible interval 0.021, 5.462), I 2 =97.4%, and OR=1.266 (95% credible interval 0.064, 28.326), I 2 =84.8%, respectively). Four trials assessed the outcomes spontaneous intestinal perforation, constipation, gastrointestinal disorder (composite outcome: gastro-oesophageal regurgitation or dilated bowel loops), age at oral feeding and cholestasis syndrome and found no differences between groups. One trial assessed the outcomes gastro-oesophageal symptoms and duration of tube feeding and found that caffeine was associated with a reduced burden of gastro-oesophageal reflux symptoms at 2 weeks (p<0.05), but not at term., Conclusions: According to this systematic review and meta-analysis, the use of caffeine at usual doses in preterm infants does not seem to be associated with significant gastrointestinal adverse effects., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Necrotizing enterocolitis (NEC) is a microbiota- and feeding-related gut inflammatory disease in preterm infants. The standard of care (SOC) treatment for suspected NEC is antibiotic treatment and reduced enteral feeding, but how SOC treatment mitigates NEC remains unclear. We explored whether SOC treatment alone or combined with an anti-inflammatory protein (inter-alpha inhibitor protein, IAIP) supplementation improves outcomes in a preterm piglet model of formula-induced NEC. Seventy-one cesarean-delivered preterm piglets were initially fed formula, developing NEC symptoms by day 3, and then randomized into CON (continued feeding) or SOC groups (feeding cessation and antibiotics), each with or without human IAIP (2×2 factorial design). By day 5, IAIP treatment did not significantly influence outcomes, whereas SOC treatment effectively reduced NEC lesions, diarrhea, and bloody stools. Notably, SOC treatment improved gut morphology and function, dampened gut inflammatory responses, altered the colonic microbiota composition, and modulated systemic immune responses. Plasma proteomic analysis revealed the effects of SOC treatment on organ development and systemic inflammatory responses. Collectively, these findings suggest that SOC treatment significantly prevents NEC progression in preterm piglets via effects on gut structure, function, and microbiota, as well as systemic immune and inflammatory responses. Timely feeding cessation and antibiotics are critical factors in preventing NEC progression in preterm infants, while the benefits of additional human IAIP treatment remain to be established., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DNN and PTS were principal investigators on the trial and thus received funding from Takeda Pharmaceuticals. IB is an employee of Baxalta Innovations GmbH, a Takeda company, and owns Takeda shares. BG was an employee of Baxalta Innovations GmbH, a Takeda company, at the time of the study. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Necrotizing enterocolitis (NEC) is common in preterm infants, especially infants less than 32 weeks gestation. Mortality from NEC is 7% and occurs in 1 out of 1000 preterm infants. Studies have shown the efficacy of an exclusive milk from mother diet in decreasing rates of NEC and associated mortality., Purpose: To evaluate the effectiveness of an existing exclusive human milk diet (EHMD) protocol on the incidence of NEC in extremely premature infants. EHMD, for the purposes of this project is defined as breast milk of mother, with or without human milk-based fortifier., Methods: A single-center retrospective quasi-experimental study. The sample included 201 infants born less than 32 weeks gestation, weighing less than 1250 grams, small for gestational age (SGA) and with low Apgar scores. Outcomes measured included incidences of NEC, mortality, and co-morbidities in infants pre- and postinitiation of an EHMD protocol., Results: Just 4.8% of the EHMD group had a NEC diagnosis compared to 10.5% of the bovine-based (BOV) group. There was a 1% mortality rate of the EHMD group as compared to 6% in the BOV group. The EHMD group had a statistically significant greater weight gain during hospitalization as compared to infants fed BOV ( P = < .05)., Implications for Practice and Research: Neonatal intensive care units should consider EHMDs for use in this infant population. Future research is needed to support dissemination of the use of EHMD as standard of practice., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 by The National Association of Neonatal Nurses.)

Lactobacillus rhamnosus GG (LGG) is a widely used and extensively researched probiotic. Probiotic effects are considered to be strain specific. We aimed to comprehensively assess the strain-specific effects of LGG in preterm infants. A systematic review of RCTs and non-RCTs to evaluate the effect of LGG in preterm infants. We followed the Cochrane methodology, and preferred reporting items for systematic reviews (PRISMA) statement for conducting and reporting this review. We searched the Cochrane central register of controlled trials, PubMed, EMBASE and CINAHL databases till December 2023. The review was registered in PROSPERO 2022 CRD42022324933. Meta-analysis of data from RCTs that used LGG as the sole probiotic showed significantly lower risk of NEC ≥Stage II [5 RCTs, n = 851, RR:0.50 (95% CI: 0.26, 0.93), P = 0.03] in the LGG group. There was no significant difference in the risk of LOS [7 RCTs, n = 1037, RR:1.08 (95% CI 0.84, 1.39), P = 0.55], mortality [3 RCTs, n = 207, RR: 0.99 (95% CI: 0.42, 2.33), P = 0.99], time to reach full feeds [2 RCTs, n = 19, SMD = 0.11 days (95% CI: -0.22, 0.45), P = 0.51] and duration of hospital stay [3 RCTs, n = 293, SMD: -0.14 days (95% CI: -0.37 to 0.09), P = 0.23]. Meta-analysis of data from non-RCTs showed no significant effect of LGG on NEC, LOS, and mortality. RCTs showed beneficial effects of LGG when used as the sole probiotic in reducing the risk of NEC, whereas observational studies did not. Strain-specific systematic review of LGG provides important data for guiding research and clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated., Objective: This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes., Study Design: We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia., Results: After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial., Conclusion: In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Necrotizing enterocolitis (NEC) is a multifactorial disease primarily affecting infants with very low birth weight (VLBW). Research has shown that the pathogenesis of NEC is associated with abnormal bacterial colonization. Synbiotics, dietary supplements containing probiotics (beneficial bacteria) and prebiotics (non-digestible food), can alter the gut microbiome., Methods: A double-blind, randomized controlled trial was conducted to assess the efficacy of PediLact®, an oral drop multi-strain synbiotic containing Lactobacillus rhamnosus, Lactobacillus reuteri, and Bifidobacterium infantis, on nutritional parameters and the occurrence of NEC in VLBW neonates. In this study, 118 VLBW neonates from neonatal intensive care units were randomly allocated in a 1:1 ratio to receive either a synbiotic or a placebo. The synbiotic administration continued until the infant was fully fed. The primary outcomes were the occurrence of NEC and the number of days required to achieve full enteral feeding. Log-binomial regression and ANOVA/ANCOVA models were used for analysis., Results: In the group that received the synbiotic, the incidence of NEC decreased significantly (adjusted RR = 0.22, 95% CI: 0.07-0.72, P value = .01; adjusted RD = -0.22, 95% CI: -0.33 to -0.12, P value < .001; NNT = 5). Additionally, feeding intolerance was less frequent in this group (adjusted RR = 0.27, 95% CI: 0.14-0.51, P value < .001; NNT = 3). Furthermore, consumption of the synbiotic was associated with significant weight gain (approximately 40 g) in infants (adjusted SMD = 0.63; 95% CI: 0.26-1.00, P value < .001). The duration of hospitalization and the time required to reach full enteral feeding were also significantly shorter in the synbiotic group (by approximately 3 days). No serious side effects were reported., Conclusion: Prescribing multi-strain synbiotics reduces the incidence of NEC in VLBW infants and has beneficial effects on breastfeeding tolerance and weight gain velocity. Therefore, physicians may consider prescribing synbiotics to VLBW neonates., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: When sufficient maternal milk is not available, donor human milk or formula are the alternative forms of enteral nutrition for very preterm or very low-birthweight (VLBW) infants. Donor human milk may retain the non-nutritive benefits of maternal milk and has been proposed as a strategy to reduce the risk of necrotising enterocolitis (NEC) and associated mortality and morbidity in very preterm or VLBW infants., Objectives: To assess the effectiveness of donor human milk compared with formula for preventing NEC and associated morbidity and mortality in very preterm or VLBW infants when sufficient maternal milk is not available., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Maternity and Infant Care (MIC) database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), from the earliest records to February 2024. We searched clinical trials registries and examined the reference lists of included studies., Selection Criteria: Randomised or quasi-randomised controlled trials comparing feeding with donor human milk versus formula in very preterm (< 32 weeks' gestation) or VLBW (< 1500 g) infants., Data Collection and Analysis: Two review authors evaluated the risk of bias in the trials, extracted data, and synthesised effect estimates using risk ratio, risk difference, and mean difference, with associated 95% confidence intervals. The primary outcomes were NEC, late-onset invasive infection, and all-cause mortality before hospital discharge. The secondary outcomes were growth parameters and neurodevelopment. We used the GRADE approach to assess the certainty of the evidence for our primary outcomes., Main Results: Twelve trials with a total of 2296 infants fulfilled the inclusion criteria. Most trials were small (average sample size was 191 infants). All trials were performed in neonatal units in Europe or North America. Five trials were conducted more than 40 years ago; the remaining seven trials were conducted in the year 2000 or later. Some trials had methodological weaknesses, including concerns regarding masking of investigators and selective reporting. Meta-analysis showed that donor human milk reduces the risk of NEC (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.37 to 0.76; I² = 4%; risk difference (RD) -0.03, 95% CI -0.05 to -0.01; 11 trials, 2261 infants; high certainty evidence). Donor human milk probably has little or no effect on late-onset invasive infection (RR 1.12, 0.95 to 1.31; I² = 27%; RD 0.03, 95% CI -0.01 to -0.07; 7 trials, 1611 infants; moderate certainty evidence) or all-cause mortality (RR 1.00, 95% CI 0.76 to 1.31; I² = 0%; RD -0.00, 95% CI -0.02 to 0.02; 9 trials, 2116 infants; moderate certainty evidence)., Authors' Conclusions: The evidence shows that donor human milk reduces the risk of NEC by about half in very preterm or VLBW infants. There is probably little or no effect on late-onset invasive infection or all-cause mortality before hospital discharge., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Preterm birth significantly contributes to mortality and morbidities, with recent studies linking these issues to gut microbiota imbalances. Probiotic supplementation shows promise in mitigating adverse outcomes in preterm infants, but optimal timing and guidelines remain unclear. This study assesses the benefits of probiotic supplementation for preterm infants without consistent guidelines. Methods: This retrospective study examined extremely low-birth-weight (ELBW) infants in neonatal intensive care units from 2017 to 2021. Mortality and preterm-related outcomes were compared between infants receiving probiotics and those not. Subgroup analyses based on probiotic initiation timing were conducted: early (≤14 days), late (>14 days), and non-probiotic groups. Results: The study included 330 ELBW infants: 206 received probiotics (60 early, 146 late), while 124 did not. Probiotic supplementation was associated with lower overall mortality (adjusted OR 0.22, 95% CI 0.09-0.48) and decreased mortality from necrotizing enterocolitis (NEC) or late-onset sepsis (LOS) (adjusted OR 0.12, 95% CI 0.03-0.45). Early probiotics reduced overall mortality, NEC/LOS-related mortality, and NEC/LOS-unrelated mortality. Late probiotics decreased overall mortality and NEC/LOS-related mortality. Early probiotic use also expedited full enteral feeding achievement. Conclusions: Probiotic supplementation reduces mortality and improves feeding tolerance in preterm infants. Establishing guidelines for probiotic use in this population is crucial.

Introduction: This article reviews the evidence for the use of different strains of probiotics in the prevention of prevalent pathologies in premature neonates. A systematic review was conducted of the use of probiotics in neonates with less than 37 weeks of gestational age, based on a search for systematic reviews and observational and experimental studies performed during the period from January 2014 to February 2021. For this purpose, the PubMed, MEDLINE and Cochrane Library databases were consulted. The aim of this article was to review the existing data on the relationship between the administration of probiotics (with different strains and doses) and the risk of necrotising enterocolitis, mortality, late sepsis and other disease parameters in premature infants. The literature search obtained 240 articles, of which we selected 16, representing a total sample of over 200,000 premature infants. Analysis of the data obtained reveals statistical evidence that the combined administration of probiotics (especially of Lactobacillus and Bifidobacterium strains) reduces the incidence of grade II or higher necrotising enterocolitis, all-cause mortality, late sepsis, length of hospital stay and time until complete enteral nutrition is achieved. However, no benefits were apparent with respect to alleviating bronchopulmonary dysplasia, retinopathy of prematurity or intraventricular haemorrhage. Further research is needed to determine the most appropriate strains, doses and treatment duration for preterm infants to achieve the health benefits identified.

Objective: To assess the association between early initiation of parenteral nutrition (PN) and body growth in preterm infants with very low birth weight (VLBW)., Design: Causal inference analysis with confounders preselected by causal diagram based on the NeoNutriNet cohort containing data of infants born between 2011 and 2014 from 13 hospitals from 5 continents., Patients: Neonates with birth weight ≤1500 g., Interventions: PN initiated within the first day of life (early PN) versus within day 2-5 (delayed PN)., Main Outcome Measures: The primary outcome was body weight z-scores at postmenstrual age (PMA) 36 weeks or early discharge or death, whichever comes first (WT z-score END). Secondary outcomes included WT z-scores at week 1 and 4 of life (WT z-scores CA1 and CA4), corresponding growth velocities (GVs), mortality and incidence of necrotising enterocolitis (NEC), and duration and episodes of antibiotic treatment., Results: In total, 2151 infants were included in this study and 2008 infants were in the primary outcome analysis. Significant associations of early PN were found with WT z-score END (adjusted mean difference, 0.14 (95% CI 0.05 to 0.23)), CA4 (β, 0.09 (0.04 to 0.14)) and CA1 (0.04 (0.01 to 0.08)), and GV PMA 36 weeks (1.02 (0.46 to 1.58)) and CA4 (1.03 (0.56 to 1.49), all p<0.001), but not with GV CA1 (p>0.05). No significant associations with mortality, incidence of NEC or antibiotic use was found (all p>0.05)., Conclusions: For VLBW infants, PN initiated within the first day of life is associated with improved in-hospital growth., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

A large proportion of prescriptions for extensively hydrolyzed cow's milk protein (CMP) in newborns are not based on any scientific data justifying the indication. Many of these prescriptions are old habits or are based on incomplete data. The aim of this article is to analyze these practices and propose recommendations. The following points are covered: (a) indications for extensively hydrolyzed formula based on studies demonstrating their benefits in these situations-newborns with a proven allergy to CMP and occasional prescription of supplements to breastfeeding; (b) possible indications not based on a high level of evidence-re-initiation of feeding due to necrotizing enterocolitis, short bowel syndrome, re-initiation of feeding of newborns following intestinal surgery, and laparoschisis if neither the mother's own milk nor milk from a lactarium is available; (c) unjustified indications-newborns at risk of atopy, prematurity, severe neurological pathologies, newborns who are hemodynamically unstable and/or have congenital cardiopathy, neonatal hypoxic-ischemic encephalopathy treated with hypothermia, and newborns with esophageal atresia or diaphragmatic hernia. By following this classification, the prescriber will be guided to use the milk best suited to the pathology, bearing in mind that each situation must be adapted individually and the tolerance and effectiveness of the food reassessed from a nutritional and functional point of view., Competing Interests: Declaration of competing interest V. Rigourd, A. Heneau, A.L. Virlouvet, A. Basset, E. Herry, B. Jaquemet, A. Lapillonne, M. Bellaiche: no conflicts of interest; P. Tounian: Carrefour, Danone, Lactalis, Materna, Mead Johnson, Nestlé, Novalac, PédiAct, Sodilac., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Very premature and/or low-birth-weight infants are at risk of developing necrotizing ulcerative enterocolitis (NEC). Prophylactic use of probiotics would change the composition of the gut microbiota and thus reduce the risk of NEC. In order to choose a probiotic at the local level, international recommendations were compared, and the available specialties were listed. Discrepancies between the different recommendations appeared, and the great variability of infant specialties available, as well as their status, did not allow us to select one. The local objective will therefore be to participate in the discussion of this subject at a national level., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

High concentrations of immunoglobulins, bioactive peptides, and growth factors are found in bovine colostrum (BC), the milk produced by cows in the first few days after parturition. Various biological functions make it increasingly used to provide nutritional support and immune protection to the offspring of many species, including humans. These biological functions include cell growth stimulation, anti-infection, and immunomodulation. The primary components and biological functions of colostrum were reviewed in the literature, and the authors also looked at its latent effects on the growth and development of neonates as well as on conditions such as infections, necrotizing enterocolitis, short bowel syndrome, and feeding intolerance. The importance of BC in neonatal nutrition, immune support, growth and development, and gut health has been demonstrated in a number of experimental and animal studies. BC has also been shown to be safe at low doses without adverse effects in newborns. BC supplementation has been shown to be efficient in preventing several disorders, including rotavirus diarrhea, necrotizing enterocolitis, and sepsis in animal models of prematurity and some newborn studies. Therefore, BC supplementation should be considered in cases where maternal milk is insufficient or donor milk is unavailable. The optimal age, timing, dosage, and form of BC administration still require further investigation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Probiotic prophylaxis has been suggested to reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in very preterm newborns. However, choosing the optimal probiotic is difficult due to variations in strain-specific effects and interactions facilitated by the use of combination species., Aims: To compare clinical outcomes of very preterm infants receiving multi or single-species probiotics., Study Design: Retrospective, single-center, cohort study., Subjects: Very preterm infants (<32 weeks' gestation) born between 2019 and 2022 at a tertiary perinatal center received either a multi-species (Lactobacillus rhamnosus 45 %, Lactobacillus casei 15 %, Lactobacillus acidophilus 15 %, Bifidobacterium infantis 15 %, Bifidobacterium bifidum 10 %; n = 228) or a single-species (Bifidobacterium breve BR03 and B632; n = 227) probiotic formulation., Main Outcome Measures: NEC, LOS, and mortality., Results: The overall incidence of NEC and LOS was 3.1 % and 13.8 %, respectively. There were no differences between the multi-species and single-species probiotic groups in the rate of NEC (3.5 % vs 2.6 %; p = 0.787), LOS (15.4 % vs 12.3 %; p = 0.416), mortality (0.9 % vs 1.8 %; p = 0.449), or composite outcome (NEC, LOS and/or death; 16.7 % vs 12.8 %; p = 0.290)., Conclusion: The clinical outcomes of very preterm newborns receiving multi vs. single-species probiotic formulations were similar in our study. In view of the sample size and low baseline rate of NEC in our unit, further trials are warranted to investigate the effects of specific probiotics for prevention of serious neonatal morbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Human milk reduces risk for necrotizing enterocolitis in preterm infants. Necrotizing enterocolitis occurs in the ileocecal region where thousands of milk protein-derived peptides have been released from digestion. Digestion-released peptides may exert bioactivity, such as antimicrobial and immunomodulatory activities, in the gut. In this study, we applied mass spectrometry-based peptidomics to characterize peptides present in colostrum before and after in vitro digestion. Sequence-based computational modeling was applied to predict peptides with antimicrobial activity. We identified more peptides in undigested samples, yet the abundances were much higher in the digested samples. Heatmapping demonstrated highly different peptide profiles between undigested and digested samples. Four peptides (α S1 -casein [157-163], α S1 -casein [157-165], β-casein [153-159] and plasminogen [591-597]) were selected, synthesized and tested against common pathogenic bacteria associated with necrotizing enterocolitis. All four exhibited bacteriostatic, though not bactericidal, activities against Klebsiella aerogenes , Citrobacter freundii and Serratia marcescens , but not Escherichia coli .

Objectives: To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage (EWLP) in hospital among extremely preterm infants (EPI) or extremely low birthweight infants (ELBWI)., Methods: A multicentre, retrospective cohort study of EPI or ELBWI born between 2017 and 2018 was conducted. Infants were classified into no ANS, partial ANS and complete ANS exposure group; three subgroups were generated by gestational age and birth weight. Multiple logistic regression and multiple linear regression were performed., Results: There were 725 infants included from 32 centres. Among no ANS, partial ANS and complete ANS exposure, there were significant differences in the proportions of bronchopulmonary dysplasia (BPD) (24.5%, 25.4% and 16.1%), necrotising enterocolitis (NEC) (6.7%, 2.0% and 2.0%) and death (29.6%, 18.5% and 13.5%), and insignificant differences in the proportions of intraventricular haemorrhage (IVH) (12.5%, 13.2% and 12.2%), and extrauterine growth restriction (EUGR) (50.0%, 56.6% and 59.5%). In the logistic regression, compared with no ANS exposure, complete ANS reduced the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91), NEC (OR 0.21, 95% CI 0.08 to 0.57) and death (OR 0.36, 95% CI 0.23 to 0.56), and partial ANS reduced the risk of NEC (OR 0.23, 95% CI 0.07 to 0.72) and death (OR 0.54, 95% CI 0.34 to 0.87). Compared with partial ANS exposure, complete ANS decreased the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91). There were insignificant associations between ANS exposure and IVH, EUGR. In the multiple linear regression, partial and complete ANS exposure increased EWLP only in the ≥28 weeks (w) and <1000 g subgroup (p<0.05)., Conclusions: Different doses of ANS (dexamethasone) exposure were protectively associated with BPD, NEC, death in hospital, but not EUGR at discharge among EPI or ELBWI. Beneficial dose-dependent associations between ANS (dexamethasone) exposure and BPD existed. ANS exposure increased EWLP only in the ≥28 w and<1000 g subgroup. ANS administration, especially complete ANS, is encouraged before preterm birth., Trial Registration Number: NCT06082414., Competing Interests: Competing interests: None., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP3) is currently being tested in phase II clinical trials in premature infants to prevent bronchopulmonary dysplasia, but its impact on the neonatal intestine remains unclear. The aim of this study was to determine whether rhIGF-1/BP3 protects against necrotizing enterocolitis (NEC) in mice and to investigate the mechanisms involved., Methods: Neonatal mice were dam fed or injected intraperitoneally with rhIGF-1/BP3 (or vehicle) and submitted to an experimental NEC model. Serum IGF-1 was assessed by ELISA and intestinal vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression by Western blot. Intestinal endothelial cell proliferation, and enterocyte proliferation and migration were examined by immunofluorescence. Pup survival and histological intestinal injury were determined., Results: In pups exposed to experimental NEC, serum IBP3-bound IGF-1 level was decreased. Exogenous rhIGF-1/BP3 preserved VEGF and VEGFR2 protein expression, decreased vascular permeability, and preserved endothelial cell proliferation in the small intestine. Furthermore, rhIGF-1/BP3 promoted enterocyte proliferation and migration, which effects were attenuated by inhibiting VEGFR2 signaling, decreased enterocyte apoptosis and decreased systemic and intestinal inflammation. rhIGF-1/BP3 improved survival and reduced the incidence of severe intestinal injury in experimental NEC., Conclusions: Exogenous rhIGF-1/BP3 protects neonatal mice against experimental NEC via multiple mechanisms., Impact: Exogenous rhIGF-1/BP3 preserves intestinal microvascular development and integrity, promotes enterocyte proliferation and migration, decreases local and systemic inflammation, and protects neonatal mice against NEC. The article adds pre-clinical evidence of a protective role for rhIGF-1/BP3 on the premature gut. It provides evidence supporting the use of rhIGF1/BP3 in premature neonates to protect against NEC., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Neonates are susceptible to inflammatory disorders such as necrotizing enterocolitis (NEC) due to their immature immune system. The timely appearance of regulatory immune cells in early life contributes to the control of inflammation in neonates, yet the underlying mechanisms of which remain poorly understood. In this study, we identified a subset of neonatal monocytes characterized by high levels of neuropilin-1 (Nrp1), termed Nrp1 high monocytes. Compared with their Nrp1 low counterparts, Nrp1 high monocytes displayed potent immunosuppressive activity. Nrp1 deficiency in myeloid cells aggravated the severity of NEC, whereas adoptive transfer of Nrp1 high monocytes led to remission of NEC. Mechanistic studies showed that Nrp1, by binding to its ligand Sema4a, induced intracellular p38-MAPK/mTOR signaling and activated the transcription factor KLF4. KLF4 transactivated Nos2 and enhanced the production of nitric oxide (NO), a key mediator of immunosuppression in monocytes. These findings reveal an important immunosuppressive axis in neonatal monocytes and provide a potential therapeutic strategy for treating inflammatory disorders in neonates., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

The nutrition of preterm infants remains contaminated by wrong beliefs that reflect inexactitudes and perpetuate old practices. In this narrative review, we report current evidence in preterm neonates and in preterm neonates undergoing surgery. Convictions that necrotizing enterocolitis is reduced by the delay in introducing enteral feeding, a slow advancement in enteral feeds, and the systematic control of residual gastric volumes, should be abandoned. On the contrary, these practices prolong the time to reach full enteral feeding. The length of parenteral nutrition should be as short as possible to reduce the infectious risk. Intrauterine growth restriction, hemodynamic and respiratory instability, and patent ductus arteriosus should be considered in advancing enteral feeds, but they must not translate into prolonged fasting, which can be equally dangerous. Clinicians should also keep in mind the risk of refeeding syndrome in case of high amino acid intake and inadequate electrolyte supply, closely monitoring them. Conversely, when preterm infants undergo surgery, nutritional strategies are still based on retrospective studies and opinions rather than on randomized controlled trials. Finally, this review also highlights how the use of adequately fortified human milk is strongly recommended, as it offers unique benefits for immune and gastrointestinal health and neurodevelopmental outcomes.

Introduction: Prevention of necrotising enterocolitis (NEC) is vital for improving neonatal outcomes. Feeding own mother's milk helps prevent NEC. Rates of own mother's milk feeding in the East Midlands are lower than the national average and the incidence of NEC is higher. The East Midlands Neonatal Operational Delivery Network (EMNODN) has created a care bundle to improve these in babies born at <32 weeks' gestation, the group at the highest risk of NEC. The bundle was introduced in September 2022 and embedded by December 2022. We will evaluate its effectiveness and conduct a process evaluation to understand barriers and facilitators to implementation., Methods and Analysis: We will conduct a retrospective cohort study (workstream 1) using data from the National Neonatal Research Database (NNRD). We will identify infants receiving any own mother's milk on day 14 and at discharge, and cases of severe NEC. We will aggregate outcomes by birth month and use interrupted time series analysis to estimate an incidence rate ratio for changes after the care bundle was embedded, relative to pre-implementation. We will model data from all other NNRD units and assess whether there are any concurrent changes to exclude confounding due to other events.We will apply the RE-AIM framework (workstream 2), supplemented by the Consolidated Framework for Implementation Research and Framework for Implementation Fidelity, to conduct a mixed methods evaluation in EMNODN units. We will triangulate data from several sources, including questionnaires and semistructured interviews with parents and healthcare professionals, and data from patient records., Ethics and Dissemination: The study has approval from the South East Scotland Research Ethics Committee 01 and the Health Research Authority and Health and Care Research Wales (IRAS 323099). Results will be disseminated via scientific journals and conferences, to neonatal service commissioners and through public-facing infographics., Trial Registration Number: NCT05934123., Competing Interests: Competing interests: SO is an honorary neonatal consultant at the University Hospitals of Derby and Burton and is the lead clinician in the team that developed the EMNODN NEC Care Bundle. HB is an honorary neonatal consultant at the Nottingham University Hospitals and was on the advisory panel of the team that developed the EMNODN NEC Care Bundle. MS is the chair of NEC UK which supports families with experience of NEC and supports breastfeeding mothers., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: Preterm infants have high zinc (Zn) requirements and are generally believed to be in a negative Zn balance in the early period of life. In this study, we aimed to investigate the effect of high-dose Zn supplementation in very low birth weight (VLBW: infants with birth weight < 1.5 kg) infants on feeding intolerance and development of mortality and/or morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS)., Study Design: This is a prospective randomized trial. VLBW preterm infants with gestational age of <32 weeks were randomly allocated on the seventh day of life to receive extra amount of supplemental Zn along with the enteral feedings (9 + 3 mg), besides regular low-dose supplementation (3 mg), from enrollment until discharge. Outcome measures were feeding intolerance, NEC (stage ≥ 2), LOS, and mortality., Results: A total of 195 infants (97 from study group and 98 from control group) were analyzed. A total of 46 (47.4%) infants in the study group and 64 (65.3%) infants in the control group ended up with feeding intolerance ( p  = 0.012). NEC was observed in 11 infants (11.2%) in the control group and only 1 infant (1%) in the study group ( p  = 0.003). There was a negative correlation between high-dose Zn supplementation and number of culture-proven LOS episodes ( p  = 0.041). This significance was also present for clinical sepsis, being higher in the control group ( p  = 0.029). No relationship between high-dose Zn supplementation and mortality and other morbidities (hemodynamically significant patent ductus arteriosus, bronchopulmonary dysplasia, retinopathy of prematurity, and severe intraventricular hemorrhage) was observed., Conclusion: Zn supplementation for VLBW infants is found to be effective to decrease feeding intolerance, NEC, and LOS episodes in this vulnerable population. Current data support the supplementation of VLBW infants with higher than regular dose of Zn., Key Points: · Higher dose of Zn supplementation is shown to be a beneficial intervention in VLBW infants.. · Zn may decrease feeding intolerance, sepsis or NEC.. · Higher than regular dose of Zn seems to be safe.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: The intestinal mucosal and immune barriers play considerable roles in the pathogenesis of necrotizing enterocolitis (NEC). The present research was designed to assess the protective effects of Lactobacillus reuteri (LR) DSM 17938 (LR 17938) on the intestinal barriers and its beneficial effects on inflammation in a neonatal mouse model of NEC., Study Design: Overall, 7-day-old 75 C57BL/6 neonatal mice were separated into three groups ( n  = 25) as follows: (1) control, (2) NEC, and (3) NEC + LR17938 (LR group). NEC mice were administered a hypertonic feeding formula and subjected to asphyxia and hypothermia. Hematoxylin and eosin (HE) staining and pathological scores were used to assess the pathological changes in the intestine. Oxidative stress was evaluated based on the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were detected to assess inflammation. Gut permeability levels, bacterial translocation, and the levels of secretory idioglobulin A (sIgA), β-defensin, and tight junction (TJ) proteins were detected to evaluate gut mucosal and immune barrier function, and gut microbial diversity was detected to assess the composition of the gut flora., Results: LR 17938 administration decreased the NEC-induced increase in intestinal scores, mortality rate, gut damage, the MDA level, and TNF-α and IL-1β expressions. Besides, LR 17938 improved the survival rate of NEC mice. Moreover, LR 17938 administration improved gut permeability levels, SOD activity and the bacterial translocation, ameliorated the expression of TJ proteins, and improved the gut microbiota compared with those of NEC mice., Conclusion: LR 17938 reduced intestinal inflammation and played a protective role in a neonatal animal model of NEC, possibly by regulating oxidative stress and exerting a protective effect on the gut mucosal and immune barriers., Key Points: · Our research indicated a protective effect of LR 17938 on gut barrier function in NEC mice.. · LR 17938may affect the diversity of gut flora, which are known to target beneficial bacteria.. · LR 17938 protected gut barrier function in the NEC pups by improving gut permeability.., Competing Interests: None declared., (Thieme. All rights reserved.)

Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H 2 receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Various approaches are employed to expedite the passage of meconium in preterm infants within the neonatal intensive care unit (NICU), with glycerine enemas being the most frequently used. Due to the potential risk of high osmolality-induced harm to the intestinal mucosa, diluted glycerine enema solutions are commonly used in clinical practice. The challenge lies in the current lack of knowledge regarding the safest and most effective concentration of glycerine enema. This research aims to ascertain the safety of different concentrations of glycerine enema solution in preterm infants., Methods and Analysis: This study protocol is for a single-centre, two-arm, parallel-group, double-blind and non-inferiority randomised controlled trial. Participants will be recruited from a NICU in a teriary class A hospital in China, and eligible infants will be randomly allocated to either the glycerine (mL): saline (mL) group in a 3:7 ratio or the 1:9 ratio group. The enema procedure will adhere to the standardised operational protocols. Primary outcomes encompass necrotising enterocolitis and rectal bleeding, while secondary outcomes encompass feeding parameters, meconium passage outcomes and splanchnic regional oxygen saturation. Analyses will compare the two trial arms based on an intention-to-treat allocation., Ethics and Dissemination: This trial is approved by the ethics committee of the Medical Ethics Committee of West China Second University Hospital of Sichuan University. The results will be published in a peer-reviewed journal., Trial Registration Number: ChiCTR2300079199., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Extremely preterm infants, defined as those born before 28 weeks' gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date., Methods: The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge., Discussion: Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide., Trial Registration: ( Clinicaltrials.gov ): NCT05604846., (© 2024. The Author(s).)

Health policy and quality improvement initiatives exist symbiotically. Quality projects can be spurred by policy decisions, such as the creation of financial incentives for high-value care. Then, advocacy can streamline high-value care, offering opportunities for quality improvement scholars to create projects consistent with evidenced-based care. Thirdly, as pediatrics and neonatology reconcile with value-based payment structures, successful quality initiatives may serve as demonstration projects, illustrating to policy-makers how best to allocate and incentivize resources that optimize newborn health. And finally, quality improvement (QI) can provide an essential link between broad reaching advocacy principles and boots-on-the-ground local or regional efforts to implement good ideas in ways that work practically in particular environments. In this paper, we provide examples of how national legislation elevated the importance of QI, by penalizing hospitals for low quality care. Using Medicaid coverage of pasteurized human donor milk as an example, we discuss how advocacy improved cost-effectiveness of treatments used as tools for quality projects related to reduction of necrotizing enterocolitis and improved growth. We discuss how the future of QI work will assist in informing the agenda as neonatology transitions to value-based care. Finally, we consider how important local and regional QI work is in bringing good ideas to the bedside and the community., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although necrotizing enterocolitis is a leading cause of morbidity and mortality among preterm infants, its underlying pathophysiology is not fully understood. Gut dysbiosis, an imbalance between commensal and pathogenic microbes, in the preterm infant is likely a major contributor to the development of necrotizing enterocolitis. In this review, we will discuss the increasing use of probiotics in the NICU, an intervention aimed to mitigate alterations in the gut microbiome. We will review the existing evidence regarding the safety and effectiveness of probiotics, and their potential to reduce rates of necrotizing enterocolitis in preterm infants., (Copyright © 2024 by the American Academy of Pediatrics.)

Introduction: Necrotizing enterocolitis (NEC) is a life-threatening condition that afflicts neonates. Breastfeeding has demonstrated to play a protective role against it. By administering lipopolysaccharides (LPS) orally in newborn rats (NBR), we have developed an experimental model to induce NEC-like gut damage. Our aim was to assess the macroscopic and microscopic appearance of the gut, to evaluate the presence of NEC and study the role of breast milk (BM)., Materials and Methods: NBR were divided into 3 groups: Group A (control, n= 10) remained with the mother, group B (LPS, n= 25) was isolated after birth, gavage-fed with special rat formula and oral LPS, then submitted to stress (hypoxia after gavage) and group c (BM, n= 12) was breastfed once after birth, then isolated, and submitted to stress like group B. On day 4, NBR were sacrificed, and intestine was harvested and assessed., Results: In the control group NEC was not present either macroscopically or histologically. Both groups submitted to stress (B and C) presented a global incidence of NEC of 73%. Most of group B developed histologic signs of NEC (85%) and group C showed a statistically lower incidence of NEC (50%, p= 0.04), playing the BM a protective role against NEC (OR= 0.19; 95% CI: 0.40-0.904)., Conclusion: Our model showed a significant incidence of NEC in NBR (73%) with the same protective role of BM as in newborn humans, achieving a reliable and reproducible experimental NEC model. This will allow us to investigate new potential therapeutic targets for a devastating disease that currently lacks treatment.

Although necrotizing enterocolitis is a leading cause of morbidity and mortality among preterm infants, its underlying pathophysiology is not fully understood. Gut dysbiosis, an imbalance between commensal and pathogenic microbes, in the preterm infant is likely a major contributor to the development of necrotizing enterocolitis. In this review, we will discuss the increasing use of probiotics in the NICU, an intervention aimed to mitigate alterations in the gut microbiome. We will review the existing evidence regarding the safety and effectiveness of probiotics, and their potential to reduce rates of necrotizing enterocolitis in preterm infants., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times., Method: Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups., Results: Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation., Conclusion: Actively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs., Trial Registration: ChiCTR1900023418 (26/05/2019)., (© 2024. The Author(s).)

Background: Insulin might be associated with changes in infant gastrointestinal microbiota. The objective of this randomized controlled trial was to assess the efficacy of two doses of recombinant human(rh) enteral insulin administration compared to placebo in intestinal microbiota., Methods: 19 preterm patients were recruited at the NICU of La Paz University Hospital (Madrid, Spain). Subjects received 2000 µIU of rh enteral insulin/ml(n = 8), 400 µIU of rh enteral insulin/ml(n = 6) or placebo(n = 5) for 28 days administered once per day. Extracted DNA from fecal samples collected at the beginning and end of treatment were analyzed. The 16S rRNA V4 region was amplified and sequenced in a Miseq(Illumina®) sequencer using 2 × 250 bp paired end. Resulting reads were filtered and analyzed using Qiime2 software. Metabolic activity was assessed by GC., Results: Gestational age and birth weight did not differ between groups. At the phylum level, both insulin treated groups increased the relative abundance of Bacillota, while Pseudomonadota decreased. No change was observed in infants receiving placebo. At the genus level, insulin at both doses showed enriching effects on Clostridium. We found a significant increase in concentrations of fecal propionate in both rh insulin treated groups., Conclusion: Rh insulin may modify neonatal intestinal microbiota and SCFAs in preterm infants., Impact Statement: Decrease of Pseudomonadota (former Proteobacteria phylum) and increase of Bacillota (former Firmicutes phylum) obtained in this study are the changes observed previously in low-risk infants for NEC. The administration of recombinant enteral insulin may modify the microbiota of preterm new-borns and SCFAs. Modulation of the microbiota may be a mechanism whereby insulin contributes to neonatal intestinal maturation and/or protection., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

▪▪▪., Competing Interests: Conflict of Interest The author reports no conflicts of interest or relevant financial relationships., (Copyright © 2024. Published by Elsevier Inc.)

Human milk is the most valuable source of nutrition for infants. The structure and function of human milk oligosaccharides (HMOs), which are key components of human milk, have long been attracting particular research interest. Several recent studies have found HMOs to be efficacious in the prevention and treatment of necrotizing enterocolitis (NEC). Additionally, they could be developed in the future as non-invasive predictive markers for NEC. Based on previous findings and the well-defined functions of HMOs, we summarize potential protective mechanisms of HMOs against neonatal NEC, which include: modulating signal receptor function, promoting intestinal epithelial cell proliferation, reducing apoptosis, restoring intestinal blood perfusion, regulating microbial prosperity, and alleviating intestinal inflammation. HMOs supplementation has been demonstrated to be protective against NEC in both animal studies and clinical observations. This calls for mass production and use of HMOs in infant formula, necessitating more research into the safety of industrially produced HMOs and the appropriate dosage in infant formula., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Implementation of exclusive human milk (EHM) feeding defined as mother's own milk or donor human milk fortified with human milk-derived fortifiers can place an economic burden on institutions. Methods: Retrospective study of very low birth weight (VLBW) infants before and after the implementation of EHM feedings. Neonatal demographics and clinical outcomes including necrotizing enterocolitis, severe retinopathy of prematurity, bronchopulmonary dysplasia, late-onset sepsis, days on parenteral nutrition (PN), and length-of-stay were collected. The net cost to the institution was estimated using published data. Results: Sixty-four infants in the pre-EHM period and 57 infants in the post-EHM period were enrolled. Net product acquisition cost in 2020 and 2021 was $884,823. The EHM feeding guideline led to a reduction in the mean length of stay and mean days of PN use by 6.3 and 6.8 days per infant, respectively. This led to a cost saving of $1,813,444 ($31,815 per infant). No significant difference in incidence of short-term morbidities was observed. Combining the cost avoidance from clinical outcomes, the estimated financial impact over 2 years excluding insurance reimbursement was an estimated $ 913,840 ($16,032 per infant). Conclusion: Implementation of EHM-based feeding in VLBW infants is a cost-effective option for neonatal intensive care units that can result in reduced length of stay and days on PN without adversely impacting short-term morbidities.

Purpose: Necrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota., Methods: Broad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5-9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids., Results: HMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth., Conclusion: This study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Necrotizing enterocolitis (NEC) is one of the diseases in neonates, with a high morbidity and mortality rate, especially in preterm infants. This review aimed to briefly introduce the latest epidemiology, susceptibility factors, and clinical diagnosis and presentation of NEC. We also organized new prevention strategies by risk factors according to different pathogeneses and then discussed new treatment methods based on Bell's staging and complications, and the classification of mild to high severity based on clinical and imaging manifestations. Such a generalization will help clinicians and researchers to gain a deeper understanding of the disease and to conduct more targeted classification, grading prevention, and exploration. We focused on prevention and treatment of the early and suspected stages of NEC, including the discovery of novel biomarkers and drugs to control disease progression. At the same time, we discussed its clinical application, future development, and shortcomings., (© 2024. The Author(s).)

The gut microbiota influences many aspects of the host, including immune system maturation, nutrient absorption and metabolism, and protection from pathogens. Increasing evidences from cohort and animal studies indicate that changes in the gut microbiota early in life increases the risk of developing specific diseases early and later in life. Therefore, it is becoming increasingly important to identify specific disease prevention or therapeutic solutions targeting the gut microbiota, especially during infancy, which is the window of the human gut microbiota establishment process. In this review, we provide an overview of current knowledge concerning the relationship between disturbances in the gut microbiota early in life and health consequences later in life (e.g., necrotizing enterocolitis, celiac disease, asthma, allergies, autism spectrum disorders, overweight/obesity, diabetes and growth retardation), with a focus on changes in the gut microbiota prior to disease onset. In addition, we summarize and discuss potential microbiota-based interventions early in life (e.g., diet adjustments, probiotics, prebiotics, fecal microbiota transplantation, environmental changes) to promote health or prevent the development of specific diseases. This knowledge should aid the understanding of early life microbiology and inform the development of prediction and prevention measures for short- and long-term health disorders based on the gut microbiota.

The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

Fecal filtrate transfer (FFT) is emerging as a safer alternative to traditional fecal microbiota transplantation (FMT) - particularly in the context of necrotizing enterocolitis (NEC), a severe gastrointestinal condition affecting preterm infants. Using a preterm piglet model, FFT has demonstrated superiority over FMT in safety and NEC prevention. Since FFT is virtually devoid of bacteria, prokaryotic viruses (bacteriophages) are assumed to mediate the beneficial effects. However, this assumption remains unproven. To address this gap, we separated virus-like particles (30 kDa to 0.45 µm) of donor feces from the residual postbiotic fluid. We then compared clinical and gut microbiota responses to these fractions with the parent FFT solution after transferring them to NEC-susceptible preterm piglets. Virome transfer was equally effective as FFT in reducing the severity of NEC-like pathology. The bacterial compositional data corroborated clinical findings as virome transfer reduced the relative abundance of several NEC-associated pathogens e.g. Klebsiella pneumoniae and Clostridium perfringens . Virome transfer diversified gut viral communities with concomitant constraining effects on the bacterial composition. Unexpectedly, virome transfer, but not residual postbiotic fluid, led to earlier diarrhea. While diarrhea may be a minor concern in human infants, future work should identify ways of eliminating this side effect without losing treatment efficacy.

Intestinal bacteria, also known as gut microbiota, are a rich ecology of microorganisms found in the human digestive tract. Extensive study has highlighted their critical relevance in preserving human health. New research has revealed that bacterial viability is not invariably necessary to induce health benefits. Postbiotics (defined soluble substances produced as a byproduct of the metabolic processes of living microbes) have thus emerged as an important topic of research. They contribute to shaping the gut microbiota, exert immune-modulation activity, and improve the integrity of the gut barrier.Alterations in preterm gut colonization associated with intestinal barrier immaturity and the increased reactivity of the intestinal mucosa to colonizing bacteria have been implicated in the pathogenesis of necrotizing enterocolitis. Postbiotics have shown promising outcomes in reducing the risk of developing NEC, lowering inflammation, encouraging the development of good bacteria, and strengthening the intestinal barrier. This is an important advancement in newborn care and highlights the potential of postbiotics to avoid severe intestinal disorders., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Importance: This study sheds light on that treatment with Clostridium tyrobutyricum but not Clostridium butyricum is entitled to protect against necrotizing enterocolitis (NEC) development potentially. The mechanisms behind the opposite effect on NEC may result in different modulation on the level of Akkermansia muciniphila , which is deeply associated with intestinal homoeostasis. Briefly, through improving the abundance of A. muciniphila to alleviate intestinal inflammation and enhance intestinal barrier integrity, C. tyrobutyricum supplement may become a promising therapy for NEC., Competing Interests: The authors declare no conflict of interest.

Exosomes are extracellular vesicles with the diameter of 30 ~ 150 nm, and are widely involved in intercellular communication, disease diagnosis and drug delivery carriers for targeted disease therapy. Therapeutic application of exosomes as drug carriers is limited due to the lack of sources and methods for obtaining adequate exosomes. Milk contains abundant exosomes, several studies have shown that milk-derived exosomes play crucial roles in preventing and treating intestinal diseases. In this review, we summarized the biogenesis, secretion and structure, current novel methods used for the extraction and identification of exosomes, as well as discussed the role of milk-derived exosomes in treating intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, colorectal cancer, and intestinal ischemia and reperfusion injury by regulating intestinal immune homeostasis, restoring gut microbiota composition and improving intestinal structure and integrity, alleviating conditions such as oxidative stress, cell apoptosis and inflammation, and reducing mitochondrial reactive oxygen species (ROS) and lysosome accumulation in both humans and animals. In addition, we discussed future prospects for the standardization of milk exosome production platform to obtain higher concentration and purity, and complete exosomes derived from milk. Several in vivo clinical studies are needed to establish milk-derived exosomes as an effective and efficient drug delivery system, and promote its application in the treatment of various diseases in both humans and animals., (© 2023. The Author(s).)

Background: The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants., Methods: MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included., Results: Probiotics (OR, 0.47; 95% CrI, 0.33-0.63), arginine (OR, 0.38; 95% CrI, 0.14-0.98), glutamine (OR, 0.30; 95% CrI, 0.079-0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037-0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69-0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54-0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40-0.79), prebiotics (OR, 0.23; 95% CrI, 0.043-0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035-0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7- -0.63) appeared to have earlier age of attainment of full feeding., Conclusions: Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To evaluate whether eliminating routine gastric residual volume (GRV) assessments would lead to quicker attainment of full feeding volumes in preterm infants., Study Design: This is a prospective randomized controlled trial of infants ≤32 weeks gestation and birthweight ≤1250 g admitted to a tertiary care NICU. Infants were randomized to assess or not assess GRV before enteral tube feedings. The primary outcome was time to attain full enteral feeding volume defined as 120 ml/kg/day. The Wilcoxon rank sum test was used to compare the days to reach full enteral feeds between the two groups., Results: 80 infants were randomized, 39 to the GRV assessing and 41 to the No-GRV assessing group. A predetermined interim analysis at 50% enrollment showed no difference in primary outcome and the study was stopped as recommended by the Data Safety Monitoring Committee. There was no significant difference in median days to reach full enteral feeds between the two groups [GRV assessment: 12d (5) vs. No-GRV assessment:13d (9)]. There was no mortality in either group, one infant in each group developed necrotizing enterocolitis stage 2 or greater., Conclusion: Eliminating the practice of gastric residual volume assessment before feeding did not result in shorter time to attain full feeding.

Introduction: The gastrointestinal and immune systems of premature infants are not fully developed, rendering them more vulnerable to severe complications like necrotizing enterocolitis. Human milk offers a rich array of bioactive factors that collectively contribute to reducing the incidence of gut infections and inflammatory conditions. When a mother's milk is unavailable, preterm infants are often provided with donor human milk processed in Human Milk Banks. However, it remains uncertain whether pasteurized milk confers the same level of risk reduction as unprocessed milk. This uncertainty may stem from the well-documented adverse effects of heat treatment on milk composition. Yet, our understanding of the comprehensive impact on protective mechanisms is limited., Methods: In this study, we conducted a comparative analysis of the effects of raw versus pasteurized milk and colostrum versus mature milk on cellular functions associated with the gut epithelial barrier and responses to inflammatory stimuli. We utilized THP-1 and HT-29 cell lines, representing monocyte/macrophages and gut epithelial cells, respectively., Results: Our observations revealed that all milk types stimulated epithelial cell proliferation. However, only raw colostrum increased cell migration and interfered with the interaction between E. coli and epithelial cells. Furthermore, the response of epithelial and macrophage cells to lipopolysaccharide (LPS) was enhanced solely by raw colostrum, with a milder effect observed with mature milk. In contrast, both raw and pasteurized milk diminished the LPS induced response in monocytes. Lastly, we examined how milk affected the differentiation of monocytes into macrophages, finding that milk reduced the subsequent inflammatory response of macrophages to LPS., Discussion: Our study sheds light on the impact of human milk on certain mechanisms that potentially account for its protective effects against necrotizing enterocolitis, highlighting the detrimental influence of pasteurization on some of these mechanisms. Our findings emphasize the urgency of developing alternative pasteurization methods to better preserve milk properties. Moreover, identifying the key components critically affected by these protective mechanisms could enable their inclusion in donor milk or formula, thereby enhancing immunological benefits for vulnerable newborns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rodríguez-Camejo, Puyol, Arbildi, Sóñora, Fazio, Siré and Hernández.)

Although necrotising enterocolitis (NEC) is a serious, life-threatening disease, improved neonatal care is increasing the number of survivors with NEC among extremely preterm neonates. Therapy is nevertheless mostly symptomatic and the mortality rate remains high, especially among neonates requiring surgery. Therefore, it is important to focus on preventing the disease and modifiable risk factors. NEC's pathophysiology is multifaceted, with key factors being immaturity of the immune and barrier protective mechanisms of the premature gut and exaggerated proinflammatory reaction to insults like gut hypoxia, enteral nutrition or microbial dysbiosis. The role of the intestinal microbiome in the pathophysiology of NEC has been a subject of research for many years, but to date no specific pathogen or type of dysbiosis has been connected with NEC development. This review assesses current knowledge as to the role of the intestinal microbiota in the pathophysiology of NEC and the possibilities for positively influencing it., Competing Interests: Competing interests: None declare, (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Our previous strain-specific systematic review (SR) showed that Lactobacillus reuteri (LR) DSM 17938 reduces necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and time to full feeds (TFF) in preterm infants. Considering progress in the field over the past 6 years, we aimed to update our SR., Methods: SR of randomized controlled trials (RCTs) and non-RCTs was conducted. MEDLINE, Embase, Emcare, Cochrane CENTRAL, and gray literature were searched in June 2023. Primary outcomes were TFF, NEC stage ≥II, LOS, and all-cause mortality. Meta-analysis was performed using random-effects model. Certainty of evidence (CoE) was summarized using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. Trial sequential analysis (TSA) was applied for outcome of NEC in RCTs., Results: Twelve RCTs (n = 2284) and four non-RCTs (n = 1616) were included. Six RCTs and three non-RCTs were new. Meta-analysis of RCTs showed LR significantly reduced TFF (mean difference, -2.70 [95% CI, -4.90 to -1.31] days; P = 0.0001), NEC stage ≥II (risk ratio [RR], 0.57 [95% CI, 0.37-0.87]; P = 0.009; eight RCTs), and LOS (RR, 0.72 [95% CI, 0.54-0.97]; P = 0.03); but not mortality (RR, 0.76 [95% CI, 0.54-1.06]; P = 0.10). TSA showed diversity-adjusted required information size (DARIS) as 3624 for NEC. Overall CoE was "very low." Meta-analysis of non-RCTs showed LR reduced NEC (odds ratio, 0.34 [95% CI, 0.15-0.77]; P = 0.01) but not LOS. LR had no adverse effects., Conclusions: Very low CoE suggests that LR DSM 17938 may reduce NEC and LOS and shorten TFF in preterm infants. Additional RCTs are required to confirm our findings., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Importance: Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants., Objective: To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials., Data Sources: MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023., Study Selection: Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants., Data Extraction and Synthesis: A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach., Main Outcomes and Measures: All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization., Results: A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively)., Conclusions and Relevance: In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Aim: We introduced routine probiotic supplementation (RPS) of preterm infants in June 2012. We previously reported that RPS reduced the incidence of necrotising enterocolitis (NEC) and mortality in such infants. In this study, we assessed if the benefits of RPS were sustained for infants in the current era., Method: We compared the outcomes of preterm infants in recent epoch 3 (RPS, 1st June 2014 to 31st December 2019) versus epoch 2 (RPS, 1st June 2012 to 31st May 2014) and epoch 1 (no RPS, 1st December 2008 to 30th November 2010). Multiple logistic and Cox regression models were used to compare the outcomes., Results: There were 645 infants in epoch 1, 712 in epoch 2 and 1715 in epoch 3. Age at full feeds was significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants <28 weeks of gestation. NEC and late-onset sepsis (LOS) were significantly lower in epoch 3 vs. 1 in infants <28 weeks. LOS and age at full feeds were significantly lower in epoch 3 vs. 2 and epoch 3 vs. 1 in infants with gestation 28 to 32 weeks., Conclusion: The benefits associated with RPS were sustained during epoch 3., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)