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Objective To investigate the mechanism of autoinducer-2(AI-2) in relieving intestinal injury in neonatal mouse model of necrotizing enterocolitis (NEC). Methods Thirty-six 7-day-old C57BL/6J mice were randomly divided into Control group (fed by mother mice), NEC group (NEC model induced by formula+lipopolysaccharide administration, hypoxia and cold stress), and NEC+AI-2 group (AI-2 solution added to the modeled formula milk), with 12 mice in each group.The body weight and survival rate of each group were recorded during the modeling period.In 3 d after modeling, the mice were euthanized, and the histopathological changes in the terminal ileum were observed using HE staining.The mRNA expression levels of aryl hydrocarbon receptor (AHR), cytochrome P450 1A1(CYP1A1), TNF-α, IL-6 and IL-22 in intestinal tissue were detected with RT-qPCR.The protein levels of AHR and CYP1A1 in intestinal tissues were measured with Western blotting.The contents of TNF-α, IL-6 and IL-22 in intestinal tissues were detected using enzyme-linked immunosorbent assay (ELISA). Results The survival rate of neonatal rats was significantly higher in the NEC+AI-2 group than the NEC group (91.7%vs 66.7%, P < 0.05).The NEC+AI-2 group had obviously lower intestinal pathological injury score (1.33±0.21 vs 2.67±0.33, P < 0.05), increased mRNA and protein levels of AHR and CYP1A1 in intestinal tissues (P < 0.05), decreased expression levels of pro-inflammatory factors TNF-α and IL-6 in intestinal tissues (P < 0.05), while increased expression level of anti-inflammatory factor IL-22(P < 0.05) when compared with the NEC group.Furthermore, the expression and activation of intestinal AHR were negatively correlated with the intestinal pathological injury score (P < 0.001). Conclusion AI-2 alleviates intestinal injury in neonatal mice with NEC by activating AHR to regulate inflammatory response.

Abstract Background Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis. Case presentation We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15. Conclusions It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns.

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

Abstract Background Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods Clinical data of NEC in preterm infants with Bell’s stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year (P

Abstract The practice of routine gastric residual aspiration in preterm infants remains controversial, with conflicting evidence regarding its impact on necrotizing enterocolitis (NEC). As front-line caregivers, nurses play a vital role in gastric aspiration procedures and must be informed by evidence. This quasi-experimental nursing study aimed to assess whether gastric aspiration is clinically relevant in reducing the risk of NEC in preterm infants. A total of 250 preterm infants from two NICUs in Egypt were allocated to the gastric aspiration (n = 125) and non-aspiration (n = 125) groups. Feeding practices, gastric residuals, and incidence/severity of NEC were compared between groups according to modified Bell’s criteria. Risk factors were analyzed using multivariate regression. There were no significant baseline differences between the groups. The gastric residual attributes and feeding outcomes did not differ substantially from aspiration. The overall incidence of NEC was 14–15%, with no significant differences in the odds of onset or progression of NEC by stage between the groups. Lower gestational age and birth weight emerged as stronger predictors of NEC. Routine gastric aspiration does not appear to directly prevent or reduce the severity of NEC in this population. Although gastric residuals retain clinical importance, study findings question assumptions that aspiration protects against NEC and informs nursing practice. Evidence-based feeding protocols must continually evolve through ongoing research on modifiable risk factors for this devastating intestinal disease in preterm infants.

Abstract 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

Abstract The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Introduction: Birth-related obstruction of umbilical blood flow may induce hypoxic insults that affect postnatal organ adaptation. Using newborn cesarean-delivered pigs, we hypothesized that cord obstruction during delivery negatively affects physiological transition and gut maturation. Further, we investigated if delayed cord clamping (DCC) improves gut outcomes, including sensitivity to formula-induced necrotizing enterocolitis (NEC)-like lesions. Methods: In experiment 1, preterm (n = 24) and near-term (n = 29) piglets were subjected to umbilical cord obstruction (UCO, 5–7 min in utero), with corresponding pigs delivered without obstruction (CON, n = 17–22). Experiment 2 assessed preterm pigs subjected to delayed cord clamping (n = 30, 60 s) or immediate cord transection with umbilical cord milking (UCM, n = 34). Postnatal vital parameters were recorded, together with a series of gut parameters after 3 days of formula feeding. Results: UCO induced respiratory-metabolic acidosis in near-term pigs at birth (pH 7.16 vs. 7.32, pCO2 12.5 vs. 9.2 kPa, lactate 5.2 vs. 2.5 mmol/L, p < 0.05). In preterm pigs, UCO increased failure of resuscitation and mortality shortly after birth (88 vs. 47%, p < 0.05). UCO did not affect gut permeability, transit time, macromolecule absorption, six digestive enzymes, or sensitivity to NEC-like lesions. In experiment 2, DCC improved neonatal hemodynamics (pH 7.28 vs. 7.20, pCO2 8.9 vs. 9.9 at 2 h, p < 0.05), with no effects on gut parameters. Conclusion: UCO and DCC affect neonatal transition and hemodynamics, but not neonatal gut adaptation or sensitivity to NEC-like lesions. Our findings suggest that the immature newborn gut is highly resilient to transient birth-related changes in cord blood flow. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damageassociated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis. Case presentation: We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15. Conclusions: It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns. [ABSTRACT FROM AUTHOR]

Streptococcus gallolyticus subspecies pasteurianus is a subtype of Streptococcus bovis (S. bovis) that has become increasingly recognized as a sepsis-causing pathogen in neonates. It is well documented that S. bovis species have a predilection to both cardiac and gastrointestinal tissue, and in adult populations, isolating these organisms in the bloodstream often triggers further evaluation for co-morbid complications such as colon cancer or endocarditis. However, no such guidance currently exists in neonatal literature. We present a case of a preterm infant with S. gallolyticus subsp. pasteurianus bacteremia presenting as necrotizing enterocolitis (NEC) not previously described in the literature. Furthermore, through a complete diagnostic evaluation, including an echocardiogram, our patient was found to have the rare complication of endocarditis. [ABSTRACT FROM AUTHOR]

Les infections bactériennes graves ont une incidence plus élevée dans la période néonatale qu'à tout autre âge pédiatrique et leur gravité est accrue en l'absence de diagnostic et de traitement précoces. L'incidence est encore plus importante chez les prématurés que chez les nouveau-nés à terme. Les signes cliniques induits sont peu spécifiques et parfois insignifiants, et les biomarqueurs sont peu performants au cours des 24 premières heures de l'infection. Pendant des décennies, cette situation a conduit à traiter trop d'enfants, pendant de longues périodes, avec des antibiotiques à large spectre. Aujourd'hui, le défi consiste à prescrire des traitements ciblés en identifiant les nouveau-nés réellement infectés. Au cours de ces dix dernières années, nous avons assisté à des changements de paradigme majeurs dont il est essentiel de tenir compte. En effet, la prise de conscience croissante de l'impact écologique de l'antibiothérapie précoce, notamment sa contribution à la résistance de certaines bactéries aux antibiotiques, implique de choisir l'antibiotique à spectre le plus étroit et des durées de traitement en adéquation réelle avec les signes d'infection. Parmi les tests biologiques, les plus importants sont les hémocultures. Au moins une hémoculture, réalisée dans des conditions d'asepsie, de volume suffisant (1 à 2 mL) et avec des flacons pédiatriques, doit être effectuée dès que la décision de traiter est prise, avant de débuter toute antibiothérapie. Les bactéries responsables des infections bactériennes néonatales précoces (IBPN) n'ont pas évolué de manière significative au cours des dernières années et restent dominées par les Streptocoques du groupe B et Escherichia coli , qui sont les principales cibles du traitement. Le SGB est largement prédominant chez les enfants nés à terme, mais la proportion d'infections dues à E. coli augmente avec la prématurité. Severe bacterial infections have a higher incidence in the neonatal period than at any other pediatric age. Incidence is even higher in premature babies than in term newborns, and severity is increased in the absence of early diagnosis and treatment. By contrast, clinical signs are nonspecific and sometimes trivial, and biomarkers perform poorly during the first 24 hours of infection. For decades, this has led to having too many children treated for extended periods with broad-spectrum antibiotics. Today, the challenge is to prescribe antibiotics in a targeted way, by identifying truly infected newborns. Over the last ten years, major paradigm shifts have occurred and should be taken into account, as a result of growing awareness of the ecological impact of early antibiotic therapy, notably antibiotic resistance, by choosing the narrowest spectrum antibiotic and stopping antibiotic therapy as soon as the diagnosis of infection has been reasonably ruled out. Among the biological tests, the most important are blood cultures. At least one blood culture, taken under aseptic conditions, of sufficient volume (1 to 2 mL), and using pediatric bottles must be taken as soon as the decision to treat has been made, before starting any antibiotic therapy. The bacteria responsible for early-onset bacterial neonatal infections (EBNI) have not changed significantly over recent years and remain dominated by Group B streptococcus and Escherichia coli , which are the main targets of treatment. GBS is largely predominant in full-term infants, but the proportion of infections due to E. coli increases with prematurity. [ABSTRACT FROM AUTHOR]

Early prediction of surgical necrotizing enterocolitis (sNEC) in preterm infants is important. However, owing to the complexity of the disease, identifying infants with NEC at a high risk for surgical intervention is difficult. We developed a machine learning (ML) algorithm to predict sNEC using perinatal factors obtained from the national cohort registry of very low birth weight (VLBW) infants. Data were collected from the medical records of 16,385 VLBW infants registered in the Korean Neonatal Network (KNN). Infants who underwent surgical intervention were identified with sNEC, and infants who received medical treatment, with medical NEC (mNEC). We used 38 variables, including maternal, prenatal, and postnatal factors that were obtained within 1 week of birth, for training. A total of 1085 patients had NEC (654 with sNEC and 431 with mNEC). VLBW infants showed a higher incidence of sNEC at a lower gestational age (GA) (p < 0.001). Our proposed ensemble model showed an area under the receiver operating characteristic curve of 0.721 for sNEC prediction. Conclusion: Proposed ensemble model may help predict which infants with NEC are likely to develop sNEC. Through early prediction and prompt intervention, prognosis of sNEC may be improved. What is Known: • Machine learning (ML)-based techniques have been employed in NEC research for prediction, diagnosis, and prognosis, with promising outcomes. • While most studies have utilized abdominal radiographs and clinical manifestations of NEC as data sources, and have demonstrated their usefulness, they may prove weak in terms of early prediction. What is New: • We analyzed the perinatal factors of VLBW infants acquired within 7 days of birth and used ML-based analysis to identify which infants with NEC are vulnerable to clinical deterioration and at high risk for surgical intervention using nationwide cohort data. [ABSTRACT FROM AUTHOR]

Background. Fetal inflammatory response syndrome (FIRS) is a pathological reaction of the fetal immune system to infection of the amnion or inflammation of the chorion, which significantly increases the risk of neonatal mortality and morbidity. Objective of the study: to study the clinical features of the course of the neonatal period in premature babies with different gestational periods against the background of FIRS. Material and methods. The course of the neonatal period was analyzed in 405 premature newborns, divided depending on the gestational age and the presence of premature rupture of the fetal membranes. The content of IL-6 in umbilical cord blood was determined in all newborns by enzyme-linked immunosorbent assay. Its value greater than 11 pg/ml was the basis for establishing a diagnosis of FIRS. The duration of respiratory support in general, artificial lung ventilation, non-invasive lung ventilation, and the need for additional oxygen, periventricular hemorrhages, and necrotizing enterocolitis were analyzed in all newborns depending on the presence of FIRS. Results. Extremely premature newborns with FIRS have a longer duration of both invasive and non-invasive ventilation, newborns from early preterm births with FIRS required non-invasive ventilation longer only in case of premature rupture of the fetal membranes. In extremely premature newborns with FIRS the duration of the additional oxygen supply increases, in newborns from early premature births this pattern was only in the case of premature rupture of the fetal membranes. Only in premature babies from very early premature births with FIRS a doubling of the frequency of hemorrhages in the ventricles of the brain and necrotizing enterocolitis was found. Conclusions. FIRS in extremely premature newborns is associated with a longer duration of invasive and non-invasive ventilation, as well as with a longer need for oxygen enrichment of inhaled air. FIRS in extremely premature newborns increase the frequency and severity of intraventricular hemorrhages and necrotizing enterocolitis. [ABSTRACT FROM AUTHOR]

Neonatal necrotizing enterocolitis (NEC) is the most common inflammatory intestinal disease in preterm infants, with a high incidence and mortality rate. The etiology and mechanisms of NEC are not yet fully understood, and multiple factors contribute to its occurrence and development. Recent studies have found that anemia is a risk factor for NEC in neonates, but the specific pathogenic mechanism remains unclear. This article reviews recent research on the relationship between anemia and NEC, providing a reference for further understanding the impact of anemia on intestinal injury and its association with NEC. [ABSTRACT FROM AUTHOR]

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods: Clinical data of NEC in preterm infants with Bell's stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results: In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year (P < 0.05). The results of univariate analysis showed that the morbidity of NEC in preterm infants was associated with premature rupture of membranes, blood transfusion, sepsis, and the of serum albumin (P < 0.05). Multivariate logistic regression analysis revealed that blood transfusion (OR = 2.232, 95% CI: 1.012–4.923) and sepsis (OR = 0.899, 95% CI: 0.809–3.915) were independent risk factors of NEC in preterm infants, while high serum albumin (OR = 0.899, 95% CI: 0.809–3.915) was an independent protective factor of NEC in preterm infants. Conclusion: The morbidity of NEC is gradually increasing. Inhibition of infection and limitation of blood transfusion are effective measures to reduce the occurrence of NEC. Meanwhile, high serum albumin is a protective factor for NEC. [ABSTRACT FROM AUTHOR]

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Introduction: The effect of the pandemic restrictions in the NICUs is not well studied. Necrotizing enterocolitis (NEC) is characterized by intestinal inflammation and bacterial invasion. This study aimed to investigate whether the incidence of NEC has changed during the COVID-19 pandemic in Sweden and whether it was associated with a change in the frequency of extremely preterm births. Methods: Data were retrieved from the Swedish Neonatal Quality Register (SNQ) for infants registered between January 2017 and December 2021 born below a gestational age of 35 weeks. The registry completeness is 98–99%. The diagnosis of NEC was the primary outcome. Generalized linear model analysis was used to calculate the risk ratio for NEC. Results: Totally 13,239 infants were included. 235 (1.8%) infants developed NEC, out of which 91 required surgical treatment. 8,967 infants were born before COVID-19 pandemic and 4,272 during. Median gestational age at birth was 32.8 weeks in both periods. The incidence of NEC was significantly lower during COVID-19 pandemic compared to the prior period (1.43 vs. 1.94%, p 0.037), but not the incidence of surgical NEC. The crude risk ratio of developing NEC during COVID-19 pandemic was 0.74 (95% CI: 0.55–0.98). The incidence of late-onset sepsis with positive culture was also declined during COVID-19 (3.21 vs. 4.15%, p value 0.008). Conclusion: While we found significant reduction in the incidence of NEC and culture-positive late-onset sepsis during the COVID-19 pandemic, the number of extremely preterm births was unchanged. [ABSTRACT FROM AUTHOR]

Objective To explore the risk factors of postoperative Hirschsprung-associated enterocolitis (HAEC) within 1 year. Methods From January 2011 to June 2021, the relevant clinical data were retrospectively reviewed for 313 children with Hirschsprung's disease (HSCR). They were assigned into two groups of postoperative HAEC (n=47) and no postoperative HAEC (n = 266). The risk factors of postoperative HAEC included patient gender, age of radical operation, microcytic hypochromic anemia, preoperative HAEC history, preoperative colostomy, pathological classification and hypoalbuminemia. Results Patient gender or age of radical operation showed no difference of statistical significance (P>0.05). And microcytic hypochromic anemia [(59.6%,28/47) υς. (35.3%, 94/266)], preoperative HAEC [(44.7%,21/47) vs. (22.6%,60/266)], preoperative colostomy [(23.4%,11/47) vs. (10.2%,27/266)], long segment or total colonic HSCR [(34.0%, 16/47) vs. (16.9%,45/266)] and hypoalbuminemia [(80.9%,38/47) vs. (66.2%, 176/266)] revealed statistically significant differences (P<0.05). Multiple Logistic regression analysis indicated that microcytic hypochromic anemia (OR=2.522,95% CI:1.301-4.887) and preoperative HAEC(OR=2.812,95% CI:1.415-5.589) were correlated with postoperative HAEC. Conclusions Complication of microcytic hypochromic anemia and preoperative HAEC are the risk factors of postoperative HAEC. Focusing upon the risk factors of postoperative HAEC can effectively lower the most serious complications of HSCR after radical operation and improve the quality-of-life of children. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical characteristics of multiple-birth preterm infants with necrotizing enterocolitis (NEC) and examine the effects of multiple births on clinical manifestations and outcomes of NEC infants. Methods In this retrospective study, 234 premature infants with NEC admitted to Shanghai Children's Hospital from July 2014 to June 2021 were included as research objects, among which 79 were multiple premature infants with NEC and 155 were single premature infants with NEC, According to the presence of single/multiple birth, they were divided into two groups of singleton (group A, n = 155) and multiple-birth (group B, n = 79). Twin group of vaginal delivery was divided into primary birth (group C, n = 9 and secondary birth (group D, n = 4) based upon birth order. Twin group was also assigned into two groups of higher birth weight (group E, n = 20) and lower birth weight (group F n = 45. And twin group was divided into two groups of concordant twins (CT, group G, n = 42 and discordant twins (DT, group H, n = 26). The latter group was further divided into DT with higher birth weight (group l, n = 5 and DT with lower birth weight (group J,n= 21). Demographic profiles (birth weight, gestational age & birth mode), clinical data (time of NEC onset, laboratory results & Bell stage), treatment (medical or surgical, intestinal perforation & extent of disease) and outcomes (postoperative complications & in-hospital mortality) were recorded. Results Seventy-nine cases of multiple preterm NEC infants were recruited, including 75 twins and 4 triplets. Seventy-five preterm NEC twins had a mean gestational age of 31. 60 weeks and a mean birth weight of 1 476.51 gram. Bell stage was 1 (n= 35), II (n = 21) and III n = 19 Eighteen cases (24%) underwent operation. As compared with group A, NEC infants in group B had a lower birth weight [1618.77 ± 481.30) g. (1 479.34 ±376.88) g, P = 0.016], higher rates of cesarean delivery [84(54.2%) vs. 65 (82.3%), P < 0.001 ] and assisted reproductive technology [11(7.1%) vs. 21 (26.6%) P < 0.001 ]. However, no differences existed in demographic profiles, clinical manifestations, laboratory results, Bell stage, surgery or outcomes (P > 0.05). There was no significant effect of birth order on demographic profiles, clinical manifestations, laboratory results, Bell stage, surgery or outcomes (P > 0.05) As compared with group E, group F had a lower birth weight [(1677.65 ±458.23) gus. (1382.89±300.81) g,P=0.019], lower WBC count [(12.31 ±4.22) ts. (9.13 plus/minus 4.01) * 109/L P = 0.023], greater intestinal lesion [5(45.4%) ts.0(0.0%), P = 0.002 ] and more postoperative complications [11(100%) 18. 3 (42.9%), P = 0.011 ] No difference existed in demographic profiles, clinical manifestations, other laboratory results, Bell stage, surgery or in-hospital mortality (P > 0.05). As compared with group G, group J had a greater gestational age [(30.95±2.44), (32.71 ±2.30) week, P = 0.027 ] and a higher rate of cesarean delivery [30 (71.4%) ts. 20 (95.2%) P = 0.045) rfloor. However, no differences existed in demographic profiles, clinical manifestations, laboratory results, Bell stage, surgery or outcomes (P > 0.05) Conclusions Multiple-birth NEC infants have no greater severity of Bell stage, more surgery, greater extent of intestinal lesion, more postoperative complications or higher in-hospital mortality. Twins with lower birth weight are prone to greater extent of intestinal lesion and more postoperative complications. However, birth order and discordance of twins have no significant effect on disease severity, surgery or in-hospital mortality. [ABSTRACT FROM AUTHOR]

Data from the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) indicate that targeting a higher (91–95%) versus lower (85–89%) pulse oximeter saturation (SpO2) range may reduce mortality and necrotizing enterocolitis (NEC) and increase retinopathy of prematurity (ROP). Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data. We used Bayes factors (BFs) to evaluate the likelihood of the data under the combination of models assuming the presence vs. absence of effect, heterogeneity, and moderation by sex. The Bayesian reanalysis showed moderate evidence in favor of no differences between SpO2 targets (BF10 = 0.30) in death or major disability, but moderate evidence (BF10 = 3.60) in favor of a lower mortality in the higher SpO2 group. Evidence in favor of differences was observed for bronchopulmonary dysplasia (BPD) (BF10 = 14.44, lower rate with lower SpO2), severe NEC (BF10 = 9.94), and treated ROP (BF10 = 3.36). The only outcome with moderate evidence in favor of sex differences was BPD. This reanalysis of the NeOProM trials confirmed that exposure to a lower versus higher SpO2 range is associated with a higher mortality and risk of NEC, but a lower risk of ROP and BPD. The Bayesian approach can help in assessing the strength of evidence supporting clinical decisions. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of prematurity. Postulated mechanisms leading to inflammatory necrosis of the ileum and colon include activation of the pathogen recognition receptor Toll-like receptor 4 (TLR4) and decreased levels of transforming growth factor beta (TGFβ). Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a novel damage-associated molecular pattern (DAMP), is a TLR4 ligand and plays a role in a number of inflammatory disease processes. To test the hypothesis that eNAMPT is involved in NEC, an eNAMPT-neutralizing monoclonal antibody, ALT-100, was used in a well-established animal model of NEC. Preterm Sprague–Dawley pups delivered prematurely from timed-pregnant dams were exposed to hypoxia/hypothermia and randomized to control—foster mother dam-fed rats, injected IP with saline (vehicle) 48 h after delivery; control + mAB—foster dam-fed rats, injected IP with 10 µg of ALT-100 at 48 h post-delivery; NEC—orally gavaged, formula-fed rats injected with saline; and NEC + mAb—formula-fed rats, injected IP with 10 µg of ALT-100 at 48 h. The distal ileum was processed 96 h after C-section delivery for histological, biochemical, molecular, and RNA sequencing studies. Saline-treated NEC pups exhibited markedly increased fecal blood and histologic ileal damage compared to controls (q < 0.0001), and findings significantly reduced in ALT-100 mAb-treated NEC pups (q < 0.01). Real-time PCR in ileal tissues revealed increased NAMPT in NEC pups compared to pups that received the ALT-100 mAb (p < 0.01). Elevated serum levels of tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin-8 (IL-8), and NAMPT were observed in NEC pups compared to NEC + mAb pups (p < 0.01). Finally, RNA-Seq confirmed dysregulated TGFβ and TLR4 signaling pathways in NEC pups that were attenuated by ALT-100 mAb treatment. These data strongly support the involvement of eNAMPT in NEC pathobiology and eNAMPT neutralization as a strategy to address the unmet need for NEC therapeutics. [ABSTRACT FROM AUTHOR]

OBJECTIVE Acetaminophen (APAP) is an alternative to indomethacin and ibuprofen for treatment of patent ductus arteriosus (PDA). The side effect profile of non-steroidal anti-inflammatory drugs (NSAIDs) presents enteral feeding safety concerns; however, the safety of enteral feeding on APAP is largely unknown. Optimal feeding strategies during pharmacological PDA treatment are unknown, leading to practice variation. This study aims to assess the incidence of adverse gastrointestinal (GI) outcomes in neonates treated with APAP for PDA closure while receiving enteral feedings. METHODS Single-center retrospective cohort study of 59 extremely low birth weight (ELBW), premature neonates who received APAP for PDA treatment divided into Low Volume (LV; ≤ 20 mL/kg/day) and High Volume (HV; > 20 mL/kg/day) enteral feeding groups. The primary outcome was the incidence of any suspected or confirmed necrotizing enterocolitis (NEC). Timing of nutrition milestones, parenteral nutrition (PN) days, and adverse outcomes (feeding intolerance, liver dysfunction, death prior to discharge) were evaluated. RESULTS The incidence of suspected or confirmed NEC was 19.5% in the LV group and 13.3% in the HV group (p = 0.593). The HV group reached full feeds 6 days sooner (18 vs 24 days, p = 0.024) and had fewer PN days (17 vs 23.5 days, p = 0.044) with no difference in adverse outcomes. CONCLUSIONS Provision of > 20 mL/kg/day of enteral feeds during APAP treatment of PDA decreased time to full feeds and PN days compared to trophic feedings (≤ 20 mL/kg/day) with no difference in adverse GI outcomes. Continuing enteral feeding during APAP PDA treatment appears safe while improving achievement of nutritional milestones. [ABSTRACT FROM AUTHOR]

Background: To determine risk factors for surgical site infection (SSI) in infants after stoma closure, to identify at-risk patients, plan timing of surgery, and implement SSI-reduction strategies. Patients and Methods: A single center retrospective comparison study of all children less than one year of age who underwent enterostomy closure (2018–2020) with SSI diagnosed through a prospective surveillance program, using criteria from Public Health England (PHE). Demographics and risk factors, types of SSI, systemic sepsis, mortality and length of stay were compared between SSI and non-SSI. Significant factors associated with SSI were analyzed in a multivariate binomial logistic regression model. Results: Eighty-nine stoma closures were performed, most commonly for necrotizing enterocolitis (NEC) and anorectal malformation. Fourteen had SSI (16%): 12 superficial and two deep; three developed systemic sepsis, but no 30-day mortality. Surgical site infection was associated with NEC (12/14 vs. 32/75; p = 0.003), younger age (median 76 vs. 89 days; p = 0.014), lower corrected gestation (cutoff: 39 weeks gestation; 11/14 vs. 27/75; p = 0.004) and lower weight (cutoff: 2.2 kg; 7/14 vs. 16/75; p = 0.032), compared with non-SSI. After correcting for age, gestation, and weight, logistic regression showed NEC was an independent predictor for SSI (odds ratio [OR], 12; 95% confidence interval [CI],1.2–125). The at-risk cohort (n = 56; 63%) had seven-fold increased risk of SSI and four-fold longer hospital stay, which may be the target for SSI-reduction strategies. Conclusions: Necrotizing enterocolitis-related stoma closure is at increased risk for SSI. Considerations for delaying stoma closure until achieving 39 weeks gestation or 2.2 kg in weight may further reduce SSI. Targeting SSI-reduction strategies using these criteria may improve resource-rationalization. [ABSTRACT FROM AUTHOR]

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health. [ABSTRACT FROM AUTHOR]

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development. [ABSTRACT FROM AUTHOR]

Purpose: To assess the predictive value of radiomics for surgical decision-making in neonatal necrotizing enterocolitis (NEC) when abdominal radiographs (ARs) do not suggest an absolute surgical indication for free pneumoperitoneum. Methods: In this retrospective study, we finally included 171 newborns with NEC and obtained their ARs and clinical data. The dataset was randomly divided into a training set (70%) and a test set (30%). We developed machine learning models for predicting surgical treatment using clinical features and radiomic features, respectively, and combined these features to build joint models. We assessed predictive performance of the different models by receiver operating characteristic curve (ROC) analysis and compared area under curve (AUC) using the Delong test. Decision curve analysis (DCA) was used to assess the potential clinical benefit of the models to patients. Results: There was no significant difference in AUC between the clinical model and the four radiomic models (P > 0.05). The XGBoost joint model had better predictive efficacy and stability (AUC, training set: 0.988, test set: 0.959). Its AUC in the test set was significantly higher than that of the clinical model (P < 0.05). DCA showed that the XGBoost joint model achieved higher net clinical benefit compared to the clinical model in the threshold probability range (0.2–0.6). Conclusion: Radiomic features based on AR are objective and reproducible. The joint model combining radiomic features and clinical signs has good surgical predictive efficacy and may be an important method to help primary neonatal surgeons assess the surgical risk of NEC neonates. [ABSTRACT FROM AUTHOR]

Human milk contains extracellular vesicles (HMEVs). Pre‐clinical models suggest that HMEVs may enhance intestinal function and limit inflammation; however, it is unknown if HMEVs or their cargo survive neonatal human digestion. This limits the ability to leverage HMEV cargo as additives to infant nutrition or as therapeutics. This study aimed to develop an EV isolation pipeline from small volumes of human milk and neonatal intestinal contents after milk feeding (digesta) to address the hypothesis that HMEVs survive in vivo neonatal digestion to be taken up intestinal epithelial cells (IECs). Digesta was collected from nasoduodenal sampling tubes or ostomies. EVs were isolated from raw and pasteurized human milk and digesta by density‐gradient ultracentrifugation following two‐step skimming, acid precipitation of caseins, and multi‐step filtration. EVs were validated by electron microscopy, western blotting, nanoparticle tracking analysis, resistive pulse sensing, and super‐resolution microscopy. EV uptake was tested in human neonatal enteroids. HMEVs and digesta EVs (dEVs) show typical EV morphology and are enriched in CD81 and CD9, but depleted of β‐casein and lactalbumin. HMEV and some dEV fractions contain mammary gland‐derived protein BTN1A1. Neonatal human enteroids rapidly take up dEVs in part via clathrin‐mediated endocytosis. Our data suggest that EVs can be isolated from digestive fluid and that these dEVs can be absorbed by IECs. [ABSTRACT FROM AUTHOR]

Objective: To know the association of abdominal ultrasound findings in preterm newborns with necrotizing enterocolitis. Method: Transverse, analytical study, patients with necrotizing enterocolitis abdominal ultrasound was performed: free fluid, large wall more than 2.5 mm, small bowel wall less than 1.1 mm, gas in portal vein, intestinal pneumatosis, decreased and/or absence of peristalsis, increase and/or absence of intestinal blood infusion. Chi square and Mann-Whitney U tests were used to establish association ultrasound findings and necrotizing enterocolitis, alpha level < 0.05, SPSS v.23.0 program. Results: 37 patients. IA stage: small intestine wall less than 1.1 mm with a total of 15 (40%), 13 (35%) decreased peristalsis 11 (29%), absence of peristalsis 8 (21.62%). IB stage: free liquid, increased blood infusion 2 (5%). IIA stage: peristalsis decreased 7 (18%), small intestine wall less than 1.1 mm 4 (10%), free liquid 3 (8%), pneumatosis 2 (5%), absent blood infusion 1 (2%). IIIA stage: 1 (2%) free liquid, thinning of small intestine wall less than 1.1 mm, absence of peristalsis and blood infusion. Conclusion: There is an association of ultrasonographic findings in patients with necrotizing enterocolitis. Most frequent finding: small bowel wall less than 1.1 mm, free fluid, decreased peristalsis. It would be important to implement it as a diagnostic method in all cases for medical and surgical decision-making. [ABSTRACT FROM AUTHOR]

This study evaluated the quality of life (QoL) in patients who have recovered from surgical necrotizing enterocolitis (NEC). This is a cross-sectional study conducted in a tertiary centre and patients who have received surgery for NEC between 2000 and 2014 were invited to participate. The Pediatric Quality of Life Inventory Generic (PedsQL™) Core Scale Version 4.0 was used as the assessment tool. Values were reported as median (interquartile rage) and compared with age-matched controls. During the study period, 90 patients were eligible for the study and 29 patients have completed the survey. There was no gender difference and the median age was 10 years (9–13 years). Nine patients have suffered from short bowel syndrome (SBS) as a result of the surgery. For the QoL assessment, 17 participants have completed both parent proxy and child-rated survey; 11 completed the parent-rated survey and 1 completed child-rated survey only. The scores for parent-rated survey were - overall: 86.4 (70.7–92.7); physical: 95.3 (83.6–100) and psychosocial: 82.5 (66.3–90.4). The scores for child-rated survey were – overall: 82.1 (73.4–96.2); physical: 96.9 (90.6–99.2) and psychosocial: 81.7 (64.2–95.8). Regarding the impact of previous SBS on the QoL, there were no significant difference in the overall score for both parent proxy and child-rated survey (SBS-ve vs + ve) (parent-rated: 87.5 vs 85.3, p = 0.849; child-rated: 81.0 vs 88.0, p = 0.503). There were also no differences in physical and psychosocial assessments (parent-rated: [physical] 95.3 vs 95.3, p = 0.267; [psychosocial] 84.2 vs 80.0, p = 0.274; child-rated: [physical] 95.3 vs 96.9, p = 0.395; [psychosocial] 79.2 vs 87.5, p = 0.611). The QoL in long-term survivors of surgical NEC without major medical illnesses is comparable to normal population. However, they may have a lower psychosocial well-being that should be addressed. Previous history of SBS does not have a significant impact on the future QoL. III. [ABSTRACT FROM AUTHOR]

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Introduction: Necrotizing enterocolitis (NEC) is a fatal disease with up to 20% mortality rates. Identifying risk factors for NEC may reduce NEC incidences. This study aims to investigate NEC-related risk factors in preterm infants. Methods: We included 27 preterm infants with NEC and 35 infants without NEC among the preterm newborns (n=1669) hospitalized in the Duzce University School of Medicine neonatal intensive care unit between 2009 and 2021. Parametric numeric data were calculated using the independent sample's t-test. Two-sample comparisons of nonparametric data were performed using the Mann-Whitney test. Pearson chi-square, Yates correction, and Fisher's exact test were also used to evaluate the categorical data. Results: Our results agree with previous studies regarding some of these findings: birth weight is lower in the NEC group (1.37±0.49 kg) than in the non-NEC group (18.3±6.5 kg) (p=0.009), with statistically similar gestational age. We couldn't show the association between NEC and multiple gestations, chorioamnionitis, preeclampsia, Apgar scores, patent ductus arteriosus, mechanical ventilation, pre-NEC red blood cell, or fresh frozen plasma transfusions. In the NEC group, thrombocyte levels before NEC were significantly lower (98 [9-2253]) (/x10³ mm³) than in the control group (222 [17-345]) (/x10³ mm³) (p=0.012). In addition, mortality rates (22.2% vs. 2.9%, respectively) (p=0.037), use of vasopressors (29.6% vs. 2.9%, respectively) (p=0.008) were markedly higher in the NEC group than in the non-NEC group. Additionally, lower birth weight (NEC group: 1367.25±493.62 vs. non-NEC group: 1831.71±651.62) (p=0.009), prolonged use of antibiotics (NEC group: 24% vs. non-NEC group: 0%) (p=0.004), and poor circulation (NEC group: 84% vs. non-NEC group: 3%) (p<0.001) were statistically significant variables. Discussion and Conclusion: NEC increases the mortality rates in preterm infants. The use of vasopressors, low birth weight, poor circulation, and antibiotics are significant risk factors for NEC, and low thrombocyte levels can lead to the prediction of NEC. [ABSTRACT FROM AUTHOR]

Summary: Necrotizing enterocolitis (NEC) is a severe intestinal disease of very preterm infants with mother’s own milk (MOM) providing protection, but the contribution of the MOM microbiota to NEC risk has not been explored. Here, we analyze MOM of 110 preterm infants (48 NEC, 62 control) in a cross-sectional study. Breast milk contains viable bacteria, but there is no significant difference in MOM microbiota between NEC and controls. Integrative analysis between MOM microbiota, human milk oligosaccharides (HMOs), and the infant gut microbiota shows positive correlations only between Acinetobacter in the infant gut and Acinetobacter and Staphylococcus in MOM. This study suggests that NEC protection from MOM is not modulated through the MOM microbiota. Thus, “‘restoring” the MOM microbiota in donor human milk is unlikely to reduce NEC, and emphasis should instead focus on increasing fresh maternal human milk intake and researching different therapies for NEC prevention.

ObjectiveTo investigate an optimal regimen of six drugs, including lactoferrin, probiotics, prebiotics, glutamine, arginine and erythropoietin (EPO), for the prevention of necrotizing enterocolitis (NEC) in preterm infants.MethodsPubMed, Embase, Ovid, The Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) investigating the efficacy of lactoferrin, probiotics, prebiotics, glutamine, arginine, and EPO in preventing NEC in preterm infants, with a cutoff date of June 20, 2024. Two authors independently screened studies and extracted all the data. Network meta-analysis (NMA) was conducted to compare the outcomes of different interventions, and group rankings were determined using the surface under the cumulative ranking curve (SUCRA).ResultsA total of 89 RCTs with 26,861 preterm infants were included. Arginine demonstrated the highest clinical efficacy in reducing the incidence of NEC, with probiotics being the next most effective and the placebo being the least effective. Lactoferrin was identified as the most effective intervention for reducing the incidence of NEC-associated sepsis. Prebiotics showed the highest effect on overall mortality, reducing the beginning of enteral feeding, and were associated with the shortest hospital stay. Glutamine significantly decreased the time to full enteral feeding.ConclusionExisting literature highlights arginine as the most efficacious pharmacological agent in preventing NEC in preterm infants. It has been shown to effectively lower the rates of NEC, septicemia, and mortality, warranting its recommendation as the first-line clinical intervention. Following this, probiotics are recommended as a second option.

Background: Necrotizing enterocolitis (NEC) is a condition characterized by acquired damage to the mucosal lining, predominantly affecting premature infants. Bioinformatics assessments uncovered a notable rise in miR-155–5p expression in the intestinal tissues of infants suffering from NEC. Nevertheless, the development of NEC's underlying mechanisms and the role of miR-155–5p are still not well understood. This research aimed to explore the role of miR-155–5p in NEC and to elucidate its underlying mechanisms. Methods: To replicate NEC in vitro, lipopolysaccharide (LPS) was employed, whereas an in vivo rat model of NEC was established using formula feeding and exposure to hypoxia. Subsequently, levels of inflammatory cytokines, cell survival, and apoptosis rates were assessed. Various biochemical indicators such as glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured utilizing a purchased diagnostic kit. For the assessment of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) within FHC cells, analysis by flow cytometry was conducted. Additionally, the technique of Western blotting was utilized to analyze the levels of ferroptosis-associated proteins. Moreover, hematoxylin and eosin (H&E) staining was carried out to observe the histopathological alterations in the intestinal tissue samples from rats with necrotizing enterocolitis (NEC). Results: Reducing miR-155–5p improved the survival of FHC cells exposed to LPS, decreased cell apoptosis, inflammation, and ferroptosis, and mitigated intestinal damage in NEC rats. Furthermore, SLC7A11 was found to be a direct target of miR-155–5p. The inhibition of miR-155–5p decreased LPS-induced inflammation and ferroptosis in both FHC cells and NEC rats by promoting SLC7A11 expression. This effect was evidenced by increased levels of ferroptosis-related proteins FTH1 and GPX4, decreased COX-2 and ACSL4 levels, lower lipid peroxidation marker MDA, reduced antioxidant markers GSH, SOD, and CAT, fewer IL-6 and TNF-α, and suppression of the IκBα/NF-κB p65 signaling pathway. Conclusions: In conclusion, reducing miR-155–5p could improve intestinal damage in NEC by inhibiting inflammation and ferroptosis. These findings may provide theoretical insights for the development of new therapies for NEC.

Background: The notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissues，contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells. Methods: To investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine's Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage. Results: The diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4. Conclusion: In the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.

Introduction: We report a rare occurrence in which a term infant with intestinal anomalous congenital bands (ACB), presented with bloody stools and necrotizing enterocolitis (NEC), instead of the typical intestinal obstruction picture. Our case differs from the reported cases of ACB in its presentation as bloody stools and necrotizing enterocolitis, rather than the classic symptoms of intestinal obstruction (IO). Case presentation: A term neonate who was admitted to the Neonatal Intensive Care Unit (NICU) because of hypoglycemia, developed bloody stools and a clinical picture of NEC. She was treated by antibiotics and kept NPO for 7 days during which her symptoms resolved. Upon refeeding and after reaching full feeding volumes, her bloody stools recurred which warranted expanding the differential diagnosis and further investigations including lower gastrointestinal (GI) contrast study. The lower GI contrast study showed multiple filling defects indicating GI obstruction. Laparotomy was performed to explore and release the cause of obstruction. Laparotomy revealed Anomalous Congenital Bands (ACB) in the colon and cecum causing almost complete obstruction of the intestinal lumen. The ACB were excised, and the stricture segments of bowel were resected, and primary anastomosis was completed. Feeding was resumed with no recurrence of symptoms. Conclusion: Anomalous congenital bands may present with bloody stools and clinical picture of NEC rather that the classic presentation of intestinal obstruction.

Aim: To examine the incidence and etiology of neurodevelopmental outcomes in very low birth weight preterm infants, maternal and perinatal risk factors, comorbidities, and clinical presentation and compare with newborns of the same gestational age who did not develop a neurodevelopmental disorder. Methods: The research was conducted at the Pediatric Clinic in KBC (Clinical Hospital Center) Osijek. All newborns born from 1 January 2018 to 31 December 2019 with birth weight < 1,500 g and gestational age < 37 weeks are included in the research. The data were collected by reviewing medical records and the hospital’s IT system. Results: In the observed period, 120 children with birth weight < 1,500 g and gestational age < 37 weeks were born. Maternal and perinatal risk factors for premature birth include autoimmune diseases of the mother, infections during pregnancy and birth complications. Early complications that accompany the selected group are RDS, ROP, NEC, IVH, sepsis, congenital heart defects and glucose metabolism disorder. Slowed motor, cognitive and speech development are mostly influenced by low body weight, higher degree of IVH, lower AS in the first minute and the presence of NEC. Significant risk factors for death are gestational age < 25 weeks, body weight < 800 g, infections in pregnancy and autoimmune diseases of the mother. Conclusion: The neurodevelopmental outcome of very low birth weight preterm infants depends on a combination of comorbidities, as well as maternal, perinatal and neonatal risk factors.

Necrotizing enterocolitis (NEC) is one of the most devasting diseases affecting preterm neonates. However, despite a lot of research, NEC’s pathogenesis remains unclear. It is known that the pathogenesis is a multifactorial process, including (1) a pathological microbiome with abnormal bacterial colonization, (2) an immature immune system, (3) enteral feeding, (3) an impairment of microcirculation, and (4) possibly ischemia-reperfusion damage to the intestine. Overall, the immaturity of the mucosal barrier and the increased expression of Toll-like receptor 4 (TLR4) within the intestinal epithelium result in an intestinal hyperinflammation reaction. Concurrently, a deficiency in counter-regulatory mediators can be seen. The sum of these processes can ultimately result in intestinal necrosis leading to very high mortality rates of the affected neonates. In the last decade no substantial advances in the treatment of NEC have been made. Thus, NEC animal models as well as in vitro models have been employed to better understand NEC’s pathogenesis on a cellular and molecular level. This review will highlight the different models currently in use to study immunological aspects of NEC.

In recent years, interest in probiotics in publications has been steadily increasing. This is associated with the discovery of the relationship between disruptions in the gut microbiome and dysfunction of the immune system, and consequently, the development of various diseases and allergies. The composition of the natural gut microbiota in newborns can undergo changes, and as a result, we can influence it both prenatally and postnatally. According to available research, factors influencing it include the timing and method of delivery, maternal antibiotic use during pregnancy and breastfeeding, as well as antibiotic use in newborns after birth, and the method of feeding the child. It is suspected that disturbances in the composition of gut microbiota from the earliest stages of life contribute to the development of disorders such as functional gastrointestinal disorders (diarrhea, constipation, irritable bowel syndrome), inflammatory bowel diseases, allergies, atopic dermatitis, neurodevelopmental disorders (autism spectrum disorders), and increased risk of obesity in later years of the child's life. When significant dysbiosis occurs, stimulating the growth of protective and nutritive autochthonous bacteria on the intestinal epithelium is difficult to achieve in any other way than using appropriately selected probiotic strains. However, it is important to remember to choose probiotics with a well-researched quantitative and qualitative composition, and to select them depending on the underlying disease, as well as the age and other conditions of the patient.

Necrotizing enterocolitis (NEC) is one of the most common and serious intestinal illnesses in newborns and seriously affects their long-term prognosis and survival. Butyrate is a short-chain fatty acid that can relieve intestinal inflammation, but its mechanism of action is unclear. Results from an in vivo neonatal rat model has shown that butyrate caused an improved recovery from NEC. These protective effects were associated with the metabolite of hesperetin, as determined by metabolomics and molecular biological analysis. Furthermore, transcriptomics combined with inhibitor assays were used to investigate the mechanism of action of hesperetin in an in vitro NEC model (IEC-6 cells exposed to LPS) to further investigate the mechanism by which butyrate attenuates NEC. The transcriptomics analysis showed that the PI3K-Akt signaling pathway was involved in the anti-NEC effect of hesperitin. Subsequently, the results using an inhibitor of PI3K (LY294002) indicated that the suppression could be explained by the hesperetin-induced expression of tight junction (TJ) proteins by potentially blocking the PI3K-Akt signaling pathway. In summary, the present study demonstrated that butyrate could improve recovery from NEC with a hesperetin metabolite, causing potential inhibition of the phosphorylation of the PI3K-Akt signaling pathway, resulting in the increased expression of TJ proteins. These findings reveal a potential new therapeutic pathway for the treatment of NEC.

IntroductionChorioamnionitis is common in preterm birth and associated with a higher risk of intestinal inflammation and necrotizing enterocolitis. The intestinal inflammation influences the enteric nervous system development. We hypothesized that inflammation and innervation in the fetal ileum may be modified by chorioamnionitis induced by repeated challenge with lipopolysaccharide and/or preexisting Ureaplasma parvum infection at very low gestational age equivalent to 60% of term.Materials and methodsTime mated ovine fetuses were exposed by intraamniotic injections to chronic Ureaplasma parvum for 24 days and/or lipopolysaccharide for 7 days, 2 days, or 7 & 2 days before delivery at 94 +/-2 days of gestational age (term at approximately 150 days). Intestinal inflammation as well as structural changes of the enteric nervous system were assessed.ResultsLipopolysaccharide exposure increased CD3 and myeloperoxidase-positive cells (p < 0.05). Repetitive exposure to lipopolysaccharide or combined Ureaplasma parvum & lipopolysaccharide exposure increased intestinal inflammation (p < 0.05). The reduction of nuclei of neurons was most significant with repetitive lipopolysaccharide exposures but could be detected in all other intervention groups compared to the control group. Astrocyte-like glial cells increased if exposure to lipopolysaccharide was only 2 days before delivery or chronic exposure to Ureaplasma parvum existed beforehand (p < 0.05).DiscussionAfter exposure to chorioamnionitis induced by Ureaplasma parvum and/or lipopolysaccharide, inflammatory responses as well as structural changes of the enteric nervous system were more pronounced the longer and the more frequent the exposure to pro-inflammatory stimuli before birth. These changes may cause functional effects of clinical importance.