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Objectives: To demonstrate the association between the dynamic movements of hyperechoic foci in portal venous gas (PVG) and patients'/sonographic outcomes after congenital heart disease or cardiac events. Methods: Thirty‐one pediatric patients requiring management of congenital heart diseases or cardiac events who had PVG on ultrasound were included in this retrospective study. The patient outcome was prognosis: dead or alive. The sonographic outcome was recovery from PVG, measured as days from PVG detection to when it diminished on ultrasound. The following sonographic findings of hyperechoic foci in PVG were compared between patients: detection within the mesenteric vein, having to‐and‐fro movements within the intrahepatic portal vein, distribution (left segment or both left and right segments) and shape (line or punctate) in the liver, and detection within the portal and hepatic veins. Comparisons were made using Fisher's exact/Mann–Whitney U test. Results: Four patients died without having recovered from PVG. A significant difference was observed in terms of the to‐and‐fro movement (with/without to‐and‐fro movement in dead vs. alive patients: 3/1 vs. 1/26, respectively; P = 0.003). Furthermore, a significant difference in sonographic outcomes was observed regarding patients with/without hyperechoic foci within the mesenteric vein (days with vs. without this finding: 2.0 ± 1.24(1–5) vs.1 ± 0(1), respectively; P = 0.011). Conclusions: In our small limited cohort, when PVG was visualized on ultrasound, close evaluation of the dynamic movement of hyperechoic foci, especially their to‐and‐fro movement within the intrahepatic portal vein and detection of hyperechoic foci within the mesenteric vein, were useful in predicting patients' outcomes and the time to PVG diminishment. [ABSTRACT FROM AUTHOR]

Background: Impaired intestinal microcirculation seems to play an important role in the pathogenesis of necrotizing enterocolitis (NEC). A previous study showed that a SrSO2 < 30% is associated with an increased risk of developing of NEC. We aimed to determine the clinical usefulness of the cut off < 30% for SrSO2 in predicting NEC in extremely preterm neonates. Methods: This is a combined cohort observational study. We added a second cohort from another university hospital to the previous cohort of extremely preterm infants. SrSO2 was measured for 1–2 h at days 2–6 after birth. To determine clinical usefulness we assessed sensitivity, specificity, positive and negative predictive values for mean SrSO2 < 30. Odds ratio to develop NEC was assessed with generalized linear model analysis, adjusting for center. Results: We included 86 extremely preterm infants, median gestational age 26.3 weeks (range 23.0-27.9). Seventeen infants developed NEC. A mean SrSO2 < 30% was found in 70.5% of infants who developed NEC compared to 33.3% of those who did not (p = 0.01). Positive and negative predictive values were 0.33 CI (0.24–0.44) and 0.90 CI (0.83–0.96), respectively. The odds of developing NEC were 4.5 (95% CI 1.4–14.3) times higher in infants with SrSO2 < 30% compared to those with SrSO2 ≥ 30%. Conclusions: A mean SrSO2 cut off ≥ 30% in extremely preterm infants between days 2–6 after birth may be useful in identifying infants who will not develop NEC. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a neonatal intestinal disease associated with oxidative stress. The targets of peroxidation and the role of the innate intestinal epithelial antioxidant defense system are ill-defined. We hypothesized that oxidative stress in NEC correlates with oxidized GSH redox potentials, lipid peroxidation, and a dysfunctional antioxidant system. Methods: Intestinal samples from infants +/− NEC were generated into enteroids and incubated with lipopolysaccharide (LPS) and hypoxia to induce experimental NEC. HPLC assayed GSH redox potentials. Lipid peroxidation was measured by flow cytometry. Immunoblotting measured glutathione peroxidase 4 (Gpx4) expression. Results: GSH redox potentials were more oxidized in NEC intestinal tissue and enteroids as compared to controls. Lipid radicals in NEC-induced enteroids were significantly increased. Human intestinal tissue with active NEC and treated enteroid cultures revealed decreased levels of Gpx4. Conclusions: The ability of neonatal intestine to mitigate radical accumulation plays a role in its capacity to overcome oxidative stress. Accumulation of lipid radicals is confirmed after treatment of enteroids with NEC-triggering stimuli. Decreased Gpx4 diminishes a cell's ability to effectively neutralize lipid radicals. When lipid peroxidation overwhelms antioxidant machinery, cellular death ensues. Identification of the mechanisms behind GSH-dependent enzyme dysfunction in NEC may provide insights into strategies for reversing radical damage. [ABSTRACT FROM AUTHOR]

The patent ductus arteriosus (PDA) treatment in very preterm infants is controversial. This study focused on preterm infants born at 28–32 weeks of gestation and analyzed the association between various PDA treatments and clinical outcomes. We conducted a retrospective cohort study of infants born at 28–32 weeks of gestation between 2016 and 2019 at 22 hospitals in the Taiwan Premature Infant Follow-up Network. We categorized the infants into four groups according to treatment strategies: medication, primary surgery, medication plus surgery, or conservative treatment. A total of 1244 infants presented with PDA, and 761 (61.1%) were treated. Medication was the predominant treatment (50.0%), followed by conservative treatment (38.9%), medication plus surgery (7.6%), and primary surgery (3.5%). The risk of mortality was not reduced in the active treatment group compared to the conservative treatment group. There was a higher prevalence of severe intraventricular hemorrhage, necrotizing enterocolitis (NEC), and any degree of bronchopulmonary dysplasia (BPD) in both the primary surgery and medication plus surgery groups than in the conservative treatment group. After adjustment, both the primary surgery and medication plus surgery groups still had higher odds ratios for the occurrence of NEC and any degree of BPD. Compared with active PDA treatment, conservative treatment for PDA did not increase the risk of mortality and morbidity in very preterm infants born at 28–32 weeks of gestation. The risks and benefits of surgery (PDA ligation) in these infants must be considered cautiously. [ABSTRACT FROM AUTHOR]

Despite advances in the management of short bowel syndrome related intestinal failure (SBS-IF), large-scale contemporary pediatric studies are scarce. The aim of this multicenter study was to assess key outcomes and clinical prognostic factors in a recent Nordic pediatric SBS-IF population. Patients with SBS-IF treated during 2010–2019, whose parenteral support (PS) started at age <1 year and continued >60 consecutive days were included and retrospectively reviewed. All six participating centers followed multidisciplinary SBS-IF management. Risk factors for PS dependency, intestinal failure associated liver disease (IFALD) and mortality were assessed with Cox regression and Kaplan Meier analyses. IFALD was defined with serum liver biochemistry levels. Among 208 patients, SBS-IF resulted from NEC in 49%, gastroschisis w/wo atresia in 14%, small bowel atresia in 12%, volvulus in 11%, and other diagnoses in 14%. Median age-adjusted small bowel length was 43% (IQR 21–80%). After median follow up of 4.4 years (IQR 2.5–6.9), enteral autonomy was reached by 76%, none had undergone intestinal transplantation, and overall survival was 96%. Half of deaths (4/8) were caused by septic complications. Although biochemical cholestasis occurred only in 3% at latest follow-up and none of deaths were directly caused by IFALD, elevated liver biochemistry (HR 0.136; P = 0.017) and shorter remaining small bowel (HR 0.941; P = 0.040) predicted mortality. Shorter remaining small bowel and colon, and presence of end-ostomy were the main predictors of PS dependency, but not IFALD. Patients with NEC reached enteral autonomy more efficiently and had decreased incidence of IFALD compared to other etiologies. Although with current multidisciplinary management, prognosis of pediatric SBS is encouraging, septic complications and IFALD still associated with the remaining low mortality rate. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is a severe inflammatory bowel disease that may lead to perforation, causing high morbidity and mortality in preterm infants. Abdominal ultrasound (AUS) has been shown to provide benefits in diagnosing and managing NEC in recent years. Objective: This study focused on the utility of AUS in the diagnosis and evaluation of surgical NEC. Patients and methods: In this retrospective study, available data of the patients diagnosed from January 2019 to June 2022 were reviewed. The sensitivity and specificity of AUS in diagnosing a perforation were analyzed. Typical cases for the application of AUS in monitoring and evaluating the progression, complications, and sequela of NEC were described. Results: There were 69 neonates diagnosed with NEC and examined by AUS, of whom eight patients developed a perforation. AUS was used for diagnosing a perforation in eight patients with key features of pneumoperitoneum and/or complex ascites, allowing us to find four locations of perforation, with a sensitivity and specificity of 100%. Conclusion: AUS plays an important role in diagnosing and evaluating surgical NEC in newborn infants, with good sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Objective Compare delivery room practices and outcomes of infants born at less than 32 weeks' gestation or less than 1,500 g who have plastic wrap/bag placement simultaneously during placental transfusion to those receiving plastic wrap/bag placement sequentially following placental transfusion. Study Design Retrospective analysis of data from a multisite quality improvement initiative to refine stabilization procedures pertaining to placental transfusion and thermoregulation using a plastic wrap/bag. Delivery room practices and outcome data in 590 total cases receiving placental transfusion were controlled for propensity score matching and hospital of birth. Results The simultaneous and sequential groups were similar in demographic and most outcome metrics. The simultaneous group had longer duration of delayed cord clamping compared with the sequential group (42.3 ± 14.8 vs. 34.1 ± 10.3 seconds, p < 0.001), and fewer number of times cord milking was performed (0.41 ± 1.26 vs. 0.86 ± 1.92 seconds, p < 0.001). The time to initiate respiratory support was also significantly shorter in the simultaneous group (97.2 ± 100.6 vs. 125.2 ± 177.6 seconds, p = 0.02). The combined outcome of death or necrotizing enterocolitis in the simultaneous group was more frequent than in the sequential group (15.3 vs. 9.3%, p = 0.038); all other outcomes measured were similar. Conclusion Timing of plastic wrap/bag placement during placental transfusion did affect duration of delayed cord clamping, number of times cord milking was performed, and time to initiate respiratory support in the delivery room but did not alter birth hospital outcomes or respiratory care practices other than the combined outcome of death or necrotizing enterocolitis. Key Points Plastic bag placement during placental transfusion is effective in stabilization of preterms. Plastic bag placement after placental transfusion is effective in stabilization of preterms. Plastic bag placement during placental transfusion and risk of death or necrotizing enterocolitis needs additional study. [ABSTRACT FROM AUTHOR]

Purpose: Necrotizing enterocolitis (NEC), an inflammatory intestinal disease common in premature infants, has been associated with the development of lung damage. Toll-like receptor 4 has been shown to regulate inflammation in the NEC lungs, however, other important inflammatory mechanisms have not been thoroughly investigated. In addition, we reported that milk-derived exosomes were able to attenuate intestinal injury and inflammation in experimental NEC. This study aims to (i) investigate the role of the NLRP3 inflammasome and NF-κB pathway in regulating lung damage during experimental NEC; and (ii) evaluate the therapeutic potential of bovine milk exosomes in reducing lung inflammation and injury during NEC. Methods: NEC was induced by gavage feeding of hyperosmolar formula, hypoxia, and lipopolysaccharide administration in neonatal mice from postnatal days 5–9. Exosomes were obtained by ultracentrifugation of bovine milk and administered during each formula feed. Results: The lung of NEC pups showed increased inflammation, tissue damage, NLRP3 inflammasome expression, and NF-κB pathway activation, which were attenuated upon exosome administration. Conclusion: Our findings suggest that the lung undergoes significant inflammation and injury following experimental NEC which are attenuated by bovine milk-derived exosomes. This emphasizes the therapeutic potential of exosomes not just on the intestine but also on the lung. [ABSTRACT FROM AUTHOR]

Background: Procalcitonin (PCT) is a biomarker for sepsis, but its utility has not been investigated in necrotizing enterocolitis (NEC). Necrotizing enterocolitis is a devastating multisystem disease of infants that in severe cases requires surgical intervention. We hypothesize that an elevated PCT will be associated with surgical NEC. Patients and Methods: After obtaining Institutional Review Board (IRB) approval (#12655), we performed a single institution retrospective case control study between 2010 and 2021 of infants up to three months of age. Inclusion criteria was PCT drawn within 72 hours of NEC or sepsis diagnosis. Control infants had a PCT drawn in the absence of infectious symptoms. Recursive partitioning (RP) identified PCT cutoffs. Categorical variable associations were tested using Fisher exact or χ2 tests. Continuous variables were tested using Wilcoxon rank sum test, Student t-test, and Kruskal-Wallis test. Adjusted associations of PCT and other covariables with NEC or sepsis versus controls were obtained via multinomial logistic regression analysis. Results: We identified 49 patients with NEC, 71 with sepsis, and 523 control patients. Based on RP, we selected two PCT cutoffs: 1.4 ng/mL and 3.19 ng/ml. A PCT of ≥1.4 ng/mL was associated with surgical (n = 16) compared with medical (n = 33) NEC (87.5% vs. 39.4%; p = 0.0015). A PCT of ≥1.4 ng/mL was associated with NEC versus control (p < 0.0001) even when adjusting for prematurity and excluding stage IA/IB NEC (odds ratio [OR], 28.46; 95% confidence interval [CI], 11.27–71.88). A PCT of 1.4–3.19 ng/mL was associated with both NEC (adjusted odds ratio [aOR], 11.43; 95% CI, 2.57–50.78) and sepsis (aOR, 6.63; 95% CI, 2.66–16.55) compared with controls. Conclusions: A PCT of ≥1.4 ng/mL is associated with surgical NEC and may be a potential indicator for risk of disease progression. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a common condition in the neonatal intensive care unit that continues to present challenges in terms of diagnosis and management. Traditionally NEC has been diagnosed and managed by clinical and radiographic findings, but US has shown promise in characterizing and prognosticating NEC. In this manuscript we review the abdominal US technique for NEC, the clinical significance of individual sonographic findings of NEC, and how US can be integrated in the clinical decision process for diagnosing and managing NEC. We also discuss the potential value-added role of a limited abdominal US protocol that focuses on the sonographic findings most indicative of a poor prognosis to include pneumoperitoneum, complex free fluid and focal fluid collections. [ABSTRACT FROM AUTHOR]

The practice of withholding feed during therapeutic hypothermia (TH) in neonates with hypoxemic ischemic encephalopathy (HIE) is based on conventions rather than evidence. Recent studies suggest that enteral feeding might be safe during TH. We systematically compared the benefits and harms of enteral feeding in infants undergoing TH for HIE. We searched electronic databases and trial registries (MEDLINE, CINAHL, Embase, Web of Science, and CENTRAL) until December 15, 2022, for studies comparing enteral feeding and non-feeding strategies. We performed a random-effects meta-analysis using RevMan 5.4 software. The primary outcome was the incidence of stage II/III necrotizing enterocolitis (NEC). Other outcomes included the incidence of any stage NEC, mortality, sepsis, feed intolerance, time to full enteral feeds, and hospital stay. Six studies ((two randomized controlled trials (RCTs) and four nonrandomized studies of intervention (NRSIs)) enrolling 3693 participants were included. The overall incidence of stage II/III NEC was very low (0.6%). There was no significant difference in the incidence of stage II/III NEC in RCTs (2 trials, 192 participants; RR, 1.20; 95% CI: 0.53 to 2.71, I2, 0%) and NRSIs (3 studies, no events in either group). In the NRSIs, infants in the enteral feeding group had significantly lower sepsis rates (four studies, 3500 participants, RR, 0.59; 95% CI: 0.51 to 0.67, I2—0%) and lower all-cause mortality (three studies, 3465 participants, RR: 0.43; 95% CI: 0.33 to 0.57, I2—0%) than the infants in the "no feeding" group. However, no significant difference in mortality was observed in RCTs (RR: 0.70; 95% CI: 0.28 to 1.74, I2—0%). Infants in the enteral feeding group achieved full enteral feeding earlier, had higher breastfeeding rates at discharge, received parenteral nutrition for a shorter duration, and had shorter hospital stays than the control group. Conclusion: In late preterm and term infants with HIE, enteral feeding appears safe and feasible during the cooling phase of TH. However, there is insufficient evidence to guide the timing of initiation, volume, and feed advancement. What is Known: • Many neonatal units withhold enteral feeding during therapeutic hypothermia, fearing an increased risk of complications (feed intolerance and necrotizing enterocolitis). • The overall risk of necrotizing enterocolitis in late-preterm and term infants is extremely low (< 1%). What is New: • Enteral feeding during therapeutic hypothermia is safe and does not increase the risk of necrotizing enterocolitis, hypoglycemia, or feed intolerance. It may reduce the incidence of sepsis and all-cause mortality until discharge. [ABSTRACT FROM AUTHOR]

Previous studies suggest that Paneth cells are involved in NEC development. Defensin alpha 6 (DEFA6) and guanylate cyclase activator 2A (GUCA2A) are selective protein markers of Paneth cells. The objective was to explore DEFA6 and GUCA2A expression in intestinal tissue samples from newborn infants with and without NEC. Tissue samples from histologically intact intestine were analyzed from 70 infants: 43 underwent bowel resection due to NEC and 27 controls were operated due to conditions such as intestinal atresia, dysmotility, aganglionosis, pseudo-obstruction or volvulus. Each tissue sample was immunohistochemically stained for DEFA6 and GUCA2A. Semi-automated digital image analysis was performed to determine protein expression. Clinical data and protein expressions were compared between the groups. DEFA6 expression was lower in the NEC group (p = 0.006). Low DEFA6 correlated with risk of developing NEC in a logistic regression analysis, independently of gestational age and birth weight (OR 0.843 [CI 0.732–0.971]; p = 0.018). GUCA2A expression did not differ between the two groups. Conclusion: Lower expression of DEFA6 together with intact GUCA2A expression indicates that NEC patients have well-defined Paneth cells but diminished defensin activity. Our results suggest that DEFA6 could be used as a biomarker for NEC. What is Known: • Previous studies of defensin activity in NEC have been inconsistent, showing that defensin levels may be increased or diminished in NEC. GUCA2A has to our knowledge never been studied in NEC. What is New: • This study benchmarks two specific Paneth cell markers (DEFA6 and GUCA2A) and their activity in individuals with and without NEC. • The key finding is that the NEC group had a lower DEFA6 expression compared to the Controls, while the expression of GUCA2A did not differ between the groups. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis (BL. infantis), alone and in combination with a human milk oligosaccharide (HMO)—sialylactose (3′SL)—on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 preterm piglets randomized between 5 treatments: (1) Preterm infant formula, (2) Donor human milk (DHM), (3) Infant formula + 3′SL, (4) Infant formula + BL. infantis, and (5) Infant formula and BL. infantis + 3′SL. NEC incidence and severity were assessed through the evaluation of tissue from all the segments of the GI tract. The gut microbiota composition was assessed both daily and terminally through 16S and whole-genome sequencing (WGS) of rectal stool samples and intestinal contents. Dietary BL. infantis and 3′SL supplementation had no effect, yet DHM significantly reduced the incidence of NEC. The abundance of BL. infantis in the gut contents negatively correlated with disease severity. Clostridium sensu stricto 1 and Clostridium perfringens were significantly more abundant in NEC and positively correlated with disease severity. Our results suggest that pre- and probiotics are not sufficient for protection from NEC in an exclusively formula-based diet. The results highlight the differences in microbial species positively associated with both diet and NEC incidence. [ABSTRACT FROM AUTHOR]

The incidence of spontaneous intestinal perforation (SIP) increases up to 10% with decreasing gestational age (GA). We aimed to explore early biomarkers for predicting SIP in preterm infants. In this case–control study, neonates born at ≤34 weeks GA diagnosed with SIP were compared with GA and/or birth-weight-matched neonates diagnosed with necrotizing enterocolitis (NEC). Laboratory markers assessed prior and adjacent to the day of SIP or NEC diagnosis were evaluated. The cohort included 16 SIP and 16 matched NEC infants. Hyperlactatemia was less frequent in SIP than in NEC infants (12% vs. 50%, p = 0.02). The platelets count was lower in SIP than in NEC infants (p < 0.001). Glucose levels strongly correlated with lactate levels (p = 0.01) only in the NEC group. The odds of being diagnosed with SIP decreased as lactate levels increased (OR = 0.607, 95% CI: 0.377–0.978, p = 0.04). Our results suggest that a combination of laboratory markers, namely glucose and lactate, could help differentiate SIP from NEC at early stages so that, in the presence of an elevated blood glucose, an increase in blood lactate was associated with a decrease in the odds of being diagnosed with SIP. [ABSTRACT FROM AUTHOR]

Peripartum antibiotics can negatively impact the developing gut microbiome and are associated with necrotizing enterocolitis (NEC). The mechanisms by which peripartum antibiotics increase the risk of NEC and strategies that can help mitigate this risk remain poorly understood. In this study, we determined mechanisms by which peripartum antibiotics increase neonatal gut injury and evaluated whether probiotics protect against gut injury potentiated by peripartum antibiotics. To accomplish this objective, we administered broad-spectrum antibiotics or sterile water to pregnant C57BL6 mice and induced neonatal gut injury to their pups with formula feeding. We found that pups exposed to antibiotics had reduced villus height, crypt depth, and intestinal olfactomedin 4 and proliferating cell nuclear antigen compared to the controls, indicating that peripartum antibiotics impaired intestinal proliferation. When formula feeding was used to induce NEC-like injury, more severe intestinal injury and apoptosis were observed in the pups exposed to antibiotics compared to the controls. Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) reduced the severity of formula-induced gut injury potentiated by antibiotics. Increased intestinal proliferating cell nuclear antigen and activation of the Gpr81-Wnt pathway were noted in the pups supplemented with LGG, suggesting partial restoration of intestinal proliferation by probiotics. We conclude that peripartum antibiotics potentiate neonatal gut injury by inhibiting intestinal proliferation. LGG supplementation decreases gut injury by activating the Gpr81-Wnt pathway and restoring intestinal proliferation impaired by peripartum antibiotics. Our results suggest that postnatal probiotics may be effective in mitigating the increased risk of NEC associated with peripartum antibiotic exposure in preterm infants. [ABSTRACT FROM AUTHOR]

Aim: Necrotizing enterocolitis (NEC) is the most lethal disease of the gastrointestinal tract of preterm infants. New and existing management strategies need clinical evaluation. Large heterogeneity exists in the selection, measurement, and reporting of outcome measures in NEC intervention studies. This hampers meta-analyses and the development of evidence-based management guidelines. We aim to develop a Core Outcome Set (COS) for NEC that includes the most relevant outcomes for patients and physicians, from moment of diagnosis into adulthood. This COS is designed for use in NEC treatment trials, in infants with confirmed NEC. Methods: This study is designed according to COS-STAD (Core Outcome Set-STAndards for Development) recommendations and the COMET (Core Outcome Measures in Effectiveness Trials) Initiative Handbook. We obtained a waiver from the Ethics Review Board and prospectively registered this study with COMET (Study 1920). We will approach 125 clinicians and/or researchers from low-middle and high-income countries based on their scientific output (using SCIVAL, a bibliometric tool). Patients and parents will be approached through local patient organisations. Participants will be separated into three panels, to assess differences in priorities between former patients and parents (1. lay panel), clinicians and researchers involved in the neonatal period (2. neonatal panel) and after the neonatal period (3. post-neonatal panel). They will be presented with outcomes currently used in NEC research, identified through a systematic review, in a Delphi process. Eligible outcome domains are also identified from the patients and parents' perspectives. Using a consensus process, including three online Delphi rounds and a final face-to-face consensus meeting, the COS will be finalised and include outcomes deemed essential to all stakeholders: health care professionals, parents and patients' representatives. The final COS will be reported in accordance with the COS-Standards for reporting (COS-STAR) statement. Conclusions: Development of an international COS will help to improve homogeneity of outcome measure reporting in NEC, will enable adequate and efficient comparison of treatment strategies, and will help the interpretation and implementation of clinical trial results. This will contribute to high-quality evidence regarding the best treatment strategy for NEC in preterm infants. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most prevalent and devastating gastrointestinal disorders in neonates. Despite advances in neonatal care, the incidence and mortality due to NEC remain high, highlighting the need to devise novel treatments for this disease. There have been a number of recent advancements in therapeutic approaches for the treatment of NEC; these involve remote ischemic conditioning (RIC), stem cell therapy, breast milk components (human milk oligosaccharides, exosomes, lactoferrin), fecal microbiota transplantation, and immunotherapy. This review summarizes the most recent advances in NEC treatment currently underway as well as their applicability and associated challenges and limitations, with the aim to provide new insight into the paradigm of care for NEC worldwide. [ABSTRACT FROM AUTHOR]

Background: Human milk–based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk–based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines. Methods: Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population. Results: Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution's size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution. Conclusions: The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants. [ABSTRACT FROM AUTHOR]

Objective: To explore the surgical risk variables in patients with necrotizing enterocolitis (NEC) and develop a nomogram model for predicting the surgical intervention timing of NEC. Methods: Infants diagnosed with NEC were enrolled in our study. We gathered information from clinical data, laboratory examinations, and radiological manifestations. Using LASSO (least absolute shrinkage and selection operator) regression analysis and multivariate logistic regression analysis, a clinical prediction model based on the logistic nomogram was developed. The performance of the nomogram model was evaluated using the receiver operating characteristic (ROC) curve, calibration curves, and decision curve analysis (DCA). Results: A surgical intervention risk nomogram based on hypothermia, absent bowel sounds, WBC > 20 × 109/L or < 5 × 109/L, CRP > 50 mg/L, pneumatosis intestinalis, and ascites was practical, had a moderate predictive value (AUC > 0.8), improved calibration, and enhanced clinical benefit. Conclusions: This simple and reliable clinical prediction nomogram model can help physicians evaluate children with NEC in a fast and effective manner, enabling the early identification and diagnosis of children at risk for surgery. It offers clinical revolutionary value for the development of medical or surgical treatment plans for children with NEC. [ABSTRACT FROM AUTHOR]

[Display omitted] • DNA methylation signature of inflammation derived in neonatal saliva samples. • Preterm infants display higher inflammatory-related DNAm than term infants. • DNAm signature associates with postnatal inflammatory conditions such as sepsis. • Inflammatory DNAm associates with alterations in brain structure in preterm infants. • Highlights the potential of immune-DNAm markers for translational medicine. Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. Higher DNAm CRP was linked to preterm status (-0.0107 ± 0.0008, compared with −0.0118 ± 0.0006 among term infants; p < 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p < 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippocampi and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures. Inflammatory-related DNAm captures the allostatic load of inflammatory burden in preterm infants. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences. [ABSTRACT FROM AUTHOR]

Preeclampsia is a multisystemic clinical syndrome characterized by the appearance of new-onset hypertension and proteinuria or hypertension and end organ dysfunction even without proteinuria after 20 weeks of pregnancy or postpartum. Residing at the severe end of the spectrum of the hypertensive disorders of pregnancy, preeclampsia occurs in 3 to 8% of pregnancies worldwide and is a major cause of maternal and perinatal morbidity and mortality, accounting for 8–10% of all preterm births. The mechanism whereby preeclampsia increases the risk of the neurodevelopmental, cardiovascular, and metabolic morbidity of the mother's offspring is not well known, but it is possible that the preeclamptic environment induces epigenetic changes that adversely affect developmental plasticity. These developmental changes are crucial for optimal fetal growth and survival but may lead to an increased risk of chronic morbidity in childhood and even later in life. The aim of this review is to summarize both the short- and long-term effects of preeclampsia on offspring based on the current literature. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is the leading basis for gastrointestinal morbidity and poses a significant risk for neurodevelopmental impairment (NDI) in preterm infants. Aberrant bacterial colonization preceding NEC contributes to the pathogenesis of NEC, and we have demonstrated that immature microbiota in preterm infants negatively impacts neurodevelopment and neurological outcomes. In this study, we tested the hypothesis that microbial communities before the onset of NEC drive NDI. Using our humanized gnotobiotic model in which human infant microbial samples were gavaged to pregnant germ-free C57BL/6J dams, we compared the effects of the microbiota from preterm infants who went on to develop NEC (MNEC) to the microbiota from healthy term infants (MTERM) on brain development and neurological outcomes in offspring mice. Immunohistochemical studies demonstrated that MNEC mice had significantly decreased occludin and ZO-1 expression compared to MTERM mice and increased ileal inflammation marked by the increased nuclear phospho-p65 of NFκB expression, revealing that microbial communities from patients who developed NEC had a negative effect on ileal barrier development and homeostasis. In open field and elevated plus maze tests, MNEC mice had worse mobility and were more anxious than MTERM mice. In cued fear conditioning tests, MNEC mice had worse contextual memory than MTERM mice. MRI revealed that MNEC mice had decreased myelination in major white and grey matter structures and lower fractional anisotropy values in white matter areas, demonstrating delayed brain maturation and organization. MNEC also altered the metabolic profiles, especially carnitine, phosphocholine, and bile acid analogs in the brain. Our data demonstrated numerous significant differences in gut maturity, brain metabolic profiles, brain maturation and organization, and behaviors between MTERM and MNEC mice. Our study suggests that the microbiome before the onset of NEC has negative impacts on brain development and neurological outcomes and can be a prospective target to improve long-term developmental outcomes. [ABSTRACT FROM AUTHOR]

To determine what modifiable interventions used in the neonatal intensive care unit (NICU) are associated with severe necrotizing enterocolitis (NEC) requiring surgical intervention. A retrospective review of patients treated for NEC at a tertiary hospital from 1991 to 2016 was performed. Patient characteristics were used to calculate propensity scores for likelihood of exposure to seven interventions: enteral feeds, use of glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antacids, antibiotics, or umbilical arterial (UAC) and venous catheters (UVC). Conditional logistic regression was used to compare the odds of having surgical NEC if exposed to each treatment. We included 195 NEC patients: 69 severe NEC managed with surgery and 126 non-severe NEC managed medically. After propensity score matching based on birth characteristics, exposure to glucocorticoids (OR 5.21, 95%CI: 1.62, 16.70), NSAIDs (OR 4.87, 95%CI: 1.67, 14.17), UVC (OR 2.53 (95%CI: 1.19, 5.73), and UAC (OR 4.91, 95%CI: 2.12, 11.37) were associated with surgical NEC in separate conditional logistic regression analyses. Including these treatments in a second round of propensity matching and conditional logistic regression revealed that glucocorticoids (OR 2.99, 95%CI: 1.01, 8.88), NSAIDs (OR 3.97, 95%CI: 1.41, 11.19), UVC (OR 3.07, 95%CI: 1.46, 6.48), and UAC (OR 5.10, 95%CI: 2.10, 12.36) were still associated with surgical NEC. After controlling for birth confounders and common NICU supportive interventions, use of glucocorticoids, NSAIDs and umbilical catheters independently increased the odds of developing severe NEC requiring surgical intervention. Case-control, Level III evidence. [ABSTRACT FROM AUTHOR]

Abstract Necrotizing enterocolitis (NEC) continues to be a devastating disease in preterm neonates and has a paucity of medical management options. Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan (GAG) in human breast milk (HM) and has been shown to reduce inflammation. We hypothesized that supplementation with CS in an experimental NEC model would alter microbial diversity, favorably alter the cytokine profile, and (like other sulfur compounds) improve outcomes in experimental NEC via the eNOS pathway. NEC was induced in 5‐day‐old pups. Six groups were studied (n = 9–15/group): (1) WT breastfed and (2) Formula fed controls, (3) WT NEC, (4) WT NEC + CS, (5) eNOS KO (knockout) NEC, and (6) eNOS KO NEC + CS. Pups were monitored for clinical sickness score and weights. On postnatal day 9, the pups were killed. Stool was collected from rectum and microbiome analysis was done with 16 s rRNA sequencing. Intestinal segments were examined histologically using a well‐established injury scoring system and segments were homogenized and analyzed for cytokine profile. Data were analyzed using GraphPad Prism with p

Background: Gastric pneumatosis is a rare condition characterized by the presence of intramural gas in the stomach wall. It is uncommon in infants and is usually caused by proximal intestinal obstruction or necrotizing enterocolitis, a serious condition typically seen in preterm babies. Case Presentation: An extremely preterm baby born at 23 weeks of gestation weighing 640 grams, with bronchopulmonary dysplasia and other comorbidities like patent ductus arteriosus, staph aureus sepsis, developed abdominal distension and non-bilious vomiting at 4 months of age. X-ray abdomen revealed gastric pneumatosis. The condition was managed with conservative measures. Conclusion: Gastric pneumatosis secondary to necrotizing enterocolitis is uncommon in infants and needs prompt evaluation and management to prevent further deterioration.

Background: Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity in preterm infants, and prevention and treatment strategies have remained largely unchanged over the past several decades. As understanding of the microbiome has increased, probiotics have been hypothesized as a possible strategy for decreasing rates of NEC, and several studies have noted significant decreases in rates of NEC after initiation of probiotics in preterm infants. However, a recent AAP report cited caution on the use of probiotic use in part because studies of probiotic use in ELBW infants are lacking. As our unit began routine use of probiotics for all infants

Background : Necrotizing enterocolitis (NEC) is a common gastrointestinal emergency among neonates which is characterized by acute intestinal inflammation and necrosis. The main risk factors for NEC are prematurity, low birth weight, and some preexisting health conditions such as congenital heart defects (CHDs). Investigation of the potential genetic predisposition to NEC is a promising approach that might provide new insights into its pathogenesis. One of the most important proteins that play a significant role in the pathogenesis of NEC is Toll-like receptor 4 (TLR4) which recognizes lipopolysaccharide found in Gram-negative bacteria. In intestinal epithelial cells, a protein encoded by the SIGIRR gene is a major inhibitor of TLR4 signaling. A few SIGIRR variants, including rare p.Y168X and p.S80Y, have already been identified in preterm infants with NEC, but their pathogenic significance remains unclear. This study aimed to investigate the spectrum of SIGIRR genetic variants in term newborns with CHD and to assess their potential association with NEC. Methods and Results: A total of 93 term newborns with critical CHD were enrolled in this study, 33 of them developed NEC. SIGIRR genetic variants were determined by Sanger sequencing of all exons. In total, eight SIGIRR genetic variants were identified, two of which were found only in newborns with NEC (P = 0.12). The rare missense p.S80Y (rs117739035) variant in exon 4 was found in two infants with NEC stage IIA. Two infants with NEC stage III and stage IB carried a novel duplication c. 102_121dup (rs552367848) variant in exon 10 that has not been previously associated with any clinical phenotype. Conclusions : The presence of both variants only in neonates who developed NEC, together with earlier published data, may suggest their potential contribution to the risk of developing NEC in term infants with CHD and allow planning larger cohort studies to clarify their relevance.

Introduction: Necrotising enterocolitis (NEC) is the most common gastrointestinal complication in pre-mature infants. There are risk factors and modifying factors that have been identified and studied over the years, but not many studies have been conducted in middle-income countries. Aims and Objectives: This study aimed to describe the maternal, obstetric and neonatal characteristics in very low birth weight (VLBW) babies with NEC in a tertiary neonatal unit in South Africa. The survival to hospital discharge in VLBW babies with NEC was also determined. Materials and Methods: This study was a retrospective, cross-sectional, observational study of VLBW babies admitted to a tertiary neonatal unit between January 2013 and December 2017. The population comprised babies

Background and Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell’s staging is routinely used to guide diagnosis, but early diagnostic signs are nonspecific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated fecal cytokine levels, coupled with gut microbiota profiles, as a noninvasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary’s or Queen Charlotte’s & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologists grouped individuals by modified Bell’s staging (healthy, NEC1, NEC2/3) and fecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays. Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota composition were observed for Bacillota (adj. P = .0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of fecal cytokine levels revealed significantly higher concentrations of IL-1α (P = .045), IL-5 (P = .0074), and IL-10 (P = .032) in Bell stage 1 NEC compared to healthy individuals. Conclusion: Differences in certain fecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis.

Abstract Background Infants with rule-out infections are responsible for the majority of empirical antibiotics treatment (EAT) in neonatal intensive care units (NICUs), particularly very preterm infants (VPIs). Antibiotic overuse has been linked to adverse outcomes. There is a paucity of data on the association between EAT and clinical outcomes (containing the nutritional outcomes) of VPIs without infection-related morbidities. Methods Clinical data of VPIs admitted in 28 hospitals in 20 provinces of China from September 2019 to December 2020 were collected. EAT of VPIs was calculated as the number of days with initial usage in the first week after birth, and then categorized into 3 groups (antibiotic exposure: none, 1-4 days, and > 4 days). Clinical characteristics, nutritional status , and the short-term clinical outcomes among 3 groups were compared and analyzed. Results In total, 1834 VPIs without infection-related morbidities in the first postnatal week were enrolled, including 152 cases (8.3%) without antibiotics, 374 cases (20.4%) with EAT ≤4 days and 1308 cases (71.3%) with EAT > 4 days. After adjusting for the confounding variables, longer duration of EAT was associated with decreased weight growth velocity and increased duration of reach of full enteral feeding in EAT > 4 days group (aβ: -4.83, 95% CI: − 6.12 ~ − 3.53; aβ: 2.77, 95% CI: 0.25 ~ 5.87, respectively) than those receiving no antibiotics. In addition, the risk of feeding intolerance (FI) in EAT > 4 days group was 4 times higher than that in non-antibiotic group (aOR: 4.14, 95%CI: 1.49 ~ 13.56) and 1.8 times higher than that in EAT ≤4 days group (aOR: 1.82, 95%CI: 1.08 ~ 3.17). EAT > 4 days was also a risk factor for greater than or equal to stage 2 necrotizing enterocolitis (NEC) than those who did not receive antibiotics (aOR: 7.68, 95%CI: 1.14 ~ 54.75) and those who received EAT ≤4 days antibiotics (aOR: 5.42, 95%CI: 1.94 ~ 14.80). Conclusions The EAT rate among uninfected VPIs was high in Chinese NICUs. Prolonged antibiotic exposure was associated with decreased weight growth velocity, longer duration of reach of full enteral feeding, increased risk of feeding intolerance and NEC ≥ stage 2. Future stewardship interventions to reduce EAT use should be designed and implemented.

Abstract Background Patients with right isomerism have accompanying complex congenital heart disease, which is characterized by pulmonary atresia and total anomalous pulmonary venous return. Balanced regulation of the systemic and pulmonary circulation is essential for successful management, especially for cases complicated with necrotizing enterocolitis (NEC). Case presentation A 6-day-old male neonate with a single ventricle, pulmonary atresia, patent ductus arteriosus (DA), and total anomalous pulmonary venous return associated with right isomerism was admitted because of dyspnea, cyanosis, and melena. The patient presented circulatory incompetence due to excessive pulmonary blood flow, resulting in NEC. The patient underwent DA banding and colectomy following continuous intravenous infusion of prostaglandin E1 at six days. Subsequently, his condition improved, reaching a systemic oxygen saturation of around 80%. He underwent a bidirectional Glenn procedure and closure of colectomy at the ages of 5 and 6 months, respectively. Conclusion DA banding can be an alternative to placing an aortopulmonary shunt, which is conventional in patients with ductus-dependent pulmonary circulation, because DA banding is feasible without cardiopulmonary bypass.

Abstract Background Abdominal ultrasonography (AUS) has been suggested to be valuable in the early detection of necrotizing enterocolitis (NEC). Objective Here, we intended to assess the efficiency of abdominal ultrasound in terms of predicting bowel resection in infants with NEC. Methods From January 2018 to March 2021, 164 hospitalized children with NEC who underwent surgical management were enrolled. The enrolled infants were separated into two groups according to whether they underwent bowel resection. We reviewed the clinical data, as well as dynamic sonographic and abdominal radiographic (AR) parameters. The potential performance of AUS parameters was identified and compared with that of AR using a logistic regression analysis and receiver operating characteristic (ROC) curve analysis. Results Several parameters were detected to be statistically significant in predicting the occurrence of bowel resection, including thick to thin transformation [p

Aim:Sustained release of inflammatory mediators, excessive inflammatory response and impaired intestinal epithelial restitution are well-known mechanisms in the pathogenesis of necrotizing enterocolitis. This study focused on the effect of resveratrol on these pathways.Materials and Methods:In this study, the rat crypt intestinal cell line (IEC-6) culture, an application of lipopolysaccharide or a cytokine mixture and a scratch migration assay model were used. Nitric oxide synthase-2 (iNOS) and cyclooxygenase-2 (COX-2), focal adhesion kinase (FAK) and its phosphorylated form (pFAK) levels were assessed.Results:IEC-6 cells covered 88% of the denuded area in the control, 54% in LPS, and 35% in cytomix groups at the 24th hour. The treatment with resveratrol at doses of 0.5, 1 and 5 μM/L before LPS resulted in the repair of 84%, 87% and 76% of the denuded areas, respectively. Likewise, with cytomix, it was 86%, 82%, and 78%. Resveratrol at a dose of 5 μM/L prevented an increase in iNOS levels. All three doses of resveratrol were effective in preventing increases in COX levels. FAK or pFAK expressions remained unchanged in all groups.Conclusion:Resveratrol, being known for its antioxidant features, suppresses excessive inflammatory response and helps preservation of mucosal integrity by conservation of epithelial restitution.

Introduction. Excessive intestinal inflammation in preterm infants is one of the key factors in the development of necrotizing enterocolitis (NEC), early- (EOS) and late-onset neonatal sepsis (LOS). Purpose - to evaluate the connection between fecal calprotectin (FC), enteral use of lactoferrin (LF), and the occurrence of NEC, EOS, and LOS in preterm infants. Materials and methods. FC was measured in 26 newborns with gestational age (GA) ≤32 weeks and birth weight ≤1500 g. Feces were collected twice: in the first 7 days of life and at the postmenstrual age (PMA) of 36 weeks. The main group included 15 infants with either EOS, LOS or NEC. The remaining 11 infants formed the comparison group. Eleven infants received LF (4 in the main group and 7 in the comparison group), which was randomly administered in the first 3 days of life. Results. FC in the first 7 days of life was higher in the main group (р>0.05). At the PMA of 36 weeks, FC decreased in the main group and increased in the comparison group (p>0.05). FC in the first week of life was higher in infants with EOS compared to newborns without the diseases (p=0.03), followed by a decrease at the PMA of 36 weeks (p=0.04). There was no significant difference in FC levels depending on the development of LOS or NEC. FC levels increased in all infants who received LF and decreased in babies who did not receive LF (p>0.05). Conclusions. The occurrence of EOS is associated with a significant increase in FC which subsequently decrease by the PMA of 36 weeks. FC in the first week of life are not associated with the development of NEC or LOS. Enteral use of LF at a dose of 100 mg/day is associated with an increase in FC levels (p>0.05). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Background. Breast milk (BM) is an important source of microRNAs (miRs). MicroRNAs are highly resistant to gastrointestinal enzymes and are well absorbed in the intestine. MiR-155 is one of the most expressed miR of BM. Currently, the effect of miR-155 of BM on the health of preterm neonates has not been almost studied. The objective was to determine the effect of miR-155 of BM on the health of preterm neonates. Materials and methods. We examined 74 newborns, who were treated in neonatal departments. We determined the level of miR-155 in the BM of 44 mothers of exclusively breastfed children. In parallel, we evaluated gene expression of the transcription factor FOXP3 in buccal smears of all neonates. Three comparison groups were selected: group 1 consisted of 32 newborns of up to 37 weeks of gestation; group 2 — of 30 preterm newborns on artificial fee­ding; control group — of 12 full-term breastfed newborns. Results. The gestational age median in group 1 was 33 (31; 34) weeks; in group 2 — 32.5 (32; 35) weeks; it was higher in the control group (p < 0.001) — 40 (39; 41) weeks. Neonatal encephalopathy as the main diagnosis occurred more often among full-term newborns (p 0.05). In group 2 compared to group 1, manifestations of necrotizing enterocolitis were detected significantly more often (p < 0.05): 30.0 ± 8.4 % vs 9.4 ± 5.2 %. The results of evaluating the miR-155 expression level in the BM of mothers of group 1 children prove that the corresponding indicator in the control group was exceeded by an ave­rage of 6.2 (4.1; 9.2) times (p < 0.001). Analysis of FOXP3 levels in buccal smears showed that all preterm newborns had significantly lower FOXP3 levels than that of full-term neonates (< 0.001). However, the expression of this factor was the lowest in group 2 (< 0.001): 0.08 (0.04; 0.16) c.u. in group 2 vs 0.21 (0.14; 0.38) c.u. in group 1. We found a direct moderate correlation between the expression levels of miR-155 of the BM and the FOXP3 in the mucosal cells of breastfed preterm neonates: r = 0.442 (p = 0.014). A significant decrease was noted in the expression of FOXP3 in children with necrotizing enterocolitis (0.11 (0.04; 0.25) c.u.) compared to newborns without such pathology (0.22 (0.09; 0.91) c.u.) (p

Highlights 1. Pathologically impaired periventricular white matter was observed in NEC neonatal rats. 2. Hypoxic-ischemic brain injury can also lead to intestinal inflammation. 3. CXCL1 and CXCR2 were significantly upregulated in intestinal and brain tissues in NEC, HIBI, and NEC+HIBI rats compared to the normal group. 4. Compared with the HIBI group, CXCL1 and CXCR2 expression continued to increase in NEC+HIBI rats.

The effectiveness of probiotics in reducing the incidence of necrotizing enterocolitis has been supported by a very large number of studies. However, the utilization of probiotics in preterm infants remains a topic of debate. This study aims to assess the rate of probiotic use in European neonatal intensive care units (NICUs), compare administration protocols, and identify barriers and concerns associated with probiotic use. An online questionnaire was distributed via email to European NICUs between October 2020 and June 2021. Different questions related to the frequency of probiotic use were proposed. Data on probiotic administration protocols and reasons for non-utilization were collected. The majority of responses were from France and Switzerland, with response rates of 85% and 89%, respectively. A total of 21% of French NICUs and 100% of Swiss NICUs reported routine probiotic use. There was significant heterogeneity in probiotic administration protocols, including variations in probiotic strains, administration, and treatment duration. The main obstacles to routine probiotic use were the absence of recommendations, lack of consensus on strain selection, insufficient scientific evidence, and concerns regarding potential adverse effects. The rate of routine probiotic administration remains low in European NICUs, with heterogeneity among protocols. Further trials are necessary to elucidate optimal treatment modalities and ensure safety of administration.

Background: Strategies to stabilize and support overall infant health by increasing the number of Bifidobacterium longum in the infant gut are of interest, but few studies have systematically addressed this issue. We aimed to evaluate the efficacy and safety of Bifidobacterium longum use in infants using meta-analysis. Methods: We searched PubMed, EMBASE, Cochrane Library of Systematic Reviews, and SinoMed for publications until 27 July 2022. The main outcomes of interest were weight gain, risk of necrotizing enterocolitis (NEC), and adverse events. Two authors independently performed study screening, risk of bias assessment, and data extraction. Outcome data were extracted from each included study and combined using mean difference (MD) or risk ratio (RR) and finally combined using a fixed-effect model or random-effect model. Results: A total of 4481 relevant studies were identified, of which 15 were found to be eligible for randomized controlled trials and were included in the meta-analysis. The combined extracted data showed that the intervention group containing Bifidobacterium longum had a significantly lower risk of NEC (RR = 0.539, 95% CI: 0.333, 0.874) compared to the control group. There was no statistical difference between the intervention and control groups regarding weight gain (MD = 0.029, 95% CI: −0.032, 0.090), the occurrence of adverse events (RR = 0.986, 95% CI: 0.843, 1.153), and serious adverse events (RR = 0.881, 95% CI: 0.493, 1.573). Conclusions: Bifidobacterium longum may significantly reduce the risk of NEC in infants as well as being safe; thus, further research evidence is needed on whether there is a benefit on weight gain.

Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia–reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.

Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease that can be seen in premature infants with high risk for morbidity and mortality. There is currently no US Food and Drug Administration (FDA) medication approved for the prevention of NEC. Despite great heterogeneity among available studies, large meta-analyses of clinical trials have demonstrated the efficacy of multiple-strain probiotics in reducing NEC and all-cause mortality. In 2020, Medical City Dallas's Level IV neonatal intensive care unit (NICU) implemented a probiotic protocol for NEC prevention. As a result, a reduction in NEC was observed, with no occurrence of probiotic-related sepsis. [ABSTRACT FROM AUTHOR]

Background Although the use of neuraxial analgesia has been shown to improve uteroplacental blood flow and maternal and fetal hemodynamics related to labor pain, possibly improving immediate outcomes in term neonates, the association between neuraxial analgesia use and outcomes in preterm neonates remains unclear.

Necrotizing enterocolitis (NEC) is one of the most fatal diseases in premature infants. Damage to the intestinal epithelial barrier (IEB) is an important event in the development of intestinal inflammation and the evolution of NEC. The intestinal epithelial monolayer formed by the tight arrangement of intestinal epithelial cells (IECs) constitutes the functional IEB between the organism and the extra-intestinal environment. Programmed death and regenerative repair of IECs are important physiological processes to maintain the integrity of IEB function in response to microbial invasion. However, excessive programmed death of IECs leads to increased intestinal permeability and IEB dysfunction. Therefore, one of the most fundamental questions in the field of NEC research is to reveal the pathological death process of IECs, which is essential to clarify the pathogenesis of NEC. This review focuses on the currently known death modes of IECs in NEC mainly including apoptosis, necroptosis, pyroptosis, ferroptosis, and abnormal autophagy. Furthermore, we elaborate on the prospect of targeting IECs death as a treatment for NEC based on exciting animal and clinical studies.

IntroductionNecrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice.MethodsIn this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups.ResultsWe detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC.DiscussionThese findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.

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.

Background: The most common inflammatory gastrointestinal disorder in newborn infants is necrotizing enterocolitis (NEC). Despite the multifactorial etiology of NEC, its pathogenesis is the same regardless of the etiology—a decrease in enteric perfusion that results in enteritis, dysmotility, necrosis, and sepsis. This study aims to evaluate whether the characteristics of NEC in infants with congenital heart disease (CHD) are different from those of classical NEC. The records of 39 NEC patients were reviewed retrospectively. Based on the presence or absence of CHD, the patients were divided into two groups. The group with NEC and CHD was named cardiogenic NEC and the other group was named classical NEC. The two groups were compared in terms of mode of delivery, gestational age, birth weight, age at onset of NEC, surgical treatment rate, NEC localization, and mortality rate. Results: The cardiogenic NEC group consisted of 25 patients, and the classical NEC group consisted of 14 patients. The results indicate that there were no differences between the two groups in terms of sex, mode of delivery, and location of the NEC. There were higher levels of gestational age, birth weight, and age at which NEC was diagnosed in the cardiogenic group. The mortality rate of the cardiogenic NEC group (72%) was higher than that of the classical NEC group (28.6%). In addition, the surgical treatment rate of the cardiogenic NEC group (84%) was higher than that of the classical NEC group (57.2%). Conclusions: The clinical course of NECs with CHD is different from that of classical NEC. In NEC, CHD can be identified as an important risk factor. [ABSTRACT FROM AUTHOR]

Objective Human milk (HM) has antibacterial properties due to the presence of immune-modulators, including lactoferrin (LF). This study will determine effect(s) of HM maturation, fortification, and storage conditions on LF levels and its antibacterial properties. Study Design HM samples (n = 30) were obtained from preterm and term mothers. The LF levels were analyzed by ELISA, and the antibacterial activity was measured after inoculation with Escherichia coli. Results The highest level of LF in preterm HM was observed in the first week of lactation. However, storage of preterm HM at 4°C decreased LF levels significantly. Both LF levels and antibacterial activity in preterm HM was lower compared with term HM, but significantly higher than donor HM even after HM-based fortification. LF supplementation of donor HM improved its antibacterial activity. Conclusion Preterm infants fed donor HM, formula, or stored HM at 4°C may benefits from LF supplementation to improve HM antibacterial properties. Key Points Milk LF levels vary with storage and maturity. Donor milk is deficient in LF even after adding HM-based fortification. Donor HM and formula fed infants may benefit from LF. [ABSTRACT FROM AUTHOR]

Objective Necrotizing enterocolitis (NEC) is an inflammatory disease of the gastrointestinal tract characterized by ischemic necrosis of the intestinal mucosa, mostly affecting premature neonates. Management of NEC includes medical care and surgical approaches, with supportive care and empirical antibiotic therapy recommended to avoid any disease progression. However, there is still no clear evidence-based consensus on empiric antibiotic strategies or surgical timing. This study was aimed to review the available evidence on the effectiveness and safety of different antibiotic regimens for NEC. Study Design MEDLINE, EMBASE, Cochrane CENTRAL, and CINAHL databases were systematically searched through May 31, 2020. Randomized controlled trials (RCTs) and nonrandomized interventions reporting data on predefined outcomes related to NEC treatments were included. Clinical trials were assessed using the criteria and standard methods of the Cochrane risk of bias tool for randomized trials, while the risk of bias in nonrandomized studies of interventions was evaluated using the ROBINS-I tool. The certainty in evidence of each outcome's effects was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results Five studies were included in this review, two RCTs and three observational studies, for a total amount of 3,161 patients. One RCT compared the outcomes of parenteral (ampicillin plus gentamicin) and oral (gentamicin) treatment with parenteral only. Three studies (one RCT and two observational) evaluated adding anaerobic coverage to different parenteral regimens. The last observational study compared two different parenteral antibiotic combinations (ampicillin and gentamicin vs. cefotaxime and vancomycin). Conclusion No antimicrobial regimen has been shown to be superior to ampicillin and gentamicin in decreasing mortality and preventing clinical deterioration in NEC. The use of additional antibiotics providing anaerobic coverage, typically metronidazole, or use of other broad-spectrum regimens as first-line empiric therapy is not supported by the very limited current evidence. Well-conducted, appropriately sized comparative trials are needed to make evidence-based recommendations. Key Points Ampicillin and gentamicin are effective in decreasing mortality and preventing clinical deterioration in NEC. Metronidazole could be added in patients with surgical NEC. No study with high-quality evidence was found. [ABSTRACT FROM AUTHOR]

To determine the association of placental pathology with the severity of necrotizing enterocolitis (NEC) in preterm infants. This single-center matched case-control study included infants with NEC (n = 107) and gestational age and birth weight-matched controls (n = 130), born between 2013 and 2020. Placentas were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement. Acute histologic chorioamnionitis with the fetal response was significantly more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p = 0.02). On regression model, infants with multiple placental pathologies (OR 2.16; 95% CI 1.01 − 4.73; p = 0.04) and maternal vascular malperfusion (OR 2.2; 95% CI 1.12 − 4.51; p = 0.02) had higher odds of either medical or surgical NEC than controls. Infants with multiple placental lesions, including placental inflammatory and vascular lesions, were at higher risk of medical or surgical NEC in the postnatal period. [ABSTRACT FROM AUTHOR]