Necrotizing Enterocolitis In Newborns Research Articles

Efficacy of Metabolic Therapy in the Complex Treatment of Necrotizing Enterocolitis in Newborns

Treatment of necrotizing enterocolitis (NEC) in newborns remains an urgent problem due to the risk of severe complications and high mortality in these patients. The search for new therapeutic technologies to reduce the number of adverse outcomes and improve the quality of life of children is one of the modern tasks of neonatology. The aim of the study was to study the clinical results of the use of Cytoflavin® (succinic acid, inosine, nicotinamide, riboflavin) as part of complex therapy in the conservative treatment of NEC in newborns. Materials. A total of 151 premature newborns with stage I—II NEC were monitored. The study group consisted of 78 infants with NEC whose treatment included cytoflavin. The comparison group consisted of 73 infants with NEC who were treated according to the traditional regimen. Results. When analyzing the course of the early neonatal period, it was revealed that the duration of mechanical ventilation in the children of the main group was significantly shorter (36.3 ± 4.9 days) compared to the second group (58.7 ± 4.8 days). Restoration of intestinal passage in children treated with cytoflavin occurred in 62.4 ± 11.0 hours, which is significantly faster than in the comparison group (98.2 ± 10.4 hours). The number of children in the study group transferred to the surgical department (6.41%) was significantly lower compared to the number of severe complications in the second group (15.06%). Conclusion. A positive result of the effect of metabolic therapy with the use of cytoflavin on the course of NEC in newborns is a significant shortening of the duration of their treatment with subsequent transfer to a physiological method of nutrition and a decrease in the incidence of severe surgical complications.

Analysis of Risk Factors for Necrotizing Enterocolitis (NEC) in Newborns: A Systematic Literature Review

Necrotizing enterocolitis (NEC) is a serious condition in newborns involving inflammation and intestinal necrosis. A number of risk factors have been identified, which complexly interact and contribute to the development of this condition. An in-depth understanding of these risk factors has major implications for the prevention, diagnosis and management of NEC in newborns. Babies born prematurely, especially before 32 weeks' gestation, have a higher risk of developing NEC. Low birth weight, regardless of prematurity status, remains a significant independent risk factor. Imbalances in blood circulation, especially in the intestines, can increase the risk of NEC. Hypotension and other medical conditions that affect blood flow to the intestines can be potential triggers. Infection and inflammation, both systemic and local, play a central role in the development of NEC. Bacterial contamination in the digestive tract can trigger an inflammatory response that contributes to the pathophysiological process of NEC. Formula feeding, especially in premature infants, is associated with an increased risk of NEC. The importance of providing exclusive breastfeeding and introducing foods slowly to protect the newborn's intestinal health. Excessive use of antibiotics or without clear indications can change the balance of intestinal microflora and increase the risk of NEC. The importance of judicious selection and use of antibiotics to minimize negative impacts on gut health.

Особенности микробиома кишечника при некротизирующим энтероколите у недоношенных новорожденных и доношенных новорожденных с врожденными пороками сердца по данным метагеномного секвенирования

Necrotizing enterocolitis (NEC) is a serious disease that predominantly affects premature infants with a birth weight of less than 1500 g. Newborns with ductus-dependent congenital heart disease (CHD) are also at risk of developing NEC, which is associated with impaired mesenteric perfusion and hypoxemia. Objective. To identify features of the intestinal microbiome composition of preterm neonates and full-term neonates with ductusdependent CHD, depending on the development of NEC. Patients and methods. A prospective observation of neonates and a retrospective “case-control” analysis (1:1 ratio) of the intestinal microbiome composition depending on the development of NEC were performed. In neonates with NEC, specimens were collected at the onset of NEC (±2 days), in patients without NEC – on the day of life, corresponding to the onset of the disease in newborns with NEC (±3 days) matched by gestational age. The intestinal composition was analyzed in 31 preterm newborns with stage IB–III NEC (subgroup N1 with early-onset NEC (days 1–7 of life) (n = 19); subgroup N2 with late-onset NEC (days 13–34 of life) (n = 12)), as well as in 31 preterm neonates without NEC (subgroup C1 of patients with specimens collected on days 2–7 of life (n = 19), subgroup C2 of patients with specimens collected on days 11–36 of life (n = 12)). Also, an analysis of the microbiome composition was performed in 14 full-term newborns with ductus-dependent CHD who developed NEC (group H1), and 14 full-term newborns with ductus-dependent CHD without NEC (group H2). Fecal specimens were collected from diapers into sterile tubes and stored at -40°C. Analysis of the intestinal microbiome was performed on Illumina MiSeq by prokaryotic 16S rRNA sequencing of amplicons with primers F515/R806 to the V4 16S rRNA variable region. A Naive Bayes classifier trained on the NCBI 16S RefSeq database was used for ASV taxonomic classification. Results. NEC stages of preterm neonates: IB – 5 children, IIA – 19, IIB – 4, III – 3. Stages of NEC in newborns with ductusdependent congenital heart disease: IB – 3 children; IIA – 11. There were no statistically significant differences in the Shannon alpha diversity index between groups (N1 and C1, N2 and C2, H1 and H2). Neonates with antibiotic exposure (ABT) at specimen collection had different beta diversity (PERMANOVA F-value: 24.534; R-squared: 0.21997; p = 0.001) and had a higher alpha diversity (Shannon index: 2.0 (0.8–2.8) vs. 1.2 (0.8–1.5), p = 0.004), primarily due to representatives of opportunistic flora. Analysis of the intestinal microbiome did not reveal bacteria, which could be interpreted as a universal marker for the development of NEC, but some features were identified. Among neonates from the “early” groups (N1 and C1), the dominant genera were more often Staphylococcus, Serratia, and Corynebacterium. Neonates with early-onset NEC (N1) had a significantly lower relative abundance of Enterococcus, Lacticaseibacillus, Clostridium, Fusobacterium, Limosilactobacillus, Agrococcus, Alkalibacterium, Ancrocorticia, Blautia, Brachybacterium, Brevibacterium, Carnobacterium, Citricoccus, Flaviflexus, Garicola, Lactococcus, Microbacterium, Phocaeicola, Propionimicrobium, Ruoffia, Stenotrophomonas compared to subgroup C1. Preterm neonates with late-onset NEC (N2) had a lower relative abundance of Bifidobacterium (p = 0.027) and Streptococcus (p = 0.037) than the comparison subgroup (C2) had. Neonates with late-onset NEC (N2) had a significantly higher relative abundance of Enterococcus than in early-onset NEC (N1) (7.83 (0.09–46.15) % vs. 0 (0–0.18) % resp., p = 0.0004), no differences were found between the comparison subgroups (C2 and C1). Preterm neonates with a longer NEC duration (n = 16, nil per os 20 (16–27) days) compared to children with a shorter duration (nil per os 10 (9.5–11) days) had several pathobionts/pathogens in fecal specimens at the NEC onset: Alkalibacterium, Brevibacterium, Flaviflexus and Ruo (Facklamia). Full-term neonates with ductus-dependent CHD and NEC (H1) had a higher relative abundance of Staphylococcus (p = 0.029), Serratia ( p = 0.011; OR = 14 (95% CI 1.43–137.3)), Pelomonas ( Roseateles) (p = 0.017), Methylobacterium (p = 0.017), and Nitrincola (p = 0.017) than neonates with CHD without NEC (H2). Conclusion. Intestinal dysbiosis may act as a predisposing background for the development of NEC, but not its main cause. The dysbiosis by antibiotic exposure is not a sufficient factor for NEC development; the mother's health, fetal development status, and the early postnatal period play a significant role. Early correction of antibiotic-induced dysbiosis may be a reasonable approach to preventing NEC. Probiotics, prebiotics, postbiotics/metabolites, live biotherapeutic products, and phages may be potential microbiome-modulating agents in neonates. Key words: necrotizing enterocolitis, ductus-dependent congenital heart disease, metagenomics, 16S rRNA sequencing, intestinal microbiome

Prenatal risk factors for neonatal necrotizing enterocolitis

The study aimed to determine the presence of a relationship between prenatal exposure to potential risk factors and the development of necrotizing enterocolitis (NEC) in premature infants. Materials and Methods: The clinical data of 99 mother-newborn couples diagnosed with Bell’s stage IIA NEC and a comparable comparison group were studied. The clinical characteristics of the main group with NEC were compared with the control group using the Student’s t-test. To assess the severity of the impact of potential risk factors, the Cochran - Mantel - Hensel method was used with the construction of a logistic regression model. Results. A statistically significant relationship was established between ampicillin prescribed to pregnant women and the occurrence of NEC in newborns. The adjusted odds ratio (OR) of prenatal ampicillin exposure was significantly greater for infants with NEC (OR 2.3, 95% CI 1.1, 4.8, P = 0.003) than for infants in the comparison group. Potential influencing factors (arterial hypertension, chorioamnionitis, artificial feeding and male sex) which also contribute to the development of NEC in newborns during prenatal antibiotic therapy, have been identified.

Некротизирующий энтероколит у новорожденных с врожденными пороками сердца: частота и факторы риска

Necrotizing enterocolitis (NEC) is a serious complication in newborns with critical congenital heart disease (CHD), prolonging hospital stay, worsening neurological prognosis, and increasing mortality. The leading role in the pathogenesis of NEC in these infants is the violation of mesenteric perfusion. A decrease in arterial blood oxygenation may be an additional risk factor for intestinal hypoxia. Objective. To assess the incidence and risk factors for NEC in full-term newborns with CHD born in 2019–2021 at the Perinatal Center of Almazov National Research Medical Center. Patients and methods. The article presents an analysis of the frequency and risk factors of NEC in children with CHD born at the Almazov National Medical Research Centre in 2019–2021. In the group of critical and duct-dependent CHD (n = 264), the overall incidence of NEC was 15.9% (42 cases). The frequency of surgical stages of NEC (IIIA) was 1.1% (3 cases). In the preoperative period, there was a trend towards a higher frequency of inotropic therapy in a subgroup of children who subsequently developed NEC. NEC in newborns with duct-dependent CHD developed mainly in the early postoperative period after cardiac surgery. In children with duct-dependent pulmonary blood flow, a higher incidence of NEC after surgery was noted compared to children with duct-dependent systemic blood flow. Conclusion. Risk factors for NEC in the postoperative period were arterial hypotension and hemodynamically significant cardiac arrhythmias. Dysbiosis of the gut microbiota and changes in microbial metabolism may be additional risk factors for NEC in children with CHD. Key words: necrotizing enterocolitis, risk factors, congenital heart disease, cardiopulmonary bypass, intestinal microbiome, metabolomics

Комплексна променева діагностика некротичного ентероколіту в новонароджених

Актуальність. Некротичний (некротизуючий) ентероколіт (НЕК) (Р77) — неспецифічне запальне захворювання, що викликається інфекційними агентами на тлі незрілості механізмів місцевого захисту та/або гіпоксично-ішемічного ушкодження слизової кишечника, схильне до генералізації з розвитком системної запальної реакції. Мета дослідження: визначити рентгенологічні та ультразвукові симптоми НЕК у новонароджених залежно від стадії захворювання. Матеріали та методи. Проаналізовані рентгенограми та дані ультразвукової діагностики (УЗД) органів черевної порожнини 32 новонароджених, із них 28 (87,5 %) — недоношених, 4 (12,5 %) — доношених. Результати. НЕК 1-ї ст. виявлений у 18,8 % випадків: гіперпневматоз кишечника — у 16,7 %, петлі у вигляді «скоб», потовщення стінок кишечника — у 83,3 %, мілкі горизонтальні рівні рідини з газом над ними — у 33,3 %. При УЗД відмічені потовщення стінок кишечника, зниження перистальтики в уражених сегментах. НЕК 2-ї ст. діагностований у 31,3 % випадків: ригідні петлі кишечника — в 30 %, статичні петлі кишечника — в 40 %. При УЗД відмічено потовщення стінок кишечника, зниження перистальтики в уражених сегментах, наявність прозорого випоту. При кольоровому допплерівському картуванні — посилений чи гіперемічний тип кровотоку кишкової стінки. НЕК 3-ї ст. діагностований у 28,1 % випадків: пневматоз стінки кишки — у 77,8 %; на тлі тіні печінки спостерігалося повітря в гілках портальної вени — у 33,3 %. При УЗД виявлені ознаки запалення з боку стінки кишечника (77,8 %), пневматоз стінки кишки (88,9 %) і поширення газу в портальній вені (44,4 %). НЕК 4-ї ст. діагностований у 21,9 % випадків, головною ознакою був пневмоперитонеум. Висновки. Основною метою променевого дослідження дітей із НЕК є виявлення всього комплексу проявів, що дозволяють якомога раніше діагностувати захворювання і визначити адекватне для даного пацієнта лікування. Ультразвукове дослідження органів черевної порожнини необхідно проводити всім пацієнтам, особливо з неспецифічними рентгенологічними або сумнівними для НЕК клінічними ознаками.

Стратегия энтерального питания новорожденных с некротизирующим энтероколитом

Study objective. To optimize the recommendations on the strategy of enteral feeding for newborn babies with necrotizing enterocolitis (NEC). Patients and methods. A single-centre, observational, prospective, analytical, cohort study of 186 infants aged from 2 days to 2 months (96 boys, 90 girls) with the verified diagnosis of NEC of varied severity, who were treated at the neonatal pathology department of Moscow G.N.Speransky Children’s City Clinical Hospital No 9 in 2016-2018. The patients were divided into 2 groups, depending on disease staging according to the Walsh and Kliegman classification: group I – 124 (66.7%) newborns with mild NEC (stage 1A, B and 2A) and group II – 62 (33.3%) patients with a severe course (stages 2B and 3A, B). Results. As has been found, maternal risk factors for the development of severe forms of NEC in newborns are: maternal age over 40 years (OR = 1.40, 95% CI 0.83–2.17), assisted reproductive technologies (OR = 2.62, 95% CI 1.79–3.66), bad obstetrical-gynaecological history (OR = 1.80, 95% CI 1.03–2.97), infectious diseases during pregnancy (OR = 1.37, 95% CI 0.69–1.90). The ranking of the risk factors present in babies themselves permitted to find a causative relation with such factors as bacteriological contamination of biological media (OR = 2.80, 95% CI 1.3–4.0), bacteremia, viremia (OR = 5.80, 95% CI 2.99–7.13), gestational age 30–32 wks (OR = 2.35, 95% CI 1.01–3.94), which were significant only for mild forms of NEC. A minimal number of severe cases was diagnosed for a combination of breastfeeding and parenteral nutrition (16.7%), development of severe NEC was more often noted when feeding was started within 5 days: breastfeeding (26.3%), formula feeding (33.3 %), mixed breast and formula feeding (5%), or in infants who did not receive feeding due to their severe condition after birth (33%) (р < 0.05). The minimal number of severe NEC cases was found among babies who remained on breast (11.1%) and mixed (11.1%) feeding after the 5th day (р < 0.05), the maximal number – in infants who started from enteral feeding and were transferred to formula feeding (50%). Prolonged enteral feeding was three times more often associated with a severe course of NEC (р < 0.001). Conclusion. As has been found, the frequency of developing severe NEC depends on the character of the first feed after birth. A risk of developing severe forms of NEC decreases in newborns on breast- or mixed feeding, in combination of breast feeding and parenteral nutrition, short courses of enteral pauses, alternation of enteral feeding and enteral pauses. The results might be used in the clinical practice of neonatologists and paediatricians for prevention and management of NEC and its possible complications in newborn infants. Key words: necrotising enterocolitis, enteral pause, enteral nutrition, neonatology, birth weight, gestational age, premature infants

Systematic large-scale meta-analysis identifies miRNA-429/200a/b and miRNA-141/200c clusters as biomarkers for necrotizing enterocolitis in newborn.

Necrotizing enterocolitis (NEC) is a critical neonatal disease with a high mortality. The possibility that miRNAs may play an important role in NEC has raised great attention. Hence, the present study identified biomarkers that affected NEC in newborn progression through miRNA and gene expression profile analysis. miRNA chip GSE68054 and gene chip GSE46619 of NEC in newborn were analyzed to screen out differentially expressed miRNA and differentially expressed genes (DEGs). Next, target genes of differentially expressed miRNA were predicted, and differentially expressed miRNA-DEG regulatory network was constructed to select key miRNAs. After gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis on target genes of key miRNAs, the target genes enriched in pathways were extracted to establish differentially expressed miRNA-DEG-disease gene network for gene interaction analysis. Targetting relationship between miRNAs and target genes was verified. A total of 15 miRNAs were differentially expressed in NEC in newborn, amongst which miR-429/200a/b and miR-141/200c clusters were poorly expressed and might play a significant role in NEC in newborn. Besides, target genes of miR-429/200a/b and miR-141/200c clusters were enriched in 11 signaling pathways. Vascular endothelial growth factor (VEGFA), E-selectin (SELE), kinase insert domain receptor (KDR), fms-related tyrosine kinase 1 (FLT1), and hepatocyte growth factor (HGF) were highly expressed in NEC in newborn, which were negatively regulated by miR-429/200a/b and miR-141/200c clusters and shared close association with disease genes. miR-429/200a/b and miR-141/200c clusters are poorly expressed while their target genes (VEGFA, SELE, KDR, FLT1, and HGF) are highly expressed in NEC in newborn, which might be identified as important biomarkers for this disease.

Role of lactadherin in intestinal barrier integrity in experimental neonatal necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is one of the most widespread and devastating gastrointestinal diseases in neonates. Destruction of the intestinal barrier is the main underlying cause of NEC. The aim of this study was to determine the role of lactadherin in preventing NEC in a neonatal rat model and investigate the molecular mechanism of lactadherin-mediated protection of the intestinal barrier. Neonatal rats were divided into three groups: dam feeding (DF), NEC (NEC), and NEC supplemented with 10 μg/(g·day) recombinant human lactadherin (NEC+L). Intestinal permeability, tissue damage, and cell junction protein expression and localization were evaluated. We found that lactadherin reduced weight loss caused by NEC, reduced the incidence of NEC from 100% to 46.7%, and reduced the mean histological score for tissue damage to 1.40 compared with 2.53 in the NEC group. Intestinal permeability of lactadherin-treated rats was significantly reduced when compared with that of the NEC group. In addition, the expression levels of JAM-A, claudin 3, and E-calcium in the ileum of NEC group animals increased compared with those in the ileum of DF group animals, and these levels decreased in the NEC+L group. Lactadherin changed the localization of claudin 3, occludin, and E-cadherin in epithelial cells. The mechanism underlying lactadherin-mediated protection of the intestinal barrier might be restoring the correct expression levels and localization of tight junction and adherent junction proteins. These findings suggest a new candidate agent for the prevention of NEC in newborns.

Vitamin A and Retinoic Acid Exhibit Protective Effects on Necrotizing Enterocolitis by Regulating Intestinal Flora and Enhancing the Intestinal Epithelial Barrier

Exaggerated inflammation that characterizes necrotizing enterocolitis (NEC) is caused by the invasion of pathogens through an immature intestinal barrier. Vitamin A (VA) and retinoic acid (RA) play important roles in the growth of epithelial tissue and in modulating immune function. To investigate the roles of VA and RA in the development of NEC. Levels of serum retinol in patients and in a NEC mouse model were detected with high-performance liquid chromatography. Bacterial communities of NEC mice treated with VA or PBS were detected by high-throughput sequencing. Invitro and invivo, levels of inflammatory factors were measured by ELISA and RT-PCR, and expression levels of claudin-1, occludin, and ZO-1 were detected by Western blotting. Transepithelial electrical resistance (TEER) was measured in Caco-2cell monolayers. The level of VA in the NEC patients was lower than in the control patients. In the NEC mice that were treated with VA versus PBS, the proportion of Escherichia-Shigella was lower, while the abundance of Bacteroides was markedly higher. Both invivo and invitro, the levels of inflammatory factors were significantly reduced, while the expression levels of claudin-1, occludin, and ZO-1 were increased, after the VA and RA treatments. Meanwhile, TEER was increased and lipopolysaccharide-induced damage was reduced in Caco-2cell monolayers after RA treatment. These results suggest that VA may regulate intestinal flora, alleviate inflammatory reactions, and enhance the intestinal epithelial barrier in NEC. Thus, VA may be an effective drug for providing protection against NEC in newborns.

Clinical significance of FABP2 expression in newborns with necrotizing enterocolitis.

This meta-analysis aimed to determine the role of human fatty acid binding protein 2 (FABP2) expression in the diagnosis of necrotizing enterocolitis (NEC) of newborns. Eligible studies for further statistical analysis were identified from various databases including PubMed, Expert Medica Database, Web of Science, Cochrane Library, Google Scholar, China BioMedicine and China National Knowledge Infrastructure. Random effects model was used, and summary standardized mean difference (SMD) with its 95% confidence interval (CI) was calculated to assess the association of FABP2 expression and NEC. Ten articles which included 572 infants (262 infants with NEC and 310 healthy controls) were included in the current meta-analysis. FABP2 showed a positive relationship with NEC of newborns (SMD=2.88, 95% CI=2.09-3.67, P<0.001). And FABP2 expression was higher in patients with advanced stage of NEC (stage III or stage II+III) than in those with early stage of NEC (stage I) (SMD=-0.48, 95% CI=-0.87 to -0.09, P=0.015). Ethnicity-stratified analysis yielded significantly different estimates with a high FABP2 expression in NEC in both Caucasians (SMD=3.16, 95% CI=1.90-4.43, P<0.001) and Asians (SMD=2.57, 95% CI=1.50-3.64, P<0.001). Sample-based subgroup analysis showed that FABP2 expression was positively correlated with neonatal NEC in both urinary- and blood-sample subgroups (all P<0.05). The results prove that the high FABP2 expression is related to the damage to intestinal cells, which may be a possible early detection marker identifying neonatal NEC.

The therapeutic effect of recombinant human trefoil factor 3 on hypoxia-induced necrotizing enterocolitis in immature rat

Trefoil peptides are a new class of regulatory peptides involved in mucosal protection and repair in the gastrointestinal tract. Among them, trefoil factor 3 (TFF3) (intestinal trefoil factor) is known to be cytoprotective in the gut. The aim of this study was to determine the effect of recombinant human trefoil factor 3 (rhTFF3) on hypoxia-induced necrotizing enterocolitis (NEC) in immature rats. In the present study, thirty-two 1-day-old Wistar rat pups were randomly divided into four groups. Group 1 served as nonhypoxic controls. Group 2 rats were subjected to hypoxia reoxygenation (H/O) and then were returned to their mothers. Groups 3 and 4 rats were subjected to H/O, were returned to their mothers, and were treated with rhTFF3 intraperitoneally (0.5 mg) and subcutaneously (0.2 mg), respectively, for the next 3 days. All animals were killed on day 4, and intestine specimens were obtained to determine the histological changes, tissue level of interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), prostaglandin E2 (PGE2), tromboxane B2 (TXB2), and nitric oxide (NO). In addition, the effects of rhTFF3 on abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) were also investigated. In neonatal NEC (group 2), necrosis of villi and crypts and, in some cases, transmural necrosis was observed under light microscopy. Tissue level of interleukin-8, tumor necrosis factor-α, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly higher than group 1. In addition, abundance of inducible nitric oxide synthase and cyclooxygenase 2 was markedly increased. In groups 3 and 4, only very slight intestinal injury was observed. The tissue level of interleukin-8, tumor necrosis factor-α, malondialdehyde, prostaglandin E2, tromboxane B2, and nitric oxide were significantly decreased in comparison to the group 2. Meanwhile, the abundance of inducible nitric oxide synthase and cyclooxygenase 2 was also marked decreased in comparison to group 2. The current study suggests a therapeutic role of TFF3 in an experimental model of NEC. Our findings may open a new insight into the treatment of NEC in newborns.