Gut Injury and the Microbiome in Neonates.

The causes of neonatal gut injury are multifactorial and include ischemia, tissue hypoxia due to anemia, excessive inflammation, deficiency of growth factors, and food protein sensitivity. The developing intestinal microbiome plays a role in some of these forms of intestinal injury but knowledge of its relative role in each remains poorly understood. Commensal bacteria are required for normal immune development and immune tolerance. Dysbiosis in the neonatal gut that alters the patterns of commensal and pathogenic bacteria may accentuate gut injury.

Recent Advances in Necrotizing Enterocolitis Research: Strategies for Implementation in Clinical Practice.

Necrotizing enterocolitis (NEC) is a complex inflammatory necrosis of the neonatal intestine, which is likely to require a multipronged approach for prevention and treatment. Despite identifying and defining NEC as a disease entity several decades back, no major progress has been made toward its early identification, treatment, or prevention. This article reviews the latest research strategies that are currently ongoing for early diagnosis and monitoring and prevention of the disease.

Animal Models of Congenital Gastrointestinal Maladies.

The gastrointestinal (GI) tract consists of a remarkable series of organs that spatially and temporally coordinate the vital process of digestion to extract key nutrients required to sustain our day-to-day functions. During development, it undergoes complex and highly specialized morphogenetic events to form functionally distinct organs. Its failure to develop properly leads to serious congenital diseases, which if left untreated are particularly devastating and often result in premature death. These GI diseases have been estimated to impact approximately 8-16 of every 10,000 newborns [1, 2]. Importantly, the clinical manifestations of these diseases are severe, with untreated cases having high mortality rates. While some disorders, such as Hirschsprung's disease, can be treated effectively with surgery, the efficacy of this management strategy is far lower for other diseases, such as necrotizing enterocolitis. Moreover, children often face complications from these surgical procedures, leading to secondary ailments. Consequently, a better understanding of gastrointestinal development is fundamental to the treatment and prevention of congenital GI maladies. This chapter will explore some of the most prevalent and biologically complex congenital diseases of the GI system, with emphasis on animal models that both elucidate their underlying causes and lay the essential groundwork for the advancement of translational medicine.

Maternal and placental risk factors associated with the development of necrotizing enterocolitis (NEC) and its severity.

BACKGROUND/PURPOSE: Antenatal factors play an important role in NEC. This study aimed to identify antenatal risk factors associated with the development of NEC, the role of the placental alterations, and the presence of prenatal signs predisposing to a severe NEC. MATERIALS/METHODS: Data of NEC patients including antenatal findings [preeclampsia, diabetes, cholestasis, abnormal antenatal umbilical artery flow (AAUF), clinical chorioamnionitis (CC), and histology of placentas] were compared to unaffected cases between 2002 and 2016 in a single center. Unaffected infants were matched for gestational age. Newborns with cardiovascular diseases were excluded. Bivariate and multivariate analyses were performed. RESULTS: We identified 136 cases and 134 controls. The group of mothers of NEC-neonates had a higher prevalence of preeclampsia, CC, and AAUF. Histology of Placentas from 123/136 cases and 126/133 unaffected newborns was available. Chorioamnionitis was significantly more present in NEC cases vs controls. There weren't differences in vascular anomalies and necrotic alterations. Multivariate analysis identified AAUF, CC and histological chorioamnionitis (HC) as predictors of NEC. Bivariate tests show that preeclampsia and HC occurred more often in severe cases of NEC. CONCLUSION: This study suggests that AAUF, CC, and HC can independently predict the risk of NEC. Preeclampsia and HC seem associated to more severe cases. LEVEL OF EVIDENCE: IIIA.

Factores perinatales en el desarrollo de enterocolitis necrotizante. Un estudio de casos y controles / Perinatal factors for necrotizing enterocolitis (NEC). A case-control study

Objetivos. Identificar factores perinatales que favorezcan el desarrollo de enterocolitis necrotizante (ECN) en las unidades de cuidados intensivos neonatales (UCIN). Métodos. Estudio de casos y controles de los recién nacidos (RN) tratados entre 2014-2015. Se evaluaron factores de riesgo materno-fetal (fiebre, corioamnionitis, cultivos rectovaginales y sufrimiento intrauterino) y neonatales (edad gestacional, canalización de vasos umbilicales, hemocultivos, sepsis, nutrición y probióticos) y su asociación a la ECN. Estudiamos también la existencia de tratamiento antibiótico y antifúngico intravenoso previo al cuadro de ECN. Se estimó la odds ratio con un nivel de significación p < 0,05. Resultados. Se analizaron 500 neonatos: 44 ECN y 456 controles. En el análisis univariante ninguno de los factores de riesgo maternos se relacionó con el desarrollo de ECN. No se encontraron diferencias significativas en los RN que recibieron alimentación enteral o probióticos. Los RN con sufrimiento fetal y los diagnosticados de sepsis precoz presentaron mayor riesgo de desarrollo de ECN (p < 0,0001). Conclusión. La pérdida de bienestar fetal y la sepsis precoz favorecen el desarrollo de ECN, que también parece aumentar con el uso de antibioterapia sistémica así como el tratamiento antifúngico profiláctico para las infecciones de catéter o intubaciones orotraqueales prolongadas

Aim of the study. The aim of this study is to identify potential perinatal risk or protective factors associated with NEC. Materials and methods. Single-center, retrospective case-control study of newborns admitted to the neonatal intensive care unit with NEC from 2014 to 2015. Clinical charts were reviewed recording maternal factors (fever, positive recto-vaginal swab and signs of corioamnionitis or fetal distress), and neonatal factors analyzed were: birth- weight and weeks gestation, umbilical vessel catheterization, time of enteral feedings and the use of probiotics, antibiotics and antifungal agents. Cases and controls were matched for all of these factors. Parametric tests were used for statistical analysis and p ≤ 0.05 deemed significant. Results. We analyzed 500 newborns of which 44 developed NEC (cases) and 456 controls. Univariate analysis did not identify any maternal risk factors for NEC. We did not found statistical differences between patients either time of enteral feedings or probiotics. Nevertheless, patients with signs of fetal distress and early sepsis had a higher risk of NEC (p ≤ 0.0001). Conclusions. Infants with history of fetal distress and signs of early sepsis are at a higher risk of NEC. The use of prophylactic catheter infection or orotracheal intubation with antifungal treatment seemed to elevate the incidence of NEC. However, antibiotic treatment couldn't be demonstrated to increase the risk of NEC

Anomalías colorrectales / Colorectal anomalies

Las anomalías colorrectales constituyen un grupo de patologías muy variadas. el objetivo de este artículo es repasar su diagnóstico y manejo inicial hasta llegar al tratamiento quirúrgico

Colorrectal diseases are very different entities. The aim of this paper is reviewing the diagnosis and initial management of them to reach the appropriate surgical treatment

Necrotizing enterocolitis in premature infants and newborns.

Necrotizing enterocolitis (NEC) is the most common acquired disease of the gastrointestinal tract (GIT) in premature infants and newborns. It is defined as an ulcerative inflammation of the intestinal wall. The clinical signs of incipient NEC are often very discrete, and range from localized intestinal symptoms to generalized signs of sepsis. NEC is classified depending on its severity into disease states according to the modified Bell's Classification. Treatment of NEC ranges, depending on its severity, from a conservative therapeutic approach to surgery with resection of the affected parts of the intestine. Mortality is considerably high in extremely small preterm infants reaching up to 42% of the affected children. Measures such as breastfeeding or alternatively nutrition with pasteurized human donor milk from a milk bank, administration of probiotics, avoidance of histamine type II receptor antagonists, and restrictive antibiotic treatment should be considered early on for prevention of NEC.

The metabolomics of necrotising enterocolitis in preterm babies: an exploratory study.

OBJECTIVE: No single diagnostic investigation is currently available for necrotising enterocolitis (NEC). We implemented a novel, untargeted, exploratory study to determine whether metabolomics can reveal early biomarker(s) of NEC. The effect of gestational age on the metabolome was also investigated. METHODS: Two serum samples were obtained from 12 preterm babies (born <30 weeks gestation) and eight term controls: sample "A" at ≤1 week of age and sample "B" once fully fed. Samples were subjected to gas chromatography-mass spectrometry. Metabolomic data was analysed by principal component analysis (PCA), univariate and network analysis. RESULTS: Sixteen metabolite features significantly differed when B samples were compared between preterm babies who subsequently developed NEC and preterm/term controls (p value <0.05). Of these seven metabolites were linked to up-regulation of IL-1ß. Significant differences in 54 metabolite features (p value <0.05) were observed between preterm and term metabolomes. Of these, 12 metabolite features were linked to one network involved in carbohydrate/lipid metabolism (p = 1 × 10(-30)). CONCLUSIONS: Metabolomic differences were observed in preterm babies at risk of NEC. However, sample sizes were insufficient to confidently identify a biomarker. Network modelling of preterm and term metabolomes suggest possible nutritional deficiency and altered pro-insulin action in preterm babies.

[Epidemiology of infections in very low birth weight infants. Polish Neonatology Network research]. / Epidemiologia Zakazen Noworodkówz Bardzo Mala Masa Urodzeniowa.badania Polskiej Sieci Neonatologicznej.

AIM OF STUDY: 1. prospective record of infections; 2. prevention of nosocomial infections by providing current data about infections, which are significant for making therapeutic decisions. MATERIAL AND METHODS: Recorded infections: early-onset sepsis (congenital), late-onset sepsis (acquired in hospital), necrotising enterocolitis (NEC), pneumonia. Infections were diagnosed and qualified on the basis of definitions of infections based on the National Nosocomial Infections Surveillance (NNIS) criteria, developed by CDC, USA, including modifications of German Neo-KISS programme. Infection control was realised as a part of common research project of "Polish Neonatology Network", appointed by the decision of the Minister of Science and Higher Education no. 669/E-215/BWSN- 0180/2008 dated 20.05.2008 r. The study was conducted by 6 Polish neonatology units, Microbiology Chair of Jagiellonian University Collegium Medicum and Institute of Theoretical and Applied Computer Science. Infants with birth weight lower than 1500 g were qualified for the study. RESULTS: Between 1.01.2009 and 31.12.2009, 910 patients were registered, i.e. 19.1% of VLBW infants born in that period. The conducted analysis showed significant differences between centres in gestational age, birth weight, hospitalisation, use of invasive procedures, antibiotics and parenteral feeding. Cumulative morbidity rate was 68.5% total. Blood infection (sepsis) was the most commonly observed type of infection: 268 cases - 43.1% of all recorded forms of infection. Pneumonia was diagnosed in 242 cases, 38.8% total. NEC constituted 12.7% studied infections (79 cases). Apart from NEC, the risk of other forms of infection differed between centres. Dominant etiologic factor of all infections were Gram-positive cocci, which constituted 565 isolated microorganisms. Among them coagulase-negative staphylococci (CNS) were the most common (41.7%), while Staphylococcus aureus was fourth most frequent etiologic factor of infections (6.3% total). CONCLUSIONS: 1. Introduction of unified definition and criteria for diagnosing infections and the use of morbidity rates enables comparative analysis of epidemiology of infections in neonatal intensive care units. 2. Due to significant differences observed between prophylactic and therapeutic procedures in various units, it is essential to propose Polish recommendations regarding control over etiology of infections and use of invasive procedures, such as intravenous catheters and ventilation. 3. It is essential to undertake action leading to fully rational antibiotic therapy, because overuse of antibiotics leads to bacterial resistance and increases incidence of infections.

Factors affecting the severity of necrotizing enterocolitis.

OBJECTIVE: The severity of necrotizing enterocolitis (NEC) ranges from mild to rapidly fatal. However, the factors determining the severity are not known. Our objective was to identify statistical associations with NEC severity using a large database. METHOD: We conducted a retrospective, multi-institutional, multiyear, study of neonates with confirmed NEC. RESULTS: Two-hundred-twenty neonates with Bell's stage ≥ II NEC had 225 NEC episodes (157 stage II and 68 stage III). In the 3 d before NEC was diagnosed, those who went on to stage III disease were more likely to have elevations in C - reactive protein (p < 0.0001), immature to total neutrophil ratio (p = 0.0005), and mean platelet volume (p = 0.0001), and low pH (p < 0.0001) and platelet count (p < 0.0001). Regression analysis indicated higher odds that NEC would be severe if there was an antecedent RBC transfusion (p < 0.0001) or if the first feedings were not colostrum (p = 0.017). The two factors best predicting death from NEC were; (1) a low pH (p = 0.0005) and (2) lack of early colostrum (p = 0.003). CONCLUSIONS: Strategies that reduce the severity of NEC would lower costs and improve outcomes. This study suggests that testable theories to accomplish this include means of; (1) reducing transfusions and (2) assuring early colostrum feedings.

Haematological abnormalities in neonatal necrotizing enterocolitis.

OBJECTIVE: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in preterm infants born prior to 32 weeks gestation or with a birth weight less than 1500 grams. In this article, we review hematological abnormalities associated with NEC. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Thrombocytopenia, disseminated intravascular coagulation, increased or decreased neutrophil counts, and hemolytic anemia are frequent events in NEC. CONCLUSIONS: NEC is associated with several hematological abnormalities, which may play a direct or indirect role in the pathogenesis of gut mucosal injury, and may also carry important prognostic information.

Plasma citrulline levels in preterm neonates with necrotizing enterocolitis.

BACKGROUND AND AIM: Citrulline is a non-protein amino acid synthesized in the small intestine. In children with short-bowel syndrome, citrulline has served as a reliable marker of the residual bowel length and parenteral nutrition (PN) independence. In the present study we aim to assess the value of citrulline measurement in preterm neonates developing necrotizing enterocolitis (NEC). METHODS: Plasma citrulline levels were measured prospectively in 17 preterm neonates with NEC stage II during the entire course of the disease. Serial citrulline determinations in 24 healthy preterm neonates on 2, 7, 14, 21 and 28 days of life (DOL), served as reference values. RESULTS: In healthy preterm neonates plasma citrulline levels showed a progressive increase in relation to age. In neonates presenting with NEC, mean citrulline levels were significantly lower as compared to controls' citrulline levels of the most approximate day of life (DOL 7: 16.85±4.2 vs 20.5±4.5 µmol/L, p<0.05; DOL 14: 18±4.2 vs 23.5±4.3 µmol/L, p<0.01; DOL 21: 17±2.5 vs 30±5.7 µmol/L, p<0.01). The optimal citrulline cut-off distinguishing NEC patient from controls was 17.75 µmol/L (sensitivity 76%, specificity 87%). Plasma citrulline at presentation correlated inversely with the duration of parenteral nutrition (r=-0.49, p<0.05). Consecutive citrulline determinations revealed that plasma citrulline increased during reintroduction and gradual increase of enteral nutrition. CONCLUSIONS: Our findings provide preliminary evidence that citrulline levels that are reduced in preterm neonates with NEC in comparison to age-matched controls and serial citrulline determinations could help to monitor improvement of functional enterocyte mass during the course and resolution of NEC.

Hypothermia: novel approaches for premature infants.

Hypothermia for hypoxic ischemic encephalopathy has recently permeated clinical practice for term infants. Speculation regarding a neuroprotective benefit of hypothermia for premature infants with HIE has been raised as a need for further research. Hypothermia for other indications including necrotizing enterocolitis with the hope of tissue preservation following injury is less well studied. A summary of evidence for hypothermia and premature infants is presented in this brief report.

Intestinal malrotation in an extremely preterm very low birthweight infant.

A case of a very low birthweight premature infant with a clinical presentation of necrotising enterocolitis that was found to have malrotation and midgut volvulus at autopsy is presented.

Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes.

Elevated concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) in fetal and neonatal compartments have been associated with an increased risk for preterm birth (PTB) and/or neonatal morbidity. The purpose of this study was to determine if the maternal serum concentration of IL-6, CRP, and MMP-9 in women at risk for PTB, who are not in labor and have intact membranes, are associated with an increased risk for PTB <32 weeks and/or neonatal morbidity. Maternal serum samples collected from 475 patients enrolled in a multicenter randomized controlled trial of single versus weekly corticosteroids for women at increased risk for preterm delivery were assayed. Serum was collected at randomization (24 to 32 weeks' gestation). Maternal serum concentrations of IL-6, CRP, and MMP-9 were subsequently determined using enzyme-linked immunoassays. Multivariate logistic regression analysis was performed to explore the relationship between maternal serum concentrations of IL-6, CRP, and MMP-9 and PTB <32 weeks, respiratory distress syndrome (RDS), chronic lung disease (CLD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and any sepsis. Maternal serum concentrations of IL-6 and CRP, but not MMP-9, above the 90th percentile at the time of randomization were associated with PTB <32 weeks. In contrast, there was no significant relationship between RDS and NEC and the maternal serum concentration of IL-6, CRP, or MMP-9 (univariate analysis). The development of CLD was associated with a high (above 90th percentile) IL-6 and CRP in maternal serum, even after adjustment for gestational age (GA) at randomization and treatment group. However, when GA at delivery was added to the model, this finding was nonsignificant. Neonatal sepsis was more frequent in neonates born to mothers with a high maternal serum concentration of CRP (>90th percentile). However, there was no significant association after adjustment for GA at randomization and treatment group. Logistic regression analysis for each analyte indicated that high maternal serum concentrations of IL-6 and CRP, but not MMP-9, were associated with an increased risk of IVH (odds ratio [OR] 4.60, 95% confidence interval [CI] 1.86 to 10.68; OR 4.07, 95% CI 1.63 to 9.50) after adjusting for GA at randomization and treatment group. Most babies (25/30) had grade I IVH. When GA at delivery was included, elevated IL-6 remained significantly associated with IVH (OR 2.77, 95% CI 1.02 to 7.09). An elevated maternal serum concentration of IL-6 and CRP are risk factors for PTB <32 weeks and subsequent development of neonatal IVH. An elevated maternal serum IL-6 appears to confer additional risk for IVH even after adjusting for GA at delivery.

Prediction of progression of definite necrotising enterocolitis to need for surgery or death in preterm neonates.

OBJECTIVE: To study the predictive abilities of laboratory parameters in the prediction of progression of definite necrotising enterocolitis (NEC) to need for surgery or death in preterm neonates. METHODS: Retrospective analysis of data (January 2001-July 2006) on all preterm (gestation < 32 weeks) neonates with definite (Stage > or = II) NEC according to the Bell's staging in a regional referral centre. Group I included those who were medically managed (medical NEC) and Group II requiring surgery (surgical NEC). Serial changes in laboratory parameters (C-reactive protein, (CRP), platelet count, plasma glucose and lactate) within 24 h before and over 72 h after the diagnosis of NEC were correlated to progression to surgery or death. RESULTS: CRP levels were significantly higher at 72 h in the surgical versus medical group. Plasma glucose and lactate levels were significantly higher when compared with the baseline levels at all time points for both groups. Receiver operator curve analysis (N = 30) indicated that significant rise in CRP [baseline to 72 h (area under the curve, AUC: 0.933, p = 0.001)] and in lactate levels [baseline to 48 h (AUC: 0.818, p = 0.047)] had a strong potential as a predictor for progression to surgery or death. CONCLUSION: Serial changes in CRP and plasma lactate level may predict progression of definite NEC to surgery or death in preterm neonates.

Neonatal complications following preterm birth.

Improvements in neonatal intensive care during the last 20 years have increased the survival of the most immature newborns at 23 weeks from 0% to 65% at some centres, although rates vary widely among neonatal care centres. University of Utah, USA data show that each week in utero after week 23 raises survival by 6-9%, to 90% by 27-28 weeks and 95% by 33 weeks. Provision of care in specialised centres to provide high-risk obstetric and neonatal intensive care, prenatal treatment with corticosteroids, postnatal treatment with surfactant and nitric oxide, and improvements in respirators and equipment to care for extremely immature infants all contribute to these changes. The increased rate of survival for extremely premature newborns has not been accompanied by an increased rate of severe intraventricular haemorrhage or neurological impairment, such as cerebral palsy. Regardless, intraventricular haemorrhage remains a significant problem, especially if associated with post-haemorrhagic hydrocephalus, leading to long-term neurological impairment and decreased survival. Necrotising enterocolitis (NEC) is more common in premature than in term newborns and is the most frequent cause of short bowel syndrome in infancy. Survival after surgery for NEC has improved during the last two decades, but complications of nutritional support produce many long-term problems. Retinopathy of prematurity (ROP) remains a frequent cause of neurosensory impairment for extremely premature newborns. Laser photocoagulation for advanced ROP is more effective than cryotherapy for preventing retinal detachment and improving visual outcomes. Despite prenatal corticosteroid treatment and postnatal surfactant administration, many extremely premature newborns still develop bronchopulmonary dysplasia. Abnormal pulmonary function may persist into adulthood, but newer ventilators and management schemes appear to be reducing this long-term morbidity. Many changes in neonatal care occur each year, but carefully controlled outcome studies are needed to evaluate the effectiveness of these newer styles of neonatal intensive care.

Drenaje peritoneal percutáneo en la enteritis necrotizante perforada / Drainage peritoneal percutáneo in the enteritis necrotizante perforated

Se presenta el primer caso en nuestro país de un niño de extremo bajo peso al nacer con enterocolitis necrotizante perforada, tratado con drenaje peritoneal percutáneo. Se expone la técnica quirúrgica y se revisa la literatura al respecto, donde se evidencia que el drenaje peritoneal es una opción terapéutica en estos pequeños pacientes, como medida de estabilización inicial antes de la realización de una laparotomía, aunque puede constituir el tratamiento definitivo en un número reducido de pacientes(AU)