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1.
Cochrane Database Syst Rev ; 2019(10)2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31684689

RESUMO

BACKGROUND: Feeding practices around the time of packed red blood cell transfusion have been implicated in the subsequent development of necrotising enterocolitis (NEC) in preterm infants. Specifically, it has been suggested that withholding feeds around the time of transfusion may reduce the risk of subsequent NEC. It is important to determine if withholding feeds around transfusion reduces the risk of subsequent NEC and associated mortality. OBJECTIVES: • To assess the benefits and risks of stopping compared to continuing feed management before, during, and after blood transfusion in preterm infants • To assess the effects of stopping versus continuing feeds in the following subgroups of infants: infants of different gestations; infants with symptomatic and asymptomatic anaemia; infants who received different feeding schedules, types of feed, and methods of feed delivery; infants who were transfused with different blood products, at different blood volumes, via different routes of delivery; and those who received blood transfusion with and without co-interventions such as use of diuretics • To determine the effectiveness and safety of stopping feeds around the time of a blood transfusion in reducing the risk of subsequent necrotising enterocolitis (NEC) in preterm infants SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11), in the Cochrane Library; MEDLINE (1966 to 14 November 2018); Embase (1980 to 14 November 2018); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 14 November 2018). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared stopping feeds versus continuing feeds around the time of blood transfusion in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality, and extracted data from the included studies. MAIN RESULTS: The search revealed seven studies that assessed effects of stopping feeds during blood transfusion. However, only one RCT involving 22 preterm infants was eligible for inclusion in the review. This RCT had low risk of selection bias but high risk of performance bias, as care personnel were not blinded to the study allocation. The primary objective of this trial was to investigate changes in mesenteric blood flow, and no cases of NEC were reported in any of the infants included in the trial. We were unable to draw any conclusions from this single study. The overall GRADE rating for quality of evidence was very low. AUTHORS' CONCLUSIONS: Randomised controlled trial evidence is insufficient to show whether stopping feeds has an effect on the incidence of subsequent NEC or death. Large, adequately powered RCTs are needed to address this issue.


Assuntos
Nutrição Enteral/métodos , Enterocolite Necrosante/prevenção & controle , Recém-Nascido Prematuro/crescimento & desenvolvimento , Enterocolite Necrosante/etiologia , Transfusão de Eritrócitos/efeitos adversos , Humanos , Recém-Nascido , Doenças do Prematuro/etiologia , Doenças do Prematuro/prevenção & controle , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Pediatr Rev ; 40(10): 517-527, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31575803

RESUMO

Necrotizing enterocolitis (NEC) has been recognized for well over 5 decades yet remains the most common life-threatening surgical emergency in the newborn. The incidence of NEC has decreased steadily in preterm and very-low-birthweight infants over several decades and is typically uncommon in term newborns and infants with a birthweight greater than 2,500 g. Evidence accumulating during the past decade, however, suggests that practitioners should consider NEC in this broader subset of term infants with chromosomal and congenital anomalies complicated by heart or gastrointestinal defects when signs and symptoms of feeding intolerance, abdominal illness, or sepsis are present. The short- and long-term consequences of NEC are devastating in all infants, and although early disease recognition and treatment are essential, promoting human milk feeding as a primary modality in prevention is critical. This article highlights our current understanding of the pathophysiology, the clinical presentation, the risk factors for NEC in term infants compared with premature infants, and the treatment of NEC and discusses strategies in the prevention of NEC. Finally, we review the long-term consequences of NEC and the importance of primary care practitioners in the long-term care of infants after hospitalization for NEC.


Assuntos
Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/terapia , Cuidado do Lactente/métodos , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/terapia , Recém-Nascido Prematuro , Diagnóstico Diferencial , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/fisiopatologia , Humanos , Recém-Nascido , Doenças do Prematuro/etiologia , Doenças do Prematuro/fisiopatologia , Fatores de Risco , Resultado do Tratamento
3.
Nat Commun ; 10(1): 3494, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375667

RESUMO

Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association. C57BL/6 mouse pups rendered anemic by timed phlebotomy and then given RBC transfusions develop NEC-like intestinal injury with prominent necrosis, inflammation, and submucosal edema/separation of the lamina propria in the ileocecal region and colon within 12-24 h. The anemic intestine is infiltrated by inflammatory macrophages, which are activated in situ by RBC transfusions via a Toll-like receptor (TLR)-4-mediated mechanism and cause bowel injury. Chelation of RBC degradation products with haptoglobin, absence of TLR4, macrophage depletion, and inhibition of macrophage activation is protective. Intestinal injury worsens with increasing severity and the duration of anemia prior to transfusion, indicating a need for the re-evaluation of current transfusion guidelines for premature infants.


Assuntos
Anemia/complicações , Enterocolite Necrosante/etiologia , Transfusão de Eritrócitos/efeitos adversos , Doenças do Recém-Nascido/etiologia , Anemia/terapia , Animais , Animais Recém-Nascidos , Ceco/patologia , Colo/patologia , Modelos Animais de Doenças , Enterocolite Necrosante/patologia , Humanos , Íleo/patologia , Recém-Nascido , Doenças do Recém-Nascido/patologia , Recém-Nascido Prematuro , Mucosa Intestinal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
4.
Eur J Pediatr Surg ; 29(4): 352-360, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31426115

RESUMO

Necrotizing enterocolitis (NEC) is a devastating intestinal disease that continues to have high morbidity and mortality among preterm neonates, despite medical advancements in neonatology and neonatal care. To investigate the pathogenesis of the disease and explore novel form of treatment, a variety of experimental models of NEC have been developed and used by various investigators. These experimental models range from in vitro evaluation of intestinal epithelial cells and intestinal organoids to in vivo models of the disease in neonatal mice, rats, and piglets. Most recently, human-derived intestinal organoids have also been developed and investigated. In this review, we will briefly discuss these experimental models and the contributions that they have made to our understanding of NEC. We will also point to the ischemia/reperfusion (I/R) model of intestinal injury which has been used as an indirect model of NEC by some investigators. Advancements in laboratory research into this devastating disease have continued to expand our knowledge on the pathogenesis and prevention of NEC as well as the effectiveness of therapeutic options for management of this severe disease.


Assuntos
Modelos Animais de Doenças , Enterocolite Necrosante , Pesquisa Médica Translacional/métodos , Animais , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/patologia , Enterocolite Necrosante/terapia , Humanos
5.
PLoS One ; 14(7): e0219268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31283781

RESUMO

INTRODUCTION: We suspected that the incidence of NEC in Denmark had increased during the last 20 years but hypothesized that this could be explained by the increased neonatal survival. METHODS: We conducted a retrospective, observational cohort study of all registered liveborn infants in Denmark in the period from January 1, 1994 to December 31, 2014. Data were obtained from the Medical Birth Registry, National Patient Register, and Cause of Death register in Denmark. The primary outcome was the registration of NEC (ICD-10: DP77.9) during a hospital admission within 6 months after birth. The statistical analysis used 'death before NEC' as a competing risk. RESULTS: The cohort consisted of 1,351,675 infants, of which 8,059 died. There was a strongly significant decreasing risk of death over the period for the all infants (p<0.0001 in all gestational age groups). In total, 994 infants were diagnosed with NEC which lead to an incidence of 7.4 per 10,000 live-born infants. During the observation period, the incidence increased from 6.3 to 7.9 per 10,000 births (p = 0.006). When accounting for 'death before NEC' as a competing risk, the increase could be explained by the increased neonatal survival. There was, however, a GA-group/epoch interaction (p = 0.008) in the cause-specific hazard ratios with a trend towards an increasing risk of NEC in the most preterm infants and a decreasing risk of NEC in the term infants. CONCLUSION: While the overall incidence of NEC increased over the study period, the overall risk of NEC did not increase when considering the increased survival. Nevertheless, there seemed to be an increased risk of NEC in the most premature infants which was masked by a decreased risk in the term infants. This study suggests that research to prevent NEC in the most preterm infants is more important now than ever.


Assuntos
Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/etiologia , Estudos de Coortes , Dinamarca/epidemiologia , Enterocolite Necrosante/prevenção & controle , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/mortalidade , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/mortalidade , Masculino , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
6.
Nutrients ; 11(7)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248006

RESUMO

BACKGROUND: For preterm infants, human milk (HM) has to be fortified to cover their enhanced nutritional requirements and establish adequate growth. Most HM fortifiers are based on bovine protein sources (BMF). An HM fortifier based on human protein sources (HMF) has become available in the last few years. The aim of this study is to investigate the impact of an HMF versus BMF on growth in extremely low birth weight (ELBW, <1000 g) infants. METHODS: This was a retrospective, controlled, multicenter cohort study in infants with a birthweight below 1000 g. The HMF group received an exclusive HM diet up to 32+0 weeks of gestation and was changed to BMF afterwards. The BMF group received HM+BMF from fortifier introduction up to 37+0 weeks. RESULTS: 192 extremely low birth weight (ELBW)-infants were included (HMF n = 96, BMF n = 96) in the study. After the introduction of fortification, growth velocity up to 32+0 weeks was significantly lower in the HMF group (16.5 g/kg/day) in comparison to the BMF group (18.9 g/kg/day, p = 0.009) whereas all other growth parameters did not differ from birth up to 37+0 weeks. Necrotizing enterocolitis (NEC) incidence was 10% in the HMF and 8% in the BMF group. CONCLUSION: Results from this study do not support the superiority of HFM over BMF in ELBW infants.


Assuntos
Alimentação Artificial , Desenvolvimento Infantil , Fórmulas Infantis , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido de Peso Extremamente Baixo ao Nascer/crescimento & desenvolvimento , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Leite Humano , Estado Nutricional , Fatores Etários , Áustria , Peso ao Nascer , Alimentação Artificial/efeitos adversos , Enterocolite Necrosante/etiologia , Idade Gestacional , Humanos , Fórmulas Infantis/efeitos adversos , Recém-Nascido de Peso Extremamente Baixo ao Nascer/metabolismo , Lactente Extremamente Prematuro/metabolismo , Recém-Nascido , Valor Nutritivo , Estudos Retrospectivos , Fatores de Tempo
7.
Am J Physiol Gastrointest Liver Physiol ; 317(1): G57-G66, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125264

RESUMO

Prenatal inflammation is a risk factor for necrotizing enterocolitis (NEC), and it increases intestinal injury in a rat NEC model. We previously showed that maldevelopment of the intestinal microvasculature and lack of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) signaling play a role in experimental NEC. However, whether prenatal inflammation affects the intestinal microvasculature remains unknown. In this study, mouse dams were injected intraperitoneally with lipopolysaccharide (LPS) or saline at embryonic day 17. Neonatal intestinal microvasculature density, endothelial cell proliferation, and intestinal VEGF-A and VEGFR2 proteins were assessed in vivo. Maternal and fetal serum TNF concentrations were measured by ELISA. The impact of TNF on the neonatal intestinal microvasculature was examined in vitro and in vivo, and we determined whether prenatal LPS injection exacerbates experimental NEC via TNF. Here we found that prenatal LPS injection significantly decreased intestinal microvascular density, endothelial cell proliferation, and VEGF and VEGFR2 protein expression in neonatal mice. Prenatal LPS injection increased maternal and fetal serum levels of TNF. TNF decreased VEGFR2 protein in vitro in neonatal endothelial cells. Postnatal TNF administration in vivo decreased intestinal microvasculature density, endothelial cell proliferation, and VEGF and VEGFR2 protein expression and increased the incidence of severe NEC. These effects were ameliorated by stabilizing hypoxia-inducible factor-1α, the master regulator of VEGF. Furthermore, prenatal LPS injection significantly increased the incidence of severe NEC in our model, and the effect was dependent on endogenous TNF. Our study suggests that prenatal inflammation increases the susceptibility to NEC, downregulates intestinal VEGFR2 signaling, and affects perinatal intestinal microvascular development via a TNF mechanism. NEW & NOTEWORTHY This report provides new evidence that maternal inflammation decreases neonatal intestinal VEGF receptor 2 signaling and endothelial cell proliferation, impairs intestinal microvascular development, and predisposes neonatal mouse pups to necrotizing enterocolitis (NEC) through inflammatory cytokines such as TNF. Our data suggest that alteration of intestinal microvascular development may be a key mechanism by which premature infants exposed to prenatal inflammation are at risk for NEC and preserving the VEGF/VEGF receptor 2 signaling pathway may help prevent NEC development.


Assuntos
Enterocolite Necrosante/metabolismo , Inflamação/metabolismo , Intestino Delgado/irrigação sanguínea , Microvasos/metabolismo , Neovascularização Fisiológica , Efeitos Tardios da Exposição Pré-Natal , Fator de Necrose Tumoral alfa/metabolismo , Animais , Permeabilidade Capilar , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/patologia , Enterocolite Necrosante/fisiopatologia , Feminino , Idade Gestacional , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/complicações , Inflamação/patologia , Inflamação/fisiopatologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microvasos/patologia , Microvasos/fisiopatologia , Gravidez , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
EBioMedicine ; 44: 71-85, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31129099

RESUMO

BACKGROUND: Increased frequency of CCR9+ CD4+ T cells in peripheral blood is linked to several gastrointestinal inflammatory diseases; however, its relationship with necrotizing enterocolitis (NEC) is not understood. We investigated whether the frequencies of CCR9+ CD4+ T cells and related subsets were increased in peripheral blood of both patients and mice with NEC. METHODS: CCR9+ CD4+ T cells and related subsets were evaluated by flow cytometry in peripheral blood collected from both patients and mice with NEC and controls. The suppressive function of CCR9+ regulatory T (Treg) cells in NEC was assessed via in vitro suppression assay. An in vitro T cell polarization assay was performed to investigate the role of proinflammatory cytokines in Treg cell polarization. In vivo Treg cell polarization analysis was performed using NEC mice treated with anti-interleukin-6 (IL-6) receptor antibody. FINDINGS: A higher proportion of CCR9+ CD4+ T cells occurred in peripheral blood of both patients and mice with NEC than in controls. Elevated CCR9+ CD4+ T cells were primarily CCR9+ IL-17-producing Treg cells, possessing features of conventional Treg cells, but their suppressive activity was seriously impaired and negatively correlated with the severity of intestinal tissue injury. IL-6 promoted polarization of CCR9+ Treg cells to CCR9+ IL-17-producing Treg cells, and blocking IL-6 signalling inhibited this conversion in vitro and ameliorated experimental NEC in vivo. INTERPRETATION: Collectively, these data suggested that CCR9+ IL-17-producing Treg cells may be a biomarker of severity and highlight the possibility that antibodies targeting IL-6R could ameliorate NEC by modulating lymphocyte balance. FUND: This work was supported by the Science and Technology Planning Project of Guangdong Province, China (2017A020215100), the Science and Technology Foundation of Guangzhou, China (201704020086 and 201604020154), the Medical Scientific Research Foundation of Guangdong Province, China (A2017304 and A2014704), and the Social Science and Technology Development Foundation of Dongguan, China (2016108101037).


Assuntos
Enterocolite Necrosante/etiologia , Enterocolite Necrosante/metabolismo , Interleucina-17/biossíntese , Ativação Linfocitária/imunologia , Receptores CCR/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Enterocolite Necrosante/diagnóstico , Feminino , Humanos , Imunomodulação , Imunofenotipagem , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Camundongos , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Índice de Gravidade de Doença , Células Th17/imunologia , Células Th17/metabolismo
9.
Am J Physiol Gastrointest Liver Physiol ; 317(1): G67-G77, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091150

RESUMO

Prenatal inflammation may predispose to preterm birth and postnatal inflammatory disorders such as necrotizing enterocolitis (NEC). Bioactive milk ingredients may help to support gut maturation in such neonates, but mother's milk is often insufficient after preterm birth. We hypothesized that supplementation with bioactive ingredients from bovine milk [osteopontin (OPN), caseinoglycomacropeptide (CGMP), colostrum (COL)] supports gut, immunity, and NEC resistance in neonates born preterm after gram-negative infection before birth. Using preterm pigs as a model for preterm infants, fetal pigs were given intraamniotic injections of lipopolysaccharide (LPS; 1 mg/fetus) and delivered 3 days later (90% gestation). For 5 days, groups of LPS-exposed pigs were fed formula (FOR), bovine colostrum (COL), or formula enriched with OPN or CGMP. LPS induced intraamniotic inflammation and postnatal systemic inflammation but limited effects on postnatal gut parameters and NEC. Relative to FOR, COL feeding to LPS-exposed pigs showed less diarrhea, NEC severity, reduced gut IL-1ß and IL-8 levels, greater gut goblet cell density and digestive enzyme activities, and blood helper T-cell fraction. CGMP improved neonatal arousal and gut lactase activities and reduced LPS-induced IL-8 secretion in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and stimulated IEC proliferation in vitro. No effects on villus morphology, circulating cytokines, or colonic microbiota were observed among groups. In conclusion, bioactive milk ingredients exerted only modest effects on gut and systemic immune parameters in preterm pigs exposed to prenatal inflammation. Short-term, prenatal exposure to inflammation may render the gut less sensitive to immune-modulatory milk effects. NEW & NOTEWORTHY Prenatal inflammation is a risk factor for preterm birth and postnatal complications including infections. However, from clinical studies, it is difficult to separate the effects of only prenatal inflammation from preterm birth. Using cesarean-delivered preterm pigs with prenatal inflammation, we documented some beneficial gut effects of bioactive milk diets relative to formula, but prenatal inflammation appeared to decrease the sensitivity of enteral feeding. Special treatments and diets may be required for this neonatal population.


Assuntos
Caseínas/administração & dosagem , Corioamnionite/dietoterapia , Enterocolite Necrosante/prevenção & controle , Alimentos Fortificados , Imunidade nas Mucosas , Fórmulas Infantis , Intestinos/imunologia , Osteopontina/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Nascimento Prematuro , Animais , Animais Recém-Nascidos , Caseínas/imunologia , Linhagem Celular , Corioamnionite/induzido quimicamente , Corioamnionite/imunologia , Corioamnionite/metabolismo , Colostro/imunologia , Modelos Animais de Doenças , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Microbioma Gastrointestinal , Idade Gestacional , Humanos , Recém-Nascido , Absorção Intestinal , Intestinos/microbiologia , Intestinos/patologia , Lipopolissacarídeos , Valor Nutritivo , Osteopontina/imunologia , Fragmentos de Peptídeos/imunologia , Permeabilidade , Gravidez , Sus scrofa
10.
Eur J Pediatr ; 178(6): 923-928, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30949889

RESUMO

Previous studies have identified numerous risk factors associated with necrotizing enterocolitis (NEC) in very low birth weight (VLBW; birth weight less than 1500 g) infants. One of the potential pathophysiological contributors could be antibiotic therapy. Our aim was to explore the association between antibiotic exposure and NEC in VLBW infants. We designed a retrospective 1:2 case-control cohort study in a level III neonatal intensive care unit. Our study group composed of VLBW infants born between January 2012 and December 2014 with a diagnosis of NEC stage IIA or greater (Bell's modified criteria). Our intent was to match every case in the study group to two controls. Our primary outcome was an association between antibiotic exposure and NEC. Twenty-two cases of NEC were matched to 32 controls. The infants who developed NEC were exposed to a statistically significantly more frequent number of antibiotic courses and to more days on any antibiotic prior to the development of NEC. There were significant differences between cases and controls with respect to the duration of exposure to gentamicin and meropenem specifically.Conclusion: The data from our study demonstrate that prolonged exposure to antibiotic therapy is associated with an increased risk of NEC among VLBW infants. Furthermore, gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC. What is known: • Early antibiotic exposure is a risk factor for the development of necrotising enterocolitis (NEC) in very low birth weight infants • Prolonged initial empirical antibiotic course for ≥ 5 days, despite sterile blood culture, is associated with an increased risk of developing NEC What is new: • The cumulative total number of days of antibiotic exposure is associated with an increased risk of developing NEC • Gentamicin and meropenem, but not other antibiotics, had a significant association with the incidence of NEC in our study.


Assuntos
Antibacterianos/efeitos adversos , Enterocolite Necrosante/etiologia , Gentamicinas/efeitos adversos , Meropeném/efeitos adversos , Estudos de Casos e Controles , Enterocolite Necrosante/epidemiologia , Feminino , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco
11.
Early Hum Dev ; 131: 75-80, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30870625

RESUMO

BACKGROUND AND AIM: Predicting necrotizing enterocolitis (NEC) might help in preventing its devastating consequences. We aimed to investigate whether early cerebral and intestinal tissue oxygen saturation (rSO2) and fractional tissue oxygen extraction (FTOE) predict the onset of NEC. STUDY DESIGN: Prospective observational case-control study. SUBJECTS: Infants with gestational age (GA) <32 weeks were included. For every NEC case we matched two controls based on GA, birth weight (BW), and a patent ductus arteriosus. OUTCOME MEASURES: Cerebral oxygenation and intestinal oxygenation were prospectively monitored two-hours daily during the first five days after birth and once a week thereafter until five weeks after birth or until NEC developed. We used Kaplan-Meier analyses to determine the ability of near-infrared spectroscopy (NIRS) measurements, including their variability, to predict the development of NEC. RESULTS: We included ten infants (median (range) GA 27.1 (24.6-29.4) weeks, BW 903 (560-1630) grams) who developed NEC at median postnatal day 13 (range: 4-43 days), and 20 matched controls. Infants with cerebral rSO2 <70% within the first 48 h after birth developed NEC significantly more often than infants with cerebral rSO2 ≥70% (odds ratio 9.00 (95% CI 1.33-61.14). Intestinal FTOE was higher in infants who developed NEC compared to controls during the last NIRS measurement at median 2 days (range: 1-7) before NEC onset (median 0.65 vs. 0.44). CONCLUSIONS: Cerebral oxygenation monitoring early after birth might be valuable in the risk assessment of NEC development. Additionally, our results suggest that intestinal oxygenation is impaired before the onset of clinical NEC.


Assuntos
Enterocolite Necrosante/etiologia , Oxigênio/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido Pequeno para a Idade Gestacional , Mucosa Intestinal , Estimativa de Kaplan-Meier , Masculino , Oxigênio/análise , Fatores de Risco , Espectroscopia de Luz Próxima ao Infravermelho/métodos
12.
J Pediatr Surg ; 54(11): 2402-2407, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30857731

RESUMO

PURPOSE: Necrotizing enterocolitis is associated with decreased intestinal perfusion and ischemia. Paneth cells, specialized epithelial cells, have been shown to regulate the intestinal vasculature and disruption of these cells has been associated with NEC. We hypothesized that Paneth cell disruption in immature mice intestine would decrease the perfusion of the intestinal microvasculature. METHODS: Paneth cells were disrupted in P14-16 mice using chemical (dithizone) and transgenic (diphtheria toxin) methodology. Six hours after Paneth cell disruption, Dylight 488 was injected directly into the left ventricle and allowed to perfuse for 5 minutes prior to intestinal harvesting. Tissue samples were evaluated with confocal fluorescence microscopy to quantify intestinal perfusion and samples were quantified by real time RT-PCR for gene expression. RESULTS: Dithizone treatment significantly decreased intestinal perfusion compared to controls (p < 0.01). However, diphtheria toxin treatment demonstrated no significant difference in perfusion (p > 0.21). Intestines from all treatment groups had similar PECAM staining, but intestines treated with dithizone had significantly decreased nNOS and iNOS gene expression compared to controls (p < 0.007). CONCLUSIONS: Paneth cell disruption significantly decreases the perfusion of the small intestinal microvasculature in a dithizone-specific manner. Dithizone has no effect on the amount of microvasculature, but does impact genes critical to nitric oxide signaling likely contributing to mesenteric vasoconstriction.


Assuntos
Ditizona/farmacologia , Intestino Delgado/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Celulas de Paneth/efeitos dos fármacos , Animais , Toxina Diftérica/farmacologia , Modelos Animais de Doenças , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/metabolismo , Enterocolite Necrosante/patologia , Isquemia/induzido quimicamente , Camundongos , Óxido Nítrico/metabolismo , Celulas de Paneth/metabolismo , Celulas de Paneth/fisiologia , Transdução de Sinais
13.
Front Biosci (Schol Ed) ; 11: 9-28, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844734

RESUMO

The etio-pathogenesis of necrotizing enterocolitis (NEC) is complex and multifactorial. Decades of research have not identified a definite etiology. Prematurity, enteral feeding, intestinal hypoxia/ischemia, inflammation and an abnormal microbiome are potential risk factors for developing this multisystem illness. Lack of specific diagnostic and prognostic markers adds to the challenges faced in managing NEC. Vascular mediators such as Nitric oxide (NO), catecholamines and endothelin (ET) regulate neonatal intestinal vascular resistance and may influence the pathophysiology of NEC. Neonatal morbidities, medications, transfusions, an altered microbiome and breast milk feeds may influence the vasculature in various ways. Better understanding of these mediators and their role in regulation of intestinal microcirculation and pathogenesis of NEC will assist in identifying strategies in prevention and management of this devastating illness.


Assuntos
Enterocolite Necrosante/etiologia , Enterocolite Necrosante/metabolismo , Intestinos/patologia , Microcirculação , Óxido Nítrico/metabolismo , Idade de Início , Animais , Arginina/uso terapêutico , Catecolaminas/metabolismo , Modelos Animais de Doenças , Cães , Endotelinas/metabolismo , Enterocolite Necrosante/fisiopatologia , Humanos , Indometacina , Recém-Nascido , Inflamação , Leite Humano , Consumo de Oxigênio , Ratos , Ovinos , Vasodilatadores/metabolismo
14.
Indian J Pediatr ; 86(4): 347-353, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30790187

RESUMO

OBJECTIVE: To evaluate the association between red blood cell (RBC) transfusion leading to necrotizing enterocolitis (NEC) within 48 h, known as transfusion-associated necrotizing enterocolitis (TANEC). METHODS: A nested case-control study using historical data was conducted in the neonatal intensive care unit of Songklanagarind Hospital, Thailand. All very low birth weight (VLBW) infants delivered between November 2009 and July 2016 were enrolled. The infants were identified as RBC transfusion received and NEC developed. Logistic regression was used to evaluate risk factors for transfusion and the association between RBC transfusion and NEC. RESULTS: Four hundred and forty-four VLBW infants were enrolled in the study. The median (interquartile range) gestational age was 29 (27, 31) wk. The overall incidence of NEC was 13%. Three (5.2%) of the NEC infants had TANEC. The infants who received RBC transfusion had a lower gestational age [odds ratio, OR 0.64; 95% confidence interval (95%CI) 0.57, 0.73, p < 0.001] and were more likely to have pneumonia (OR 9.86; 95%CI 5.02, 19.35, p < 0.001) or to have received H2 blocker (OR 2.92; 95%CI 1.73, 4.93, p < 0.001). The ORs (95% CI) after adjusting for confounders, the association between RBC transfusion and NEC for transfusions ≤2 d, >2 to 4 d, and > 4 to 6 d prior to NEC were 1.83 (0.41, 8.16; p = 0.43), 1.7 (0.26, 11.16; p = 0.58) and 1.19 (0.31, 4.62; p = 0.80) respectively. CONCLUSIONS: After controlling of confounders, no evidence of association was found between RBC transfusion and TANEC.


Assuntos
Enterocolite Necrosante/etiologia , Transfusão de Eritrócitos/efeitos adversos , Recém-Nascido de muito Baixo Peso , Estudos de Casos e Controles , Enterocolite Necrosante/epidemiologia , Transfusão de Eritrócitos/métodos , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Fatores de Risco , Tailândia/epidemiologia
15.
An Pediatr (Barc) ; 91(4): 251-255, 2019 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-30777716

RESUMO

INTRODUCTION: Patent ductus arteriosus (PDA) is considered a risk factor for necrotising enterocolitis (NEC) and other gastrointestinal complications in preterm infants. The aim of this study is to determine whether there is a higher incidence of abdominal surgery and the associated morbidity and mortality in preterm infants who require treatment due to a significant PDA. METHODS: An observational study was conducted that included preterm infants with <37 weeks of gestational age, and a diagnosis of PDA in the last 10 years. Depending on the treatment received, the patients were divided into 3 groups: medical (A), medical and surgical (B), and no treatment (C). An analysis was performed on the pre- and peri-natal variables, as well as the incidence of gastrointestinal complications (NEC, and need for surgery for this reason), and overall mortality. RESULTS: The study included a sample of 144 patients, of whom 91 were assigned to group A, 16 to B, and 37 to C. The mean gestational age by groups was 28, 26.7, and 30.1 weeks, respectively. The mean birth weight was 1083.9 gr, 909.3 gr, and 1471.2 gr, respectively. As regards the incidence of NEC, a total of 21, 5, and 5 cases, respectively, were found in each group, with 43%, 60% and 35%, respectively requiring abdominal surgery. Mortality by groups was 12%, 19%, and 3%, respectively CONCLUSION: Patients who required treatment for a significant PDA had a higher incidence of gastrointestinal complications and higher mortality than untreated patients, with no statistically significant differences being found. In the group of patients that required treatment, lower gestational age and birth weight, could explain the increase in morbidity and mortality found in these patients.


Assuntos
Abdome/cirurgia , Permeabilidade do Canal Arterial/terapia , Enterocolite Necrosante/cirurgia , Gastroenteropatias/cirurgia , Recém-Nascido Prematuro , Peso ao Nascer , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/etiologia , Feminino , Gastroenteropatias/epidemiologia , Gastroenteropatias/etiologia , Idade Gestacional , Humanos , Incidência , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco
16.
Neonatology ; 115(3): 256-262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699425

RESUMO

OBJECTIVE: To evaluate the effect of early total enteral feeding (ETEF) when compared with conventional enteral feeding (CEF) in stable very-low-birth-weight (VLBW; 1,000-1,499 g) infants on the postnatal age (in days) at attaining full enteral feeds. METHODS: In this unblinded randomised controlled trial, 180 infants were allocated to an ETEF (n = 91) or a CEF group (n = 89). Feeds were initiated as total enteral feeds in the ETEF group and as minimal enteral nutrition (20 mL/kg) in the CEF group. The rest of the day's requirement in the CEF group was provided as parenteral fluids. The primary outcome was postnatal age at attaining full enteral feeds. The secondary outcomes included episodes of feed intolerance, incidence of sepsis and necrotising enterocolitis (NEC), and duration of hospital stay. RESULTS: The baseline variables including birth weight and gestational age were similar in the two groups. The infants of the ETEF group attained full enteral feeds earlier than those of the CEF group (6.5 ± 1.5 vs. 10.1 ± 4.1 days postnatal age; mean difference -3.6 [-4.5 to -2.7]; p < 0.001). Total episodes of feed intolerance and clinical sepsis were fewer, with a shorter duration of hospital stay, in the ETEF group (15.5 vs. 19.6 days) (p = 0.01). The incidence of NEC was similar in the two groups. CONCLUSION: ETEF in stable VLBW infants results in earlier attainment of full feeds and decreases the duration of hospital stay without any increased risk of feed intolerance or NEC.


Assuntos
Nutrição Enteral/métodos , Recém-Nascido de muito Baixo Peso , Nutrição Enteral/efeitos adversos , Enterocolite Necrosante/etiologia , Feminino , Idade Gestacional , Humanos , Incidência , Índia , Recém-Nascido , Tempo de Internação/estatística & dados numéricos , Masculino , Nutrição Parenteral Total , Sepse/etiologia
17.
BMC Pediatr ; 19(1): 2, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606146

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease of intestinal inflammation that primarily affects premature infants. A potential risk factor for necrotizing enterocolitis is exposure of the premature neonatal intestine to environmental bacteria and their proinflammatory products such as lipopolysaccharide. The metalloenzyme alkaline phosphatase (ALP) has been shown to reduce lipopolysaccharide-mediated inflammation. Additionally, premature rat pups have reduced alkaline phosphatase activity and expression as compared to full term pups. To explore the possibility that the human premature neonatal intestine has a paucity of alkaline phosphatase activity, we measured endogenously produced intestinal alkaline phosphatase activity in meconium as a function of gestational age. To test whether breast milk could serve as a source of exogenous alkaline phosphatase to the neonatal intestine through ingestion, we measured alkaline phosphatase activity in breast milk across a range of time points post-birth. METHODS: Alkaline phosphatase activity was quantified in 122 meconium samples from infants of gestational ages ranging from 24 to 40 weeks and in 289 breast milk samples collected from 78 individual mothers between days 2-49 post-birth. RESULTS: We observed a strong positive correlation between the meconium alkaline phosphatase activity and gestational age, with preterm infants having lower meconium alkaline phosphatase activities than early term or term infants. Breast milk alkaline phosphatase activity was highest in the first week post-birth, with peak alkaline phosphatase activity at day 2 post-birth, followed by relatively low alkaline phosphatase activity in weeks 2-7. CONCLUSIONS: Our results are consistent with the two major risk factors for necrotizing enterocolitis development, preterm birth and lack of breast milk feeding, both contributing to a paucity of alkaline phosphatase activity and impaired capacity to detoxify proinflammatory bacterial products such as lipopolysaccharide.


Assuntos
Fosfatase Alcalina/metabolismo , Enterocolite Necrosante/etiologia , Intestinos/enzimologia , Leite Humano/enzimologia , Fosfatase Alcalina/análise , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Leite Humano/química
18.
Eur J Pediatr Surg ; 29(3): 290-297, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29723880

RESUMO

INTRODUCTION: Prematurity, formula feeding, and early weaning strongly influence enterocyte differentiation. Intestinal alkaline phosphatase (IAP), an endogenous protein expressed in the intestines, is one enzyme that is affected by these factors. IAP supplementation decreases the severity of necrotizing enterocolitis (NEC) injury. We, therefore, hypothesized that prematurity predisposes this population to NEC due to IAP deficiency and investigated IAP expression and function in a neonatal rat model. MATERIALS AND METHODS: Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on consecutive days of life both after vaginal or cesarean birth and following either breast or formula feeding. RESULTS: Compared with controls, cesarean delivery and formula feeding are associated with lower levels of IAP. The formula-fed pups continued to have low baseline IAP activity. Neither prematurity nor formula feeding led to differences of intestinal injury. CONCLUSION: Prematurity and formula feeding are associated with inhibition of IAP expression and activity. Both may increase the risk of NEC and early enteral supplementation of IAP to newborns at risk of NEC may be of therapeutic benefit.


Assuntos
Fosfatase Alcalina/deficiência , Enterocolite Necrosante/etiologia , Doenças do Prematuro/etiologia , Isoenzimas/deficiência , Fosfatase Alcalina/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Cesárea/efeitos adversos , Enterocolite Necrosante/metabolismo , Humanos , Fórmulas Infantis/efeitos adversos , Recém-Nascido , Doenças do Prematuro/metabolismo , Isoenzimas/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Risco
19.
Pediatr Neonatol ; 60(2): 129-134, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30100520

RESUMO

BACKGROUND: To examine whether polymorphisms in the VEGFA gene lead to low VEGFA production in peripheral blood and increased risk of NEC in the Chinese Han population. MATERIAL AND METHODS: Thirty NEC patients and 80 control subjects were enrolled. Six VEGFA single-nucleotide polymorphisms (SNPs) were performed using the SEQUENOM MassARRAY platform assay. The concentration of VEGFA in the plasma was measured using an enzyme-linked immunosorbent assay. RESULTS: The rs699947 and rs833061 VEGF-A SNPs were found to be associated with low plasma levels and high risk of NEC. CONCLUSION: Our results suggested that, if validated in larger studies, screening for VEGFA SNPs and plasma levels might be useful as a risk factor for NEC in the future.


Assuntos
Enterocolite Necrosante/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Grupo com Ancestrais do Continente Asiático/genética , China/etnologia , Enterocolite Necrosante/etiologia , Predisposição Genética para Doença , Humanos , Fator A de Crescimento do Endotélio Vascular/sangue
20.
Eur J Pediatr Surg ; 29(1): 14-22, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30112744

RESUMO

AIM: The main purpose of this study was to investigate if necrotizing enterocolitis (NEC) has a different presentation and outcome in patients with congenital heart defect (CHD) (cardiogenic NEC) from those without (classical NEC). MATERIALS AND METHODS: A systematic review of the literature on the characteristics of infants with NEC and CHD was performed by three independent investigators using a defined strategy (PubMed, Cochrane, Embase, and Web of Science). A meta-analysis was conducted on studies comparing NEC in infants with CHD and non-CHD infants using RevMan 5.3. RESULTS: Systematic review: Of 7,291 abstracts screened, 126 full-text articles were analyzed and 51 studies were included. NEC had an incidence of 5.1% in CHD infants (7,728/151,046, range 0-24%) and 0.8% in non-CHD infants (26,430/3,256,891, range 0.1-8.9%; p < 0.0001). In very low birth weight infants, NEC occurred in 6.3% of CHD patients (6,361/100,454pts) and in 8.9% of non-CHD (23,201/257,794pts; p < 0.0001). In CHD cases, NEC occurred before cardiac surgery in 48% cases and surgery for NEC was required in 31% infants (2,037/6,683). Meta-analysis: In eight comparative studies, the incidence of NEC was higher in CHD infants (6%, 768/13,145) than in infants with no CHD (0.9%, 32,625/3,354,323pts; p < 0.00001, odds ratio [OR] 1.84, 95% confidence interval [CI] 1.7-1.9). The overall mortality was higher in infants with CHD and NEC (38%, 243/640) than in those without CHD (27%, 6651/24810; p < 0.00001, OR 3.4, 95% CI 2.8-4.1). CONCLUSION: This is the first evidence-based study showing that infants with cardiogenic NEC have different demographics and outcomes than those with classical NEC. The risk of developing NEC and the mortality rate are higher among infants with CHD than in those without. Conversely, the need for intestinal surgery is lower in babies with cardiogenic NEC than in those with classical NEC. Further studies are needed to establish preventative and management interventions that are specific to infants with or at risk of developing cardiogenic NEC.


Assuntos
Enterocolite Necrosante/etiologia , Cardiopatias Congênitas/complicações , Enterocolite Necrosante/mortalidade , Enterocolite Necrosante/cirurgia , Medicina Baseada em Evidências , Cardiopatias Congênitas/cirurgia , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Fatores de Risco , Resultado do Tratamento
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