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1.
Cochrane Database Syst Rev ; 10: CD005496, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058137

RESUMO

BACKGROUND: Intestinal dysbiosis may contribute to the pathogenesis of necrotising enterocolitis (NEC) in very preterm or very low birth weight infants. Dietary supplementation with probiotics to modulate the intestinal microbiome has been proposed as a strategy to reduce the risk of NEC and associated mortality and morbidity.  OBJECTIVES: To determine the effect of supplemental probiotics on the risk of NEC and mortality and morbidity in very preterm or very low birth weight infants. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 2) in the Cochrane Library; MEDLINE Ovid (1946 to 17 Feb 2020), Embase Ovid (1974 to 17 Feb 2020), Maternity & Infant Care Database Ovid (1971 to 17 Feb 2020), the Cumulative Index to Nursing and Allied Health Literature (1982 to 18 Feb 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing probiotic supplementation with placebo or no probiotics in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratio (RR), risk difference (RD), and mean difference. We used the GRADE approach to assess the certainty of evidence for effects on NEC, all-cause mortality, late-onset infection, and severe neurodevelopmental impairment. MAIN RESULTS: We included 56 trials in which 10,812 infants participated. Most trials were small (median sample size 149). Lack of clarity on methods to conceal allocation and mask caregivers or investigators were the main potential sources of bias in about half of the trials. Trials varied by the formulation of the probiotics. The most commonly used preparations contained Bifidobacterium spp., Lactobacillus spp., Saccharomyces spp., and Streptococcus spp. alone or in combinations. Meta-analysis showed that probiotics may reduce the risk of NEC: RR 0.54, 95% CI 0.45 to 0.65 (54 trials, 10,604 infants; I² = 17%); RD -0.03, 95% CI -0.04 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 25 to 50. Evidence was assessed as low certainty because of the limitations in trials design, and the presence of funnel plot asymmetry consistent with publication bias. Sensitivity meta-analysis of trials at low risk of bias showed a reduced risk of NEC: RR 0.70, 95% CI 0.55 to 0.89 (16 trials, 4597 infants; I² = 25%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100. Meta-analyses showed that probiotics probably reduce mortality (RR 0.76, 95% CI 0.65 to 0.89; (51 trials, 10,170 infants; I² = 0%); RD -0.02, 95% CI -0.02 to -0.01; NNTB 50, 95% CI 50 to 100), and late-onset invasive infection (RR 0.89, 95% CI 0.82 to 0.97; (47 trials, 9762 infants; I² = 19%); RD -0.02, 95% CI -0.03 to -0.01; NNTB 50, 95% CI 33 to 100). Evidence was assessed as moderate certainty for both these outcomes because of the limitations in trials design. Sensitivity meta-analyses of 16 trials (4597 infants) at low risk of bias did not show an effect on mortality or infection. Meta-analysis showed that probiotics may have little or no effect on severe neurodevelopmental impairment (RR 1.03, 95% CI 0.84 to 1.26 (five trials, 1518 infants; I² = 0%). The certainty on this evidence is low because of limitations in trials design and serious imprecision of effect estimate. Few data (from seven of the trials) were available for extremely preterm or extremely low birth weight infants. Meta-analyses did not show effects on NEC, death, or infection (low-certainty evidence). AUTHORS' CONCLUSIONS: Given the low to moderate level of certainty about the effects of probiotic supplements on the risk of NEC and associated morbidity and mortality for very preterm or very low birth weight infants, and particularly for extremely preterm or extremely low birth weight infants, further, large, high-quality trials are needed to provide evidence of sufficient quality and applicability to inform policy and practice.


Assuntos
Infecção Hospitalar/prevenção & controle , Enterocolite Necrosante/prevenção & controle , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Probióticos/uso terapêutico , Causas de Morte , Enterocolite Necrosante/mortalidade , Humanos , Recém-Nascido , Infusões Parenterais/métodos , Probióticos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Medicine (Baltimore) ; 99(37): e22166, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925782

RESUMO

We aim to summarize the evidence focusing on the effects of various doses of human milk on the risk of neonatal necrotizing enterocolitis (NEC). The eligible articles in the study were those investigating the association between human milk and NEC published before June 26, 2019, in the PubMed, EMBASE, the Cochrane Library, VIP database, CNKI database, and Wangfang database. The included criteria were as follows: premature infants of <37 weeks; randomly controlled trials (RCTs); those fed by mother's own milk or donor human milk; studies focused on the comparison of human milk and formula milk, involving various breast milk doses; and NEC-related studies. Compared with the exclusive formula, the incidence of NEC in the infants fed by exclusive human milk was significantly lower. The incidence of NEC in the infants fed by exclusive human milk was significantly lower than that of partial human milk [risk ratio (RR) = 0.54, 95% confidence interval (95% CI): 0.36-0.79, P < .05]. The incidence of NEC in the infants fed mainly by human milk was significantly lower than that of mainly fed by formula. Incidence of NEC in the infants fed by exclusive human milk was significantly lower than that of any formula (RR = 0.49, 95% CI: 0.34-0.71, P < .05). In summary, this meta-analysis was based on the RCTs involving the prevention of NEC using human milk. Exclusive human milk and partial human milk reduced the incidence of NEC in premature infants, especially in the those fed by high proportion of human milk. In addition, more RCTs are needed to further validate such conclusion.


Assuntos
Enterocolite Necrosante/prevenção & controle , Doenças do Prematuro/prevenção & controle , Leite Humano , Humanos , Fórmulas Infantis , Recém-Nascido , Recém-Nascido Prematuro , Bancos de Leite , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
PLoS One ; 15(8): e0237182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764797

RESUMO

Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNFα, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis (LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1ß in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1ß, TNF-α and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.


Assuntos
Enterocolite Necrosante/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/crescimento & desenvolvimento , Exposição Materna , Probióticos/administração & dosagem , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/microbiologia , Bifidobacterium longum subspecies infantis , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/patologia , Fezes/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interleucina-1beta/administração & dosagem , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lactobacillus acidophilus , Camundongos
5.
J Agric Food Chem ; 68(26): 7014-7023, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32515192

RESUMO

Neonatal necrotizing enterocolitis (NEC) is a common and devastating disease. The objective of this research was to investigate the protective mechanisms of milk polar lipids (MPLs) on the attenuation of lipopolysaccharides (LPS)-induced intestinal inflammation and apoptosis. MPLs were extracted from buttermilk and analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A neonatal NEC rat model was used to investigate the effects of MPLs on NEC and its underlying mechanisms. Hematoxylin-eosin (H&E) staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay were used to observe intestinal morphological changes and intestinal epithelial cell apoptosis, which showed that MPLs could reduce NEC symptoms and intestinal apoptosis. The expressions of IL-6, IL-8, and TNF-α in the MPL group was significantly downregulated (P < 0.05), and the expression levels of IL-10 were significantly upregulated (P < 0.05). At the same time, MPLs also significantly reduced (P < 0.05) activation of the LPS-induced TLR4/NF-κB signaling pathway. Furthermore, MPLs inhibit apoptosis by reducing the expressions of Bax, caspase-9, and caspase-3 and by increasing the expression of Bcl-2. In conclusion, MPLs could reduce NEC symptoms in mice by inhibiting cell inflammation and protecting against intestinal apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Enterocolite Necrosante/prevenção & controle , Células Epiteliais/citologia , Mucosa Intestinal/efeitos dos fármacos , Lipídeos/administração & dosagem , Leite/química , Animais , Leitelho/análise , Enterocolite Necrosante/genética , Enterocolite Necrosante/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Lipídeos/química , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Acta Cir Bras ; 35(4): e202000401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555935

RESUMO

PURPOSE: To evaluate the effect of N-Acetylcysteine (NAC) in newborn rats submitted to hypoxia and reoxygenation (H/R) conditions in an experimental model of necrotizing enterocolitis. METHODS: Eight pregnant rats and their 70 cubs were used (5 groups) and exposed to H/R conditions and received NAC at different times. The animals in the H/R groups were placed in a gas chamber (100% CO2) for 10 minutes and then reoxygenated for 10 minutes (100% O2), twice a day for the first three days of life, with a six-hour span between events. On the third day of life, the animals were anesthetized, laparotomized and the intestines were resected. RESULTS: The H/R and NAC groups showed changes in the intestinal wall in relation to the number, height and width of the villi when compared to the control group (p<0.0001), but with better preservation of structures in the NAC group. There were no differences between groups regarding the number (%) of mitoses. CONCLUSION: The administration of NAC decreased the lesions in the intestinal wall of rats submitted to H/R, therefore suggesting that this drug can be used to prevent the development of necrotizing enterocolitis in newborns.


Assuntos
Acetilcisteína/farmacologia , Enterocolite Necrosante/prevenção & controle , Hipóxia/patologia , Íleo/efeitos dos fármacos , Íleo/patologia , Substâncias Protetoras/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Gravidez , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
7.
PLoS One ; 15(6): e0233612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479520

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of neonates, especially premature neonates. To date, there is no prophylactic treatment against NEC, except breast milk and slow increase in enteral feeding, and there is no antenatal prophylaxis. AIMS: To assess possible protective effects of antenatal N-Acetyl Cysteine (NAC) against the intestinal pathophysiological changes associated with NEC in a rat model of NEC and against its associated mortality. METHODS: Newborn Sprague-Dawley rats were divided into 5 groups: control (n = 33); NEC (n = 32)-subjected to hypoxia and formula feeding for 4 days to induce NEC; NEC-NAC (n = 34)-with induced NEC and concomitant postnatal NAC administration; NAC-NEC (n = 33)-born to dams treated with NAC for the last 3 days of pregnancy starting at gestational age of 18 days, and then subjected to induced NEC after birth; NAC-NEC-NAC (n = 36)-subjected to induced NEC with both prenatal and postnatal NAC treatment. At day of life 5, weight and survival of pups in the different groups were examined, and pups were euthanized. Ileal TNF-α, IL-6, IL-1ß, IL-10, NFkB p65, iNOS and cleaved caspase 3 protein levels (western blot) and mRNA expression (RT-PCR) were compared between groups. RESULTS: Pup mortality was significantly reduced in the NAC-NEC-NAC group compared to NEC (11% vs. 34%, P<0.05). Ileal protein levels and mRNA expression of all injury markers tested except IL-10 were significantly increased in NEC compared to control. These markers were significantly reduced in all NAC treatment groups (NEC-NAC, NAC-NEC, and NAC-NEC-NAC) compared to NEC. The most pronounced decrease was observed in the NAC-NEC NAC group. CONCLUSIONS: Antenatal NAC decreases injury markers and mortality associated with NEC in a rat model. Antenatal administration of NAC may present a novel approach for NEC prophylaxis in pregnancies with risk for preterm birth.


Assuntos
Acetilcisteína/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Enterocolite Necrosante/prevenção & controle , Depuradores de Radicais Livres/uso terapêutico , Acetilcisteína/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Caspase 3/metabolismo , Enterocolite Necrosante/tratamento farmacológico , Enterocolite Necrosante/metabolismo , Feminino , Depuradores de Radicais Livres/administração & dosagem , Interleucinas/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
8.
Vet Immunol Immunopathol ; 224: 110059, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32408182

RESUMO

There are currently no licensed vaccines against Clostridium perfringens which causes necrotic enteritis in poultry. Chitosan nanoparticles were formulated with native (CN) or toxoids (CT) of extracellular proteins (ECP) of C. perfringens, both surface-tagged with Salmonella flagellar proteins. In a pH stability assay, CN and CT nanoparticles released 6% and 0% of their protein at 8.0 pH. In a protein release assay, CN and CT nanoparticles released 16% and 10% of their protein respectively at 7.4 pH after 24 h. CN and CT nanoparticles incubated at 100 µg/mL PBS with Chicken RBCs released 1% and 0% hemoglobin respectively. Ninety broilers were randomly assigned to treatments; sham-vaccinated (Control), CN-vaccinated (CN), and CT-vaccinated (CT). Each bird was orally gavaged with 50 µg vaccine in 0.5 mL PBS or 0.5 mL PBS only on d 0, 3, 7 and 14 of age. At 21 d of age, the CN group had higher anti-ECP IgA than control (P < 0.05). At 21 d of age, the CN and CT group had higher anti-ECP IgA than control (P < 0.05). At 17 d of age, the CN group had higher anti-flagellar IgG than control (P < 0.05). At 10 d of age, the CN group had higher anti-flagellar IgA than control (P < 0.05). Splenic T cells from chickens in the CN and CT group ex-vivo stimulated with 0.05 mg/mL ECP, had higher proliferation control (P < 0.05, P < 0.01 respectively). Splenic T cells from chickens in the CN and CT groups ex-vivo stimulated with 0.1 mg/mL ECP had proliferation than control (P < 0.05). Pooled serum from 17 d of age CN and CT-vaccinated birds partially neutralized toxins in 50 µg of ECP (P < 0.05). Pooled serum from 28 d of age CN-vaccinated birds also partially neutralized toxins in 50 µg of ECP. The result from this study indicates the potential for chitosan loaded with Clostridium perfringens extracellular proteins to be applied to necrotic enteritis challenge studies.


Assuntos
Vacinas Bacterianas/imunologia , Quitosana/química , Infecções por Clostridium/veterinária , Enterocolite Necrosante/veterinária , Nanopartículas/química , Administração Oral , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Neutralizantes/sangue , Antígenos de Bactérias/imunologia , Toxinas Bacterianas/imunologia , Galinhas/imunologia , Galinhas/microbiologia , Infecções por Clostridium/imunologia , Infecções por Clostridium/prevenção & controle , Clostridium perfringens , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/prevenção & controle , Flagelos/imunologia , Imunogenicidade da Vacina , Imunoglobulina A/análise , Imunoglobulina G/sangue , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/microbiologia , Doenças das Aves Domésticas/prevenção & controle , Salmonella , Vacinas Atenuadas/imunologia
9.
Obstet Gynecol ; 135(6): 1387-1397, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32459431

RESUMO

OBJECTIVE: To estimate whether improvement in outcomes from antenatal corticosteroid treatment in extremely and very preterm twins is similar to that observed in singletons, and to investigate whether antenatal corticosteroid treatment has different effects according to chorionicity or birth order. METHODS: This population-based study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, from gestational ages of 24 0/7 to 31 6/7 weeks of gestation. After propensity score matching, univariate logistic and interaction analyses were performed to compare short-term (neonatal period) and medium-term (3 years of age) outcomes of the children of mothers who received antenatal corticosteroids with those of children of mothers who did not receive antenatal corticosteroids. We focused on differences between singletons and twins, between monochorionic and dichorionic twins and between the first and second twin. RESULTS: The study comprised 23,502 singletons and 6,546 twins. Antenatal corticosteroid treatment was associated with significant decreased short-term neurologic outcomes in both singletons and twins. However, antenatal corticosteroid treatment was associated with significantly decreased mortality (odds ratio [OR] 0.61; 95% CI 0.53-0.70), respiratory distress syndrome (OR 0.71, 95% CI 0.67-0.76), and cerebral palsy (OR 0.85, 95% CI 0.72-0.99) in singletons but not in twins (OR 0.89, 95% CI 0.68-1.17; OR 0.99, 95% CI 0.87-1.12; and OR 0.82, 95% CI 0.61-1.11, respectively). No association was found between chorionicity and the efficacy of antenatal corticosteroid treatment on outcomes. Further, no association was found between birth order and the efficacy of antenatal corticosteroid treatment on outcomes, except for periventricular leukomalacia and necrotizing enterocolitis (interaction: P=.02 and P=.04, respectively). CONCLUSION: Antenatal corticosteroid treatment in twins was associated with a beneficial effect on short-term neurologic outcomes only, without improvement in other short-term and medium-term outcomes. There was no difference related to chorionicity.


Assuntos
Corticosteroides/uso terapêutico , Doenças em Gêmeos/prevenção & controle , Gravidez de Gêmeos , Nascimento Prematuro/mortalidade , Paralisia Cerebral/prevenção & controle , Enterocolite Necrosante/prevenção & controle , Feminino , Idade Gestacional , Humanos , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Recém-Nascido Prematuro , Japão , Leucomalácia Periventricular/prevenção & controle , Modelos Logísticos , Masculino , Morbidade , Gravidez , Nascimento Prematuro/fisiopatologia , Cuidado Pré-Natal/métodos , Sistema de Registros , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Gêmeos
10.
Sci Rep ; 10(1): 6448, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296092

RESUMO

Neonatal necrotizing enterocolitis (NEC) is a serious gastrointestinal disease with high death rate in premature infants. Fish oil (FO) and its constituents have been shown to ameliorate intestinal inflammation and mucosal damage. However, the underlying mechanism of action is not known. In the present study, we divided Sprague-Dawley rats into three groups: control group, NEC model group, and FO pre-feeding+NEC model group. Briefly, one week before NEC modeling, in addition to being fed with milk, the FO pre-feeding+NEC modeling group was fed with FO, the NEC group was fed with saline, and the control group was only inserted a gastric-tube for 7 days. Subsequently, histological assay, Western blot, and ELISA were performed. Pretreatment with FO attenuated the NEC symptoms, alleviated intestinal pathological injury, and decreased the expressions of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, pretreatment with FO reduced the expressions of endoplasmic reticulum stress (ERS) related proteins, caspase-12, and glucose-regulated protein 78 (GRP78). In addition, intestinal histopathological scores showed a significant positive correlation with intestinal expressions of IL-6, TNF-α, and caspase-12. Collectively, these results indicate that ERS pathway might be involved in the effect of FO in alleviating intestinal mucosal inflammation and injury in rats with NEC.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Enterocolite Necrosante/prevenção & controle , Óleos de Peixe/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Administração Oral , Animais , Animais Recém-Nascidos , Caspase 12/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/imunologia , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/patologia , Proteínas de Choque Térmico/metabolismo , Humanos , Interleucina-6/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
11.
Nutrients ; 12(3)2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32235769

RESUMO

Objective: To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/Bifidobacterium infantis probiotics on the outcomes of preterm infants <29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. METHODS: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants <29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. RESULTS: 5954 (76.5%) infants received L. acidophilus/B. infantis prophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224; 95% CI: 2.82-4.35; p < 0.001) but not in the F group (effect size B = -0.06; 95% CI: -3.05-0.28; p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69; 95% CI: 0.59-0.79; p < 0.001). CONCLUSION: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk.


Assuntos
Bifidobacterium longum subspecies infantis , Suplementos Nutricionais , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Prematuro/fisiologia , Lactobacillus acidophilus , Leite Humano , Probióticos/administração & dosagem , Enterocolite Necrosante/prevenção & controle , Feminino , Idade Gestacional , Humanos , Fórmulas Infantis , Recém-Nascido , Masculino , Profilaxia Pré-Exposição , Sepse/prevenção & controle
12.
Cochrane Database Syst Rev ; 3: CD007137, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32232984

RESUMO

BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies. AUTHORS' CONCLUSIONS: We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.


Assuntos
Nutrição Enteral , Enterocolite Necrosante/prevenção & controle , Doenças do Prematuro/prevenção & controle , Lactoferrina/administração & dosagem , Probióticos/administração & dosagem , Sepse/prevenção & controle , Administração Oral , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Causas de Morte , Doença Crônica , Enterocolite Necrosante/epidemiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Lactobacillus rhamnosus , Pneumopatias/epidemiologia , Micoses/epidemiologia , Micoses/prevenção & controle , Números Necessários para Tratar , Ensaios Clínicos Controlados Aleatórios como Assunto , Retinopatia da Prematuridade/epidemiologia
13.
Nutrients ; 12(3)2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32192165

RESUMO

Background: Suboptimal nutritional status of a newborn is a risk factor for short- and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89-1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.


Assuntos
Enterocolite Necrosante , Mortalidade Infantil , Estado Nutricional , Probióticos/uso terapêutico , Sepse , Vitamina A/uso terapêutico , Países em Desenvolvimento , Enterocolite Necrosante/mortalidade , Enterocolite Necrosante/prevenção & controle , Humanos , Lactente , Recém-Nascido , Ensaios Clínicos Controlados Aleatórios como Assunto , Sepse/mortalidade , Sepse/prevenção & controle
14.
Arch. argent. pediatr ; 118(1): e8-e15, 2020-02-00. tab, ilus
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1095409

RESUMO

Introducción. Los probióticos y prebióticos presentan beneficios potenciales en la inflamacióncrónica de las mucosas, incluida la prevención de la enterocolitis necrosante. No obstante, los mecanismos y resultados de estos efectos inmunomoduladores son confusos. El objetivo fue investigar la respuesta de las citocinas a Lactobacillus y Bifidobacterium asociados con fructo- y galactooligosacáridos (simbióticos) y lactoferrina en recién nacidos de muy bajo peso al nacer.Población y métodos. Se asignó aleatoriamente a lactantes con ≤32 semanas de gestación y ≤1500 g de peso para recibir simbióticos o 1 ml de agua destilada como placebo desde la primera alimentación hasta el alta. Se obtuvieron muestras de sangre los días posnatales 0 ± 2, 14 ± 2 y 28 ± 2, y se midieron interferón-γ, interleucina (IL)-5, IL-10 e IL-17A.Resultados. En el grupo del estudio (n = 25), la concentración de IL-10 disminuyó a lo largo del estudio (p = 0,011), pero no cambió en el grupo de referencia. La concentración de IL-5 se mantuvo constante los primeros 14 días y luego disminuyó significativamente (p= 0,042) en el grupo del estudio, mientras que aumentó en los primeros 14 días (p = 0,019) y luego disminuyó en 28 días (p = 0,011) en el grupo de referencia (n = 25).La concentración de otras citocinas no cambió a lo largo del estudio.Conclusión. El uso combinado de probióticos con oligosacáridos y lactoferrina estuvo asociado con una disminución en la concentración de IL-10, pero no se observó un cambio en las otras citocinas.


Introduction. Probiotics and prebiotics, which are multifunctional agents, have potential benefits in chronic mucosal inflammation, including the prevention of necrotizing enterocolitis. However, the mechanisms and the results of these immunomodulatory effects are not clear. This study aimed to investigate the cytokine response to the combination of Lactobacillus and Bifidobacterium together with fructo- and galacto-oligosaccharides (symbiotic) and lactoferrin in very low birth weight neonates.Population and Methods. Infants ≤ 32 GWs and ≤ 1,500 g were randomly assigned to receive a symbiotic combination or 1 ml distilled water as placebo starting with the first feed until discharge. Blood samples were obtained at postnatal 0 ± 2, 14 ± 2, and 28 ± 2 days, and the serum levels of interferon-γ, interleukin (IL)-5, IL-10, and IL-17A were measured.Results. In the study group (n = 25), the IL-10 levels decreased throughout the study period (p = 0.011) but did not change in the control group. The IL-5 levels remained steady in the first 14 days and decreased significantly thereafter (p = 0.042) in the study group, whereas they increased in the first 14 days (p = 0.019), and then decreased in 28 days (p = 0.011) in the control group (n = 25). The levels of the other cytokines did not change throughout the study period.Conclusion.The combined use of probiotics with oligosaccharides and lactoferrin was associated with a decrease in IL-10 levels, but no change was observed in the other cytokines.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Citocinas/análise , Probióticos/uso terapêutico , Prebióticos , Simbióticos/administração & dosagem , Lactoferrina/administração & dosagem , Oligossacarídeos/uso terapêutico , Turquia , Estudos Prospectivos , Citocinas/sangue , Recém-Nascido de muito Baixo Peso , Enterocolite Necrosante/prevenção & controle , Leite Humano
15.
Int J Surg ; 76: 79-87, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32109650

RESUMO

AIM: To evaluate the safety and efficacy of Lactobacillus for preventing necrotizing enterocolitis (NEC) in preterm infants. METHODS: We searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases from inception to September 2019. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to compare outcomes. We also performed a subgroup analysis of the incidence of NEC. Moreover, a sensitivity analysis was performed to examine the stability of the results. A Begg funnel plot was generated to detect publication bias. Two reviewers assessed trial quality and extracted data independently. This work has been reported in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement and the Assessing the Methodological Quality of Systematic Reviews guidelines. Statistical analysis was performed using standard procedures in Review Manager 5.2 software. RESULTS: Twenty-three randomized, placebo-controlled studies (N = 4686 participants) were included in this analysis. Comparing the Lactobacillus and control groups, a significant reduction was found in the incidence of NEC (RR 0.34, 95% CI 0.25-0.46; P < 0.00001) and death (RR 0.48, 95% CI 0.36-0.64; P < 0.00001). No significant difference in the incidence of sepsis was found between the Lactobacillus and placebo groups (RR 0.90, 95% CI 0.72-1.12; P = 0.34). CONCLUSIONS: Lactobacillus is safe and can prevent necrotizing enterocolitis in preterm infants.


Assuntos
Enterocolite Necrosante/prevenção & controle , Recém-Nascido Prematuro , Lactobacillus , Probióticos/uso terapêutico , Humanos , Lactente , Recém-Nascido , Sepse
16.
Nutrients ; 12(2)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093194

RESUMO

Necrotizing enterocolitis, a potentially fatal intestinal inflammatory disorder affecting primarily premature infants, is a significant cause of morbidity and mortality in neonates. While the etiology of the disease is, as yet, unknown, a number of risk factors for the development of necrotizing enterocolitis have been identified. One such risk factor, formula feeding, has been shown to contribute to both increased incidence and severity of the disease. The protective influences afforded by breastfeeding are likely attributable to the unique composition of human milk, an extremely potent, biologically active fluid. This review brings together knowledge on the pathogenesis of necrotizing enterocolitis and current thinking on the instrumental role of one of the more prominent classes of bioactive components in human breast milk, glycosaminoglycans.


Assuntos
Enterocolite Necrosante/prevenção & controle , Glicosaminoglicanos/farmacologia , Doenças do Prematuro/prevenção & controle , Leite Humano/química , Substâncias Protetoras/farmacologia , Aleitamento Materno , Enterocolite Necrosante/etiologia , Enterocolite Necrosante/patologia , Feminino , Humanos , Fórmulas Infantis/efeitos adversos , Recém-Nascido , Doenças do Prematuro/etiologia , Doenças do Prematuro/patologia , Masculino , Fatores de Risco
17.
Trials ; 21(1): 170, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046760

RESUMO

BACKGROUND: Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks' gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother's own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed. METHODS: Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks' gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks' corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks' corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors. DISCUSSION: Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants. TRIAL REGISTRATION: Chinese Clinical Trial Registry; #ChiCTR1900020577; registered January 1, 2019; http://www.chictr.org.cn/showprojen.aspx?proj=34276.


Assuntos
Nutrição Enteral/métodos , Enterocolite Necrosante/epidemiologia , Congelamento/efeitos adversos , Recém-Nascido Prematuro/fisiologia , Leite Humano/fisiologia , Método Duplo-Cego , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/fisiopatologia , Enterocolite Necrosante/prevenção & controle , Feminino , Conservação de Alimentos/métodos , Idade Gestacional , Mortalidade Hospitalar , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Nutrients ; 12(2)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085587

RESUMO

This review aims to discuss the role of nutrition and feeding practices in necrotizing enterocolitis (NEC), NEC prevention, and its complications, including surgical treatment. A thorough PubMed search was performed with a focus on meta-analyses and randomized controlled trials when available. There are several variables in nutrition and the feeding of preterm infants with the intention of preventing necrotizing enterocolitis (NEC). Starting feeds later rather than earlier, advancing feeds slowly and continuous feeds have not been shown to prevent NEC and breast milk remains the only effective prevention strategy. The lack of medical treatment options for NEC often leads to disease progression requiring surgical resection. Following resection, intestinal adaptation occurs, during which villi lengthen and crypts deepen to increase the functional capacity of remaining bowel. The effect of macronutrients on intestinal adaptation has been extensively studied in animal models. Clinically, the length and portion of intestine that is resected may lead to patients requiring parenteral nutrition, which is also reviewed here. There remain significant gaps in knowledge surrounding many of the nutritional aspects of NEC and more research is needed to determine optimal feeding approaches to prevent NEC, particularly in infants younger than 28 weeks and <1000 grams. Additional research is also needed to identify biomarkers reflecting intestinal recovery following NEC diagnosis individualize when feedings should be safely resumed for each patient.


Assuntos
Enterocolite Necrosante/prevenção & controle , Fenômenos Fisiológicos da Nutrição do Lactente , Leite Humano , Animais , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/cirurgia , Humanos , Lactente , Fórmulas Infantis , Recém-Nascido , Recém-Nascido Prematuro , Intestinos/cirurgia , Leite , Nutrição Parenteral
19.
Nutrients ; 12(2)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32092925

RESUMO

Human breast milk is the optimal source of nutrition for infant growth and development. Breast milk fats and their downstream derivatives of fatty acids and fatty acid-derived terminal mediators not only provide an energy source but also are important regulators of development, immune function, and metabolism. The composition of the lipids and fatty acids determines the nutritional and physicochemical properties of human milk fat. Essential fatty acids, including long-chain polyunsaturated fatty acids (LCPUFAs) and specialized pro-resolving mediators, are critical for growth, organogenesis, and regulation of inflammation. Combined data including in vitro, in vivo, and human cohort studies support the beneficial effects of human breast milk in intestinal development and in reducing the risk of intestinal injury. Human milk has been shown to reduce the occurrence of necrotizing enterocolitis (NEC), a common gastrointestinal disease in preterm infants. Preterm infants fed human breast milk are less likely to develop NEC compared to preterm infants receiving infant formula. Intestinal development and its physiological functions are highly adaptive to changes in nutritional status influencing the susceptibility towards intestinal injury in response to pathological challenges. In this review, we focus on lipids and fatty acids present in breast milk and their impact on neonatal gut development and the risk of disease.


Assuntos
Gorduras na Dieta/administração & dosagem , Ácidos Graxos Essenciais/administração & dosagem , Intestinos/crescimento & desenvolvimento , Lipídeos/administração & dosagem , Leite Humano/química , Enterocolite Necrosante/prevenção & controle , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Recém-Nascido Prematuro/crescimento & desenvolvimento , Masculino , Estado Nutricional
20.
Cochrane Database Syst Rev ; 2: CD004863, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048730

RESUMO

BACKGROUND: Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES: To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions: To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives: Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs: To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance: To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives: To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS: This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment. Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low. Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate. Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low. Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the ESA group (weighted mean difference (WMD) 8.22, 95% CI 6.52 to 9.92; I2 = 97% (high heterogeneity); 3 studies, 981 children). The quality of the evidence was low. The total volume of RBCs transfused per infant was reduced by 7 mL/kg. The number of RBC transfusions per infant was minimally reduced, but the number of donors to whom infants who were transfused were exposed was not significantly reduced. Data show no significant difference in risk of stage ≥ 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.24, 95% CI 0.81 to 1.90; typical RD 0.01, 95% CI -0.02 to 0.04; I2 = 0% (no heterogeneity) for RR; I2 = 34% (low heterogeneity) for RD; 8 studies, 1283 infants). Mortality was not affected, but results show significant reductions in the incidence of intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL). AUTHORS' CONCLUSIONS: Early administration of ESAs reduces the use of red blood cell (RBC) transfusions, the volume of RBCs transfused, and donor exposure after study entry. Small reductions are likely to be of limited clinical importance. Donor exposure probably is not avoided, given that all but one study included infants who had received RBC transfusions before trial entry. This update found no significant difference in the rate of ROP (stage ≥ 3) for studies that initiated EPO treatment at less than eight days of age, which has been a topic of concern in earlier versions of this review. Early EPO treatment significantly decreased rates of IVH, PVL, and NEC. Neurodevelopmental outcomes at 18 to 22 months and later varied in published studies. Ongoing research should evaluate current clinical practices that will limit donor exposure. Promising but conflicting results related to the neuro protective effect of early EPO require further study. Very different results from the two largest published trials and high heterogeneity in the analyses indicate that we should wait for the results of two ongoing large trials before drawing firm conclusions. Administration of EPO is not currently recommended because limited benefits have been identified to date. Use of darbepoetin requires further study.


Assuntos
Hematínicos/administração & dosagem , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido Prematuro/sangue , Anemia Neonatal/sangue , Anemia Neonatal/prevenção & controle , Enterocolite Necrosante/sangue , Enterocolite Necrosante/prevenção & controle , Eritropoese , Eritropoetina/administração & dosagem , Eritropoetina/sangue , Humanos , Recém-Nascido , Ensaios Clínicos Controlados Aleatórios como Assunto , Retinopatia da Prematuridade/sangue , Retinopatia da Prematuridade/prevenção & controle
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