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Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis.
Ananthan, A, Balasubramanian, H, Rao, S, Patole, S
Advances in nutrition (Bethesda, Md.). 2018;(3):238-246
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Abstract
Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
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Standardized Feeding Protocols to Reduce Risk of Necrotizing Enterocolitis in Fragile Infants Born Premature or with Congenital Heart Disease: Implementation Science Needed.
Gephart, SM, Moore, EF, Fry, E
Critical care nursing clinics of North America. 2018;(4):457-466
Abstract
Although a unit-adopted standardized feeding protocol (SFP) for neonates is standard of care, implementation strategies for SFPs vary across neonatal and pediatric intensive care. Besides improving growth and reducing feeding interruptions, SFPs reduce risk for necrotizing enterocolitis in infants with heart disease or born premature. The purpose of this article is to bridge the gap between recommended and actual care using SFPs.
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Initiation of Enteral Feeding After Necrotizing Enterocolitis.
Hock, AM, Chen, Y, Miyake, H, Koike, Y, Seo, S, Pierro, A
European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie. 2018;(1):44-50
Abstract
INTRODUCTION Management of necrotizing enterocolitis (NEC) consists of cessation of enteral feeding, intravenous antibiotic administration, and supportive treatment. There is no evidence-based recommendation regarding when to restart feeding after a NEC episode. We performed a systematic review and meta-analysis to examine the effect of timing of enteral feeding reinitiation on NEC recurrence. METHODS MEDLINE, Embase, Google scholar, and Cochrane databases were searched. Human studies evaluating enteral feeding timing with a primary outcome of NEC recurrence were included. A total of 2,257 titles or abstracts were screened, and 47 full-text articles were analyzed. A systematic review and meta-analysis comparing NEC recurrence and other associated outcomes between early (<5 days after NEC diagnosis) and delayed (>5 days) initiation of enteral feeding after NEC were performed according to the PRISMA statement. The meta-analysis data were analyzed using RevMan 5.3 to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Two retrospective observational studies met the inclusion criteria, comprising 56 cases in which enteral feeding was started early and 35 cases of delayed enteral feeding initiation. There were no randomized controlled trials (RCTs). The recurrence rates of NEC were unchanged between early (5.4%) and delayed (8.6%) enteral feeding groups (pooled OR = 0.61; 95% CI: 0.12-3.16; p = 0.56; I2 = 0%). Catheter-related sepsis (pooled OR = 0.20; 95% CI: 0.01-3.29; p = 0.26; I2 = 67%) and post-NEC stricture (pooled OR = 0.28; 95% CI: 0.07-1.18; p = 0.08; I2 = 23%) rates were not different between early and delayed enteral feeding groups. CONCLUSION Initiating early enteral feeding, within 5 days of NEC diagnosis, is not associated with adverse outcomes, including NEC recurrence. In addition, catheter-related sepsis and post-NEC stricture rates were unchanged between early and delayed enteral feeding groups after NEC. However, the quality of the evidence from the review of literature is suboptimal. A further RCT is needed to confirm these results.
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Neurodevelopmental outcomes following necrotizing enterocolitis.
Hickey, M, Georgieff, M, Ramel, S
Seminars in fetal & neonatal medicine. 2018;(6):426-432
Abstract
Necrotizing enterocolitis (NEC), a gastrointestinal emergency predominantly affecting premature infants, is associated with increased risk for poor neurodevelopmental outcomes. NEC often strikes during a period of rapid and dynamic neurologic development when the brain is particularly vulnerable to insults and nutrient deficits. The pathogenesis of neurodevelopmental impairment following NEC is likely multifactorial, with both nutritional and non-nutritional factors at play. Follow-up testing that ensures early detection and intervention for impairments is crucial to optimize neurodevelopmental outcomes following NEC. A multifaceted approach to follow-up after NEC is necessary, with close monitoring of growth, serial developmental assessments, neurologic examinations, hearing and vision testing and neuroimaging. Further research is needed to understand the pathogenesis of neurodevelopmental impairment following NEC, to identify more targeted follow-up tests, and to discover interventions aimed at optimizing neurodevelopmental outcomes following NEC.
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Low Diversity of Human Milk Oligosaccharides is Associated with Necrotising Enterocolitis in Extremely Low Birth Weight Infants.
Wejryd, E, Martí, M, Marchini, G, Werme, A, Jonsson, B, Landberg, E, Abrahamsson, TR
Nutrients. 2018;(10)
Abstract
Difference in human milk oligosaccharides (HMO) composition in breast milk may be one explanation why some preterm infants develop necrotizing enterocolitis (NEC) despite being fed exclusively with breast milk. The aim of this study was to measure the concentration of 15 dominant HMOs in breast milk during the neonatal period and investigate how their levels correlated to NEC, sepsis, and growth in extremely low birth weight (ELBW; <1000 g) infants who were exclusively fed with breast milk. Milk was collected from 91 mothers to 106 infants at 14 and 28 days and at postmenstrual week 36. The HMOs were analysed with high-performance anion-exchange chromatography with pulsed amperometric detection. The HMOs diversity and the levels of Lacto-N-difucohexaose I were lower in samples from mothers to NEC cases, as compared to non-NEC cases at all sampling time points. Lacto-N-difucohexaose I is only produced by secretor and Lewis positive mothers. There were also significant but inconsistent associations between 3'-sialyllactose and 6'-sialyllactose and culture-proven sepsis and significant, but weak correlations between several HMOs and growth rate. Our results suggest that the variation in HMO composition in breast milk may be an important factor explaining why exclusively breast milk fed ELBW infants develop NEC.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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Abstract
BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Nutrition Management of Necrotizing Enterocolitis.
Christian, VJ, Polzin, E, Welak, S
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2018;(4):476-482
Abstract
Necrotizing enterocolitis (NEC) is one of the most significant causes of morbidity and mortality among premature infants. The exact cause is considered multifactorial and related to gastrointestinal immaturity, inflammation and enteral feeding. The role of nutrition is vitally important in NEC. The main modifiable risk factor is the introduction and advancement of enteral feedings. After an infant has recovered from NEC, enteral feeds should be cautiously resumed to prevent injury from prolonged use of parenteral nutrition. The logistics of how, when, and what to feed are somewhat unclear and often depend on the severity of the disease. For patients with an enterostomy, refeeding the distal intestine with the small-intestinal ostomy output may improve bowel growth and prevent long-term complications.
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Physiological effects of prebiotics and its role in prevention of necrotizing enterocolitis in preterm neonates.
Garg, BD, Balasubramanian, H, Kabra, NS
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018;(15):2071-2078
Abstract
Necrotizing enterocolitis (NEC) is one of the most serious gastrointestinal emergencies in very low birth weight (VLBW) preterm neonates, affecting 7-14% of these neonates. Due to the seriousness of the disease, prevention of NEC is the most important goal. Current evidence from systematic review and meta-analysis revealed that probiotics are the most promising intervention in reduction of the incidence of NEC in VLBW neonates. As per the evidence, prebiotics modulate the composition of human intestine microflora to the benefit of the host by suppression of colonization of harmful microorganism and/or the stimulation of bifidobacterial growth, decreased stool viscosity, reduced gastrointestinal transit time, and better feed tolerance. Prebiotics may be potential alternatives or adjunctive therapies to probiotics, despite a lack of evidence supporting its clinical efficacy in prevention of NEC. In this article, we discuss evidence-based physiological effects of prebiotics and its therapeutic role in prevention of NEC.
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Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration.
Askie, LM, Darlow, BA, Finer, N, Schmidt, B, Stenson, B, Tarnow-Mordi, W, Davis, PG, Carlo, WA, Brocklehurst, P, Davies, LC, et al
JAMA. 2018;(21):2190-2201
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IMPORTANCE There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. OBJECTIVE To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. DESIGN, SETTING, AND PARTICIPANTS Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation. EXPOSURES Spo2 target range that was lower (85%-89%) vs higher (91%-95%). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. RESULTS A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). CONCLUSIONS AND RELEVANCE In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.
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Maternal probiotic supplementation for prevention of morbidity and mortality in preterm infants.
Grev, J, Berg, M, Soll, R
The Cochrane database of systematic reviews. 2018;(12):CD012519
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Abstract
BACKGROUND Inflammation may contribute to preterm birth and to morbidity of preterm infants. Preterm infants are at risk for alterations in the normal protective microbiome. Oral probiotics administered directly to preterm infants have been shown to decrease the risk for severe necrotizing enterocolitis (NEC) as well as the risk of death, but there are safety concerns about administration of probiotics directly to preterm infants. Through decreasing maternal inflammation, probiotics may play a role in preventing preterm birth and/or decreasing the inflammatory milieu surrounding delivery of preterm infants, and may alter the microbiome of the preterm infant when given to mothers during pregnancy. Probiotics given to mothers after birth of preterm infants may effect infant bacterial colonization, which could potentially reduce the incidence of NEC. OBJECTIVES 1. To compare the efficacy of maternal probiotic administration versus placebo or no intervention in mothers during pregnancy for the prevention of preterm birth and the prevention of morbidity and mortality of infants born preterm.2. To compare the efficacy of maternal probiotic administration versus placebo, no intervention, or neonatal probiotic administration in mothers of preterm infants after birth on the prevention of mortality and preterm infant morbidities such as NEC. 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 21 March 2017), Embase (1980 to 21 March 2017), and CINAHL (1982 to 21 March 2017). 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 We included randomized controlled trials in the review if they administered oral probiotics to pregnant mothers at risk for preterm birth, or to mothers of preterm infants after birth. Quasi-randomized trials were eligible for inclusion, but none were identified. Studies enrolling pregnant women needed to administer probiotics at < 36 weeks' gestation until the trimester of birth. Probiotics considered were of the genera Lactobacillus, Bifidobacterium or Saccharomyces. DATA COLLECTION AND ANALYSIS We used the standard methods of the Cochrane Collaboration and Cochrane Neonatal to determine the methodologic quality of studies, and for data collection and analysis. MAIN RESULTS We included 12 eligible trials with a total of 1450 mothers and 1204 known infants. Eleven trials administered probiotics to mothers during pregnancy and one trial administered probiotics to mothers after birth of their preterm infants. No studies compared maternal probiotic administration directly with neonatal administration. Included prenatal trials were highly variable in the indication for the trial, the gestational age and duration of administration of probiotics, as well as the dose and formulation of the probiotics. The pregnant women included in these trials were overall at low risk for preterm birth. In a meta-analysis of trial data, oral probiotic administration to pregnant women did not reduce the incidence of preterm birth < 37 weeks (typical risk ratio (RR) 0.92, 95% confidence interval (CI) 0.32 to 2.67; 4 studies, 518 mothers and 506 infants), < 34 weeks (typical risk difference (RD) 0.00, 95% CI -0.02 to 0.02; 2 studies, 287 mothers and infants), the incidence of infant mortality (typical RD 0.00, 95% CI -0.02 to 0.02; 2 studies, 309 mothers and 298 infants), or the gestational age at birth (mean difference (MD) 0.15, 95% CI -0.33 to 0.63; 2 studies, 209 mothers with 207 infants).One trial studied administration of probiotics to mothers after preterm birth and included 49 mothers and 58 infants. There were no significant differences in the risk of any NEC (RR 0.44, 95% CI 0.13 to 1.46; 1 study, 58 infants), surgery for NEC (RR 0.15, 95% CI 0.01 to 2.58; 1 study, 58 infants), death (RR 0.66, 95% CI 0.06 to 6.88; 1 study, 58 infants), and death or NEC (RR 0.53, 95% CI 0.19 to 1.49; 1 study, 58 infants). There was an improvement in time to reach 50% enteral feeds in infants whose mothers received probiotics, but the estimate is imprecise (MD -9.60 days, 95% CI -19.04 to -0.16 days; 58 infants). No other improvement in any neonatal outcomes were reported. The estimates were imprecise and do not exclude the possibility of meaningful harms or benefits from maternal probiotic administration. There were no cases of culture-proven sepsis with the probiotic organism. The GRADE quality of evidence was judged to be low to very low due to inconsistency and imprecision. AUTHORS' CONCLUSIONS There is insufficient evidence to conclude whether there is appreciable benefit or harm to neonates of either oral supplementation of probiotics administered to pregnant women at low risk for preterm birth or oral supplementation of probiotics to mothers of preterm infants after birth. Oral supplementation of probiotics to mothers of preterm infants after birth may decrease time to 50% enteral feeds, however, this estimate is extremely imprecise. More research is needed for post-natal administration of probiotics to mothers of preterm infants, as well as to pregnant mothers at high risk for preterm birth.