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Probiotics for Preventing Necrotizing Enterocolitis in Preterm Infants: A Network Meta-Analysis.
Beghetti, I, Panizza, D, Lenzi, J, Gori, D, Martini, S, Corvaglia, L, Aceti, A
Nutrients. 2021;(1)
Abstract
BACKGROUND Recent evidence supports a role of probiotics in preventing necrotizing enterocolitis (NEC) in preterm infants. METHODS A systematic review and network meta-analysis of randomized controlled trials (RCTs) on the role of probiotics in preventing NEC in preterm infants, focusing on the differential effect of type of feeding, was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A random-effects model was used; a subgroup analysis on exclusively human milk (HM)-fed infants vs. infants receiving formula (alone or with HM) was performed. RESULTS Fifty-one trials were included (10,664 infants, 29 probiotic interventions); 31 studies (19 different probiotic regimens) were suitable for subgroup analysis according to feeding. In the overall analysis, Lactobacillus acidophilus LB revealed the most promising effect for reducing NEC risk (odds ratio (OR), 0.03; 95% credible intervals (CrIs), 0.00-0.21). The subgroup analysis showed that Bifidobacterium lactis Bb-12/B94 was associated with a reduced risk of NEC stage ≥2 in both feeding type populations, with a discrepancy in the relative effect size in favour of exclusively HM-fed infants (OR 0.04; 95% CrIs <0.01-0.49 vs. OR 0.32; 95% CrIs 0.10-0.36). CONCLUSIONS B. lactis Bb-12/B94 could reduce NEC risk with a different size effect according to feeding type. Of note, most probiotic strains are evaluated in few trials and relatively small populations, and outcome data according to feeding type are not available for all RCTs. Further trials are needed to confirm the present findings.
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Bifidobacterium and Lactobacillus for preventing necrotizing enterocolitis in very-low-birth-weight preterm infants: a systematic review and meta-analysis.
Jiao, X, Fu, MD, Wang, YY, Xue, J, Zhang, Y
World journal of pediatrics : WJP. 2020;(2):135-142
Abstract
BACKGROUND The therapeutic effect of Bifidobacterium and Lactobacillus on necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants was controversial, and we aimed to explore the exact impact of the two probiotics. METHODS The PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched for studies published from January 1, 2010 to February 28, 2019. Results were combined with fixed-effect model or random-effect model with specific conditions. Sensitivity analysis was conducted by the trim-and-fill method, and the Begger's and Egger's test were used to measure publication bias. RESULTS The meta-analysis included 16 original articles with 4632 very-low-birth-weight preterm infants. With respect to the intervention of Bifidobacterium, we estimated non-significant decrease in the morbidity of NEC with a risk ratio (RR) of 0.75 [95% confidence internal (CI) 0.56-1.01, P = 0.06]. Regarding the effect of Lactobacillus, there was no evidence of significant lower risk in the incidence of NEC (RR = 0.67, 95% CI 0.39-1.17, P = 0.16). The use of mixture of probiotics (Bifidobacterium and Lactobacillus) reduced the risk of NEC in the probiotics group (RR = 0.45, 95% CI 0.25-0.80, P = 0.007). CONCLUSION The mixture of Bifidobacterium and Lactobacillus could prevent the morbidity of NEC in very-low-birth-weight preterm infants. But Bifidobacterium or Lactobacillus alone did not show this effect.
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Protective effects of different doses of human milk on neonatal necrotizing enterocolitis.
Zhang, B, Xiu, W, Dai, Y, Yang, C
Medicine. 2020;(37):e22166
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Abstract
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.
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Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis.
Chi, C, Buys, N, Li, C, Sun, J, Yin, C
European journal of clinical nutrition. 2019;(5):657-670
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BACKGROUND/OBJECTIVES Prebiotics are increasingly recognized as an effective measure to promote health and prevent adverse health outcomes in preterm infants. We aimed to systematically review the randomized controlled trials (RCTs) in this area. SUBJECTS/METHODS Relevant studies from January 2000 to June 2018 were searched and selected from PubMed, Medline, Scopus, and the Cochrane Library. RCTs were included if they involved preterm infant participants, included a prebiotic intervention group, measured incidence of sepsis, feeding intolerance, mortality, time to full enteral feeding, necrotizing enterocolitis (NEC), length of hospital stay, and stool frequency as outcomes. RESULTS Eighteen RCTs (n = 1322) were included in the final meta-analysis. Participants who took prebiotics showed significant decreases in the incidence of sepsis (with a risk ratio (RR) of 0.64, 95% CI: 0.51, 0.78), mortality (RR = 0.58. 95% CI: 0.36, 0.94), length of hospital stay (mean difference (MD): -5.18, 95% CI: -8.94, -1.11), and time to full enteral feeding (MD: -0.99, 95% CI: -1.15, 0.83). The pooled effects showed no significant differences between intervention and control groups in relation to the morbidity rate of NEC (RR = 0.79, 95% CI: 0.44, 1.44) or feeding intolerance (RR = 0.87, 95% CI: 0.52, 1.45). CONCLUSIONS The results showed that the use of prebiotics with preterm infants is safe and can decrease the incidence of sepsis, mortality, length of hospital stay, and time to full enteral feeding but not 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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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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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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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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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.
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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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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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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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Withholding Feeds and Transfusion-Associated Necrotizing Enterocolitis in Preterm Infants: A Systematic Review.
Jasani, B, Rao, S, Patole, S
Advances in nutrition (Bethesda, Md.). 2017;(5):764-769
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Limited evidence exists to support the withholding of feeds during packed red blood cell (PRBC) transfusion to reduce the incidence of transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants. The aim of the manuscript was to systematically review studies reporting the effect of implementing a policy of withholding feeds on the incidence of TANEC in preterm infants. The following databases were searched for relevant studies published between the databases' inception and December 2016: PubMed, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index of Nursing and Allied Health Literature, and Pediatric Academic Societies Abstract Archive. Other relevant sources were also searched. There were no restrictions on study design. Studies reporting on the incidence of TANEC (stage ≥2 necrotizing enterocolitis within 48-72 h) after implementation of a policy of withholding feeds in the peritransfusion period in preterm infants were included. This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. There were no randomized controlled trials (RCTs). Pooled results from 7 non-RCTs (n = 7492) showed that withholding feeds during PRBC transfusion significantly reduced the incidence of TANEC (RR: 0.47; 95% CI: 0.28, 0.80; P = 0.005; I2 = 11%). The overall quality of evidence was moderate on GRADE analysis. These findings suggest that withholding feeds during the peritransfusion period may reduce the risk of TANEC in preterm infants. Adequately powered RCTs are needed to confirm these findings.