Gayatri Athalye-Jape

Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis.

CONTEXT: Late-onset sepsis (LOS) is a major cause of mortality and morbidity in preterm infants. Despite various preventive measures, its incidence continues to remain high, hence the urgent need for additional approaches. One such potential strategy is supplementation with probiotics. The updated Cochrane Review (2014) did not find benefits of probiotics in reducing the risk of LOS in preterm infants (19 studies, N = 5338). Currently there are >30 randomized controlled trials (RCTs) of probiotics in preterm infants that have reported on LOS. OBJECTIVES: To conduct a systematic review including all relevant RCTs. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in June and August 2015. STUDY SELECTION: RCTs comparing probiotics versus placebo/no probiotic were included. DATA EXTRACTION: Relevant data were extracted independently by 3 reviewers. RESULTS: Pooled results from 37 RCTs (N = 9416) using fixed effects model meta analysis showed that probiotics significantly decreased the risk of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; relative risk, 0.86; 95% confidence interval, 0.78–0.94; P = .0007; I2 = 35%; number needed to treat, 44). The results were significant even after excluding studies with high risk of bias. CONCLUSIONS: Probiotic supplementation reduces the risk of LOS in preterm infants.

Benefits of probiotics on enteral nutrition in preterm neonates: a systematic review

INTRODUCTION The optimization of enteral nutrition is a priority in preterm neonates worldwide. Probiotics are known to improve gut maturity and function in preterm neonates. To our knowledge, previous systematic reviews have not adequately assessed the effects of probiotic supplementation on enteral nutrition in preterm neonates. OBJECTIVE We assessed the evidence on effects of probiotics on enteral nutrition in preterm neonates. DESIGN A systematic review of randomized controlled trials (RCTs) of probiotic supplementation in preterm (gestation <37 wk) or low-birth-weight (birth weight <2500 g) neonates was conducted. With the use of the Cochrane Neonatal Review Group strategy, we searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Cumulative Index of Nursing and Allied Health Literature databases and proceedings of Pediatric Academic Society meetings in April 2014. RESULTS A total of 25 RCTs (n = 5895) were included in the review. A meta-analysis (random-effects model) of data from 19 of 25 trials (n = 4527) estimated that the time to full enteral feeds was shorter in the probiotic group (mean difference: -1.54 d; 95% CI: -2.75, -0.32 d; P < 0.00001, I(2) = 93%). Other benefits included fewer episodes of feed intolerance, better weight gain and growth velocity, decreased transition time from orogastric to breast feeds, and increased postprandial mesenteric flow. There were no adverse effects of probiotic supplementation. CONCLUSIONS Probiotics reduced the time to full enteral feeds in preterm neonates. Additional research is necessary to assess the optimal dose, duration, and probiotic strain or strains used specifically for facilitating enteral nutrition in this population.

Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants

BACKGROUND Inhibitors of gastric acid (IGA) are used for upper gastrointestinal bleeding or gastroesophageal reflux in preterm infants. The resultant increase in gastric pH may enhance the growth of pathogens and increase the risk of necrotizing enterocolitis (NEC). Our systematic review examined the association between IGA and NEC in preterm infants. METHODS Standard methodology of systematic reviews was followed. PubMed, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched in August 2012. RESULTS One case-control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA, were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4, 2.27, p < 0.00001). The prospective cohort study found higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p < 0.001). CONCLUSIONS Exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants.

Lactobacillus reuteri DSM 17938 as a Probiotic for Preterm Neonates: A Strain-Specific Systematic Review

INTRODUCTION Prevention of necrotizing enterocolitis (NEC) while optimizing enteral nutrition (EN) is a priority in preterm neonates. Lactobacillus reuteri DSM 17938 (L reuteri) is known to improve gut motility. Previous systematic reviews have not adequately assessed the effects of L reuteri in improving feed tolerance in preterm neonates. OBJECTIVE To assess the effects of L reuteri in preterm neonates. DESIGN A systematic review of randomized controlled trials (RCTs) and non-RCTs of L reuteri was conducted. We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL databases and proceedings of Pediatric Academic Society meetings in December 2014. RESULTS Six RCTs (n = 1778) and 2 non-RCTs (n = 665) were included. Meta-analysis of RCTs estimated that the time to full feeds (mean difference [MD], -1.34 days; 95% confidence interval [CI], -1.81 to -0.86; 2 RCTs), duration of hospitalization (-10.77 days; 95% CI, -13.67 to -7.86; 3 RCTs), and late-onset sepsis (LOS) (relative risk [RR], 0.66; 95% CI, 0.52 to 0.83; 4 RCTs) were reduced in the L reuteri group. Mortality (RR, 0.79; 95% CI, 0.57-1.09; 3 RCTs) and ≥ stage II NEC (RR, 0.69; 95% CI, 0.47-1.01; 3 RCTs) were reduced but statistically not significant. There were no adverse effects of supplementation. Both non-RCT studies showed significant improvement in the incidence of NEC with L reuteri supplementation. CONCLUSIONS Evidence from a limited number of studies suggests that L reuteri supplementation has the potential to reduce the risk of NEC and LOS while facilitating EN in preterm infants. Larger definitive RCTs are needed to confirm these findings.

Progress in the field of necrotising enterocolitis--year 2012.

Abstract Necrotising enterocolitis (NEC) continues to have significant mortality, and morbidity including neurodevelopmental impairment, especially in extreme preterm neonates needing surgery for the illness. The incidence of NEC has not changed significantly despite the advances in neonatal care. Preventing NEC thus remains a priority. Protecting the intestinal barrier function and controlling the excessive proinflammatory response by the preterm gut are perhaps the most important areas for research toward achieving this goal. Improved understanding of the role of innate immunity in the pathogenesis of the illness and progress in other areas means that novel strategies may become available for the prevention and treatment of NEC. Probiotics significantly reduce the risk of NEC. Evidence indicates that bovine lactoferrin could reduce both, sepsis and NEC. As new frontiers (e.g. oral erythropoietin, heparin binding epithelial growth factor, therapeutic hypothermia and stem cell therapy) are being explored, the benefits of antenatal glucocorticoids, breast milk and standardised feeding regimes must not be forgotten. Preventing sepsis and avoiding undue prolonged exposure to antibiotics and antacids will be equally important. Considering the multiple complex pathways involved in its pathogenesis, adopting a package of potentially better practices will be the most appropriate strategy for prevention and treatment of NEC.

Probiotics in very preterm infants: the PiPS trial

We respectfully disagree with the conclusions made by Kate Costeloe and colleagues (Feb 13, p 649). There is a signifi cant discrepancy regarding the dose of Bifidobacterium breve BBG-001 (appendix). The authors claim that despite the decay during the trial, the administered dose remained above the recommended threshold (108–109 colony-forming units [CFU], ie, 100 million–1 billion CFU). However, the dose of 100 million CFU is far below the dose administered in their pilot study (1 billion CFU) and the dose used by Hiroyuki Kitajima and colleagues (0·5 billion CFU) that had suggested benefits. Despite this low dose, infants colonised with B breve had clinically significant benefits for all outcomes. Our unadjusted analysis based on their raw data suggests statistically signifi cant benefi ts (table). Hence, their conclusion against BBG-001 is not justifi ed, as signifi cant benefi ts of this strain have not been ruled out. If a minimum guaranteed dose at or above that used in the pilot study was assured throughout the trial, signifi cant differences might have occurred between the two groups despite cross contamination. The 95% CI for the primary analysis supports this possibility. A truly large trial detecting a clinically signifi cant minimum eff ect size (eg, 20%) would need several thousand participants at least. Costeloe and colleagues question the validity of meta-analyses, which is inappropriate considering the limitations of PiPS trial and the increasing agreement about protection by probiotics, via shared beneficial pathways. Given the significant cross contamination (49%), analysis of the intention-totreat population was a futile exercise. Satsuki Totsu reported benefits of Bifidobacterium bifidum in preterm infants in a cluster randomised trial. In cluster randomised controlled rials, patients allocated to the supplement do not have the issue of cross contamination.

Effects of probiotics on experimental necrotizing enterocolitis -a systematic review and meta-analysis

BackgroundMeta-analyses of randomized controlled trials (RCTs) suggest that probiotics decrease the risk of necrotizing enterocolitis (NEC) in preterm infants. Many animal RCTs have evaluated probiotics for preventing NEC. We systematically reviewed the literature on this topic.MethodsThe protocol for systematic review of animal intervention studies (SYRCLE) was followed. Medline, Embase, ISI Web of Science, e-abstracts from the Pediatric Academic Society meetings, and other neonatal conferences were searched in December 2015 and August 2016. RCTs comparing probiotics vs. placebo/no probiotic were included.ResultsA total of 29 RCTs were included (Rats: 16, Mice: 7, Piglets: 3, Quail: 2, Rabbit: 1; N~2,310), with 21 reporting on histopathologically confirmed NEC; remaining 8 assessed only pathways of probiotic benefits. Twenty of the 21 RCTs showed that probiotics significantly reduced NEC. Pooling of data was possible for 16/21 RCTs. Meta-analysis using random-effects model showed that probiotics significantly decreased the risk of NEC (203/641 (31.7%) vs. 344/571 (60.2%); relative risk: 0.51; 95% confidence interval (CI): 0.42–0.62; P<0.00001; I2=44%; number needed to treat: 4; 95% CI: 2.9, 4.3).ConclusionProbiotics significantly reduced NEC via beneficial effects on immunity, inflammation, tissue injury, gut barrier, and intestinal dysbiosis.

Para-probiotics for Preterm Neonates—The Next Frontier

Current evidence supports the use of probiotics in preterm neonates for prevention of necrotizing enterocolitis, mortality and late onset sepsis. Despite the strong evidence, the uptake of this intervention has not been universal due to concerns including probiotic sepsis, pro-inflammatory response and transmission of antibiotic resistance. Critically ill extremely preterm neonates with potentially compromised gut integrity are at higher risk of probiotic sepsis due to translocation. In most countries, probiotics are sold as food supplements with poor quality control. The traditional definition of probiotics as “live microorganisms” has been challenged as many experts have questioned the importance of viability in the context of the beneficial effects of probiotics. Paraprobiotics (ghost probiotics), are defined as non-viable microbial cells (intact or broken) or crude cell extracts (i.e., with complex chemical composition), which, when administered (orally or topically) in adequate amounts, confer a benefit on the human or animal consumer. Current evidence indicates that paraprobiotics could be safe alternatives to probiotics in preterm neonates. High-quality pre-clinical and clinical studies including adequately powered randomised controlled trials (RCTs) are warranted in preterm neonates to explore this new frontier.

Bifidobacterium breve M-16V as a Probiotic for Preterm Infants: A Strain-Specific Systematic Review:

INTRODUCTION Bifidobacterium breve M-16V has been used as a probiotic in preterm infants. Probiotic strain-specific data are essential to guide clinical practice. OBJECTIVE To assess effects of B breve M-16V in preterm neonates. DESIGN A systematic review of randomized controlled trials (RCTs) and non-RCTs of B breve M-16V in preterm infants was conducted. Multiple databases, proceedings of Pediatric Academy Society, and other relevant conferences were searched in September 2016 and on January 5, 2017. RESULTS Five RCTs (n = 482) and 4 non-RCTs (n = 2496) were included. Of the 5 RCTs, 4 carried high/unclear risk of bias in many domains. Meta-analysis (fixed effects model) of RCTs showed no significant benefits on stage ≥2 necrotizing enterocolitis, late-onset sepsis, mortality, and postnatal age at full feeds. Meta-analysis of non-RCTs showed significant benefits on (1) late-onset sepsis-3 studies (n = 2452), odds ratio = 0.56 (95% CI, 0.45-0.71), P < .0001; (2) mortality-2 studies (n = 2319), odds ratio = 0.61 (95% CI, 0.44-0.84), P = .002; and (3) postnatal age at full feeds (days)-2 studies (n = 361), mean difference, -2.42 (95% CI, -2.55 to -2.3), P < .00001. There were no adverse effects from B breve M-16V. On Grading of Recommendations, Assessment, Development, and Evaluation analysis, the overall quality of evidence was deemed very low. CONCLUSIONS Current evidence is limited regarding the potential of B breve M-16V in preterm neonates. Adequately powered, preferably cluster RCTs are needed to confirm these findings.