Probiotics for Preterm Infants: a strain specific systematic review and network meta-analysis

Several randomised controlled trials (RCTs) on the use of probiotics to reduce morbidity and mortality in preterm infants have provided inconsistent results. Whilst meta-analyses that group all of the used strains together, suggest efficacy, it is not possible to determine the most effective strain which is more relevant to the clinician. We therefore used a network meta-analysis (NMA) approach in order to identify strains with greatest efficacy

Probiotics and Preterm Infants: A Position Paper by the ESPGHAN Committee on Nutrition and the ESPGHAN Working Group for Probiotics and Prebiotics

More than 10,000 preterm infants have participated in randomised controlled trials on probiotics worldwide, suggesting that probiotics in general could reduce rates of necrotising enterocolitis (NEC), sepsis, and mortality. However, answers to relevant clinical questions as to which strain to use, at what dosage, and how long to supplement, are not available. On the other hand, an increasing number of commercial products containing probiotics are available from sometimes suboptimal quality. Also, a large number of units around the world are routinely offering probiotic supplementation as the standard of care despite lacking solid evidence. Our recent network meta-analysis identified probiotic strains with greatest efficacy regarding relevant clinical outcomes for preterm neonates. Efficacy in reducing mortality and morbidity was found for only a minority of the studied strains or combinations. In the present position paper, we aim to provide advice which specific strains might potentially be used and which strains should not be used. Besides, we aim to address safety issues of probiotic supplementation to preterm infants, who have reduced immunological capacities and occasional indwelling catheters. For example, quality reassurance of the probiotic product is essential, probiotic strains should be devoid of transferable antibiotic resistance genes, and local microbiologists should be able to routinely detect probiotic sepsis. Provided all safety issues are met, there is currently a conditional recommendation (with low certainty of evidence) to provide either L. rhamnosus GG ATCC53103 or the combination of B. infantis Bb-02, B. lactis Bb-12, and Str. thermophilus TH-4 in order to reduce NEC rates

Probiotics for the management of pediatric gastrointestinal disorders: position paper of the ESPGHAN Special Interest Group on Gut Microbiota and Modifications

Probiotics, defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, are widely used despite uncertainty regarding their efficacy and discordant recommendations about their use. The ESPGHAN Special Interest Group on Gut Microbiota and Modifications provides updated recommendations for the use of probiotics for the management of selected pediatric gastrointestinal disorders

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN

Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this. Impact: The recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines for pediatric parenteral nutrition provided updated guidance for providing parenteral nutrition to infants and children, including recommendations for practice.However, in several areas there was a lack of evidence to guide practice, or research questions that remained unanswered. This paper summarizes the key priorities for research in pediatric parenteral nutrition, and ranks them in order of importance according to expert opinion

Patterns of Early Gut Colonization Shape Future Immune Responses of the Host

The most important trigger for immune system development is the exposure to microbial components immediately after birth. Moreover, targeted manipulation of the microbiota can be used to change host susceptibility to immune-mediated diseases. Our aim was to analyze how differences in early gut colonization patterns change the composition of the resident microbiota and future immune system reactivity. Germ-free (GF) mice were either inoculated by single oral gavage of caecal content or let colonized by co-housing with specific pathogen-free (SPF) mice at different time points in the postnatal period. The microbiota composition was analyzed by denaturing gradient gel electrophoresis for 16S rRNA gene followed by principal component analysis. Furthermore, immune functions and cytokine concentrations were analyzed using flow cytometry, ELISA or multiplex bead assay. We found that a single oral inoculation of GF mice at three weeks of age permanently changed the gut microbiota composition, which was not possible to achieve at one week of age. Interestingly, the ex-GF mice inoculated at three weeks of age were also the only mice with an increased pro-inflammatory immune response. In contrast, the composition of the gut microbiota of ex-GF mice that were co-housed with SPF mice at different time points was similar to the gut microbiota in the barrier maintained SPF mice. The existence of a short GF postnatal period permanently changed levels of systemic regulatory T cells, NK and NKT cells, and cytokine production. In conclusion, a time window exists that enables the artificial colonization of GF mice by a single oral dose of caecal content, which may modify the future immune phenotype of the host. Moreover, delayed microbial colonization of the gut causes permanent changes in the immune system

Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants: carrot study

<p>Abstract</p> <p>Background</p> <p>Prevention of serious infections in preterm infants is a challenge, since prematurity and low birth weight often requires many interventions and high utility of devices. Furthermore, the possibility to administer enteral nutrition is limited due to immaturity of the gastrointestinal tract in the presence of a developing immune system. In combination with delayed intestinal bacterial colonisation compared with term infants, this may increase the risk for serious infections. Acidic and neutral oligosaccharides play an important role in the development of the immune system, intestinal bacterial colonisation and functional integrity of the gut. This trial aims to determine the effect of enteral supplementation of acidic and neutral oligosaccharides on infectious morbidity (primary outcome), immune response to immunizations, feeding tolerance and short-term and long-term outcome in preterm infants. In addition, an attempt is made to elucidate the role of acidic and neutral oligosaccharides in postnatal modulation of the immune response and postnatal adaptation of the gut.</p> <p>Methods/Design</p> <p>In a double-blind placebo controlled randomised trial, 120 preterm infants (gestational age <32 weeks and/or birth weight <1500 gram) are randomly allocated to receive enteral acidic and neutral oligosaccharides supplementation (20%/80%) or placebo supplementation (maltodextrin) between day 3 and 30 of life. Primary outcome is infectious morbidity (defined as the incidence of serious infections). The role of acidic and neutral oligosaccharides in modulation of the immune response is investigated by determining the immune response to DTaP-IPV-Hib(-HBV)+PCV7 immunizations, plasma cytokine concentrations, faecal Calprotectin and IL-8. The effect of enteral acidic and neutral oligosaccharides supplementation on postnatal adaptation of the gut is investigated by measuring feeding tolerance, intestinal permeability, intestinal viscosity, and determining intestinal microflora. Furthermore, short-term and long-term outcome are evaluated.</p> <p>Discussion</p> <p>Especially preterm infants, who are at increased risk for serious infections, may benefit from supplementation of prebiotics. Most studies with prebiotics only focus on the colonisation of the intestinal microflora. However, the pathways how prebiotics may influence the immune system are not yet fully understood. Studying the immune modulatory effects is complex because of the multicausal risk of infections in preterm infants. The combination of neutral oligosaccharides with acidic oligosaccharides may have an increased beneficial effect on the immune system. Increased insight in the effects of prebiotics on the developing immune system may help to decrease the (infectious) morbidity and mortality in preterm infants.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN16211826.</p

ADEPT - Abnormal Doppler Enteral Prescription Trial

<p>Abstract</p> <p>Background</p> <p>Pregnancies complicated by abnormal umbilical artery Doppler blood flow patterns often result in the baby being born both preterm and growth-restricted. These babies are at high risk of milk intolerance and necrotising enterocolitis, as well as post-natal growth failure, and there is no clinical consensus about how best to feed them. Policies of both early milk feeding and late milk feeding are widely used. This randomised controlled trial aims to determine whether a policy of early initiation of milk feeds is beneficial compared with late initiation. Optimising neonatal feeding for this group of babies may have long-term health implications and if either of these policies is shown to be beneficial it can be immediately adopted into clinical practice.</p> <p>Methods and Design</p> <p>Babies with gestational age below 35 weeks, and with birth weight below 10th centile for gestational age, will be randomly allocated to an "early" or "late" enteral feeding regimen, commencing milk feeds on day 2 and day 6 after birth, respectively. Feeds will be gradually increased over 9-13 days (depending on gestational age) using a schedule derived from those used in hospitals in the Eastern and South Western Regions of England, based on surveys of feeding practice. Primary outcome measures are time to establish full enteral feeding and necrotising enterocolitis; secondary outcomes include sepsis and growth. The target sample size is 400 babies. This sample size is large enough to detect a clinically meaningful difference of 3 days in time to establish full enteral feeds between the two feeding policies, with 90% power and a 5% 2-sided significance level. Initial recruitment period was 24 months, subsequently extended to 38 months.</p> <p>Discussion</p> <p>There is limited evidence from randomised controlled trials on which to base decisions regarding feeding policy in high risk preterm infants. This multicentre trial will help to guide clinical practice and may also provide pointers for future research.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN: 87351483</p