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

ABSTRACTObjectives: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.Methods:A PubMed search identified placebo-controlled or head-to-head RCTs investigating probiotics in preterm infants. From trials that recorded mortality, necrotising enterocolitis (NEC), late-onset sepsis (LOS), or time until full enteral feeding (TUFEF) as outcomes, data were extracted and Bayesian hierarchical random effects models were run to construct a NMA.Results:Fifty-one RCTs involving 11,231 preterm infants were included. Most strains or combinations of strains were only studied in one or a few RCTs. Only 3 out of 25 studied probiotic treatment combinations showed significant reduction in mortality rates. Seven treatments reduced NEC incidence, 2 reduced LOS, and 3 reduced TUFEF. There was no clear overlap of strains which were effective on multiple outcome domains.Conclusions:This NMA showed efficacy in reducing mortality and morbidity only in a minority of the studied strains or combinations. This may be due to an inadequate number, or size, of RCTs, or due to a true lack of effect for certain species. Further large and adequately powered RCTs using strains with the greatest apparent efficacy will be needed in order to more precisely define optimal treatment strategies. Objectives: 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. Methods: A PubMed search identified placebo-controlled or head-to-head RCTs investigating probiotics in preterm infants. From trials that recorded mortality, necrotising enterocolitis (NEC), late-onset sepsis (LOS), or time until full enteral feeding (TUFEF) as outcomes, data were extracted and Bayesian hierarchical random effects models were run to construct a NMA. Results: Fifty-one RCTs involving 11,231 preterm infants were included. Most strains or combinations of strains were only studied in one or a few RCTs. Only 3 out of 25 studied probiotic treatment combinations showed significant reduction in mortality rates. Seven treatments reduced NEC incidence, 2 reduced LOS, and 3 reduced TUFEF. There was no clear overlap of strains which were effective on multiple outcome domains. Conclusions: This NMA showed efficacy in reducing mortality and morbidity only in a minority of the studied strains or combinations. This may be due to an inadequate number, or size, of RCTs, or due to a true lack of effect for certain species. Further large and adequately powered RCTs using strains with the greatest apparent efficacy will be needed in order to more precisely define optimal treatment strategies. Address correspondence and reprint requests to Johannes B. van Goudoever, Department of Paediatrics, Emma Children's Hospital-AMC & VU University Medical Center, Amsterdam, The Netherlands, Meibergdreef 9, 1100 DD Amsterdam, The Netherlands (e-mail: h.vangoudoever@amc.nl; h.vangoudoever@vumc.nl). Received 23 October, 2017 Accepted 14 January, 2018 Trial identification number and URL: PROSPERO CRD42017064847; http://ift.tt/2BIKEXE Hopefully, collaborators can be categorized as an author and indexed in PubMed, and appear after clicking the collaborators link in PubMed. Then, even if you search in PubMed on one of the collaborator authors, PubMed recognizes it as an author. See for example: http://ift.tt/2np5wPk Sources of support: Preparation of the manuscript was made possible by an unrestricted ESPGHAN grant Disclosure of funding: No funding from the NIH, Welcome Trust, or HHMI. Preparation of the manuscript was made possible by an unrestricted ESPGHAN grant. Conflicts of interest and sources of funding: Besides general disclosures, authors were specifically asked whether they have had any financial relationship (including grant support) in the previous two years with any company that sells probiotic strain(s) or products containing such strain(s). C.H.P. van den Akker has nothing to declare on this specific topic, but his institution has received financial support for travel reimbursements, honorarium for lectures, and consultancy fees from Nutricia, Baxter, Nestl, Nutrition Institute, and Nestl,. J.B. van Goudoever has nothing to declare on this specific topic, but his institution has received financial support for grants, travel reimbursements, honorarium for lectures, and consultancy fees from Abbott, Baxter, Danone, Hipp, Mead Johnson Nutrition, Nestl, Nutrition Institute, Nutricia, Prolacta, and United Pharmaceuticals. He is founder and director of the Dutch Donor Human Milk Bank, member of the National Human Milk council and National Health Council. H. Szajewska has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Arla, BioGaia, Biocodex, Danone, Dicofarm, Hipp, Nestl,, Nestl, Nutrition Institute, Nutricia, Mead Johnson, Merck, and Sequoia. N.D. Embleton has nothing to declare on this specific topic, but he has received lecture honoraria, and his institution has received research support from Nutricia, Prolacta Biosciences and Nestl, Nutrition Institute. He has provided un-paid scientific advice to Neobiomics, a non-profit organisation. I. Hojsak has participated as a clinical investigator for BioGaia and Chr Hansen. D. Reid has nothing to disclose. R. Shamir has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott, Danone Institute International, Enzymotec, Nestl, Nutrition Institute, and Nutricia. Collaborators: R. Berni Canani participated as a clinical investigator, and/or speaker for Alk Bello, DMG, Dicofarm, Humana, Kraft-Heinz, Mead Johnson Nutrition, Menarini, Nestl,, Nutricia, United Pharmaceuticals, and Wyeth. M. Domell"f has nothing to declare on this specific topic, but he has participated as a speaker, advisory board member, and/or clinical researcher for Baxter, Danone/Nutricia, Nestl,, Semper/Hero, and Wyeth. A. Guarino has participated in basic research supported by Biocodex, Mead Johnson and Dicofarm and in clinical trials and/or advisory boards and/or conference grant by Menarini and Biocodex. F. Indrio has participated as a clinical investigator and /or consultant and/or speaker for Arla Food, BioGaia, Noos, Nestl,, Nestl, Nutrition Institute, and Wyeth. S. Kolacek has participated as a clinical investigator, and/or speaker for Abbott, Arla, BioGaia, Chr. Hansen, Danone, Dukat, Nestl,, Nutricia, and MSD. W.A. Mihatsch declares that he studied the effects of BB12 in preterm infants and that he or his institution received financial support for grants, travel reimbursements, honorarium for lectures, and consultancy fees from Abbott, Baxter, Danone, Hipp, Humana, Mead Johnson, Nestl,, and Prolacta. He is member of the nutrition committee of the German Paediatric Society R. Orel has participated as a clinical investigator or speaker for Medis, Nutricia, Ewopharma, BioGaia, United Pharmaceuticals, Danone, Abbvie, and MSD. Y. Vandenplas has participated as a clinical investigator, and/or advisory board member, and/or consultant, and/or speaker for Abbott Nutrition, Aspen, BioGaia, Biocodex, Danone, Hero, Kabrita, Nestl, Nutrition Institute, Nutricia, Mead Johnson Nutrition, Merck, Olygose, Orafti, Phacobel, Rontis, Sari Husada, United Pharmaceuticals, Wyeth, and Yakult. Z. Weizman has participated as a clinical investigator, and/or consultant and/or speaker for BioCodex, BioGaia, Hipp, Materna, Mead Johnson, Nestl,, and Sensus. Author contributions: C.H.P. van den Akker, J.B. van Goudoever, and H. Szajewska proposed the idea of a network meta-analysis, were involved in the study design, selected appropriate studies, collected data, performed analyses, and wrote the manuscript. N.D. Embleton, I. Hojsak, and R. Shamir were involved in the study design and interpretation of results, and critically reviewed and approved the latest version of the manuscript. D. Reid developed software for this network meta-analysis and helped improving network models. R. Berni Canani, M. Domell"f, A. Guarino, F. Indrio, S. Kolacek, W.A. Mihatsch, R. Orel, Y. Vandenplas, and Z. Weizman critically reviewed and approved the latest version of the manuscript. Collaborators: [INCREMENT][INCREMENT]Roberto Berni Canani,[INCREMENT][INCREMENT]Alfredo Guarino,[INCREMENT][INCREMENT] Department of Translational Medical Sciences and European Laboratory for the Investigation of Food Induced Diseases and CEINGE Advanced Biotechnologies and Task Force on Investigations on Microbiome, University Federico II, Naples Italy; ++Magnus Domell"f, ++ Department of Clinical Sciences, Paediatrics, Ume+ University, Ume+, Sweden; **Flavia Indrio, ** Department of Paediatric Gastroenterology division, Ospedale Pediatrico Giovanni XXIII University of Bari Italy; oSanja Kolacek, ○ Children's Hospital Zagreb, University of Zagreb School of Medicine, Croatia; §§Walter A. Mihatsch, §§ Department of Paediatrics, Ulm University and Helios Hospital Pforzheim, Germany; ooRok Orel, ○ University Medical Centre Ljubljana, University Children's Hospital Ljubljana, Department of Gastroenterology, Hepatology and Nutrition; ##Yvan Vandenplas, ## Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium; [Combining Tilde][Combining Tilde]Zvi Weizman, [Combining Tilde][Combining Tilde]Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jpgn.org). © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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