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Probiotics, Prebiotics, and Synbiotics for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis of Randomized Trials

26 Pages Posted: 19 Mar 2019

See all articles by Behnam Sadeghirad

Behnam Sadeghirad

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Ivan D. Florez

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Rebecca L. Morgan

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Farid Foroutan

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Yaping Chang

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Dena Zeraatkar

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Malgorzata M. Bala

Jagiellonian University in Krakow - Medical College

Shaneela Shahid

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Taoying Lu

Guangzhou University of Chinese Medicine

Long Ge

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Joseph Beyene

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Martin Offringa

University of Toronto - Child Health Evaluative Sciences

Philip M. Sherman

University of Toronto - The Hospital for Sick Children - SickKids

Enas el Gouhary

McMaster University - Faculty of Health Sciences

Gordon H. Guyatt

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Bradley Johnston

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI); Dalhousie University - Department of Community Health and Epidemiology; University of Toronto - Systematic Overviews through Advancing Research Technology (SORT)

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Abstract

Background: Bacteriotherapy and modulation of intestinal microbiome by administering probiotics, prebiotics, or both have long been suggested to prevent morbidity and mortality in premature infants. Our objective was to assess the comparative effectiveness of different prophylactic strategies in a network meta-analysis (NMA) of randomized trials.

Methods: We searched MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane Central, BIOSIS Previews, and Google Scholar from inception up until December 1, 2018· All-cause mortality, severe necrotizing enterocolitis (NEC - Bell stage II or more), and culture proven sepsis were our a priori primary outcomes. We used a frequentist approach for NMA and assessed the certainty of evidence using the GRADE approach.

Findings: We included 79 trials involving 17,655 preterm infants. Multiple-strain probiotics alone proved the only intervention with moderate- or high-quality evidence of reduced all-cause mortality relative to placebo (OR = 0·67; 95% CI: 0·52, 0·87; high certainty; absolute risk reduction = 1·5%). Compared to placebo, multiple-strain probiotics (OR = 0·35; 95% CI: 0·26, 0·47; moderate certainty; absolute risk reduction = 4·1%), and single-strain probiotics alone (OR = 0·63; 95% CI: 0·46, 0·86; moderate certainty; absolute risk reduction = 2·3%) or in combination with lactoferrin (OR = 0·04; 95% CI: 0·01, 0·62; moderate certainty; absolute risk reduction = 6·2%) were among the interventions with moderate- or high-quality evidence that significantly reduced severe NEC. Among the intervention with moderate- or high-quality evidence relative to placebo, single-strain probiotics combined with lactoferrin (OR = 0·27; 95% CI: 0·10, 0·72; moderate certainty; absolute risk reduction = 11·00%) or alone (OR = 0·80; 95% CI: 0·65, 0·99; moderate certainty; absolute risk reduction = 2·6%) and lactoferrin alone (OR = 0·44; 95% CI: 0·27, 0·74; moderate certainty; absolute risk reduction = 5·1%) demonstrated statistically significant reduction in culture proven late-onset sepsis.

Interpretation: Moderate-to-high certainty evidence demonstrates the superiority of single and multi-strain probiotics over alternative preventive treatments. Synbiotics (multiple-strain probiotics in combination with prebiotics) provide the largest reduction in morbidity and mortality in preterm infants but this is supported by only low-to-very low certainty evidence; thus, prioritizing synbiotics in future trials may provide important insights.

Funding: Mitacs in partnership with Nestlé Canada.

Declaration of Interest: PMS is the recipient of research support provided by Lallemand Human Nutrition Inc. (Montreal, Quebec, Canada) through a Mitacs Accelerates Internship awarded to Shaiya Robinson, PhD. PMS has received honoraria for CME activities from Nestle Nutrition, Abbott Nutrition, and Mead Johnson Nutrition.

Suggested Citation

Sadeghirad, Behnam and Florez, Ivan D. and Morgan, Rebecca L. and Foroutan, Farid and Chang, Yaping and Zeraatkar, Dena and Bala, Malgorzata M. and Shahid, Shaneela and Lu, Taoying and Ge, Long and Beyene, Joseph and Offringa, Martin and Sherman, Philip M. and Gouhary, Enas el and Guyatt, Gordon H. and Johnston, Bradley, Probiotics, Prebiotics, and Synbiotics for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis of Randomized Trials (March 18, 2019). Available at SSRN: https://ssrn.com/abstract=3354688 or http://dx.doi.org/10.2139/ssrn.3354688

Behnam Sadeghirad

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Ivan D. Florez

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Rebecca L. Morgan

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Farid Foroutan

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Yaping Chang

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Dena Zeraatkar

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Malgorzata M. Bala

Jagiellonian University in Krakow - Medical College

Grzegorzecka 20
Kraków, 31-531
Poland

Shaneela Shahid

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Taoying Lu

Guangzhou University of Chinese Medicine

Guangzhou
China

Long Ge

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Joseph Beyene

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI)

Hamilton, Ontario L8N 3Z5
Canada

Martin Offringa

University of Toronto - Child Health Evaluative Sciences ( email )

Toronto, Ontario
Canada

Philip M. Sherman

University of Toronto - The Hospital for Sick Children - SickKids

555 University Ave
Toronto, Ontario M5G 1X8
Canada

Enas el Gouhary

McMaster University - Faculty of Health Sciences

Canada

Gordon H. Guyatt

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI) ( email )

Hamilton, Ontario L8N 3Z5
Canada

Bradley Johnston (Contact Author)

McMaster University - Department of Health Research Methods, Evidence, and Impact (HEI) ( email )

Hamilton, Ontario L8N 3Z5
Canada

Dalhousie University - Department of Community Health and Epidemiology ( email )

Halifax
Canada

University of Toronto - Systematic Overviews through Advancing Research Technology (SORT) ( email )

Toronto
Canada

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