Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials

doi:10.1053/j.gastro.2020.05.096

Gastroenterology

Volume 159, Issue 2, August 2020, Pages 467-480

https://doi.org/10.1053/j.gastro.2020.05.096 Get rights and content

Background & Aims

We aimed to compare the effectiveness of single- vs multiple-strain probiotics in a network meta-analysis of randomized trials.

Methods

We searched MEDLINE, Embase, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, BIOSIS Previews, and Google Scholar through January 1, 2019, for studies of single-strain and multistrain probiotic formulations on the outcomes of preterm, low-birth-weight neonates. We used a frequentist approach for network meta-analysis and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence. Primary outcomes included all-cause mortality, severe necrotizing enterocolitis (NEC) (Bell stage II or more), and culture-proven sepsis.

Results

We analyzed data from 63 trials involving 15,712 preterm infants. Compared with placebo, a combination of 1 or more Lactobacillus species (spp) and 1 or more Bifidobacterium spp was the only intervention with moderate- or high-quality evidence of reduced all-cause mortality (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.39–0.80). Among interventions with moderate- or high-quality evidence for efficacy compared with placebo, combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp, Bifidobacterium animalis subspecies lactis, Lactobacillus reuteri, or Lactobacillus rhamnosus significantly reduced severe NEC (OR, 0.35 [95% CI, 0.20–0.59]; OR, 0.31 [95% CI, 0.13–0.74]; OR, 0.55 [95% CI, 0.34–0.91]; and OR, 0.44 [95% CI, 0.21–0.90], respectively). There was moderate- or high-quality evidence that combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp and Saccharomyces boulardii reduced the number of days to reach full feeding (mean reduction of 3.30 days [95% CI, reduction of 5.91–0.69 days]). There was moderate- or high-quality evidence that, compared with placebo, the single-species product B animalis subsp lactis or L reuteri significantly reduced duration of hospitalization (mean reduction of 13.00 days [95% CI, reduction of 22.71–3.29 days] and mean reduction of 7.89 days [95% CI, reduction of 11.60–4.17 days], respectively).

Conclusions

In a systematic review and network meta-analysis of studies to determine the effects of single-strain and multistrain probiotic formulations on outcomes of preterm, low-birth-weight neonates, we found moderate to high evidence for the superiority of combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp vs single- and other multiple-strain probiotic treatments. The combinations of Bacillus spp and Enterococcus spp, and 1 or more Bifidobacterium spp and Streptococcus salivarius subsp thermophilus, might produce the largest reduction in NEC development. Further trials are needed.

Section snippets

Materials and Methods

We produced this NMA as a secondary analysis of an unpublished systematic review and protocol based on the protocol registered with PROSPERO (CRD42018085566).⁹^,¹⁰ The results of this analysis inform the “American Gastroenterological Association Institute Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders.”¹¹

Results

Additional results can be found in the Supplementary Figures 1–15 and Supplementary Tables 1–12.

Discussion

In this systematic review and NMA comparing the effectiveness of different probiotic combinations for the prevention of mortality and morbidity in preterm infants, we found, across a number of outcomes, that few single- and multiple-strain probiotics are more effective than placebo, with no difference in the evidence of harms (ie, sepsis). High-certainty evidence indicates that combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp are best for the prevention of all-cause

Conclusion

Moderate- to high-certainty evidence shows the superiority of combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp over alternative single- and multiple-strain probiotic treatments. The 2 combinations of Bacillus spp and Enterococcus spp and of Bifidobacterium spp and S salivarius subsp thermophilus may provide the largest reduction in the development of NEC, but this is supported by only low to very low certainty of evidence. Multicenter and large RCTs should be

Acknowledgements

The authors would like to acknowledge the contributions of Joseph Beyene, Martin Offringa, and Philip M. Sherman.

Members of the McMaster Probiotic, Prebiotic, and Synbiotic Work Group: Yaping Chang (Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada), Ivan D. Florez (Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada, and Department of Pediatrics, University of Antioquia, Medellin,

References (105)

R.L. Goldenberg et al.
Epidemiology and causes of preterm birth
Lancet
(2008)
G.A. Preidis et al.
Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era
Gastroenterology
(2009)
R.M. Patel et al.
Probiotics and necrotizing enterocolitis
Semin Pediatr Surg
(2018)
M. Walsh et al.
Necrotizing enterocolitis: treatment based on staging criteria
Pediatr Clin North Am
(1986)
E.A. Akl et al.
Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid
J Clin Epidemiol
(2012)
R. Brignardello-Petersen et al.
Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis
J Clin Epidemiol
(2018)
A. Kapiki et al.
The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants
Early Hum Dev
(2007)
F. Indrio et al.
The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns
J Pediatr
(2008)
A. Bin-Nun et al.
Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates
J Pediatr
(2005)
T.D. Braga et al.
Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial
Am J Clin Nutr
(2011)

D. Chrzanowska-Liszewska et al.

The effect of Lactobacillus rhamnosus GG supplemented enteral feeding on the microbiotic flora of preterm infants-double blinded randomized control trial

Early Hum Dev

(2012)

C. Costalos et al.

Enteral feeding of premature infants with Saccharomyces boulardii

Early Hum Dev

(2003)

K. Costeloe et al.

Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial

Lancet

(2016)

S. Hays et al.

Probiotics and growth in preterm infants: a randomized controlled trial, PREMAPRO study

Clin Nutr

(2016)

P. Manzoni et al.

Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial

Early Hum Dev

(2014)

C. Rouge et al.

Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial

Am J Clin Nutr

(2009)

I. Sadowska-Krawczenko et al.

Lactobacillus rhamnosus ATC A07FA for preventing necrotizing enterocolitis in very-low-birth-weight preterm infants: a randomized controlled trial (preliminary results) [Polish]

Pediatr Pol

(2012)

O. Serce et al.

Efficacy of Saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: a randomised controlled trial

Early Hum Dev

(2013)

Z. Stratiki et al.

The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants

Early Hum Dev

(2007)

E. Van Niekerk et al.

Probiotics, feeding tolerance, and growth: a comparison between HIV-exposed and unexposed very low birth weight infants

Nutrition

(2014)

L. Xu et al.

A double-blinded randomized trial on growth and feeding tolerance with Saccharomyces boulardii CNCM I-745 in formula-fed preterm infants

J Pediatr (Rio J)

(2016)

J.A. Martin et al.

Preterm births – United States, 2006 and 2010

MMWR Suppl

(2013)

J. Neu et al.

Necrotizing enterocolitis

N Engl J Med

(2011)

B.L. Frost et al.

New medical and surgical insights into neonatal necrotizing enterocolitis: a review

JAMA Pediatr

(2017)

Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria

K. AlFaleh et al.

Probiotics for prevention of necrotizing enterocolitis in preterm infants

Cochrane Database Syst Rev

(2014)

B. Sadeghirad et al.

Comparative effectiveness of prophylactic therapies for necrotizing enterocolitis in preterm infants: protocol for a network meta-analysis of randomized trials

Int J Prev Med

(2018)

B. Sadeghirad et al.

Probiotics, prebiotics, and synbiotics for prevention of mortality and morbidity in preterm infants: a systematic review and network meta-analysis of randomized trials

G.A. Preidis et al.

AGA technical review on the role of probiotics in the management of gastrointestinal disorders

Gastroenterology

(2020)

M.J. Bell et al.

Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging

Ann Surg

(1978)

J.P.T. Higgins et al.

The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials

BMJ

(2011)

Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, version 5.1.0. The Cochrane...

S.P. Hozo et al.

Estimating the mean and variance from the median, range, and the size of a sample

BMC Med Res Methodol

(2005)

I.R. White

Network meta-analysis

Stata J

(2015)

I.R. White et al.

Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression

Res Synth Methods

(2012)

A. Chaimani et al.

Visualizing assumptions and results in network meta-analysis: the network graphs package

Stata J

(2015)

R.M. Harbord et al.

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Stat Med

(2006)

J.P.T. Higgins et al.

Measuring inconsistency in meta-analyses

BMJ

(2003)

G. Lu et al.

Assessing evidence inconsistency in mixed treatment comparisons

J Am Stat Assoc

(2006)

J.P. Higgins et al.

Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies

Res Synth Methods

(2012)

G.H. Guyatt et al.

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

BMJ

(2008)

M.A. Puhan et al.

A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis

BMJ

(2014)

Y. Li et al.

Effects of Bifidobacterium breve supplementation on intestinal flora of low birth weight infants

Pediatr Int

(2004)

E. Coleta et al.

Oral supplementation with probiotics in premature infants-a randomised clinical trial

Intensive Care Med

(2013)

N. Koksal et al.

Effect of probiotic support on feeding intolerance and mortality at preterm infants

J Perinat Med

(2015)

C. Wang et al.

Effects of oral administration of Bifidobacterium breve on fecal lactic acid and short-chain fatty acids in low birth weight infants

J Pediatr Gastroenterol Nutr

(2007)

N. Zeber-Lubecka et al.

Effect of Saccharomyces boulardii and mode of delivery on the early development of the gut microbial community in preterm infants

PLoS One

(2016)

A. Partty et al.

Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial

J Pediatr

(2013)

M. Al-Hosni et al.

Probiotics-supplemented feeding in extremely low-birth-weight infants

J Perinatol

(2012)

S. Arora et al.

To study the role of probiotics in the prevention of necrotizing enterocolitis in preterm neonates

Int J Contemp Pediatrics

(2017)

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The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants.
MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included.
Probiotics (OR, 0.47; 95% CrI, 0.33–0.63), arginine (OR, 0.38; 95% CrI, 0.14–0.98), glutamine (OR, 0.30; 95% CrI, 0.079–0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037–0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69–0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54–0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40–0.79), prebiotics (OR, 0.23; 95% CrI, 0.043–0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035–0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7– -0.63) appeared to have earlier age of attainment of full feeding.
Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements.
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These studies indicated that FMT has great potential in promoting the development of the gut microbiota and intestinal immune system of premature infants. Probiotics are live microorganism preparations with presumed health benefits, which have been widely used as an early intervention strategy in premature infants [111]. It has been demonstrated that probiotic supplements can improve the development of gut microbiota and the gastrointestinal environment of premature infants, resulting in a positive effect on the development and maturation of the intestinal immune system more closely resembling that of full-term infants [97].
Preterm birth is the leading cause of death in children under the age of five. One of the major factors contributing to the high risk of diseases and deaths in premature infants is the incomplete development of the intestinal immune system. The gut microbiota has been widely recognized as a critical factor in promoting the development and function of the intestinal immune system after birth. However, the gut microbiota of premature infants is at high risk of dysbiosis, which is highly associated with adverse effects on the development and education of the early life immune system. Early intervention can modulate the colonization and development of gut microbiota and has a long-term influence on the development of the intestinal immune system.
This review aims to summarize the characterization, interconnection, and underlying mechanism of gut microbiota and intestinal innate immunity in premature infants, and to discuss the status, applicability, safety, and prospects of different intervention strategies in premature infants, thus providing an overview and outlook of the current applications and remaining gaps of early intervention strategies in premature infants.
This review is focused on three key concepts. Firstly, the gut microbiota of premature infants is at high risk of dysbiosis, resulting in dysfunctional intestinal immune system processes. Secondly, contributing roles of early intervention have been observed in improving the intestinal environment and promoting gut microbiota colonization, which is significant in the development and function of gut immunity in premature infants. Thirdly, different strategies of early intervention, such as probiotics, fecal microbiota transplantation, and nutrients, show different safety, applicability, and outcome in premature infants, and the underlying mechanism is complex and poorly understood.
Maternal melatonin supplementation shapes gut microbiota and protects against inflammation in early life
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Gut microbiota colonization is critical for immune education and nutrient metabolism. Research shows that melatonin has beneficial effects as a therapy for many diseases via modulating gut dysbiosis. However, it is unclear whether melatonin alters gut microbiota colonization in early life.
In the experimental group (Mel), mice were intraperitoneally injected with melatonin at 10 mg/kg body weight for embryonic days 14–16 and received drinking water containing 0.4 mg/mL melatonin until 28 days postpartum. In the control group (Ctrl), mice were injected with the same volume of 2.5% ethanol in saline and provided with standard water. Two more groups were created by treating neonatal mice with 20 mg/kg lipopolysaccharide (LPS) to induce inflammation, resulting in the groups Ctrl + LPS and Mel + LPS, respectively. We examined the gut microbiota of the neonatal mice in the Ctrl and Mel group on Days 7, 14, 21, and 28 post-birth. On Day 14, melatonin and short-chain fatty acids (SCFAs) concentrations were measured in the Ctrl and Mel group and the mice were treated with LPS to be evaluated for intestinal injury and inflammatory response 15 h post treatment. According to the result of the SCFAs concentrations, some neonatal mice were intraperitoneally injected with 500 mg/kg sodium butyrate (SB) from Days 11–13, intraperitoneally injected with 20 mg/kg LPS on Day 14, and then euthanized by carbon dioxide inhalation the next morning. Intestinal injury and inflammatory responses were evaluated in the Ctrl + LPS and SB + LPS groups, respectively.
By Day 14, it was evident that maternal melatonin supplementation significantly increased the relative abundance of Firmicutes in the ileal [61.03 (35.35 – 76.18) % vs. 98.02 (86.61 – 99.01) %, P = 0.003] and colonic [73.88 (69.77 – 85.99) % vs. 96.16 (94.57 – 96.34) %, P = 0.04] microbiota, the concentration of melatonin (0.79 ± 0.49 ng/ml vs. 6.11 ± 3.48 ng/ml, P = 0.008) in the gut lumen, and the fecal butyric acid (12.91 ± 5.74 μg/g vs. 23.58 ± 10.71 μg/g, P = 0.026) concentration of neonatal mice. Melatonin supplementation, and sodium butyrate treatment markedly alleviated intestinal injury and decreased inflammatory factors in neonatal mice.
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Necrotizing enterocolitis (NEC) is an infectious and inflammatory intestinal disease that is the most common surgical emergency in the premature patient population. Although the etiology of the disease is multifactorial, intestinal dysbiosis is a hallmark of this disease. Based on this, probiotics may play a therapeutic role in NEC by introducing beneficial bacteria with immunomodulating, antimicrobial, and anti-inflammatory functions into the gastrointestinal tract. Currently, there is no Food and Drug Administration (FDA)-approved probiotic for the prevention and treatment of NEC. All probiotic clinical studies to date have administered the bacteria in their planktonic (free-living) state. This review will discuss established probiotic delivery systems including planktonic probiotics, prebiotics, and synbiotics, as well as novel probiotic delivery systems such as biofilm-based and designer probiotics. We will also shed light on whether or not probiotic efficacy is influenced by administration with breast milk. Finally, we will consider the challenges associated with developing an FDA-approved probiotic for NEC.
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: Conflicts of interest These authors disclose the following: Adam V. Weizman has served on an advisory board for AbbVie, Ferring, Janssen, and Takeda and as a speaker for AbbVie and Janssen. Behnam Sadeghirad received funding from Mitacs Canada and Accelerate Internship, in partnership with Nestlé Canada, to support his graduate student stipend. Mitacs is a national, not-for-profit organization that has designed and delivered research and training programs in Canada working with universities, companies, and both federal and provincial governments. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The remaining authors disclose no conflicts.

: Funding National Institute of Health provided support for Geoffrey Preidis (NIH K08 DK113114) and for Purna Kashyap (NIH DK114007).

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Original ResearchFull Report: Clinical—Alimentary TractProbiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials

Background & Aims

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Conclusion

Acknowledgements

Lancet

Gastroenterology

Semin Pediatr Surg

Pediatr Clin North Am

J Clin Epidemiol

J Clin Epidemiol

Early Hum Dev

J Pediatr

J Pediatr

Am J Clin Nutr

Early Hum Dev

Early Hum Dev

Lancet

Clin Nutr

Early Hum Dev

Am J Clin Nutr

Pediatr Pol

Early Hum Dev

Early Hum Dev

Nutrition

J Pediatr (Rio J)

Preterm births – United States, 2006 and 2010

MMWR Suppl

Necrotizing enterocolitis

N Engl J Med

New medical and surgical insights into neonatal necrotizing enterocolitis: a review

JAMA Pediatr

Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria

Probiotics for prevention of necrotizing enterocolitis in preterm infants

Cochrane Database Syst Rev

Comparative effectiveness of prophylactic therapies for necrotizing enterocolitis in preterm infants: protocol for a network meta-analysis of randomized trials

Int J Prev Med

Probiotics, prebiotics, and synbiotics for prevention of mortality and morbidity in preterm infants: a systematic review and network meta-analysis of randomized trials

AGA technical review on the role of probiotics in the management of gastrointestinal disorders

Gastroenterology

Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging

Ann Surg

The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials

BMJ

Estimating the mean and variance from the median, range, and the size of a sample

BMC Med Res Methodol

Network meta-analysis

Stata J

Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression

Res Synth Methods

Visualizing assumptions and results in network meta-analysis: the network graphs package

Stata J

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Stat Med

Measuring inconsistency in meta-analyses

BMJ

Assessing evidence inconsistency in mixed treatment comparisons

J Am Stat Assoc

Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies

Res Synth Methods

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

BMJ

A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis

BMJ

Effects of Bifidobacterium breve supplementation on intestinal flora of low birth weight infants

Pediatr Int

Oral supplementation with probiotics in premature infants-a randomised clinical trial

Intensive Care Med

Effect of probiotic support on feeding intolerance and mortality at preterm infants

J Perinat Med

Effects of oral administration of Bifidobacterium breve on fecal lactic acid and short-chain fatty acids in low birth weight infants

J Pediatr Gastroenterol Nutr

Effect of Saccharomyces boulardii and mode of delivery on the early development of the gut microbial community in preterm infants

PLoS One

Original Research
Full Report: Clinical—Alimentary Tract
Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials