Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials

Wang, Quanzhen; Dong, Jing; Zhu, Yimin

doi:10.1016/j.jpedsurg.2011.09.064

Cited by 171 publications

(143 citation statements)

References 42 publications

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“…The failure to show a reduction in NEC or mortality is at variance with a number of meta-analyses, 27,[30][31][32]35,63 including the most recent Cochrane review, and with the recently published large multicentre ProPrems trial 41 that recruited in Australia and New Zealand and which, while failing to find evidence of benefit for either sepsis or mortality, did show a protective effect for NEC (2.0% active intervention group vs. 4.4% placebo group). Interestingly, the time of onset of NEC Bell stage ≥ 2 at a postmenstrual age of 30 weeks is earlier in the PiPS trial than in the data based on a Canadian population, but is similar to preliminary data for time of onset of serious (surgical and/or fatal) NEC at a median postmenstrual age of 30 weeks (interquartile range 28-32 weeks' postmenstrual age) in a 2-year prospective cohort of 14,294 babies born between 23 and 31 completed weeks of gestation admitted to neonatal units in England in 2012 and 2013.…”

Section: Probiotics In Preterm Infants Trial Results: Outcomesmentioning

confidence: 99%

“…In the context of the wide range of products used in previously published trials 34,63,73 it is too simplistic to simply dismiss this result as being because we chose the wrong product. The evidence we have, as discussed earlier, from laboratory, animal and limited human data all suggests that different bacterial strains have different protective roles at the intestinal mucosal surface; this is biologically plausible and explains why we are dependent on such an enormous range of commensals for good health.…”

Section: Generalisability Of the Resultsmentioning

confidence: 99%

“…Two published meta-analyses 34,63 attempt to group trials to study the effects of different organisms and combinations, but they fail to reach clear conclusions and highlight the need for further study.…”

Section: The Choice Of Probioticmentioning

confidence: 99%

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A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial

Costeloe

Bowler

Brocklehurst

et al. 2016

Health Technol Assess

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BackgroundNecrotising enterocolitis (NEC) and late-onset sepsis remain important causes of death and morbidity in preterm babies. Probiotic administration might strengthen intestinal barrier function and provide protection; this is supported by published meta-analyses, but there is a lack of large well-designed trials.ObjectiveTo test the use of the probioticBifidobacterium brevestrain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants.DesignDouble-blind, randomised, placebo-controlled trial.SettingRecruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation.ParticipantsBabies born between 23 and 30 weeks’ gestation and randomised within 48 hours of birth. Exclusions included life-threatening or any gastrointestinal malformation detected within 48 hours of birth and no realistic chance of survival.InterventionsActive intervention: 1 ml ofB. breveBBG-001 in one-eighth-strength infant formula Neocate®(Nutricia Ltd, Trowbridge, UK), (6.7 × 107to 6.7 × 109colony-forming units) per dose administered enterally. Placebo: 1 ml of one-eighth-strength infant formula Neocate. Started as soon as practicable and continued daily until 36 weeks’ postmenstrual age.Main outcome measuresPrimary outcomes were an episode of bloodstream infection, with any organism other than a skin commensal, in any baby between 72 hours and 46 weeks’ postmenstrual age; an episode of NEC Bell stage ≥ 2 in any baby; and death before discharge from hospital. Secondary outcomes included stool colonisation withB. breve.ResultsIn total, 654 babies were allocated to receive probiotic and 661 to receive placebo over 37 months from July 2010. Five babies were withdrawn; 650 babies from the probiotic group and 660 from the placebo group were included in the primary analysis. Baseline characteristics were well balanced. There was no evidence of benefit for the primary outcomes {sepsis: 11.2% vs. 11.7% [adjusted relative risk (RR) 0.97, 95% confidence interval (CI) 0.73 to 1.29]; NEC Bell stage ≥ 2: 9.4% vs. 10.0% [adjusted RR 0.93, 95% CI 0.68 to 1.27]; and death: 8.3% vs. 8.5% [adjusted RR 0.93, 95% CI 0.67 to 1.30]}.B. brevecolonisation status was available for 1186 (94%) survivors at 2 weeks’ postnatal age, of whom 724 (61%) were positive: 85% of the probiotic group and 37% of the placebo group. There were no differences for subgroup analyses by minimisation criteria and by stool colonisation withB. breveat 2 weeks. No harms associated with the interventions were reported.LimitationsCross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen.ConclusionsThis is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants.Future work recommendationsThe increasing understanding of the pathogenesis of NEC and sepsis will inform the choice of probiotics for testing and better define the target population. Future Phase III trials should incorporate monitoring of the quality and viability of the intervention and colonisation rates of participants; cluster design should be considered.Trial registrationCurrent Controlled Trials ISRCTN05511098 and EudraCT 2006-003445-17.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 66. See the NIHR Journals Library website for further project information.

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Section: Probiotics In Preterm Infants Trial Results: Outcomesmentioning

confidence: 99%

Section: Generalisability Of the Resultsmentioning

confidence: 99%

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A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial

Costeloe

Bowler

Brocklehurst

et al. 2016

Health Technol Assess

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“…Other authors suggested that the replacement of these commensal strains may restore microbiota equilibria and gives a preventive role against HAEC. The most studied probiotic strains in this regard are Lactobacillus, Bifidobacterium, Saccharomyces, and Streptococcus sp [16,17].…”

Section: Editorialmentioning

confidence: 99%

Intestinal Microbiota: A Big World of Evolving Knowledge

Manfredi¹

2014

Clin Microbiol

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“…Investigators have hypothesized that by altering the balance of the intestinal microbiome away from 'unfriendly' pathogenic bacteria in favor of 'friendly' bacteria, the incidence of NEC and NEC-related mortality may be reduced. Many RCTs have been presented, and meta-analyses of these trials suggest that probiotics may reduce the incidence of NEC and NEC-related mortality [4,5,6]. However, caution has been advised that routine probiotics use cannot yet be recommended.…”

mentioning

confidence: 99%