Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants

Mihatsch, Walter A.; Braegger, Christian; Décsi, Támas; Kolaček, Sanja; Lanzinger, Hartmut; Mayer, Benjamin; Moreno, Luis A.; Pohlandt, Frank; Puntis, John; Shamir, Raanan; Stadtmüller, Ulrich; Szajewska, Hania; Turck, Dominique; Goudoever, Johannes B. van

doi:10.1016/j.clnu.2011.09.004

Cited by 159 publications

(129 citation statements)

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“…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%

“…Some authors have strongly advocated a change of practice to routine use 29 because of the apparent association with a reduction in NEC and death, as suggested in a series of meta-analyses, [30][31][32] whereas others have recommended caution because of the heterogeneity of the participants and of the interventions and the methodological failings of some trials. 33,34 At the time of writing, 11 RCTs designed to study the efficacy of a bacterial probiotic intervention, with late-onset sepsis and/or NEC and/or death as the primary outcome, have been published in English. These trials account for 4396 of the 5529 (80%) babies randomised in 20 trials included in the most recent Cochrane review of probiotics to prevent NEC in preterm babies.…”

Section: Scientific Backgroundmentioning

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: The Choice Of Probioticmentioning

confidence: 99%

Section: Scientific Backgroundmentioning

confidence: 99%

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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“…In 2012, Mihatsch and colleagues systematically analysed the level of evidence of published randomised controlled trials on probiotics in preterm babies in order to evaluate whether a statistically confirmatory basis could be provided to recommend routine probiotic use in very low birth weight babies (VLBW) to prevent NEC, sepsis, death and feeding tolerance. This study applied robust and validated methods to assess the quality of individual trials used in prior meta-analyses and reported that only 2 of 15 trials provided Level of Evidence (LoB) 1b neither of which supported the use of probiotics in preterm babies [65]. In the absence of confirmatory studies, many researchers agreed that a number of these concerns could only be addressed by further large randomised controlled trials.…”

Section: Probiotics For the Prevention Of Necmentioning

confidence: 99%

Probiotics and necrotizing enterocolitis

2015

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“…A recent systematic review performed by Mihatsch et al (46) reported that there is insufficient evidence to recommend routine probiotics. However there is encouraging data which justifies the further investigation regarding the efficacy and safety of specific probiotics in circumstances of high local incidence of severe NEC.…”

Section: Probiotic Prophylaxis In Necmentioning

confidence: 99%

Probiotic Use for the Prevention of Necrotizing Enterocolitis in Preterm Infants

Sarı¹,

Dilmen²

2012

Probiotics

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Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants

Cited by 159 publications

References 73 publications

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

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

Probiotics and necrotizing enterocolitis

Probiotic Use for the Prevention of Necrotizing Enterocolitis in Preterm Infants

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