Elsevier

The Lancet

Volume 387, Issue 10019, 13–19 February 2016, Pages 649-660
The Lancet

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

https://doi.org/10.1016/S0140-6736(15)01027-2Get rights and content

Summary

Background

Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants.

Methods

In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17.

Findings

Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68–1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73–1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67–1·30]). No probiotic-associated adverse events were reported.

Interpretation

There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants.

Funding

UK National Institute for Health Research Health Technology Assessment programme.

Introduction

Necrotising enterocolitis is the most serious gastrointestinal disease of the preterm infant. Necrotising enterocolitis and sepsis are increasingly important contributors to mortality as a consequence of more preterm infants surviving the first week of life.1 The onset of both conditions is often rapidly progressive with involvement of multiple organ systems and an intense inflammatory response, reflected among survivors by poor growth and developmental delay.2 Treatment of the diseases, once established, is unlikely to be wholly successful, and preventive treatments are urgently needed.

The pathogenesis of necrotising enterocolitis is complex and remains incompletely understood, involving immaturity of the barrier function of the intestinal mucosa so that it might be invaded and possibly translocated by potentially pathogenic bacteria. Similar mechanisms are likely to be involved in cases of late-onset sepsis when the infecting organism originates from a reservoir within the intestine.3

The importance of a diverse intestinal microbiome for continued good health in later life has been long recognised. These bacteria have a range of roles, many involving the intestinal immunological defences, resisting colonisation and possible invasion of the intestinal wall by pathogens. After preterm birth, acquisition of the microbiome is slow, typically less diverse, and dominated by Enterobacteriaceae with relatively few of the lactobacilli and bifidobacteria, which are typical of the term breast-fed infant. The contribution of abnormal patterns of the intestinal microbiota to the clinical onset of necrotising enterocolitis and sepsis is not clear, but there is an accumulating body of evidence reporting distinct perturbations of the gut microbiota in the period preceding the onset of clinical illness.4

The hypothesis supporting the use of probiotic bacteria to prevent necrotising enterocolitis and sepsis is that their administration to the preterm infant will encourage gut microbiota resembling that of the term infant, strengthen intestinal barrier function, and, thereby, protect the infant. Further, because the administered bacterial strains are similar to those acquired by healthy infants it seems unlikely that the intervention will harm.

Research in context

Evidence before this study

Extensive and regular searches of the literature written in English were conducted and we identified a small number of trials of probiotic in preterm infants, none with sepsis, and only one with necrotising enterocolitis as a primary outcome in a trial with multiple exclusions and very low incidence. The first Cochrane review of the topic was published in 2008, including a total of 11 trials with a meta-analysis suggesting reduced necrotising enterocolitis and death, but with no effect on sepsis. The authors commented on the heterogeneity of the trial participants and interventions, the difficulty of extracting outcome data for the high risk group below 1000 g birthweight, and the need for large trials.

Added value of this study

To the best of our knowledge, this study is the largest and the first statistically powerful published trial of the efficacy of a probiotic to reduce necrotising enterocolitis and sepsis in the preterm population. The population is likely to be more representative than the total population in recent meta-analyses. Furthermore, this is the first trial systematically to study stool colonisation in both groups of the trial and to emphasise both the incomplete colonisation in the active and the high cross colonisation in the placebo group. This trial reinforces the message from others that, in the short term, probiotic interventions are safe.

Implications of all the available evidence

The current results support the view that strains should be assessed separately and challenge the validity of combining trials of different interventions in meta-analyses. It is not plausible that cross colonisation with administered probiotic is confined to this trial; routine use of probiotic is likely to modify the gut microbiota of infants other than those for whom it is prescribed. We conclude that at the present time the evidence from clinical trials does not support the routine use of probiotics to prevent necrotising enterocolitis and sepsis in the preterm infant.

The most recent Cochrane review of this topic5 includes 24 studies involving more than 5500 infants, and makes a recommendation for their routine use for all preterm infants. However, concerns about the rigour of many of the published trials and the appropriateness of combining them in meta-analyses have constrained their introduction into routine practice.6 We designed a trial that aimed to address previous failings of published trials with sufficient numbers to give clear answers about the prevention of necrotising enterocolitis and sepsis in an unselected population of preterm infants, using a single strain probiotic product, Bifidobacterium breve BBG-001, and monitoring colonisation of stool samples.

Section snippets

Study design and participants

In this multicentre blinded randomised controlled phase 3 study (the PiPs trial), we recruited infants born between 23 weeks and 0 days, and 30 weeks and 6 days of gestation from 24 hospitals within 60 miles of London; continuing care before discharge from hospital was provided at a further 33 sites. Those infants with a potentially lethal malformation or any malformation of the gastrointestinal tract apparent by 48 h and those with no realistic chance of survival were ineligible. Written

Results

Between July 1, 2010, and July 31, 2013, 1315 infants were recruited, of whom 654 were allocated to probiotic and 661 to placebo. Five had consent withdrawn, thus 650 were analysed in the probiotic group and 660 in the placebo group (figure 1). On average, 84% (SD 26) of planned doses were given to infants in each group. Interruptions to the dosage regime were reported for 416 (32%) infants, 76 of whom discontinued the intervention permanently; 14 in each group at the request of the parents and

Discussion

This trial shows no evidence of benefit of B breve BBG-001 in this population, for any of the primary or secondary outcomes. The strengths of this trial are three-fold: first, its size, which combined with the reported rates of necrotising enterocolitis and sepsis, provide it with statistical power to give clear answers; second, the combination of early recruitment, broad eligibility criteria, and early commencement of the intervention whether or not milk feeding had begun, which we believe has

References (36)

  • JE Berrington et al.

    Deaths in preterm infants: changing pathology over 2 decades

    J Pediatr

    (2012)
  • RM Torrazza et al.

    Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis

    PLoS One

    (2014)
  • K Alfaleh et al.

    Probiotics for prevention of necrotizing enterocolitis in preterm infants

    Cochrane Database Syst Rev

    (2014)
  • A guide to what is a medicinal product'. MHRA Guidance Note No 8

  • J Fujimoto et al.

    Identification and quantification of viable Bifidobacterium breve strain Yakult in human faeces by using strain-specific primers and propidium monoazide

    J Appl Microbiol

    (2011)
  • MJ Bell et al.

    Neonatal necrotizing enterocolitis. Therapeutic decisions based on clinical staging

    Ann Surg

    (1978)
  • JV Freeman et al.

    Cross sectional stature and weight reference curves for the UK, 1990

    Arch Dis Child

    (1995)
  • Stata Statistical Software: Release 13

    (2013)
  • Cited by (289)

    • Probiotics and novel probiotic delivery systems

      2023, Seminars in Pediatric Surgery
    • Healthcare-Associated Infections

      2023, Avery's Diseases of the Newborn
    View all citing articles on Scopus

    Members listed at the end of the paper

    View full text