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

  • 2016-02
  • The Lancet 387(10019)
    • K. Costeloe
    • P. Hardy
    • E. Juszczak
    • M. Wilks
    • M. Millar

Abstract

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 Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group.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.

Research Insights

SupplementHealth OutcomeEffect TypeEffect Size
Bifidobacterium brevePrevention of Necrotising EnterocolitisNeutral
Small
Bifidobacterium breveReduced Incidence of Late-Onset SepsisNeutral
Small
Bifidobacterium breveReduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve Bb-03Increased Late-Onset Sepsis IncidenceNeutral
Small
Bifidobacterium breve Bb-03Reduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve Bb-03Reduced Necrotising EnterocolitisNeutral
Small
Bifidobacterium breve Bb-18Increased Late-Onset Sepsis IncidenceNeutral
Small
Bifidobacterium breve Bb-18Reduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve Bb-18Reduced Severity of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve BBr60Reduced Necrotising EnterocolitisNeutral
Small
Bifidobacterium breve Bbr8Increased Late-Onset Sepsis IncidenceNeutral
Small
Bifidobacterium breve Bbr8Reduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve Bbr8Reduced Severity of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve BR-03Increased Sepsis IncidenceNeutral
Small
Bifidobacterium breve BR-03Reduced MortalityNeutral
Small
Bifidobacterium breve BR-03Reduced Severity of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve HA-129Increased Late-Onset Sepsis IncidenceNeutral
Small
Bifidobacterium breve HA-129Reduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve HA-129Reduced Severity of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve IDCC 4401Reduced Incidence of Late-Onset SepsisNeutral
Small
Bifidobacterium breve IDCC 4401Reduced Mortality RateNeutral
Small
Bifidobacterium breve IDCC 4401Reduced Necrotising EnterocolitisNeutral
Small
Bifidobacterium breve R0070Reduced Incidence of Late-Onset SepsisNeutral
Small
Bifidobacterium breve R0070Reduced Incidence of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve R0070Reduced Mortality Rate Before DischargeNeutral
Small
Bifidobacterium breve UABbr-11Incidence of Late-Onset SepsisNeutral
Small
Bifidobacterium breve UABbr-11Incidence of Necrotizing EnterocolitisNeutral
Small
Bifidobacterium breve UABbr-11Reduced Mortality Rate Before DischargeNeutral
Small

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