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NIHR Signal A trial of probiotics for treating sepsis in very premature babies poses more questions than it answers

Published on 23 December 2015

doi: 10.3310/signal-000172

Contrary to a previous review of trials, this large, NIHR-funded trial found that probiotic treatment did not prevent two common life-threatening conditions in very premature babies. The conditions were necrotising enterocolitis, which is a severe gut inflammation/infection that can result in the death of intestinal tissue, and sepsis (blood poisoning) from bacteria that have crossed from the gut into the bloodstream.

This trial used a single strain of a harmless bacterium, known as a “probiotic”, prepared to high quality standards fit for medicines, and chosen because it is commonly used in dietary supplements. That no benefit was found, raises questions about the research design, such as whether the most effective strain had been used or whether the previous review’s findings were subject to bias, for example by combining results from different strains of bacteria. It is too early to make firm recommendations about whether probiotics should be used for this purpose.

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Why was this study needed?

Medical advances have meant that more very premature babies are surviving birth. Unfortunately, such babies are at risk from two devastating conditions related to the inability of immature intestines to act as a barrier to bacteria: necrotising enterocolitis and sepsis. In babies born before 28 weeks and weighing less than 1500g, an estimated 11% develop necrotising enterocolitis and 36% acquire sepsis. Mortality of babies with these conditions may be as high as 30%. Therefore, there is a lot of interest in safe, effective measures to prevent these conditions.

In 2014, a Cochrane review pooled results from 24 small trials and recommended that probiotics could help prevent necrotising enterocolitis, but not sepsis in preterm infants. However, trials in the review used different probiotics and so the results are hard to interpret practically. The current study aimed to assess the effectiveness of a single promising strain of probiotic produced to medicine standards.

What did this study do?

This randomised controlled trial was carried out at 24 hospitals in southeast England, involving 1,315 babies born between the 23rd and 31st weeks of pregnancy. Within 48 hours of birth, the babies were randomly allocated to receive either probiotic solution or similarly cloudy infant formula as a placebo, added to their feed. Neither hospital staff nor families were told which babies were receiving probiotic. The probiotic contained a strain of a harmless bacterium called Bifidobacterium breve BBC-001, which was produced by the Yakult company. The trial’s main outcomes were death before discharge from hospital, definite necrotising enterocolitis, or sepsis, shown by finding bacteria (apart from those from skin) in a blood culture.

What did it find?

  • Necrotising enterocolitis developed in similar proportions of babies in both groups: 9% in the probiotic group compared with 10% in the feed-only group (adjusted risk ratio [RR] 0.93, 95% confidence interval [CI] 0.68 to 1.27).
  • Sepsis developed in similar proportions of babies in both groups: 11% in the probiotic group compared with 12% in the feed-only group (adjusted RR 0.97, 95% CI 0.73 to 1.29).
  • Deaths before discharge from hospital occurred at a similar rate in both groups: 8% in the probiotic group compared with 9% in the feed-only group (adjusted RR 0.93, 95% CI 0.67 to 1.30).
  • The characteristics of babies were similar between the two groups, including whether they had received breast milk.
  • By two weeks after birth, stool samples from 94% of the living babies showed that the probiotic bacterium Bifidobacterium breve BBC-001 was present in 85% of the babies who had received probiotic and 37% of babies who had received feed only.
  • There were no adverse events related to receiving probiotic.

What does current guidance say on this issue?

We could not identify any UK guidance on probiotic use for premature babies to prevent necrotising enterocolitis or sepsis. International guidance on using probiotics to prevent necrotising enterocolitis was published in 2011. However, the authors of this guidance warned that there were gaps in knowledge about how to use probiotics, that each strain should be tested to make sure that it works and is safe, and that probiotics for premature babies should be manufactured to a high standard.

What are the implications?

This trial’s findings pose more questions than they answer. The results showed that Bifidobacterium breve BBC-001 probiotic strain did not prevent necrotising enterocolitis or sepsis in premature babies in a typical population of premature babies in southeast England, compared with no probiotic treatment. Such findings are contrary to previous reviews and some trials. In the absence of UK guidance, it is too early to recommend approaches to take in practice. However, the trial did shed light on how future trials could be designed, with respect to the importance of researching the effectiveness of individual strains as opposed to administering mixtures of bacteria, and how to ensure high standards of probiotic manufacture.

Citation

Costeloe K, Hardy P, Juszczak E, et al; Probiotics in Preterm Infants Study Collaborative Group. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet. 2015; Nov 25. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 05/501/04).

Bibliography

Abrahamsson, T. Not all probiotic strains prevent necrotising enterocolitis in premature infants. Lancet. 2015; Nov 25. [Epub ahead of print].

AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Syst Rev. 2014;(4):CD005496.

Deshpande GC, Rao SC, Keil AD, et al. Evidence-based guidelines for use of probiotics in preterm neonates. BMC medicine. 2011;9(1):92.

Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010; August.

Why was this study needed?

Medical advances have meant that more very premature babies are surviving birth. Unfortunately, such babies are at risk from two devastating conditions related to the inability of immature intestines to act as a barrier to bacteria: necrotising enterocolitis and sepsis. In babies born before 28 weeks and weighing less than 1500g, an estimated 11% develop necrotising enterocolitis and 36% acquire sepsis. Mortality of babies with these conditions may be as high as 30%. Therefore, there is a lot of interest in safe, effective measures to prevent these conditions.

In 2014, a Cochrane review pooled results from 24 small trials and recommended that probiotics could help prevent necrotising enterocolitis, but not sepsis in preterm infants. However, trials in the review used different probiotics and so the results are hard to interpret practically. The current study aimed to assess the effectiveness of a single promising strain of probiotic produced to medicine standards.

What did this study do?

This randomised controlled trial was carried out at 24 hospitals in southeast England, involving 1,315 babies born between the 23rd and 31st weeks of pregnancy. Within 48 hours of birth, the babies were randomly allocated to receive either probiotic solution or similarly cloudy infant formula as a placebo, added to their feed. Neither hospital staff nor families were told which babies were receiving probiotic. The probiotic contained a strain of a harmless bacterium called Bifidobacterium breve BBC-001, which was produced by the Yakult company. The trial’s main outcomes were death before discharge from hospital, definite necrotising enterocolitis, or sepsis, shown by finding bacteria (apart from those from skin) in a blood culture.

What did it find?

  • Necrotising enterocolitis developed in similar proportions of babies in both groups: 9% in the probiotic group compared with 10% in the feed-only group (adjusted risk ratio [RR] 0.93, 95% confidence interval [CI] 0.68 to 1.27).
  • Sepsis developed in similar proportions of babies in both groups: 11% in the probiotic group compared with 12% in the feed-only group (adjusted RR 0.97, 95% CI 0.73 to 1.29).
  • Deaths before discharge from hospital occurred at a similar rate in both groups: 8% in the probiotic group compared with 9% in the feed-only group (adjusted RR 0.93, 95% CI 0.67 to 1.30).
  • The characteristics of babies were similar between the two groups, including whether they had received breast milk.
  • By two weeks after birth, stool samples from 94% of the living babies showed that the probiotic bacterium Bifidobacterium breve BBC-001 was present in 85% of the babies who had received probiotic and 37% of babies who had received feed only.
  • There were no adverse events related to receiving probiotic.

What does current guidance say on this issue?

We could not identify any UK guidance on probiotic use for premature babies to prevent necrotising enterocolitis or sepsis. International guidance on using probiotics to prevent necrotising enterocolitis was published in 2011. However, the authors of this guidance warned that there were gaps in knowledge about how to use probiotics, that each strain should be tested to make sure that it works and is safe, and that probiotics for premature babies should be manufactured to a high standard.

What are the implications?

This trial’s findings pose more questions than they answer. The results showed that Bifidobacterium breve BBC-001 probiotic strain did not prevent necrotising enterocolitis or sepsis in premature babies in a typical population of premature babies in southeast England, compared with no probiotic treatment. Such findings are contrary to previous reviews and some trials. In the absence of UK guidance, it is too early to recommend approaches to take in practice. However, the trial did shed light on how future trials could be designed, with respect to the importance of researching the effectiveness of individual strains as opposed to administering mixtures of bacteria, and how to ensure high standards of probiotic manufacture.

Citation

Costeloe K, Hardy P, Juszczak E, et al; Probiotics in Preterm Infants Study Collaborative Group. Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial. Lancet. 2015; Nov 25. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 05/501/04).

Bibliography

Abrahamsson, T. Not all probiotic strains prevent necrotising enterocolitis in premature infants. Lancet. 2015; Nov 25. [Epub ahead of print].

AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Syst Rev. 2014;(4):CD005496.

Deshpande GC, Rao SC, Keil AD, et al. Evidence-based guidelines for use of probiotics in preterm neonates. BMC medicine. 2011;9(1):92.

Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010; August.

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

Published on 25 November 2015

Costeloe K, Hardy P, Juszczak E, Wilks M, Millar MR.

Lancet The , 2015

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.

Expert commentary

Despite improvements in neonatal care, necrotising enterocolitis and late onset sepsis continue to be serious, feared complications of prematurity that cause substantial mortality and morbidity. Identifying treatments for these remains a high priority for neonatal researchers. Costeloe and colleagues are to be praised for undertaking a well powered study of a pharmaceutical quality probiotic in 1315 very premature infants. The result of the study is disappointing in concluding that B. breve BBG-001 does not improve outcomes or death. It is likely that this organism is not effective but it is possible that cross contamination may have affected these results or that alternative timing or dosing regimens might be beneficial. Researchers should now shift focus to answering these questions or assessing other pharmaceutical quality products. Without further evidence, B. breve BBG-001 should only be used as part of an ethically approved trial.

Jon Dorling, Consultant Neonatologist and Clinical Associate Professor, Nottingham University Hospitals & University of Nottingham