Probiotics for prevention of necrotizing enterocolitis in preterm infants

AlFaleh, Khalid; Bassler, Dirk

doi:10.1002/14651858.cd005496.pub2

Cited by 227 publications

(259 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%

“…Analysis of time-to-event outcomes, such as reaching full enteral feeding, used survival analysis techniques. An additional subgroup analysis was performed post hoc by birthweight above or below 1 kg to facilitate comparison with data from the published ProPrems trial 41 and to address recommendations made in successive systematic reviews 30,32,35 concerning routine administration of probiotics in these birthweight categories.…”

Section: Methodsmentioning

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.…”

Section: Scientific Backgroundmentioning

confidence: 99%

“…The importance of gestational age as a risk factor is apparent within the trial data, with all three primary outcomes falling sharply with increasing gestation age within this target range (see Figure 7), but the greater number of births at higher gestational age means that the need for effective prevention remains high. Cochrane reviews of the role of probiotics to prevent NEC prior to that published in 2014 30,32 argued that the evidence of efficacy in preterm babies with a birthweight > 1 kg supported routine use. More recently, with publication of the ProPrems trial, 41 that recommendation has been extended to include the extremely low-birthweight group with birthweight < 1 kg.…”

Section: The Trial Populationmentioning

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: Methodsmentioning

confidence: 99%

Section: Scientific Backgroundmentioning

confidence: 99%

Section: The Trial Populationmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics [12,[14][15][16][17][18][19][20]. Hoyos et al [18] noted an almost threefold reduction in the incidence of NEC after the administration of probiotics that included Lactobacillus acidophilus and Bifidobacterium infantis.…”

Section: Possible Treatment For Necmentioning

confidence: 99%

Using a mathematical model to analyze the role of probiotics and inflammation in necrotizing enterocolitis

Arciero

Ermentrout

Rubin

et al. 2009

Journal of Critical Care

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Background: Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract of pre-term babies and is thought to be related to the physiological immaturity of the intestine and altered levels of normal flora in the gut. Understanding the factors that contribute to the pathology of NEC may lead to the development of treatment strategies aimed at re-establishing the integrity of the epithelial wall and preventing the propagation of inflammation in NEC. Several studies have shown a reduced incidence and severity of NEC in neonates treated with probiotics (beneficial bacteria species).

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