Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis

Fernández-Carrocera, Luis Alberto; Solis-Herrera, Aide; Cabanillas-Ayón, Marisol; Gallardo-Sarmiento, Rocío Beatriz; García-Pérez, Carmina Sarisol; Montaño-Rodríguez, Rosalba; Echaniz-Aviles, María Olga Leticia

doi:10.1136/archdischild-2011-300435

Cited by 123 publications

(101 citation statements)

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“…Breast milk feeding initiation rates were high (96.9%) in both groups, compared with other studies. 13,14,[22][23][24]33 Our findings emphasize the importance of performing well-powered trials of probiotic administration in very preterm infants in different settings.…”

Section: Discussionmentioning

confidence: 96%

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

Tobin²,

et al. 2013

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BACKGROUND AND OBJECTIVE: Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis (NEC) in preterm infants, with unclear effect on late-onset sepsis. This study aimed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. METHODS: A prospective multicenter, double-blinded, placebo-controlled, randomized trial compared daily administration of a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 109 total organisms) with placebo (maltodextrin) in infants born before 32 completed weeks’ gestation weighing <1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. RESULTS: Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zealand were randomized. Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%; relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to treat 43, 95% confidence interval 23 to 333). CONCLUSIONS: The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe.

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Section: Discussionmentioning

confidence: 96%

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

Tobin²,

et al. 2013

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“…102 Numerous studies have evaluated the use of probiotics to supplement colonization of the preterm gut with commensal flora, and thereby reducing the incidence of NEC. [103][104][105][106][107] However, there has been wide variation in the timing, dose, and formulation of probiotics used in the various trials. A Cochrane systematic review evaluating the use of probiotics in the prevention of NEC showed a statistically significant reduction in the incidence of NEC and mortality in the probiotics group (NEC RR 0.35, 95% CI 0.24-0.52 and mortality RR 0.40, 95% CI 0.27-0.60).…”

Section: Current Research Focus Probioticsmentioning

confidence: 99%

Necrotizing enterocolitis: current perspectives

Yajamanyam

Rasiah²,

Ewer³

2014

RRN

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Necrotizing enterocolitis is the most common gastrointestinal emergency in neonates, particularly in those born very preterm. It is a leading cause of morbidity and mortality, especially in extremely low birth weight infants. Despite extensive research, the pathophysiology of necrotizing enterocolitis remains unclear and therapeutic options are limited. Multiple risk factors have been reported, but most are associated with prematurity and its complications. This makes management very challenging in vulnerable preterm infants. In this review, we focus on the risk factors and some of the current research in this area, particularly studies aimed at early detection and potential preventive measures for this potentially lethal condition.

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“…The B. lactis used by Mihatsch et al 36 was checked monthly to ensure the viability and purity of the product together with the 24-hour stability of the prepared suspension. The six-strain product used by Fernández-Carrocera et al 40 (four strains of Lactobacillus, one of B. infantis and one of S. thermophilus) was checked twice against the manufacturer's quality control register and the ABC Dophilus used for the ProPrems trial 41 was imported under licence into Australia. Each batch was then subjected to independent confirmation of taxonomy and quality by checking the probiotic content using polymerase chain reaction (PCR) and the purity by culture.…”

Section: Qualitymentioning

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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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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Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis

Abstract: Probiotics may offer potential benefits for premature infants and are a promising strategy in the reduction of the risk of NEC in preterm newborns.

Cited by 123 publications

References 31 publications

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

Necrotizing enterocolitis: current perspectives

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

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