Prophylactic Probiotics to Prevent Death and Nosocomial Infection in Preterm Infants

Rojas, Mario A.; Lozano, Juan Manuel; Rojas, María Ximena; Rodríguez, Viviana; Sepúlveda, Martín Alonso Rondón; Bastidas, Jaime; Pérez, Luis; Rojas, Catherine; Ovalle, Oscar; Garcia-Harker, Jorge E.; Tamayo, María; Ruiz, Gloria; Ballesteros, Adriana Linares; Archila, Maria M.; Arevalo, Mauricio

doi:10.1542/peds.2011-3584

Cited by 139 publications

(129 citation statements)

References 41 publications

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“…Our finding of a lack of effect of the probiotic combination on definite lateonset sepsis is consistent with most, 14,[19][20][21][22][23][24][25][26][27][28][29] but not all, 13,28,[30][31][32] RCTs, as well as published systematic reviews and meta-analyses. [8][9][10] Interestingly, our study suggests a differential benefit of this probiotic combination on late-onset sepsis and possibly NEC of Bell stage 2 or more in infants born at 28 to 31 6 weeks' gestation.…”

Section: Discussionsupporting

confidence: 87%

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: Discussionsupporting

confidence: 87%

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

Tobin²,

et al. 2013

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“…With the exception of a multicentre trial published in 2012 and recruiting babies of birthweight up to 2000 g, 39 the probiotic intervention was given either in milk or, in one study, 42 separately but coincident with the start of feeding. This suggests that babies with perceived contraindications to starting feeds, who are likely to be those babies at highest risk of NEC, might be excluded or have deferred entry to the trials.…”

Section: Scientific Backgroundmentioning

confidence: 99%

“…This was not associated with increased late-onset sepsis in these babies. Of the 12 clinical trials listed in Table 1, all of which were designed to study clinical outcomes, five reported higher rates of sepsis in the active arm than in the placebo arm, 19,21,23,37,39 although only one was statistically significant. 23 These trials use various definitions of late-onset sepsis.…”

Section: Safetymentioning

confidence: 99%

“…those babies with growth restriction and evidence of intrauterine hypoxia); thus, delaying the probiotic until some milk is tolerated will inevitably delay its administration. For example, the protocol for the ProPrems trial 74 involved early recruitment within 72 hours of birth but the intervention was not started until at least 1 ml of milk was being tolerated every 4 hours; consequently, the intervention was not started until a median age of 5 days (interquartile range 4-7 days), 41 whereas in the two published trials 39,42 the intervention was started irrespective of feeding at a median age of 2 days 39 and 1 day. 42 We were successful in that the median age at randomisation in the PiPS trial was 35 hours (see Table 7) with the median age at the first dose of intervention being 44 hours; this was earlier than the median age at first feed, which was 3 days.…”

Section: Timing Of Start Of Interventionmentioning

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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“…However, recently published result of multi-centre, doubleblinded randomized placebo-controlled trial conducted in 9 NICUs in Columbia showed probiotic supplementation did not reduce rate of NEC significantly 42 . Some other earlier reports also demonstrated lesser decline of incidence of NEC after probiotic supplementation.…”

Section: Studies On Use Of Probiotics In Preterm Infantsmentioning

confidence: 94%

Probiotics in Neonatal Infection :A Review

Moni

Shamsuzzaman

Shahidullah

2017

Bangladesh J Med Microbiol

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Prophylactic Probiotics to Prevent Death and Nosocomial Infection in Preterm Infants

Cited by 139 publications

References 41 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

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

Probiotics in Neonatal Infection :A Review

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