Elsevier

The Lancet

Volume 369, Issue 9573, 12–18 May 2007, Pages 1614-1620
The Lancet

Articles
Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: a systematic review of randomised controlled trials

https://doi.org/10.1016/S0140-6736(07)60748-XGet rights and content

Summary

Background

Results of recent clinical trials suggest that probiotic supplementation reduces the risk of necrotising enterocolitis in preterm neonates. We aimed to systematically review randomised controlled trials evaluating efficacy and safety of any probiotic supplementation (started within first 10 days, duration ≥7 days) in preventing stage 2 or greater necrotising enterocolitis in preterm neonates (gestation <33 weeks) with very low birthweight (<1500 g).

Methods

We followed the standard search strategy of the Cochrane Neonatal Review Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL databases, and proceedings of the Pediatric Academic Society meetings (from 1980) and Pediatric Gastroenterology conferences (from 1980) in November, 2006.

Results

Seven of 12 randomised controlled trials retrieved (n=1393) were eligible for inclusion in the analysis. Meta-analysis using a fixed effects model estimated a lower risk of necrotising enterocolitis (relative risk 0·36, 95% CI 0·20–0·65) in the probiotic group than in controls. Risk of sepsis did not differ significantly between groups (0·94, 0·74–1·20). Risk of death was reduced in the probiotic group (0·47, 0·30–0·73). The time to full feeds was significantly shorter in the probiotic group (weighted mean difference −2·74 days, 95% CI −4·98 to −0·51) than in controls.

Conclusion

Probiotics might reduce the risk of necrotising enterocolitis in preterm neonates with less than 33 weeks' gestation. However, the short-term and long-term safety of probiotics needs to be assessed in large trials. Unanswered questions include the dose, duration, and type of probiotic agents (species, strain, single or combined, live or killed) used for supplementation.

Introduction

Necrotising enterocolitis is the commonest gastrointestinal emergency in neonates. It is mainly associated with prematurity, since full-term neonates account only for 5–25% of all cases.1, 2 The incidence of the condition is reported to be 5–10% in neonates of very low birthweight (<1500 g).2 Neonates of extremely low birthweight (<1000 g) with gestation of less than 28 weeks are most susceptible.3 Mortality (20–40%) and morbidity, including long term neurodevelopmental impairment, after a definite diagnosis of necrotising enterocolitis continue to be high, especially in neonates with extremely low birthweight.4, 5 The pathogenesis is poorly understood, despite decades of research.6 An interplay of various factors including hypoxia, colonisation with pathogenic microbes, formula feeding, sepsis, and intestinal ischemia-reperfusion injury against the background of an immature and vulnerable gut (the single most important risk factor) is proposed to contribute to the inflammatory cascade that in some situations precipitates necrotising enterocolitis.6

Probiotics are defined as live microbial supplements that colonise the gut while providing benefits to the host.7 The benefits of probiotics such as bifidobacteria, and lactobacilli include changes in intestinal permeability, enhanced mucosal IgA responses, and increased production of anti-inflammatory cytokines.7, 8 Bifidobacteria have also been shown to release less endotoxin than do gram negative bacteria; inducing the release of less amounts of inflammatory mediators such as tumour necrosis factor α (TNFα).9 The rationale for the recent trials of probiotics in preterm neonates is derived from the role of inappropriate gastrointestinal colonisation by bacteria in the pathogenesis of necrotising enterocolitis,8 results of a cohort study by Hoyos and colleagues,10 and data from animal models of the illness.11, 12 The scientific basis and simplicity of the intervention, along with results of clinical trials, suggest that probiotic supplementation could help to prevent necrotising enterocolitis.

Our aim was to do a systematic review of randomised controlled trials (RCTs) to evaluate the efficacy and safety of probiotic supplementation in prevention of necrotising enterocolitis in preterm neonates of very low birthweight.

Section snippets

Procedures

We followed guidelines from the Cochrane neonatal review group, the Centre for Reviews and Dissemination,13 and the QUOROM statement14 for undertaking and reporting this systematic review and meta-analysis. The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, Issue 4, 2006), Medline (1966–2006), Embase (1980–2006), CINAHL (Cumulative Index of Nursing and Allied Health Literature) databases, and proceedings of the Pediatric Academic Society meetings (published in

Results

Of 59 potentially relevant citations obtained by the search, only 12 were randomised controlled trials in preterm infants involving the use of probiotics.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Seven trials were finally included in the analysis after extracting data from the publications20, 21, 22, 23, 24, 25, 26 and obtaining additional data from investigators.20, 22, 24, 25, 26 Three were excluded because of an absence of clinically relevant data even after contacting the investigators.

Discussion

Our results show a significant reduction in the risk of necrotising enterocolitis and in overall mortality after probiotic supplementation in preterm neonates with very low birthweight, compared with controls. The risk of death due to definite necrotising enterocolitis did not differ significantly between the groups. The numbers were too small to study this issue by stratification according to the stage of disease. In view of the beneficial effects of probiotics on gastrointestinal maturity and

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