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