口服益生菌预防早产儿严重坏死性小肠结肠炎疗效和安全性的Meta分析

The effect of oral probiotics on the prevention of necrotizing enterocolitis in preterm infants:a meta-analysis of its efficacy and safety

目的评价口服益生菌预防早产儿严重坏死性小肠结肠炎(NEC)的疗效和安全性。方法制定原始文献的纳入标准、排除标准及检索策略,检索PubMed、EMBASE、Ovid、Springer、中国期刊全文数据库、万方数据库、维普中文科技期刊数据库及中国生物医学文献光盘数据库等。应用Cochrane协作网推荐的方法评价文献质量。采用RevMan 4.22软件对满足纳入标准的有关口服益生菌预防早产儿严重NEC(Ⅱ期及以上)的RCT研究进行Meta分析。主要观察指标为严重NEC的发生率、总病死率、NEC相关病死率和院内感染导致脓毒症的发生率。结果共检索到107篇文献,符合纳入标准的10项RCT研究(共2 117例早产儿)进入Meta分析,文献质量评价8篇为A级,1篇为B级,1篇为C级。各研究间的基线水平差异较大,出生体重,胎龄,益生菌应用的种类、剂量、开始应用时间和治疗持续时间等均有差异。Meta分析结果表明,益生菌组可显著降低严重NEC的发生率和总病死率,OR分别为0.34(95%CI:0.22～0.55,P<0.000 1)和0.36(95%CI:0.22～0.58,P<0.000 1)。无证据表明预防性口服益生菌可减少院内感染导致脓毒症的发生率和NEC相关的病死率,OR分别为0.94(95%CI:0.62～1.42)和0.48(95%CI:0.16～1.47)。所有研究均未见口服益生菌导致相应菌株全身感染的发生。结论预防性口服益生菌可显著降低早产儿严重NEC的发生率和总病死率。对低出生体重儿可给予口服益生菌预防NEC的发生。现有的研究尚不能证实预防性口服益生菌对超低出生体重儿的疗效和安全性。有关超低出生体重儿预防性口服益生菌的安全性和疗效仍有待大规模的临床多中心RCT研究予以明确。

Objective To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and sepsis in preterm infants. Methods Standard search strategy for the Cochrane Neonatal Review Group was performed by two review authors. Searches were made in PubMed, EMBASE, Ovid,Springer and CNKI databases with the terms Preterm or newborn or infants or very low birth weight or extremely low birth weight and probiotics or lactobacillus or bifidobactrium or saccharomyces and necrosis enterocolitis. Only randomized or quasi-randomized controlled trials which involved enteral administration of any live microbial supplement （probiotics） and measured at least one prespecified clinical outcome such as morbidity of severe NEC, sepsis or mortality were considered. Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodological quality of the trials. RevMan 4.22 software was used to make meta analysis. Results 107 literatures were reviewed. The studies including full-term infants RCTs （ n = 52 ）, reviews （ n = 17 ）, commentators（ n =4）, documents not meeting the major results of the meta analysis （n = 15 ）, case-control studies （n = 3 ）, self- control studies （ n = 2 ）, not randomized studies （ n = 2 ）, data undetailed and to contact the author unsuccessfully studies （ n = 10 ） were excluded. Ten eligible trials randomizing 2 117 infants（ 1 056 of treatment group and 1 061 of control group） were included. The results of quality assessment were that 8 studies were A, 1 was B and 1 was C. Included trials were highly variable with regard to enrollment criteria such as birth weight and gestational age, baseline risk of NEC in the control group, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight（ELBW） infants were few. In a meta analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC （ stage Ⅱ or above） （ OR = 0.34, 95% CI：0.22 -0.55 ） and mortality（ OR = 0. 36,95% CI：0.22 -0.58 ）. There was no evidence on significant incidence reduction in nosocomial sepsis（ OR = 0. 94,95% CI： 0. 62 - 1.42 ） or in NEC-related deaths （OR =0.48,95% CI： 0. 16 - 1.47 ）. The hospilized days were longer in treatment group than that in control group（P 〈0. 01 ）. The included trials were reported no systemic infection with the probiotics supplemental organism. Conclusions Enteral supplementation of probiotics reduced the risk of severe NEC and mortality in preterm infants. This analysis supports a change in practice in premature infants 〉 1 000 g at birth. The safety and efficacy of administration of probiotic snpplements couldnt be made in ELBW. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.