Centre for Paediatrics, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.
National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.
Lancet. 2016 Feb 13;387(10019):649-660. doi: 10.1016/S0140-6736(15)01027-2. Epub 2015 Nov 28.
Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants.
In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17.
Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68-1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73-1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67-1·30]). No probiotic-associated adverse events were reported.
There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants.
UK National Institute for Health Research Health Technology Assessment programme.
益生菌可能会降低早产儿患坏死性小肠结肠炎和晚发性败血症的风险。然而，人们对一些试验的严谨性和普遍性表示担忧，而且对于是否应该常规使用益生菌仍存在分歧。我们旨在检验短双歧杆菌 BBG-001 对降低早产儿坏死性小肠结肠炎、晚发性败血症和死亡的有效性。
在这项多中心、随机对照的 3 期研究（PiPS 试验）中，我们在英格兰东南部的 24 家医院招募了出生胎龄在 23 至 30 周之间、出生后 48 小时内的婴儿。婴儿通过最小化算法随机分组程序以 1:1 的比例随机分配到益生菌或安慰剂组。益生菌干预措施是将短双歧杆菌 BBG-001 悬浮在稀释的元素婴儿配方奶粉中，每日给予 8.2 至 9.2log10CFU 的剂量，口服给予；安慰剂为单独的稀释婴儿配方奶粉。临床医生和家属对分组情况进行了设盲。主要结局是坏死性小肠结肠炎（Bell 分期 2 或 3 期）、出生后 72 小时以上血培养阳性败血症和出院前死亡。所有的主要分析均采用意向治疗。该试验在 ISRCTN 注册，编号为 05511098，在 EudraCT 注册，编号为 2006-003445-17。
2010 年 7 月 1 日至 2013 年 7 月 31 日，共招募了 1315 名婴儿；其中 654 名被分配到益生菌组，661 名被分配到安慰剂组。5 名婴儿在随机分组后撤回了同意书，因此益生菌组有 650 名婴儿和安慰剂组有 660 名婴儿进行了分析。益生菌组和安慰剂组的主要结局发生率无显著差异。益生菌组有 61 名（9%）婴儿发生坏死性小肠结肠炎，安慰剂组有 66 名（10%）（调整风险比 0.93（95%CI 0.68-1.27）；益生菌组有 73 名（11%）婴儿发生败血症，安慰剂组有 77 名（12%）（0.97（0.73-1.29）；益生菌组有 54 名（8%）婴儿在出院前死亡，安慰剂组有 56 名（9%）（0.93（0.67-1.30）。未报告益生菌相关的不良事件。
在该人群中，该干预措施没有证据表明有获益；该结果不支持常规使用短双歧杆菌 BBG-001 预防极早产儿的坏死性小肠结肠炎和晚发性败血症。
英国国家卫生研究所卫生技术评估计划。
