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
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
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DOI：
10.3310/hta20660
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发表时间：
2016-08-01
影响因子：
3.6
通讯作者：
Millar, Michael R.
中科院分区：
文献类型：
--
作者：
Costeloe, Kate;Bowler, Ursula;Millar, Michael R.
背景：坏死性小肠结肠炎(NEC)和迟发性败血症仍然是早产儿死亡和发病的重要原因。益生菌给药可能会增强肠道屏障功能并提供保护；这得到了已发表的荟萃分析的支持，但缺乏大型精心设计的试验。目的：在监测参与者的益生菌定植的同时，测试益生菌短双歧杆菌菌株BBG-001在预防NEC、迟发性败血症和早产儿死亡方面的使用。设计：双盲、随机、安慰剂对照试验。设置：在24家医院进行招募，随机方案使用最小化算法。父母、临床医生和结果评估员对分配视而不见。参与者：在怀孕23到30周之间出生的婴儿，在出生后48小时内随机分配。排除包括在出生后48小时内检测到危及生命的或任何胃肠道畸形，并且没有实际的生存机会。干预：积极干预：1毫升1毫升短杆菌BBG-001在八分之一强度的婴儿配方奶粉Neocate(R)(纽崔西亚有限公司，英国特罗布里奇)，(6.7×10(7)至6.7×10(9)个集落形成单位)肠内注射。安慰剂：1毫升八分之一强度的婴儿配方奶粉。主要结果：主要结果是72小时至46周的婴儿发生血流感染，任何非皮肤共生体；任何婴儿出现NEC Bell期发作；以及出院前死亡。结果：从2010年7月开始的37个月中，总共有654名婴儿被分配接受益生菌治疗，661名婴儿接受安慰剂治疗。5名婴儿被撤回；益生菌组的650名婴儿和安慰剂组的660名婴儿被纳入初步分析。基线特征平衡良好。没有证据表明主要结果受益：败血症：11.2%比11.7%[调整后相对风险(RR)0.97，95%可信区间(CI)0.73至1.29]；NEC Bell分期和GT；=2：9.4%比10.0%[调整后RR 0.93，95%CI 0.68至1.27]；死亡：8.3%比8.5%[调整后相对风险0.93，95%CI 0.67至1.30]}。B.出生后2周的1186名(94%)幸存者可获得短暂定居状态，其中724名(61%)呈阳性：益生菌组85%，安慰剂组37%。根据最小化标准进行的亚组分析和在2周时用B.breve进行的粪便定植没有差异。没有报道与干预相关的危害。限制：安慰剂组的交叉殖民可能会降低统计能力和混淆结果；分析表明这种情况并没有发生。结论：这是迄今为止最大的益生菌干预试验。它没有显示出有益的证据，也不支持对早产儿常规使用益生菌。
Background: Necrotising 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.Objective: To test the use of the probiotic Bifidobacterium breve strain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants.Design: Double-blind, randomised, placebo-controlled trial.Setting: Recruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation.Participants: Babies 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.Interventions: Active intervention: 1 ml of B. breve BBG-001 in one-eighth-strength infant formula Neocate (R) (Nutricia Ltd, Trowbridge, UK), (6.7 x 10(7) to 6.7 x 10(9) colony-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 measures: Primary 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 with B. breve.Results: In 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. breve colonisation 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 with B. breve at 2 weeks. No harms associated with the interventions were reported.Limitations: Cross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen.Conclusions: This 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.