Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial
Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial
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DOI：
10.1016/s0140-6736(18)32221-9
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发表时间：
2019-02-02
期刊：
影响因子：
168.9
通讯作者：
Bradburn, Mike
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文献类型：
--
作者：
Griffiths, James;Jenkins, Paula;Bradburn, Mike
背景医院内获得性感染是极早产儿发病和死亡的重要原因。一些小型试验表明，用乳铁蛋白（一种从牛奶中加工的抗菌蛋白）补充早产儿的肠内饮食可以预防感染和相关并发症。这个大的随机对照试验的目的是收集数据，以提高有效性和适用性的证据，从以前的试验，通知practice.Methods在这个随机安慰剂对照试验，我们招募了非常早产儿出生前32周的妊娠在37家英国医院和年轻的72小时随机。排除标准是存在严重的先天性异常，预期肠内禁食超过14天，或没有现实的生存前景。合格的婴儿被随机分配（1：1）接受肠内牛乳铁蛋白（150 mg/kg/天;最大300 mg/天;乳铁蛋白组）或蔗糖（相同剂量;对照组），每天一次，直到月经后34周。招募中心、妊娠（完整周数）、性别和单胎妊娠与多胎妊娠的网络随机化最小化。父母，照顾者和结果评估员不知道组分配。主要结局是微生物学证实或临床疑似迟发性感染（发生在出生后>72小时），通过计算两组之间的相对风险比（95%CI），在所有可获得主要结局数据的参与者中进行评估。该试验注册为国际标准随机对照试验编号88261002。结果我们在2014年5月7日至2017年9月28日期间招募了2203名参与者，其中1099名被分配到乳铁蛋白组，1104名被分配到对照组。4名婴儿撤回或未经确认同意，乳铁蛋白组有1098名婴儿，蔗糖组有1101名婴儿。2182名婴儿（乳铁蛋白组1098名中的1093名[99.5%]，对照组1101名中的1089名[99.0]）的主要结局数据可用于纳入改良的意向治疗分析。干预组1093名婴儿中有316名（29%）晚发性感染，对照组1089名婴儿中有334名（31%）晚发性感染。经最小化因素校正的风险比为0.95（95% CI 0.86-1.04; p=0.233）。试验期间，乳铁蛋白组婴儿发生了16起严重不良事件，对照组婴儿发生了10起严重不良事件。乳铁蛋白组中的两个事件（一例便血和一例肠穿孔后死亡）被评估为可能与试验干预有关。解释肠内补充牛乳铁蛋白不能降低极早产儿迟发性感染的风险。这些数据不支持其常规使用，以防止晚发型感染和相关的发病率或死亡率在非常早产儿。资助英国国家卫生研究所卫生技术评估计划（10/57/49）。版权所有（c）2019作者。由Elsevier Ltd.出版，这是一篇开放获取文章，CC BY-NC-ND 4.0许可证。
Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99.5%] of 1098 in the lactoferrin group and 1089 [99.0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0.95 (95% CI 0.86-1.04; p=0.233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49). Copyright (c) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.