Lancet. 2019 Feb 2;393(10170):423-433. doi: 10.1016/S0140-6736(18)32221-9. Epub 2019 Jan 8.
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.
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.
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 Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group.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.
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.
UK National Institute for Health Research Health Technology Assessment programme (10/57/49).
医院获得性感染是极低出生体重儿发病率和死亡率的一个重要原因。几项小型试验表明，在极低出生体重儿的肠内饮食中补充乳铁蛋白（一种从牛奶中加工而成的抗菌蛋白）可以预防感染及其相关并发症。本项大型随机对照试验的目的是收集数据，以增强以前试验证据的有效性和适用性，为实践提供信息。
在这项随机安慰剂对照试验中，我们在英国 37 家医院招募了胎龄<32 周且随机分组时<72 小时的早产儿。排除标准为存在严重先天性异常、预期肠内禁食时间超过 14 天或无实际生存可能。符合条件的婴儿被随机分配（1:1）接受牛乳铁蛋白（150mg/kg/天；最大 300mg/天；乳铁蛋白组）或蔗糖（相同剂量；对照组），每天一次，直至出生后 34 周。基于网络的随机分组尽量使招募地点、胎龄（完成周数）、性别和单胎或多胎妊娠的比例达到均衡。父母、护理人员和结果评估人员不知道分组情况。主要结局为微生物学证实或临床疑似的晚发性感染（发生在出生后>72 小时），对于所有有主要结局数据的参与者，通过计算两组之间的相对风险比及其 95%置信区间来评估。该试验在国际标准随机对照试验注册处登记，编号为 88261002。
我们于 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 名婴儿的同意被撤回或未经证实，1098 名婴儿在乳铁蛋白组，1101 名婴儿在对照组。2182 名婴儿（乳铁蛋白组 1093 名[99.5%]，对照组 1101 名[99.0%]）的主要结局数据可用于意向治疗分析。干预组 316 名（29%）婴儿发生晚发性感染，对照组 334 名（31%）婴儿发生晚发性感染。调整最小化因素后的风险比为 0.95（95%CI 0.86-1.04；p=0.233）。在试验期间，乳铁蛋白组有 16 名婴儿发生严重不良事件，对照组有 10 名婴儿发生严重不良事件。乳铁蛋白组的两起事件（一例粪便带血和一例肠穿孔后死亡）被评估为可能与试验干预有关。
肠内补充牛乳铁蛋白并不能降低极低出生体重儿晚发性感染的风险。这些数据不支持其常规用于预防极低出生体重儿的晚发性感染及其相关发病率或死亡率。
英国国家卫生与保健优化研究所卫生技术评估计划（10/57/49）。
