Enteral lactoferrin supplementation for very preterm infants: a randomised controlled trial

The ELFIN Trial Investigators Group; William McGuire

doi:10.1016/ S0140-6736(18)32390-0

Enteral lactoferrin supplementation for very preterm infants: a randomised controlled trial

The ELFIN Trial Investigators Group, William McGuire

Centre for Reviews and Dissemination

Research output: Contribution to journal › Article › peer-review

Abstract

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. Objective To determine whether enteral supplementation with bovine lactoferrin reduces the risk of late-onset infection (acquired >72 hours after birth) and other morbidity and mortality in very preterm infants. Design Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks’ of gestation, sex, and single versus multiple birth. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born <32 weeks’ gestation aged <72 hours at trial enrolment. Interventions Eligible infants were allocated individually (1:1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose placebo (same dose) once daily from trial entry until 34 weeks’ postmenstrual age. Parents, caregivers, and outcome assessors were unaware of group assignment. Outcomes Primary outcome Microbiologically-confirmed or clinically-suspected late-onset infection. Secondary outcomes Microbiologically-confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD, and mortality; days of receipt of antimicrobials until 34 weeks’ postmenstrual age; length of stay in hospital; length of stay in intensive care, high dependency, and special care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 (99%). In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: adjusted risk ratio (RR) 0.95 [95% confidence interval (CI) 0.86, 1.04]. There were no significant differences in any secondary outcomes: microbiologically-confirmed infection [RR 1.05 (99% CI 0.87, 1.26)]; mortality [RR 1.05 (99% CI 0.66, 1.68)]; NEC [RR 1.13 (99% CI 0.68, 1.89)]; ROP [RR 0.89 (99% CI 0.62, 1.28)]; BPD [RR 1.01 (99% CI 0.90, 1.13)]; or a composite of infection, NEC, ROP, BPD, and mortality [RR 1.01 (99% CI 0.94, 1.08)]. There were no differences in days of receipt of antimicrobials, length of stay in hospital, or in intensive care, high dependency, or special care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for the sucrose group. Limitations Estimates of effect for rarer secondary outcomes are less precise. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality, or other morbidity in very preterm infants. Future Work We plan to increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. We are conducting a mechanistic study in a subgroup of trial participants to explore whether lactoferrin supplementation affects the intestinal microbiome and metabolite profile. Funding National Institute for Health Research Health Technology Assessment programme (10/57/49). Trial registration ISRCTN88261002 https://doi.org/10.1186/ISRCTN88261002 Ethics approval National Research Ethics Service Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118, 02/04/2013).

Original language	English
Number of pages	11
Journal	Health technology assessment
Early online date	8 Jan 2019
DOIs	https://doi.org/10.1016/ S0140-6736(18)32390-0
Publication status	E-pub ahead of print - 8 Jan 2019

Bibliographical note

Access to Document

10.1016/ S0140-6736(18)32390-0

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial
© 2019 The Author(s).
Final published version, 354 KBLicence: CC BY-NC-ND

Cite this

@article{d0bcdbad2aaa49a7918e2047f6cfd331,

title = "Enteral lactoferrin supplementation for very preterm infants: a randomised controlled trial",

abstract = "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{\textquoteright}s milk, prevents infections and associated complications. Objective To determine whether enteral supplementation with bovine lactoferrin reduces the risk of late-onset infection (acquired >72 hours after birth) and other morbidity and mortality in very preterm infants. Design Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks{\textquoteright} of gestation, sex, and single versus multiple birth. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born <32 weeks{\textquoteright} gestation aged <72 hours at trial enrolment. Interventions Eligible infants were allocated individually (1:1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose placebo (same dose) once daily from trial entry until 34 weeks{\textquoteright} postmenstrual age. Parents, caregivers, and outcome assessors were unaware of group assignment. Outcomes Primary outcome Microbiologically-confirmed or clinically-suspected late-onset infection. Secondary outcomes Microbiologically-confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD, and mortality; days of receipt of antimicrobials until 34 weeks{\textquoteright} postmenstrual age; length of stay in hospital; length of stay in intensive care, high dependency, and special care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 (99%). In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: adjusted risk ratio (RR) 0.95 [95% confidence interval (CI) 0.86, 1.04]. There were no significant differences in any secondary outcomes: microbiologically-confirmed infection [RR 1.05 (99% CI 0.87, 1.26)]; mortality [RR 1.05 (99% CI 0.66, 1.68)]; NEC [RR 1.13 (99% CI 0.68, 1.89)]; ROP [RR 0.89 (99% CI 0.62, 1.28)]; BPD [RR 1.01 (99% CI 0.90, 1.13)]; or a composite of infection, NEC, ROP, BPD, and mortality [RR 1.01 (99% CI 0.94, 1.08)]. There were no differences in days of receipt of antimicrobials, length of stay in hospital, or in intensive care, high dependency, or special care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for the sucrose group. Limitations Estimates of effect for rarer secondary outcomes are less precise. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality, or other morbidity in very preterm infants. Future Work We plan to increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. We are conducting a mechanistic study in a subgroup of trial participants to explore whether lactoferrin supplementation affects the intestinal microbiome and metabolite profile. Funding National Institute for Health Research Health Technology Assessment programme (10/57/49). Trial registration ISRCTN88261002 https://doi.org/10.1186/ISRCTN88261002 Ethics approval National Research Ethics Service Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118, 02/04/2013). ",

author = "{The ELFIN Trial Investigators Group} and William McGuire",

note = "{\textcopyright} 2019 The Author(s). ",

year = "2019",

month = jan,

day = "8",

doi = "10.1016/ S0140-6736(18)32390-0",

language = "English",

journal = "Health technology assessment",

issn = "1366-5278",

publisher = "NHS National Institute for Health Research",

}

TY - JOUR

T1 - Enteral lactoferrin supplementation for very preterm infants

T2 - a randomised controlled trial

AU - The ELFIN Trial Investigators Group

AU - McGuire, William

PY - 2019/1/8

Y1 - 2019/1/8

N2 - 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. Objective To determine whether enteral supplementation with bovine lactoferrin reduces the risk of late-onset infection (acquired >72 hours after birth) and other morbidity and mortality in very preterm infants. Design Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks’ of gestation, sex, and single versus multiple birth. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born <32 weeks’ gestation aged <72 hours at trial enrolment. Interventions Eligible infants were allocated individually (1:1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose placebo (same dose) once daily from trial entry until 34 weeks’ postmenstrual age. Parents, caregivers, and outcome assessors were unaware of group assignment. Outcomes Primary outcome Microbiologically-confirmed or clinically-suspected late-onset infection. Secondary outcomes Microbiologically-confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD, and mortality; days of receipt of antimicrobials until 34 weeks’ postmenstrual age; length of stay in hospital; length of stay in intensive care, high dependency, and special care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 (99%). In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: adjusted risk ratio (RR) 0.95 [95% confidence interval (CI) 0.86, 1.04]. There were no significant differences in any secondary outcomes: microbiologically-confirmed infection [RR 1.05 (99% CI 0.87, 1.26)]; mortality [RR 1.05 (99% CI 0.66, 1.68)]; NEC [RR 1.13 (99% CI 0.68, 1.89)]; ROP [RR 0.89 (99% CI 0.62, 1.28)]; BPD [RR 1.01 (99% CI 0.90, 1.13)]; or a composite of infection, NEC, ROP, BPD, and mortality [RR 1.01 (99% CI 0.94, 1.08)]. There were no differences in days of receipt of antimicrobials, length of stay in hospital, or in intensive care, high dependency, or special care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for the sucrose group. Limitations Estimates of effect for rarer secondary outcomes are less precise. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality, or other morbidity in very preterm infants. Future Work We plan to increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. We are conducting a mechanistic study in a subgroup of trial participants to explore whether lactoferrin supplementation affects the intestinal microbiome and metabolite profile. Funding National Institute for Health Research Health Technology Assessment programme (10/57/49). Trial registration ISRCTN88261002 https://doi.org/10.1186/ISRCTN88261002 Ethics approval National Research Ethics Service Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118, 02/04/2013).

AB - 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. Objective To determine whether enteral supplementation with bovine lactoferrin reduces the risk of late-onset infection (acquired >72 hours after birth) and other morbidity and mortality in very preterm infants. Design Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks’ of gestation, sex, and single versus multiple birth. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born <32 weeks’ gestation aged <72 hours at trial enrolment. Interventions Eligible infants were allocated individually (1:1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose placebo (same dose) once daily from trial entry until 34 weeks’ postmenstrual age. Parents, caregivers, and outcome assessors were unaware of group assignment. Outcomes Primary outcome Microbiologically-confirmed or clinically-suspected late-onset infection. Secondary outcomes Microbiologically-confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD, and mortality; days of receipt of antimicrobials until 34 weeks’ postmenstrual age; length of stay in hospital; length of stay in intensive care, high dependency, and special care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 (99%). In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: adjusted risk ratio (RR) 0.95 [95% confidence interval (CI) 0.86, 1.04]. There were no significant differences in any secondary outcomes: microbiologically-confirmed infection [RR 1.05 (99% CI 0.87, 1.26)]; mortality [RR 1.05 (99% CI 0.66, 1.68)]; NEC [RR 1.13 (99% CI 0.68, 1.89)]; ROP [RR 0.89 (99% CI 0.62, 1.28)]; BPD [RR 1.01 (99% CI 0.90, 1.13)]; or a composite of infection, NEC, ROP, BPD, and mortality [RR 1.01 (99% CI 0.94, 1.08)]. There were no differences in days of receipt of antimicrobials, length of stay in hospital, or in intensive care, high dependency, or special care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for the sucrose group. Limitations Estimates of effect for rarer secondary outcomes are less precise. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality, or other morbidity in very preterm infants. Future Work We plan to increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. We are conducting a mechanistic study in a subgroup of trial participants to explore whether lactoferrin supplementation affects the intestinal microbiome and metabolite profile. Funding National Institute for Health Research Health Technology Assessment programme (10/57/49). Trial registration ISRCTN88261002 https://doi.org/10.1186/ISRCTN88261002 Ethics approval National Research Ethics Service Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118, 02/04/2013).

U2 - 10.1016/ S0140-6736(18)32390-0

DO - 10.1016/ S0140-6736(18)32390-0

M3 - Article

SN - 1366-5278

JO - Health technology assessment

JF - Health technology assessment

ER -