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

Griffiths, James; Jenkins, Paula; Vargova, Monika; Bowler, Ursula; Juszczak, Edmund; King, Andrew; Linsell, Louise; Murray, David; Partlett, Christopher; Patel, Mehali; Berrington, Janet; Dorling, Jon; Embleton, Nicholas D.; Heath, Paul T.; Oddie, Sam; McGuire, William; Ainsworth, Sean; Boyle, Elaine; Clarke, Paul; Craig, Stanley; Johnson, Kathryn; Mactier, Helen; Scorrer, Tim; Ledwidge, Mary; Story, Imogen; Holder, Gemma; Ohadike, Pamela; Ellis, Sarah; Vaikute, Rima; Gowda, Girish; Yates, Helen; Garg, Shalabh; Pilling, Elizabeth; Roehr, Charles; Batra, Dushyant; Gibson, David; Johnson, Mark; Kumar, Yadlapalli; Bartle, David; Peters, Colin; Quine, David; Gupta, Richa; Matthes, Jean; Kennea, Nigel; Reynolds, Peter; Geethanath, Ruppa; Janakiraman, Sundaram; Vasu, Vimal; Manjunatha, C.M.

Authors

James Griffiths

Paula Jenkins

Monika Vargova

Ursula Bowler

Edmund Juszczak

Andrew King

Louise Linsell

David Murray

CHRIS PARTLETT Chris.Partlett@nottingham.ac.uk
Assistant Professor of Medical Statistics and Clinical Trials

Mehali Patel

Janet Berrington

Jon Dorling

Nicholas D. Embleton

Paul T. Heath

Sam Oddie

William McGuire

Sean Ainsworth

Elaine Boyle

Paul Clarke

Stanley Craig

Kathryn Johnson

Helen Mactier

Tim Scorrer

Mary Ledwidge

Imogen Story

Gemma Holder

Pamela Ohadike

Sarah Ellis

Rima Vaikute

Girish Gowda

Helen Yates

Shalabh Garg

Elizabeth Pilling

Charles Roehr

Dushyant Batra

David Gibson

Mark Johnson

Yadlapalli Kumar

David Bartle

Colin Peters

David Quine

Richa Gupta

Jean Matthes

Nigel Kennea

Peter Reynolds

Ruppa Geethanath

Sundaram Janakiraman

Vimal Vasu

C.M. Manjunatha



Abstract

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license 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).

Journal Article Type Article
Publication Date Feb 2, 2019
Journal The Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 393
Issue 10170
Pages 423-433
APA6 Citation Griffiths, J., Jenkins, P., Vargova, M., Bowler, U., Juszczak, E., King, A., …Manjunatha, C. (2019). Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet, 393(10170), 423-433. https://doi.org/10.1016/s0140-6736%2818%2932221-9
DOI https://doi.org/10.1016/s0140-6736%2818%2932221-9
Keywords General Medicine
Publisher URL https://www.sciencedirect.com/science/article/pii/S0140673618322219
Additional Information This article is maintained by: Elsevier; Article Title: Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial; Journal Title: The Lancet; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/S0140-6736(18)32221-9; CrossRef DOI link to the associated document: https://doi.org/10.1016/S0140-6736(18)32390-0; Content Type: article; Copyright: © 2019 The Author(s). Published by Elsevier Ltd.

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