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

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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 usually processed from cow's milk, prevents infections and associated complications.

Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) were recruited within 72 hours of birth from 37 UK hospitals. Infants were allocated randomly (1:1) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation used an algorithm minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected late-onset infection until hospital discharge. The trial was registered with the International Standard Randomised Controlled Trial Number 88261002.

Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group.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 were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.81, 1.10). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both).

Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants.

Trial Registration Number: The trial was registered with the International Standard Randomised Controlled Trial Number 88261002.

Funding: The ELFIN trial was funded by the UK National Institute for Health Research Health Technology Assessment programme (10/57/49).

Declaration of Interest: EJ is a member of the NIHR HTA General Board; WM is a member of the NIHR HTA Commissioning Board and the HTA Journals Library Editorial Board. JD is a member of the NIHR HTA Clinical Evaluation and Trials Board. PTH, WM, EJ, LL report receipt of funding from NIHR, outside the submitted work. NDE reports grants from Prolacta Biosciences US, grants from Danone Early Life Nutrition, personal fees from Nestle Nutrition Institute, and personal fees from Baxter, outside the submitted work.

Ethical Approval: The trial protocol was approved by the National Research Ethics Service (NRES) Committee East Midlands - Nottingham 2 (Ref: 13/EM/0118). Local approval and site-specific assessments were obtained from the NHS Trusts for trial sites.

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Contributors

Author: J. Dorling

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