Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT

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 or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) 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 births. Setting UK neonatal units between May 2014 and September 2017. Participants Infants born at < 32 weeks’ gestation and 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) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. 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; and length of stay in intensive care, high-dependency and special-care settings. Results Of 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay 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 infants in the sucrose group. Conclusions Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants. Future work 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. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants. Trial registration Current Controlled Trials ISRCTN88261002. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation.

A Review of the Immunomodulating Components of Maternal Breast Milk and Protection Against Necrotizing Enterocolitis

“…A systematic review and meta-analysis reviewed nine RCTs and showed that prophylactic lactoferrin significantly reduced the incidence of late-onset sepsis and NEC (Bell's stage II or greater) [17]. Most recently, a large randomized control trial of 2203 infants contrasted these prior findings, demonstrating that enteral supplementation with bovine lactoferrin did not reduce NEC or the incidence of infection or mortality [18].…”

Bakterielle Infektionen bei Neugeborenen. Leitlinie der GNPI, DGPI, DGKJ und DGGG. (S2k-Level, AWMF-Leitlinien-Register-Nr. 024/008, April 2018)

“…He et al kamen in einem systematischenReviewderbisdahinveröffentlichtenrandomisierten Studien mit insgesamt 1834 Patienten zum Ergebnis, dass die oraleGabevonLaktoferrineinesignifikanteReduktionderKulturpositiven LOS, der NEC und der Mortalität durch Infektionen bewirkte [136]. Allerdings waren die in diesem Review eingeschlossenen Studien u. a. hinsichtlich der Inzidenz der Pilzsepsis sehr heterogen.IndernachdemReviewvonHeetal.veröffentlichten ELFIN Studie mit 2.203 Patienten hatte die Gabe von bovinem Lak-toferrinkeinenEinflussaufdasRisikoderLOS(RR0,95;95%CI0,86-1,04; p = 0,233) [137,138]. Somit kann nach aktuellem Stand die routinemäßige prophylaktische Gabe von bovinem Laktoferrin bei Frühgeborenen nicht empfohlen werden.…”

Lactoferrin Reduces Necrotizing Enterocolitis Severity by Upregulating Intestinal Epithelial Proliferation

“…[8][9][10] Though several studies investigated multiple aspects of lactoferrin function, the underlying mechanism of its protective effect during NEC progression remains unclear, and its protective effects on the early stages of NEC is still controversial. 2,11 Therefore, we sought to elucidate the mechanisms driving lactoferrinmediated protection during NEC progression, especially focused on its regulation of inflammation and cell proliferation. Furthermore, we administered lactoferrin on healthy pup mice to verify its safety and test for adverse effects.…”