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

Health technology assessment

Dec 2018

DOI: 10.3310/HTA22740

Citations:30

Influential Citations:0

Interventional (Human) Studies

COI

Enhanced Details

Methods

UK multicentre, parallel-group randomized, placebo-controlled trial in very preterm infants (<32 weeks' gestation) <72 hours old at randomisation; written informed parental consent; exclusions: severe congenital anomaly, no realistic survival, or anticipated enteral fasting >14 days; recruitment through 37 neonatal units and continuing care in 97 units.

Intervention

Bovine lactoferrin 150 mg/kg/day (max 300 mg/day), started when enteral feeds reached 12 ml/kg/day, continued daily until 34 weeks' postmenstrual age (up to 70 days), administered via nasogastric/orogastric tube or orally, mixed in sterile water plus expressed breast milk or formula.

Results

Primary outcome: late-onset infection occurred in 28.9% of the lactoferrin group vs 30.7% in placebo (adjusted RR 0.95, 95% CI 0.81–1.10). Secondary outcomes showed no significant differences in microbiologically confirmed infection, all-cause mortality, NEC, ROP, BPD or a composite major morbidity; days of antimicrobials and length of stay were similar. There were 16 SAEs in the lactoferrin group vs 10 in the placebo group, with 2 SAEs possibly related to the intervention. Conclusion: Enteral bovine lactoferrin at 150 mg/kg/day did not reduce late-onset infection or other major morbidities in very preterm infants; routine use is not supported. Future research should explore other preventive strategies and mechanisms; evidence does not support a clinically meaningful benefit or subgroup effects.

Limitations

Primary outcome combined clinically suspected and microbiologically confirmed infections, which may be misclassified due to diagnostic variability; reliance on antibiotic duration to define infection; potential culture contamination; no long-term outcomes or economic analysis reported due to lack of clinical effectiveness.

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. show less