Does bovine lactoferrin prevent late-onset neonatal sepsis?
Authors: Lex W Doyle, Jeanie L Y Cheong
Journal: The Lancet (2019)

Prevention of late-onset neonatal sepsis (LOS) in infants born very preterm (<32 weeks' gestation) is paramount because of its associated mortality and morbidity. Lactoferrin has antimicrobial properties and could be preventive.1Legrand D Overview of lactoferrin as a natural immune modulator.J Pediatr. 2016; 173: S10-S15Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar Lactoferrin concentrations in human breastmilk vary little with gestational age and fall over time after birth;2Trend S Strunk T Lloyd ML et al.Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum.Br J Nutr. 2016; 115: 1178-1193Crossref PubMed Scopus (62) Google Scholar they are lower in infant formulas.3Donovan SM The role of lactoferrin in gastrointestinal and immune development and function: a preclinical perspective.J Pediatr. 2016; 173: S16-S28Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar Importantly, very preterm infants have low enteral intakes in the first days after birth, and this can persist for weeks. Consequently, infants born very preterm might benefit from supplemental lactoferrin to prevent LOS. In a 2017 Cochrane review,4Pammi M Suresh G Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev. 2017; 6 (CD007137.)Crossref PubMed Scopus (94) Google Scholar enteral lactoferrin was found not only to reduce the rate of any LOS (risk ratio [RR] 0·59, 95% CI 0·40–0·87; p=0·008; from six trials including 886 participants) but also of necrotising enterocolitis (0·40, 0·18–0·86; p=0·02; from four trials including 750 participants). Five randomised controlled trials (RCTs) assessed bovine lactoferrin and one tested human recombinant lactoferrin. However, the quality of all the included studies was low. The authors of the review made no recommendation to introduce bovine lactoferrin into clinical practice. In The Lancet, the ELFIN Trial Investigators Group reports its large multicentre RCT,5ELFIN Trial Investigators GroupEnteral lactoferrin supplementation for very preterm infants: a randomised controlled trial.Lancet. 2019; (published online Jan 8.)http://dx.doi.org/10.1016/S0140-6736(18)32221-9Google Scholar which was designed to address the limitations of the existing evidence in the use of bovine lactoferrin to prevent LOS. They recruited 2203 infants born at less than 32 weeks' gestation and younger than 72 h from 37 sites around the UK in just under 3·5 years. Infants were randomly allocated to receive either bovine lactoferrin (150 mg/kg daily, once the infants were receiving at least 12 mL/kg per day enterally) or an equal volume of sucrose placebo until 34 weeks' gestation. Bovine lactoferrin had little effect on the primary endpoint of LOS (316 [29%] of 1093 infants in the lactoferrin group and 334 [31%] of 1089 in the control group developed LOS; adjusted RR 0·95, 95% CI 0·86–1·04; p=0·233). Importantly, lactoferrin had little effect on other clinically important outcomes including mortality (1·05, 0·66–1·68; p=0·782) and the combined outcome of mortality with LOS, necrotising enterocolitis, or bronchopulmonary dysplasia (1·01, 0·94–1·08; p=0·743). The study design and governance appear exemplary. Infants were at equal risk of reaching the endpoint through randomisation, other clinical care was equal because of effective blinding, the primary clinically important outcome of LOS was known for all but 1% (n=23) of those enrolled, the infants were representative of very preterm infants in high-income countries, and treatment compliance was excellent. Moreover, they reported other clinically important outcomes including mortality, necrotising enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity, and the combined outcome of death with any LOS, necrotising enterocolitis, bronchopulmonary dysplasia, or retinopathy of prematurity. The study progressed on schedule, with the appropriate surveillance of safety, and the results have been reported promptly. Although the intent was to apply for funding for later neurodevelopmental follow-up of survivors, the investigators argued that the absence of an effect on the primary outcome meant that bovine lactoferrin was unlikely to be introduced clinically and that follow-up was not required. Acquiring funding for follow-up would also be challenging in the absence of any clear short-term effects of bovine lactoferrin. What do these results mean for clinical practice? Combining the results of the ELFIN trial5ELFIN Trial Investigators GroupEnteral lactoferrin supplementation for very preterm infants: a randomised controlled trial.Lancet. 2019; (published online Jan 8.)http://dx.doi.org/10.1016/S0140-6736(18)32221-9Google Scholar with those already in the Cochrane review4Pammi M Suresh G Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev. 2017; 6 (CD007137.)Crossref PubMed Scopus (94) Google Scholar in a standard meta-analysis, the effect of bovine lactoferrin on LOS becomes marginal (RR 0·89, 95% CI 0·79–1·00; p=0·06), and the effect on necrotising enterocolitis almost disappears (0·92, 0·67–1·26; p=0·60). However, combining an excellent quality, large RCT with multiple smaller RCTS of low quality is suboptimal to justify clinical care. The ELFIN investigators are planning a meta-analysis, presumably of individual participant data, with other trials, some of which are large and unreported, which will provide more robust evidence to help guide clinical care, so the final verdict might take a while yet. The role of bovine lactoferrin in more mature infants or in low-income or middle-income countries is unclear. Neonatal sepsis is common and is an important cause of mortality in neonatal units in low-income and middle-income countries.6Tran HT Doyle LW Lee KJ Dang NM Graham SM A high burden of late-onset sepsis among newborns admitted to the largest neonatal unit in central Vietnam.J Perinatol. 2015; 35: 846-851Crossref PubMed Scopus (19) Google Scholar, 7Tran HT Doyle LW Lee KJ Dang NM Graham SM Morbidity and mortality in hospitalised neonates in central Vietnam.Acta Paediatr. 2015; 104: e200-e205Crossref PubMed Scopus (18) Google Scholar A small RCT was positive in reducing sepsis, but most cases occurred after discharge home, suggesting different mechanisms for sepsis in some low-income or middle-income settings.8Kaur G Gathwala G Efficacy of bovine lactoferrin supplementation in preventing late-onset sepsis in low birth weight neonates: a randomized placebo-controlled clinical trial.J Trop Pediatr. 2015; 61: 370-376Crossref PubMed Scopus (41) Google Scholar For now, it would be unwise to use bovine lactoferrin in clinical practice, or to embark on new RCTs of bovine lactoferrin to reduce LOS in very preterm infants in high-income countries. As indicated by the ELFIN investigators, future research to reduce LOS and necrotising enterocolitis in very preterm infants should look beyond bovine lactoferrin supplementation. New therapeutic options to prevent LOS seem unlikely. Attempts at passive immune therapy with bovine lactoferrin5ELFIN Trial Investigators GroupEnteral lactoferrin supplementation for very preterm infants: a randomised controlled trial.Lancet. 2019; (published online Jan 8.)http://dx.doi.org/10.1016/S0140-6736(18)32221-9Google Scholar or monoclonal anti-staphylococcal antibodies9Shah PS Kaufman DA Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants.Cochrane Database Syst Rev. 2009; 2 (CD006449.)Google Scholar have not been convincing. The balance of evidence does not favour routine prevention with antimicrobials.10Taylor JE Tan K Lai NM McDonald SJ Antibiotic lock for the prevention of catheter-related infection in neonates.Cochrane Database Syst Rev. 2015; 6 (CD010336.)Google Scholar Although probiotics do not reduce LOS, they do reduce necrotising enterocolitis and mortality,11AlFaleh K Anabrees J Probiotics for prevention of necrotizing enterocolitis in preterm infants.Cochrane Database Syst Rev. 2014; 4 (CD005496.)Google Scholar and are being introduced into clinical practice.12Viswanathan S Lau C Akbari H Hoyen C Walsh MC Survey and evidence based review of probiotics used in very low birth weight preterm infants within the United States.J Perinatol. 2016; 36: 1106-1111Crossref PubMed Scopus (31) Google Scholar There is good evidence for hand hygiene as part of a package of care designed to reduce LOS.13Pammi M Weisman LE Late-onset sepsis in preterm infants: update on strategies for therapy and prevention.Expert review of anti-infective therapy. 2015; 13: 487-504PubMed Google Scholar The key to reducing LOS is likely to be in decreasing the number and duration of procedures, such as assisted breathing technologies and parenteral nutrition, that involve foreign bodies, which are potential conduits for the low virulence culprits of LOS. We report grants from the National Health and Medical Research Council of Australia for fellowship support, various randomised clinical trials, epidemiological studies, and support for a Centre of Research Excellence. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trialEnteral 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. Full-Text PDF Open Access