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Preterm baby in neonatal unit being monitored

NIHR Signal Does an antibacterial milk protein reduce infection in premature babies?

Published on 2 April 2019

doi: 10.3310/signal-000755

Lactoferrin, a protein found in human and cows milk, does not appear to protect premature infants from late-onset infections. When given to babies born before 32 weeks, their risk of acquiring infections, such as sepsis, was virtually the same as those in the control group, about 30%.

Late-onset infections, those occurring 72 hours or more after birth, are a significant cause of illness and even death in newborns. Premature babies are particularly vulnerable. This very large UK based NIHR funded study looked at whether this risk could be lessened by bolstering their immune system with lactoferrin.

A recent Cochrane review had shown that while much of the existing evidence found lactoferrin to be of benefit, it was of poor quality and could not be relied upon. Indeed, findings from this study strengthen the case against it as it seems to make little difference to neonatal outcomes.

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Why was this study needed?

Premature babies are vulnerable to infection due to their underdeveloped immune systems and the invasive procedures they have to undergo. It is estimated that 20 to 30% will acquire an infection during their first few weeks of life.

Such babies often can’t feed normally so need artificial feeding. This may be intravenous or by a tube into their stomach, known as enteral feeding. They then miss out on some of the health benefits of natural milk, which has many antimicrobial properties.

Previous studies have suggested that adding lactoferrin to enteral feeds may reduce infections, but the numbers of babies have been too small to provide a definitive result. This large trial helps address the knowledge gap.

What did this study do?

The Enteral Lactoferrin in Neonates (ELFIN) randomised controlled trial involved 37 UK sites and a total of 2,203 babies enrolled less than 72 hours after birth.

The intervention group received lactoferrin, obtained from cow’s milk in powder form. When mixed with water and either breast or formula milk the liquid looked similar to the control group’s mixture (which had sucrose added instead). The dose of lactoferrin was 150mg/kg body weight per day, up to a maximum of 300mg/day. The dose was administered once a day and this continued until 34 weeks gestation.

This large, multi-centre trial was of high quality, with 98% of the infants completing their allocated intervention, thus providing robust evidence.

What did it find?

  • No difference was found between groups for the primary outcome of microbiologically or clinically suspected late-onset bloodstream infection. It occurred in 316/1,093 (29%) of the lactoferrin group compared with 334/1,089 (31%) of the control group (adjusted risk ratio [aRR] 0.95, 95% confidence interval [CI] 0.86 to 1.04).
  • Similarly, lactoferrin did not affect mortality. There were 71/1,076 (7%) deaths in the lactoferrin group compared with 68/1,076 (6%) in the control group (aRR 1.05, 95% CI 0.66 to 1.68).
  • There was no difference in necrotising enterocolitis (a serious bowel disorder), which affected 63/1,085 (6%) of the lactoferrin group compared to 56/1,084 (5%) of the control group (aRR 1.13, 95% CI 0.68 to 1.89).
  • There were 16 (1.5%) serious adverse events in the lactoferrin group, two of which may have been related to the trial intervention. Ten (0.9%) adverse events were observed in the control group.

What does current guidance say on this issue?

There are no specific guidelines regarding the use of lactoferrin for the prevention of infection in premature babies. Great Ormond Street Hospital does produce a guideline on enteral feeding in general. This highlights the fact that the incidence of infections in premature neonates receiving human milk is lower due to anti-infective agents including prebiotics, probiotics, immunoglobulins and lactoferrin.

What are the implications?

When lactoferrin was given to babies born before 32 weeks, their risk of acquiring infections, such as sepsis, was virtually the same as those in the control group, about 30%.

This study of more than double the total number of infants from previous trials shows that the addition of lactoferrin to premature infants’ feeds is unnecessary.  The threat of late-onset infection remains. 

As well as further research into anti-infective agents we must remain focused on what we know works, such as hand hygiene and other infection control procedures.

Citation and Funding

ELFIN trial investigators group. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423-33.

This project was funded by the NIHR Technology Assessment Programme (10/57/49).

Bibliography

Doyle L, Cheong J. Does bovine lactoferrin prevent late-onset neonatal sepsis? Lancet. 2019; 393(10170):382-84.

Griffiths J, Jenkins P, Vargova M et al. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Health Technol Assess. 2018;22(74). 

GOSH. Nutrition: enteral nutrition for the preterm infant. London: Great Ormond Street Hospital; 2016.

Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.

Martin A, Ghadge A, Manzoni P et al; LIFT Collaborative Study Group. Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge. BMJ Open. 2018;8(10):e023044.

Why was this study needed?

Premature babies are vulnerable to infection due to their underdeveloped immune systems and the invasive procedures they have to undergo. It is estimated that 20 to 30% will acquire an infection during their first few weeks of life.

Such babies often can’t feed normally so need artificial feeding. This may be intravenous or by a tube into their stomach, known as enteral feeding. They then miss out on some of the health benefits of natural milk, which has many antimicrobial properties.

Previous studies have suggested that adding lactoferrin to enteral feeds may reduce infections, but the numbers of babies have been too small to provide a definitive result. This large trial helps address the knowledge gap.

What did this study do?

The Enteral Lactoferrin in Neonates (ELFIN) randomised controlled trial involved 37 UK sites and a total of 2,203 babies enrolled less than 72 hours after birth.

The intervention group received lactoferrin, obtained from cow’s milk in powder form. When mixed with water and either breast or formula milk the liquid looked similar to the control group’s mixture (which had sucrose added instead). The dose of lactoferrin was 150mg/kg body weight per day, up to a maximum of 300mg/day. The dose was administered once a day and this continued until 34 weeks gestation.

This large, multi-centre trial was of high quality, with 98% of the infants completing their allocated intervention, thus providing robust evidence.

What did it find?

  • No difference was found between groups for the primary outcome of microbiologically or clinically suspected late-onset bloodstream infection. It occurred in 316/1,093 (29%) of the lactoferrin group compared with 334/1,089 (31%) of the control group (adjusted risk ratio [aRR] 0.95, 95% confidence interval [CI] 0.86 to 1.04).
  • Similarly, lactoferrin did not affect mortality. There were 71/1,076 (7%) deaths in the lactoferrin group compared with 68/1,076 (6%) in the control group (aRR 1.05, 95% CI 0.66 to 1.68).
  • There was no difference in necrotising enterocolitis (a serious bowel disorder), which affected 63/1,085 (6%) of the lactoferrin group compared to 56/1,084 (5%) of the control group (aRR 1.13, 95% CI 0.68 to 1.89).
  • There were 16 (1.5%) serious adverse events in the lactoferrin group, two of which may have been related to the trial intervention. Ten (0.9%) adverse events were observed in the control group.

What does current guidance say on this issue?

There are no specific guidelines regarding the use of lactoferrin for the prevention of infection in premature babies. Great Ormond Street Hospital does produce a guideline on enteral feeding in general. This highlights the fact that the incidence of infections in premature neonates receiving human milk is lower due to anti-infective agents including prebiotics, probiotics, immunoglobulins and lactoferrin.

What are the implications?

When lactoferrin was given to babies born before 32 weeks, their risk of acquiring infections, such as sepsis, was virtually the same as those in the control group, about 30%.

This study of more than double the total number of infants from previous trials shows that the addition of lactoferrin to premature infants’ feeds is unnecessary.  The threat of late-onset infection remains. 

As well as further research into anti-infective agents we must remain focused on what we know works, such as hand hygiene and other infection control procedures.

Citation and Funding

ELFIN trial investigators group. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423-33.

This project was funded by the NIHR Technology Assessment Programme (10/57/49).

Bibliography

Doyle L, Cheong J. Does bovine lactoferrin prevent late-onset neonatal sepsis? Lancet. 2019; 393(10170):382-84.

Griffiths J, Jenkins P, Vargova M et al. Enteral lactoferrin to prevent infection for very preterm infants: the ELFIN RCT. Health Technol Assess. 2018;22(74). 

GOSH. Nutrition: enteral nutrition for the preterm infant. London: Great Ormond Street Hospital; 2016.

Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.

Martin A, Ghadge A, Manzoni P et al; LIFT Collaborative Study Group. Protocol for the Lactoferrin Infant Feeding Trial (LIFT): a randomised trial of adding lactoferrin to the feeds of very-low birthweight babies prior to hospital discharge. BMJ Open. 2018;8(10):e023044.

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

Published on 8 January 2019

The Elfin Investigators' Group,

The Lancet , 2019

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. 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.

Expert commentary

Very preterm babies are at high risk of infection, and tragically a number of babies die as a result of this complication. Therefore, much effort has been made to investigate practices or interventions which would reduce the incidence and severity of infection in this group. Lactoferrin, a protein found in milk, has been thought to protect against infection but there are concerns that previous studies were too small or were not sufficiently well designed.

In this very large study, half of the study population of preterm babies received cow’s milk lactoferrin from shortly after birth, and the incidence of infection compared with those who did not. There was no difference in rates of infection between the two groups.

This indicates that there is no role for lactoferrin in preventing infection, which is important given that this is a cow’s milk protein and so there is a theoretical risk of harm.

Dr J M Hawdon, Responsible Officer, Consultant Neonatologist, Royal Free London NHS Foundation Trust

The commentator declares no conflicting interests

Expert commentary

Several small trials have previously suggested that giving preterm infants lactoferrin may decrease their chances of developing an infection and some other complications like necrotising enterocolitis. The recently published ELFIN study, the largest study to date, has shown no benefit of supplementing preterm infants with lactoferrin.

Unless the just concluded LIFT (Lactoferrin Infant Feeding Trial) shows a significant benefit, it seems reasonable to conclude that giving lactoferrin to preterm infants does not decrease infections or necrotising enterocolitis. We need to explore other options to minimise infections and other complications of prematurity.

Dr Minesh Khashu, Lead Neonatologist, Poole Hospital NHS Foundation Trust

The commentator declares no conflicting interests

Expert commentary

Preterm babies have low intake of lactoferrin, a protein found in breast milk that has anti-microbial properties, because of delays in establishing milk feeds. A systematic review found the incidence of infection decreased by 40% in preterm babies given lactoferrin.

This well-conducted study shows no difference in outcomes in babies given lactoferrin or placebo, demonstrating that systematic reviews albeit with large numbers and impressive effect sizes should be interpreted with caution.

It is plausible that recent changes in practice of faster establishment of milk feeds and fewer days spent on intravenous nutrition may have accounted for the lack of benefit of supplementation with lactoferrin.

Dr Sabita Uthaya, Consultant Neonatologist, Chelsea and Westminster NHS Foundation Trust

The commentator is currently a co-investigator on an unrelated study with Nicholas Embleton who is one of the trial investigators listed