MANUSCRIPT CITATION

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet. 2019;393(10170):423-433. doi: 10.1016/S0140-6736(18)32221-9. PMID: 30635141

REVIEWED BY

Aishath Rizma Moosa
Trainee in Paediatrics
University Hospitals of Leicester NHS Trust

Yifei Wang
Attending neonatologist
Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

Elaine M Boyle
Professor of Neonatal Medicine
University of Leicester, Leicester, UK

TYPE OF INVESTIGATION

Treatment

QUESTION

(P) In neonates born at less than 32 weeks of gestation and younger than 72 h at randomization, (I) does enteral lactoferrin supplementation  (C) compared to sucrose (O) decrease the rate of  microbiologically confirmed or clinically suspected late onset infection (T) during the birth hospitalization?

METHODS

• Design: Multi-centre randomized placebo-controlled trial
• Allocation: 1:1 ratio
• Blinding: The study was blinded to participants’ parents, caregivers, clinicans and investigators as well as outcome assessors. The placebo was made visually indistinguishable from bovine lactoferrin once mixed with milk.
• Follow-up period: Infants were followed to discharge from hospital
• Setting: 37 hospitals in the United Kingdom between May 2014and September 2017.
• Patients:
  • Inclusion criteria
    • gestational age less than 32 weeks
    • less than 72 hours of age at time of randomization
    • parental consent for participation
  • Exclusion criteria
    • presence of a severe congenital anomaly
    • anticipated enteral fasting for longer than 14 days
    • infants with no prospect of survival.
• Intervention:
  • For Lactoferrin group: Enteral bovine lactoferrin ( 150 mg/kg per day; maximum 300mg/day)
  • For Placebo group: Enteral Sucrose ( 150mg/kg per day; maximum 300mg/day)
  • Both groups received the study drug until 34 weeks postmenstrual age.
  • The study intervention was started once the infant’s enteral feed volume was more than 12 mL/kg per day, and was administered once daily via gastric tube
• Outcomes: 
  • Primary outcome: Microbiologically confirmed or clinically suspected late-onset infection from trial entry to discharge from hospital. The primary outcome was initially assessed locally, but then subjected to central independent review by a blinded end-point committee.
  • Secondary outcomes: microbiologically confirmed infection; all cause mortality to hospital discharge; Bell’s Stage 2 or 3 necrotizing enterocolitis (NEC), severe retinopathy of prematurity (ROP) requiring medical or surgical treatment; bronchopulmonary dysplasia (BPD), defined as the need for oxygen therapy or respiratory support at 36 weeks postmenstrual age; a composite measure of invasive infection, major morbidity (NEC, ROP, BPD) and mortality; total number of days of antibiotics per infant until 34 weeks postmenstrual age; total length of hospital stay until discharge home; number of days receiving intensive, high dependency or special care, as defined by the British Association of Perinatal Medicine categories of care. Reports of late onset infection and NEC were subject to independent assessment by blinded end-point review.
• Analysis and Sample Size: The sample size of 2200 was calculated based on the ability to detect an absolute risk reduction of 5-5.8%, with 90% power at a significance level of 5%. This assumed a primary outcome control event rate of between 18% and 24% and allowed for loss to follow-up of 5%.
• Patient follow-up: 1093/1099 (99.4%) recruits randomized to the intervention group were included in the primary outcome modified intention-to-treat analysis. 1089/1104 (98.6%) in the control group were included. Consent was unconfirmed or withdrawn for 4 infants (1 intervention; 3 controls) and primary outcome data were unavailable for 5 infants in the lactoferrin group and 12 infants in the control group.

MAIN RESULTS

TABLE 1: Demographic characteristics

TABLE 2: Primary and secondary outcomes

Of the 2182 children analyzed:

Primary Outcome: 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimization factors was 0·95 (95% CI 0·86–1·04; p=0·233).

Secondary Outcomes: There was no difference in all prespecified secondary outcomes. During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.

CONCLUSION

Enteral supplementation with bovine lactoferrin did not reduce the risk of late onset infection in infants born at less than 32 weeks of gestation in this large randomized controlled trial. The results do not support its use in clinical practice to prevent late onset infection or associated morbidity and mortality in very preterm infants.

COMMENTARY

Late onset sepsis is a major cause of morbidity and mortality in neonates, but predominantly in preterm infants. In survivors, it can prolong length of hospital stay, worsen long-term neurodevelopmental outcomes and increase the associated social burden of disease (1). Lactoferrin, a mammalian iron‐binding whey glycoprotein with important bacteriostatic and anti-inflammatory properties, plays a role in promoting growth of probiotic bacteria in the gut(2).

A recent Cochrane review suggested reductions in both sepsis and necrotizing enterocolitis with oral lactoferrin supplementation(3). Many of these studies enrolled small numbers and had limitations in study design and implementation. The ELFIN randomised, placebo-controlled trial is the largest trial of this intervention.  A major strength lies in the large number (>2000) of participating babies with more than 99% of outcome data being available. Important consideration was given to limit bias for the study;randomization was successful in balancing baseline demographic and prognostic characteristics. Measures were put in place to define the spectrum of late onset infection in order to reduce potential sources of bias. This is in contrast to most previous studies, in which only culture-proven late onset sepsis was used as a marker(4).

This does not necessarily completely rule out bias. The primary outcome used encompasses both microbiologically confirmed and clinically suspected late onset infection, from trial entry until hospital discharge. Although these results were confirmed, using pre-defined criteria, by masked central end-point review committees, clinically suspected late-onset infection remains a subjective outcome. As it accounts for more than 40 percent of the cases in this study, this might be considered a confounding factor.

Based on the GRADE system (grading of recommendation, assessment, development and evaluation), due to the relative imprecision of the primary outcome and inconsistency of the main result, lactoferrin is not recommended as a routine intervention to prevent late onset sepsis in very preterm infants. Although other trials of lactoferrin are ongoing (Mooselmokadem trial; NCT01821989, estimated n = 180), NEOLACTO (NCT01525316, n = 414) and LIFT (ACTRN12611000247976, target sample size of 1500), it would be difficult to anticipate that these would bring about a change in the grade of recommendation, unless a substantial positive effect were seen in the largest of these trials.

Although the risk of adverse outcomes in more mature preterm infants is generally lower, the effect size, favoring lactoferrin, was larger in this study in infants born at 30 or more weeks of gestation. Although not statistically significant, this finding may be clinically relevant. Lactoferrin promotes growth of probiotic bacteria, so this finding begs the question of whether this effect could be related to lower rates of exclusive breast milk feeding and more restricted use of broad spectrum antibiotics in larger infants.

Evidently, there is still a need for novel research into the use of alternative interventions as adjuvants in preventing late onset sepsis, and reducing mortality and morbidity in the very preterm population. Is there, for example, a need for further large scale studies to look at the effectiveness of using lactoferrin in combination with probiotic therapy or other interventions designed to decrease infection risk (5)?

REFERENCES

1. Vergnano S, Menson E, Kennea N, et al. Neonatal infections in England: the NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed. 2011;96(1):F9-F14.
2. Sánchez L, Calvo M, Brock JH. Biological role of lactoferrin. Arch Dis Child. 1992;67(5):657-61.
3. Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.
4. Kaur 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(5):370-6.
5. Manzoni P, Rinaldi M, Cattani S, et al. Bovine lactoferrin supplementation for prevention of late onset sepsis in very low-birth-weight neonates: a randomized trial. 2009;302(13):1421-8.