Lactoferrin infant feeding trial_Canada (LIFT_Canada): protocol for a randomized trial of adding lactoferrin to feeds of very-low-birth-weight preterm infants

Over 15 million infants are born preterm (< 37 weeks gestation worldwide [1]. In developed countries such as Canada, Australia and the United States, very low birth weight infants (VLBW < 1500 g) preterm infants account almost 1.5% of all births [2‐4]. In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity (ROP), late-onset sepsis (LOS), or significant necrotizing enterocolitis (NEC) [2]. Each of these morbidities has been associated with a substantial risk of childhood impairments [5‐7].

Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions [8, 9]. Lactoferrin has been shown to be effective against infection when tested in animals and in the laboratory [10‐12]. The systemic effects of oral lactoferrin are generally thought to be indirect and probably are initiated by contact with intestinal epithelial cells and gut-associated lymphoid tissue (GALT) [13, 14]. Lactoferrin and other similar products in human milk create an environment for growth of beneficial bacteria in the gut, reducing colonization with pathogenic bacteria. However, most VLBW infants receive insufficient human lactoferrin from human breast milk in the first months of life, resulting in suboptimal protection [15]. Because human lactoferrin is expensive, bovine lactoferrin has been considered as an alternate supplement to improve this suboptimal protection, as it has at least 70% amino acid homology with human lactoferrin with the same N-terminal peptide [16]. With the properties outlined, lactoferrin has emerged as a potential new tool for the prevention of serious neonatal morbidities.

There have been 6 randomized controlled trials involving almost 1100 preterm infants that have evaluated oral bovine lactoferrin (bLF) in the most recent Cochrane review (2017) [17].

The review showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI − 0.10 to − 0.02; and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI − 0.06 to − 0.01. Lactoferrin supplementation did not have an effect on “all-cause mortality” (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI − 0.05 to 0). Lactoferrin supplementation to enteral feeds with or without probiotics decreased late-onset sepsis involving bacterial and fungal organisms but not chronic lung disease or length of hospital stay. Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and periventricular leukomalacia. However, because of the moderate to low quality of the evidence as per the GRADE criteria [18], the Cochrane review called for the results of at least the 6 additional ongoing trials including LIFT_Canada to provide data to enhance the quality of the evidence.

Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. Pooled data suggests benefit in some outcomes, in particular late onset sepsis. Benefit may be augmented in conjunction with current aspects of care such as use of human milk and probiotics in the vulnerable infants. It is hoped that the results of LIFT_Canada alone and pooled with LIFT_ANZ may help to clarify the situation.