Bovine Lactoferrin for Preterm Infant Sepsis: What the LIFT and Cochrane Updates Show

Late-onset sepsis remains a major cause of morbidity and mortality in very low birthweight preterm infants. Bovine lactoferrin — an iron-binding glycoprotein abundant in colostrum — emerged in the 2010s as a promising preventive supplement after early Italian trials suggested substantial reductions in sepsis rates. Two large pragmatic trials and a 2024 Cochrane update have now landed; the result is a more measured but still notable picture.

Why lactoferrin became plausible

Bovine lactoferrin is structurally similar to human lactoferrin and survives heat treatment, which makes it suitable for supplementation. Mechanistically it has direct antibacterial activity (sequestering iron from pathogens), antifungal effects, immunomodulatory effects on innate immune cells, and possibly prebiotic effects on infant intestinal Bifidobacterium colonization. The Manzoni 2009 trial in Italy reported a dramatic 70% relative reduction in late-onset sepsis in very low birthweight infants given oral bovine lactoferrin, alone or with Lactobacillus rhamnosus GG.

Several smaller trials reproduced the direction of effect, and a 2014 Cochrane review found moderate-quality evidence supporting reduction in late-onset sepsis with bovine lactoferrin in this population. The mechanism, the magnitude of effect, and the favorable safety profile made it a leading candidate for adoption into NICU protocols.

The big pragmatic trials told a different story

The ELFIN trial in the UK, published in 2019, randomized 2,203 very preterm infants to bovine lactoferrin or sucrose placebo daily until 34 weeks' postmenstrual age. The primary outcome — late-onset sepsis — occurred in 29% of lactoferrin and 31% of placebo infants. The difference was not statistically significant. Mortality, necrotizing enterocolitis, and bronchopulmonary dysplasia all showed no benefit.

The LIFT trial in Australia and New Zealand, published 2020 (n=1542 infants), also found no significant reduction in death or major morbidity from bovine lactoferrin supplementation. A 2024 updated Cochrane review pooled 12 trials with over 5,500 infants and concluded that bovine lactoferrin probably has little or no effect on late-onset sepsis or all-cause mortality in preterm infants. The previous favorable signal disappeared when the larger, methodologically stronger trials were included.

Why the early trials looked so positive

Two explanations dominate. First, small early trials with high event rates in their control arms had unstable effect estimates that overstated true benefit; this is a well-recognized pattern in neonatal sepsis trials and in supplement trials generally. Second, NICU baseline sepsis rates have fallen substantially over the past 15 years due to improved central line care, antibiotic stewardship, and breast milk feeding promotion. A supplement that might have helped at higher baseline rates may simply not move the needle at modern lower event rates.

The Italian trials also used a specific lactoferrin product (Pharmaferm) at specific doses; some heterogeneity in formulation across trials may contribute to between-trial variability, but it does not appear to explain the trial-size dependent pattern.

What this means for practice

Current evidence does not support routine bovine lactoferrin supplementation in preterm infants for sepsis prevention. The 2024 Cochrane and the major NICU professional societies do not recommend it as standard care. Some units continue use based on a still-low risk profile and on the possibility that specific high-risk subgroups (extremely low birthweight, those with poor enteral feed advancement) might benefit, but this is not well supported by the pooled data.

The clearer wins in late-onset sepsis prevention in this population remain: early human milk feeding (parental own breast milk preferred, donor milk where unavailable), strict central line bundles, antimicrobial stewardship, and probiotic prophylaxis with specific evidence-supported strains (the latter still controversial after the FDA warning following the 2023 infant death linked to a probiotic product in a preterm neonate).

Bottom line

Two large pragmatic trials and a 2024 Cochrane update converge on the conclusion that bovine lactoferrin supplementation does not meaningfully reduce late-onset sepsis or mortality in preterm infants. Earlier positive findings were not replicated in the larger trials. Routine NICU use is not currently supported by evidence.