Preventing Sepsis in Preterm Infants with Bovine Lactoferrin: A Randomized Trial Exploring Immune and Antioxidant Effects.

Background/Objectives: Late-onset neonatal sepsis (LOS) remains a leading cause of morbidity and mortality in very low birth weight (VLBW) infants (<1500 g and/or gestational age <32 weeks), with limited preventive strategies. We evaluated whether early enteral bovine lactoferrin (bLf), given its antimicrobial, immunomodulatory, and antioxidant properties, reduces LOS and improves immunologic, antioxidant, and hematologic markers in these infants. Methods: In this randomized, double-blind, placebo-controlled trial, 103 VLBW infants received bLf (150 mg/kg/day; n = 50) or the placebo (n = 53) within 72 h of birth for four weeks or until discharge. Outcomes included culture-confirmed LOS, mortality, and major morbidities. Risk ratios (RRs) were calculated, adjusting for gestational age, human milk intake, and ventilatory support when ≥25 events occurred. Pre/post changes in cytokines, total antioxidant capacity (TAC), and hemoglobin (Hb) were analyzed for interaction effects (time x intervention). Results: bLf reduced LOS (adjusted RR 0.54; 95% CI 0.31-0.93; p = 0.028), without differences in other morbidities or mortality. bLf preserved MCP-1 levels, declining in the placebo group (interaction p = 0.022). Among LOS infants receiving bLf, IL-6 remained stable and MCP-1 increased, while both declined in other groups (interaction p = 0.007 for IL-6; p = 0.052 for MCP-1). Although TAC showed a non-significant interaction, the placebo group declined (p = 0.002), while bLf remained stable (p = 0.400) in the post hoc analysis. In non-transfused infants, bLf increased Hb by 0.9 g/dL vs. controls (p = 0.028). Conclusions: Early bLf supplementation safely reduces LOS in VLBW infants and may support immunologic, antioxidant, and hematologic stability.