Oral Lactoferrin Supplementation to Prevent Late-Onset Neonatal Sepsis
Abstract & Commentary
By Hal B. Jenson, MD, FAAP, Professor of Pediatrics, Tufts University School of Medicine, and Chief Academic Officer, Baystate Medical Center, Springfield, MA Dr. Jenson reports no financial relationships relevant to this field of study, is Associate Editor for Infectious Disease Alert.
Synopsis: Supplemental oral bovine lactoferrin, either alone or in combination with Lactobacillus rhamnosus GG, reduces the incidence of late-onset sepsis among very low-birth-weight newborns.
Source: Manzoni P, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates. JAMA. 2009;302:1421-1428.
A prospective, multi-center, double-blind, placebo-controlled, randomized clinical trial was conducted of oral supplementation of bovine lactoferrin (BLF) alone or in combination with the probiotic Lactobacillus rhamnosus GG (LGG) to reduce the incidence of late onset sepsis (> 72 hours after birth) in very low birth-weight (VLBW) (< 1,500 g) newborns. BLF was administered in a single, daily dose of 100 mg orally for four weeks for newborns 1000-1500 g and for six weeks for newborns < 1000 g. The study was conducted from October 2007 through July 2008 in Italy, and included 472 neonates randomized to BLF (n = 153), BLF plus LGG (n = 151), or placebo (n = 168). There were no significant differences in the demographic, clinical, breast milk vs. formula feeding, or management characteristics of the three groups.
The incidence of late-onset sepsis in VLBW neonates was significantly lower among infants receiving BLF (9/153; 5.9%) or BLF plus LGG (7/151; 4.6%) than in the control group receiving placebo (29/168; 17.3%). Gestational age was a statistically significant predictor of late-onset sepsis (odds ratio, 0.71; 95% CI, 0.57-0.89 for each additional gestational week). After controlling for risk factors, the odds ratio for late-onset sepsis among VLBW neonates was 0.32 (95% CI, 0.14-0.77; p = 0.01) for BLF vs. placebo and 0.21 (95% CI, 0.08-0.55; p = 0.002) for BLF plus LGG vs. placebo. The effects of BLF and BLS plus LGG were significant for extremely low-birth-weight (< 1,000 g) newborns (n = 167), as well as for newborns weighing less than 750 g (n = 39).
Sepsis-attributable mortality was similarly lower in the BLF (0/153; 0%) and BLF plus LGG (1/151; 0.7%) groups than in the control group receiving placebo (8/168; 4.8%), with p = 0.008 and p = 0.04, respectively. Necrotizing enterocolitis of stage II or greater occurred less frequently with BLF plus LGG (0/151; 0%) vs. placebo (10/168; 16.0%), with p = 0.02 with no significant difference between BLF (3/153; 1.9%) vs. placebo, with p = 0.09.
Decreased risk with BLF and BLF plus LGG was observed for both bacterial and fungal infections, with comparable distribution of infecting pathogens among the groups. Fungal colonization rates were similar among the three groups. The incidence rates of late-onset sepsis among untreated newborns exclusively fed maternal milk vs. exclusively formula, and the decreases among treated newborns exclusively fed maternal milk vs. exclusively formula, were similar, suggesting that maternal milk alone does not confer the protective benefits of supplemental BLF. There were no intolerances or adverse effects associated with the treatments, though the study was underpowered to detect adverse events.
Commentary
Lactoferrin is a major whey mammalian milk glycoprotein that is important in innate immunity, resulting from iron sequestration that makes iron unavailable to support microbial growth, or a disintegrating effect on microbial cell membranes. The concentration of lactoferrin peaks in colostrum at 6 g/L and then decreases to 1 5 g/L, with a slower decrease in the maternal milk of mothers of premature newborns. Human and bovine lactoferrin share 77% amino acid homology, and BLF has higher in vitro antimicrobial activity. Most BLF passes through the stomach and is largely excreted unchanged in the stool. Some is converted by pepsin and low pH into lactoferrin, an antimicrobial peptide that can kill ingested pathogens and bind endotoxin. In this study, the administration of BLF reduced the incidence of bacterial and fungal pathogens. There were no significant differences in pathogens among treated and untreated groups, though a trend was observed for greater reduction in gram-positive and fungal infections compared with gram-negative infections in the treated groups.
LGG is a probiotic that interacts with BLF to boost defenses of the immature intestinal tract. The benefit of LGG in this study is uncertain, as the study was not sufficiently powered to detect a difference in outcome between the BLF alone vs. the BLF plus LGG groups. LGG has been reported to reduce fungal enteric colonization, which was not observed in this study.
The long-term impact of BLF administration remains to be confirmed. A study of recombinant human lactoferrin (150 mg/kg orally every 12 hours) to prevent neonatal infections among VLBW newborns is in progress.
A prospective, multi-center, double-blind, placebo-controlled, randomized clinical trial was conducted of oral supplementation of bovine lactoferrin (BLF) alone or in combination with the probiotic Lactobacillus rhamnosus GG (LGG) to reduce the incidence of late onset sepsis (> 72 hours after birth) in very low birth-weight (VLBW) (< 1,500 g) newborns.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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