Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials

Abstract

Background Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain. Aim To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk. Study Design This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM. Results (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18–0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16–0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71–0.96; p = 0.01). Conclusion Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

Lactoferrin Expression Is Not Associated with Late-Onset Sepsis in Very Preterm Infants

“…Available secondary analyses of the small subset of exclusively formula-fed infants raise the question of whether these patients may benefit from lactoferrin supplementation, but the current data are insufficient to address this with certainty [17, 18]. Furthermore, we found that human lactoferrin has greater activity against common neonatal pathogens in vitro, with an early trial of recombinant human lactoferrin (talactoferrin) demonstrating no safety concerns and a trend towards lower sepsis rates in the treatment arm.…”

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

“…An interim analysis of the primary composite endpoint and of survival to discharge using the Haybittle-Peto [28] approach in the first 250 infants enrolled in the study in Canada. The procedure involves evaluating the test statistic calculated under the null hypothesis against a boundary of 3 standard deviations (equivalent to χ 2 = 9, with a p-value of 0.0027.…”

“…Similarly, a meta-analysis of the effect of bLF on late onset sepsis in 1891 preterm infants who were not fed exclusively mother's own milk in two RCTs of bLF supplementation [25,27,28], a relative risk of late onset sepsis to be reduced to 0.82 (95% 0.71-0.96; P = 0.01), with moderate heterogeneity (I 2 = 0.64) and asymmetric funnel plot, consistent with small study effects, or true differences between trials in effectiveness or underlying patient risk [29].…”

Is Mother’s Own Milk Lactoferrin Intake Associated with Reduced Neonatal Sepsis, Necrotizing Enterocolitis, and Death?

“…The ELFIN [15] study in the UK used a dose of 150 mg/kg of bovine LF, with no significant protective effect against LOS, suggesting that probably a higher dose is needed on top of the amount that neonates are already receiving from MOM. A recent study by Manzoni et al [27] evaluated the effect of bovine LF supplementation from 2 previous clinical trials and compared the effect among infants receiving only formula and mixed feeds. This study suggested that bovine LF supplementation may have a benefit among infants who do not receive MOM, and that probably there is no advantage of giving more LF to infants who are already receiving good quantities of MOM.…”