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.

Keywords

lactoferrin - sepsis - VLBW neonates - preterm infants - Candida - infection - human milk - formula milk

• References

• 1 Manzoni P, Rinaldi M, Cattani S. , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009; 302 (13) 1421-1428
• 2 Akin IM, Atasay B, Dogu F. , et al. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Am J Perinatol 2014; 31 (12) 1111-1120
• 3 Ochoa TJ, Zegarra J, Cam L. , et al. Randomized controlled trial of lactoferrin for prevention of sepsis in peruvian neonates less than 2500 g. Pediatr Infect Dis J 2015; 34 (06) 571-576
• 4 Kaur G, Gathwala G. Efficacy of bovine lactoferrin supplementation in preventing late-onset sepsis in low birth weight neonates: a randomized placebo-controlled clinical trial. J Trop Pediatr 2015; 61 (05) 370-376
• 5 Sherman MP, Adamkin DH, Niklas V. , et al. Randomized controlled trial of talactoferrin oral solution in preterm infants. J Pediatr 2016; 175: 68-73.e3
• 6 Barrington KJ, Assaad M-A, Janvier A. The Lacuna trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant. J Perinatol 2016; 36 (08) 666-669
• 7 Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2017; 6: CD007137
• 8 ELFIN Trial Investigators Group. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet 2019; 393 (10170): 423-433
• 9 Manzoni P, Mostert M, Stronati M. Lactoferrin for prevention of neonatal infections. Curr Opin Infect Dis 2011; 24 (03) 177-182
• 10 Trend S, Strunk T, Hibbert J. , et al. Antimicrobial protein and peptide concentrations and activity in human breast milk consumed by preterm infants at risk of late-onset neonatal sepsis. PLoS One 2015; 10 (02) e0117038
• 11 Manzoni P, Meyer M, Stolfi I. , et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. Early Hum Dev 2014; 90 (Suppl. 01) S60-S65
• 12 National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. Approved Standard M27- A. Wayne, PA: National Committee for Clinical Laboratory Standards; 1997
• 13 Hope WW, Castagnola E, Groll AH. , et al; ESCMID Fungal Infection Study Group. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect 2012; 18 (Suppl. 07) 38-52
• 14 Manzoni P, Pedicino R, Stolfi I. , et al; Task Force per le infezioni fungine neonatali del GSIN; Socieà Italiana di Neonatologia. Criteria for the diagnosis of systemic fungal infections in newborns: a report from the Task Force on neonatal fungal infections of the GSIN. [in Italian] Pediatr Med Chir 2004; 26 (02) 89-95
• 15 Hylander MA, Strobino DM, Dhanireddy R. Human milk feedings and infection among very low birth weight infants. Pediatrics 1998; 102 (03) E38
• 16 Manager R. (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre; 2014
• 17 Furman L, Taylor G, Minich N, Hack M. The effect of maternal milk on neonatal morbidity of very low-birth-weight infants. Arch Pediatr Adolesc Med 2003; 157 (01) 66-71
• 18 Ronayne de Ferrer PA, Baroni A, Sambucetti ME, López NE, Ceriani Cernadas JM. Lactoferrin levels in term and preterm milk. J Am Coll Nutr 2000; 19 (03) 370-373
• 19 Albenzio M, Santillo A, Stolfi I. , et al. Lactoferrin levels in human milk after preterm and term delivery. Am J Perinatol 2016; 33 (11) 1085-1089