Download PDF
Am J Perinatol 2023; 40(06): 680-687
DOI: 10.1055/s-0041-1730433
Original Article

Is Lactoferrin Supplementation Beneficial for All Preterm Infants?

Amrita Nayak 
1   Department of Pediatrics, NYU Langone Hospital-Long Island, Mineola, New York
,
Caterina Tiozzo
1   Department of Pediatrics, NYU Langone Hospital-Long Island, Mineola, New York
2   Women and Children Research Laboratory, NYU Long Island School of Medicine, Mineola, New York
,
Xinhua Lin
2   Women and Children Research Laboratory, NYU Long Island School of Medicine, Mineola, New York
,
Claudia Mejia
2   Women and Children Research Laboratory, NYU Long Island School of Medicine, Mineola, New York
,
Ellen Gurzenda
2   Women and Children Research Laboratory, NYU Long Island School of Medicine, Mineola, New York
,
Maureen Kim
1   Department of Pediatrics, NYU Langone Hospital-Long Island, Mineola, New York
,
Nazeeh Hanna
1   Department of Pediatrics, NYU Langone Hospital-Long Island, Mineola, New York
2   Women and Children Research Laboratory, NYU Long Island School of Medicine, Mineola, New York
› Author Affiliations Funding None.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective Human milk (HM) has antibacterial properties due to the presence of immune-modulators, including lactoferrin (LF). This study will determine effect(s) of HM maturation, fortification, and storage conditions on LF levels and its antibacterial properties.

Study Design HM samples (n = 30) were obtained from preterm and term mothers. The LF levels were analyzed by ELISA, and the antibacterial activity was measured after inoculation with Escherichia coli.

Results The highest level of LF in preterm HM was observed in the first week of lactation. However, storage of preterm HM at 4°C decreased LF levels significantly. Both LF levels and antibacterial activity in preterm HM was lower compared with term HM, but significantly higher than donor HM even after HM-based fortification. LF supplementation of donor HM improved its antibacterial activity.

Conclusion Preterm infants fed donor HM, formula, or stored HM at 4°C may benefits from LF supplementation to improve HM antibacterial properties.

Key Points

  • Milk LF levels vary with storage and maturity.

  • Donor milk is deficient in LF even after adding HM-based fortification.

  • Donor HM and formula fed infants may benefit from LF.

Keywords

human milk - necrotizing enterocolitis - nutrition - lactoferrin - human milk fortifier

Authors' Contributions

N.H., A.N., and C.T. contributed in conceptualization of the study. A.N., C.T., and X.L. participated in data curation, developed methodology, and designed visualization. C.T. and X.L. assisted in format analysis. A.N. and N.H. helped in acquiring fund and procured resources. E.G., C.M., and X.L. performed investigation. N.H. provided supervision. A.N., C.T., M.K., and N.H. approved validation. A.N. dedicated in writing original draft. C.T., X.L., M.K., and N.H. involved in reviewing and editing the draft.




Publication History

Received: 03 February 2021

Accepted: 19 April 2021

Article published online:
31 May 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Telang S. Lactoferrin: a critical player in neonatal host defense. Nutrients 2018; 10 (09) E1228
    CrossrefPubMedSearch in Google Scholar
  • 2 Maffei D, Schanler RJ. Human milk is the feeding strategy to prevent necrotizing enterocolitis!. Semin Perinatol 2017; 41 (01) 36-40
    CrossrefPubMedSearch in Google Scholar
  • 3 Jahani S, Shakiba A, Jahani L. The antimicrobial effect of lactoferrin on gram-negative and gram-positive bacteria. Int J Infect 2015; 3 (02) e27954
    PubMedSearch in Google Scholar
  • 4 Rai D, Adelman AS, Zhuang W, Rai GP, Boettcher J, Lönnerdal B. Longitudinal changes in lactoferrin concentrations in human milk: a global systematic review. Crit Rev Food Sci Nutr 2014; 54 (12) 1539-1547
    CrossrefPubMedSearch in Google Scholar
  • 5 Velonà T, Abbiati L, Beretta B. et al. Protein profiles in breast milk from mothers delivering term and preterm babies. Pediatr Res 1999; 45 (5 pt 1): 658-663
    CrossrefPubMedSearch in Google Scholar
  • 6 Turin CG, Zea-Vera A, Rueda MS. et al; NEOLACTO Research Group. Lactoferrin concentration in breast milk of mothers of low-birth-weight newborns. J Perinatol 2017; 37 (05) 507-512
    CrossrefPubMedSearch in Google Scholar
  • 7 Manzoni P. Clinical studies of lactoferrin in neonates and infants: an update. Breastfeed Med 2019; 14 (S1, 1) S25-S27
    CrossrefPubMedSearch in Google Scholar
  • 8 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Rollo DE, Radmacher PG, Turcu RM, Myers SR, Adamkin DH. Stability of lactoferrin in stored human milk. J Perinatol 2014; 34 (04) 284-286
    CrossrefPubMedSearch in Google Scholar
  • 10 O'Connor DL, Ewaschuk JB, Unger S. Human milk pasteurization: benefits and risks. Curr Opin Clin Nutr Metab Care 2015; 18 (03) 269-275
    CrossrefPubMedSearch in Google Scholar
  • 11 Morriss Jr. FH, Moore M, Gibson T, West MS. Motility of the small intestine in preterm infants who later have necrotizing enterocolitis. J Pediatr 1990; 117 (1 pt 2): S20-S23
    CrossrefPubMedSearch in Google Scholar
  • 12 Arroyo G, Ortiz Barrientos KA, Lange K. et al. Effect of the various steps in the processing of human milk in the concentrations of IgA, IgM, and lactoferrin. Breastfeed Med 2017; 12 (07) 443-445
    CrossrefPubMedSearch in Google Scholar
  • 13 Johnston WH, Ashley C, Yeiser M. et al. Growth and tolerance of formula with lactoferrin in infants through one year of age: double-blind, randomized, controlled trial. BMC Pediatr 2015; 15 (01) 173
    CrossrefPubMedSearch in Google Scholar
  • 14 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
    CrossrefPubMedSearch in Google Scholar
  • 15 Meyer MP, Alexander T. Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. J Neonatal Perinatal Med 2017; 10 (03) 249-255
    CrossrefPubMedSearch in Google Scholar
  • 16 Manzoni P, Militello MA, Rizzollo S. et al; Italian Task Force for the Study Prevention of Neonatal Fungal Infections; the Italian Society of Neonatology. 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. Am J Perinatol 2019; 36 (S 02): S120-S125
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 McGuire W. Enteral lactoferrin supplementation for very preterm infants: a randomised controlled trial. Health Technol Assess 2019; 22 (74) 1-60
    PubMedSearch in Google Scholar
  • 18 van Berkel PH, Geerts ME, van Veen HA, Mericskay M, de Boer HA, Nuijens JH. N-terminal stretch Arg2, Arg3, Arg4 and Arg5 of human lactoferrin is essential for binding to heparin, bacterial lipopolysaccharide, human lysozyme and DNA. Biochem J 1997; 328 (pt 1): 145-151
    CrossrefPubMedSearch in Google Scholar
  • 19 Woodman T, Strunk T, Patole S, Hartmann B, Simmer K, Currie A. Effects of lactoferrin on neonatal pathogens and bifidobacterium breve in human breast milk. PLoS One 2018; 13 (08) e0201819
    CrossrefPubMedSearch in Google Scholar
  • 20 Elrod KC, Moore WR, Abraham WM, Tanaka RD. Lactoferrin, a potent tryptase inhibitor, abolishes late-phase airway responses in allergic sheep. Am J Respir Crit Care Med 1997; 156 (2 pt 1): 375-381
    CrossrefPubMedSearch in Google Scholar
  • 21 Medidi S. The roles of lactoferrin as privileged glycoprotein in health and disease. Pharmanest 2014; 5: 2091-2097
    PubMedSearch in Google Scholar
  • 22 Nibbering PH, Ravensbergen E, Welling MM. et al. Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant bacteria. Infect Immun 2001; 69 (03) 1469-1476
    CrossrefPubMedSearch in Google Scholar
  • 23 Manzoni P. Clinical benefits of lactoferrin for infants and children. J Pediatr 2016; 173 (suppl): S43-S52
    CrossrefPubMedSearch in Google Scholar
  • 24 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
    CrossrefPubMedSearch in Google Scholar
  • 25 Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2017; 6: CD007137
    PubMedSearch in Google Scholar
  • 26 Manzoni P, Stolfi I, Messner H. et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections–the Italian Society of Neonatology. Bovine lactoferrin prevents invasive fungal infections in very low birth weight infants: a randomized controlled trial. Pediatrics 2012; 129 (01) 116-123
    CrossrefPubMedSearch in Google Scholar
  • 27 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
    CrossrefPubMedSearch in Google Scholar
  • 28 Ochoa TJ, Zegarra J, Cam L. et al; NEOLACTO Research Group. 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
    CrossrefPubMedSearch in Google Scholar
  • 29 Underwood MA. Human milk for the premature infant. Pediatr Clin North Am 2013; 60 (01) 189-207
    CrossrefPubMedSearch in Google Scholar
  • 30 Christen L, Lai CT, Hartmann B, Hartmann PE, Geddes DT. The effect of UV-C pasteurization on bacteriostatic properties and immunological proteins of donor human milk. PLoS One 2013; 8 (12) e85867
    CrossrefPubMedSearch in Google Scholar
  • 31 Fabrizio V, Trzaski JM, Brownell EA. et al. Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. Cochrane Database Syst Rev 2020; 11 (11) CD013465
    CrossrefPubMedSearch in Google Scholar
  • 32 Cardoso M, Virella D, Macedo I, Silva D, Pereira-da-Silva L. Customized human milk fortification based on measured human milk composition to improve the quality of growth in very preterm infants: a mixed-cohort study protocol. Int J Environ Res Public Health 2021; 18 (02) 823
    CrossrefPubMedSearch in Google Scholar
  • 33 Ochoa TJ, Zegarra J, Bellomo S. et al; NEOLACTO Research Group. Randomized controlled trial of bovine lactoferrin for prevention of sepsis and neurodevelopment impairment in infants weighing less than 2000 grams. J Pediatr 2020; 219: 118-125.e5
    CrossrefPubMedSearch in Google Scholar
  • 34 Tarnow-Mordi WO, Abdel-Latif ME, Martin A. et al; LIFT collaborators. The effect of lactoferrin supplementation on death or major morbidity in very low birthweight infants (LIFT): a multicentre, double-blind, randomised controlled trial. Lancet Child Adolesc Health 2020; 4 (06) 444-454
    CrossrefPubMedSearch in Google Scholar
  • 35 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
    CrossrefPubMedSearch in Google Scholar
  • 36 Razak A, Hussain A. Lactoferrin supplementation to prevent late-onset sepsis in preterm infants: a meta-analysis. Am J Perinatol 2019
    PubMedSearch in Google Scholar
  • 37 Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2020; 3 (05) CD007137
    PubMedSearch in Google Scholar
  • 38 Hanna N, Ahmed K, Anwar M, Petrova A, Hiatt M, Hegyi T. Effect of storage on breast milk antioxidant activity. Arch Dis Child Fetal Neonatal Ed 2004; 89 (06) F518-F520
    CrossrefPubMedSearch in Google Scholar
  • 39 Bertino E, Peila C, Cresi F. et al. Donor human milk: effects of storage and heat treatment on oxidative stress markers. Front Pediatr 2018; 6: 253
    CrossrefPubMedSearch in Google Scholar
  • 40 Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK. Canadian Neonatal Network. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics 2012; 129 (02) e298-e304
    CrossrefPubMedSearch in Google Scholar
  • 41 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
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Manzoni P, Dall'Agnola A, Tomé D. et al. Role of lactoferrin in neonates and infants: an update. Am J Perinatol 2018; 35 (06) 561-565
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Jiang R, Du X, Lönnerdal B. Comparison of bioactivities of talactoferrin and lactoferrins from human and bovine milk. J Pediatr Gastroenterol Nutr 2014; 59 (05) 642-652
    CrossrefPubMedSearch in Google Scholar
  • 44 Bergin SP, Thaden JT, Ericson JE. et al; Antibacterial Resistance Leadership Group. Neonatal escherichia coli bloodstream infections: clinical outcomes and impact of initial antibiotic therapy. Pediatr Infect Dis J 2015; 34 (09) 933-936
    CrossrefPubMedSearch in Google Scholar