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Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives

Abstract

Studies in adults have shown that the oropharyngeal route can be used to effectively and safely administer interferon-α, an immune cell-derived cytokine, to patients who are unable to tolerate its parenteral administration. The mechanism for this appears to be the stimulatory effects of the cytokine, on the oropharyngeal-associated lymphoid tissue system. Own mother's colostrum (OMC) is rich in cytokines and other immune agents that provide bacteriostatic, bacteriocidal, antiviral, anti-inflammatory and immunomodulatory protection against infection. OMC may be especially protective for the extremely low birth weight (ELBW) infant in the first days of life; however clinical instability typically precludes enteral feedings during this period. Oropharyngeal administration is a potential alternative method of providing OMC. Oropharyngeal administration of OMC may have immunomodulatory effects on the recipient infant, and would be especially beneficial to the ELBW infant who would otherwise remain nil per os during the first days of life.

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References

  1. El-Mohandes A, Picard M, Simmens S, Keiser JF . Use of human milk in the intensive care nursery decreases the incidence of nosocomial sepsis. J Perinatol 1997; 17: 130–134.

    CAS  PubMed  Google Scholar 

  2. 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: 66–71.

    Article  PubMed  Google Scholar 

  3. Hylander MA, Strobino DM, Dhanireddy R . Human milk feedings and infection among very low birth weight infants. Pediatrics 1998; 102: E38.

    Article  CAS  PubMed  Google Scholar 

  4. Ronnestad A, Abrahamsen TG, Medbo S, Reigstad H, Lossius K, Kaaresen PI et al. Late-onset septicemia in a Norwegian national cohort of extremely premature infants receiving very early full human milk feeding. Pediatrics 2005; 115: e269–e276.

    Article  PubMed  Google Scholar 

  5. Schanler RJ, Schulman RJ, Lau C . Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999; 103: 1150–1156.

    Article  CAS  PubMed  Google Scholar 

  6. Neville MC . Anatomy and physiology of lactation. Pediatr Clin North Am 2001; 48: 13–34.

    Article  CAS  PubMed  Google Scholar 

  7. Montagne P, Cuilliere ML, Mole C, Bene MC, Faure G . Immunological and nutritional composition of human milk in relation to prematurity and mother's parity during the first 2 weeks of lactation. J Pediatr Gastroenterol Nutr 1999; 29: 75–80.

    Article  CAS  PubMed  Google Scholar 

  8. Buescher ES . Anti-inflammatory characteristics of human milk: how, where and why. Adv Exp Med Biol 2001; 501: 207–222.

    Article  CAS  PubMed  Google Scholar 

  9. Buescher ES, Malinowska I . Soluble receptors and cytokine antagonists in human milk. Pediatr Res 1996; 40: 839–844.

    Article  CAS  PubMed  Google Scholar 

  10. Buescher ES, McWilliams-Koeppen P . Soluble tumor necrosis factor-alpha (TNF-alpha) receptors in human colostrum and milk bind to TNF-alpha and neutralize TNF-alpha bioactivity. Pediatr Res 1998; 44: 37–42.

    Article  CAS  PubMed  Google Scholar 

  11. Garofalo RP, Goldman AS . Cytokines, chemokines and colony-stimulating factors in human milk: the 1997 update. Biol Neonate 1998; 74: 134–142.

    Article  CAS  PubMed  Google Scholar 

  12. Rodríguez NA, Miracle DJ, Meier PP . Sharing the science on human milk feedings with mothers of very low birth weight infants. J Obstet Gynecol Neonatal Nurs 2005; 34: 109–119.

    Article  PubMed  Google Scholar 

  13. Mathur NB, Dwarkadas AM, Sharma VK, Saha K, Jain K . Anti-infective factors in preterm colostrum. Acta Paediatr Scand 1990; 79: 1039–1044.

    Article  CAS  PubMed  Google Scholar 

  14. Grumach AS, Carmona RC, Lazarotti D, Ribeiro MA, Rozentraub RB, Racz ML et al. Immunological factors in milk from Brazilian mothers delivering small-for-date term neonates. Acta Paediatr 1993; 82: 284–290.

    Article  CAS  PubMed  Google Scholar 

  15. Goldman AS, Garza C, Nichols B, Johnson CA, Smith EO, Goldblum RM . Effects of prematurity on the immunologic system in human milk. J Pediatr 1982; 101: 901–905.

    Article  CAS  PubMed  Google Scholar 

  16. Araujo ED, Goncalves AK, Cornetta M, Cunha H, Cardoso ML, Morais SS et al. Evaluation of the secretory immunoglobulin A levels in the colostrum and milk of mothers of term and preterm infants. Braz J Infect Dis 2005; 9: 357–362.

    PubMed  Google Scholar 

  17. Dvorak B, Fituch CC, Williams CS, Hurst NM, Schanler RJ . Increased epidermal growth factor levels in human milk of mothers with extremely premature infants. Pediatr Res 2003; 54: 15–19.

    Article  CAS  PubMed  Google Scholar 

  18. Koenig A, de Albuquerque Diniz EM, Barbosa SF, Vaz FA . Immunologic factors in human milk: the effects of gestational age and pasteurization. J Hum Lact 2005; 21: 439–443.

    Article  PubMed  Google Scholar 

  19. Ronayne de Ferrer PA, Baroni A, Sambucetti ME, Lopez NE, Cernadas JMC . Lactoferrin levels in term and preterm milk. J Am Coll Nutr 2000; 19: 370–373.

    Article  CAS  PubMed  Google Scholar 

  20. LaGamma E, Brown L . Feeding practices for infants weighing less than 1500 g at birth and the pathogenesis of necrotizing enterocolitis. Clin Perinatol 1994; 21: 271–306.

    Article  CAS  Google Scholar 

  21. Westerbeek E, van den Berg A, Lafeber HN, Knol J, Fetter WPF, van Elburg RM . The intestinal bacterial colonization in preterm infants: a review of the literature. Clin Nutr 2006; 25: 361–368.

    Article  PubMed  Google Scholar 

  22. Hutchinson V, Cummins JM . Low-dose oral interferon in patients with AIDs. Lancet 1987; 2: 1530–1531.

    Article  CAS  PubMed  Google Scholar 

  23. Koech DK, Obel AO, Minowada J, Hutchinson VA, Cummins JM . Low dose oral alpha-interferon therapy for patients seropositive for human immunodeficiency virus type-1 (HIV-1). Mol Biother 1990; 2: 91–95.

    CAS  PubMed  Google Scholar 

  24. Caban J, Mossor-Ostrowska J, Zyrkowska-Bieda T, Zejc M, Janas-Skulina U, Ciesla A et al. Treatment of chronic viral hepatitis B with oral mucosal administration of natural human interferon alpha lozenges. Arch Immunol Ther Exp 1993; 41: 229–235.

    CAS  Google Scholar 

  25. Zielinska W, Paszkiewicz J, Korczak A, Wlasiuk M, Zoltowska A, Szutowicz A et al. Treatment of fourteen chronic active HBsAg+, HBeAg+ hepatitis patients with low dose natural human interferon alpha administered orally. Arch Immunol Ther Exp 1993; 41: 241–251.

    CAS  Google Scholar 

  26. Bocci V . The oropharyngeal delivery of interferons: where are we and where do we need to go? J Interferon Cytokine Res 1999; 19: 859–861.

    Article  CAS  PubMed  Google Scholar 

  27. Bocci V . Absorption of cytokines via oropharyngeal-associated lymphoid tissues. Clin Pharmacokinet 1991; 21: 411–417.

    Article  CAS  PubMed  Google Scholar 

  28. Bocci V, von Bremen K, Corradeschi F, Luzzi E, Paulesu L . What is the role of cytokines in human colostrum? J Biol Regul Homeost Agents 1991; 5: 121–124.

    CAS  PubMed  Google Scholar 

  29. Roitt I, Brostoff J, Male D . Immunology (6th edn) Mosby, St. Louis, 2001.

    Google Scholar 

  30. Benjamini E, Sunshine G, Leskowitz S . Immunology; A Short Course. Wiley-Liss: New York, 1996.

    Google Scholar 

  31. Brod S . Gut response: therapy with ingested immunomodulatory proteins. Arch Neurol 1997; 54: 1300–1302.

    Article  CAS  PubMed  Google Scholar 

  32. Butcher E, Picker L . Lymphocyte homing and homeostasis. Science 1996; 272: 60–66.

    Article  CAS  PubMed  Google Scholar 

  33. Kociba GJ, Garg RC, Khan KNM, Reiter JA, Chatfield RC . Effects of orally administered interferon-alpha on the pathogenesis of feline leukemia virus-induced erythroid aplasia. Comp Haematol Int 1995; 5: 79–83.

    Article  CAS  Google Scholar 

  34. Lecce JG, Cummins JM, Richards AB . Treatment of rotavirus infection in neonate and weanling pigs using natural human interferon alpha. Mol Biother 1990; 2: 211–216.

    CAS  PubMed  Google Scholar 

  35. Moore BR . Clinical application of interferons in large animal medicine. J Am Vet Med Assoc 1996; 208: 1711–1715.

    CAS  PubMed  Google Scholar 

  36. Stanton GJ, Lloyd RE, Sarzotti M, Blalock JE . Protection of mice from Semliki Forest virus infection by lymphocytes treated with low levels of interferon. Mol Biother 1989; 1: 305–310.

    CAS  PubMed  Google Scholar 

  37. Blalock JE, Baron S, Johnson HM, Stanton GJ . Transmission of IFN-induced activities by cell to cell communication. Tex Rep Biol Med 1982; 41: 344–349.

    CAS  Google Scholar 

  38. Yasui H, Proietti E, Vignaux F, Eid P, Gresser I . Inhibition by mouse alpha interferon of the multiplication of alpha interferon resistant friend erythroleukemia cells cocultured with mouse hepatocytes. Cancer Res 1990; 50: 3533–3539.

    CAS  PubMed  Google Scholar 

  39. Butcher EC . The regulation of lymphocytes traffic. Curr Top Microbiol Immunol 1986; 128: 85–122.

    Article  CAS  PubMed  Google Scholar 

  40. Bocci V . Immunomodulators as local hormones: new insights regarding their clinical utilization. J Biol Response Mod 1985; 4: 340–352.

    CAS  PubMed  Google Scholar 

  41. Boccoli G, Masciulli R, Ruggeri EM, Carlini P, Giannella G, Montesoro G et al. Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose interleukin 2 bolus treatment. Cancer Res 1990; 50: 5795–5800.

    CAS  PubMed  Google Scholar 

  42. Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A et al. Tumour necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 1986; 163: 1433–1450.

    Article  CAS  PubMed  Google Scholar 

  43. Fleishmann Jr WR, Koren S, Fleischmann CM . Orally administered interferons exert their white blood cell suppressive effects via a novel mechanism. Proc Soc Exp Biol Med 1992; 201: 200–207.

    Article  Google Scholar 

  44. Pacini A, Maioli M, Bocci V, Pessina GP . Studies on tumor necrosis factor (TNF) III: Plasma disappearance curves after intramuscular, subcutaneous, intraperitoneal, and oral administration of human recombinant TNF. Cancer Drug Deliv 1987; 4: 17–23.

    Article  CAS  PubMed  Google Scholar 

  45. Paulesu L, Corradeschi F, Nicoletti C, Bocci V . Oral administration of human recombinant interferon-alpha in rats. Int J Pharm 1988; 46: 199–202.

    Article  CAS  Google Scholar 

  46. Siafakas CG, Anatolitou F, Fusunyan RD, Walker WA, Sanderson IR . Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatr Res 1999; 45: 652–657.

    Article  CAS  PubMed  Google Scholar 

  47. Calhoun DA, Lunoe M, Du Y, Christensen RD . Granulocyte colony-stimulating factor is present in human milk and its receptor is present in human fetal intestine. Pediatrics 2000; 105: e7.

    Article  CAS  PubMed  Google Scholar 

  48. Calhoun DA, Lunoe M, Du Y, Staba SI, Christensen RD . Concentrations of granulocyte colony-stimulating factor in human milk after in vitro stimulations of digestion. Pediatr Res 1999; 46: 767–771.

    Article  CAS  PubMed  Google Scholar 

  49. Tovoy MG, Meritet JF, Guymarho J, Maury C . Mucosal cytokine therapy: marked antiviral and antitumor activity. J Interferon Cytokine Res 1999; 19: 911–921.

    Article  Google Scholar 

  50. Eid P, Meritet JF, Maury C, Lasfar A, Weill D, Tovey MG . Oromucosal interferon therapy: pharmacokinetics and pharmacodynamics. J Interferon Cytokine Res 1999; 19: 157–169.

    Article  CAS  PubMed  Google Scholar 

  51. Fleischmann Jr WR, Koren S . Systemic effects of orally administered interferons and interleukin-2. J Interferon Cytokine Res 1999; 19: 829–839.

    Article  PubMed  Google Scholar 

  52. Brod S . Effect of oral administration of type 1 interferon on experimental autoimmune encephalomyelitis. In: Reder AT (ed). Interferon Therapy in Multiple Sclerosis. Marcel Dekker: New York, 1997, pp 245–286.

    Google Scholar 

  53. Dhingra K, Duvic M, Hymes S, McLaughlin P, Rothberg J, Gutterman JU . A phase -1 clinical study of low-dose oral interferon alpha. J Immunother 1993; 14: 51–55.

    Article  CAS  Google Scholar 

  54. Witt PL, Goldstein D, Storer BE, Grossberg SE, Flashner M, Colby CB et al. Absence of biological effects of orally administered interferon-beta. J Interferon Res 1992; 12: 411–413.

    Article  CAS  PubMed  Google Scholar 

  55. Zielinska W, Paszkiewicz J, Korczak A, Wlasiuk M, Zoltowska A, Szutowicz A et al. Treatment of six patients with chronic active HCV hepatitis with low dose natural human interferon alpha administered orally. Arch Immunol Ther Exp 1993; 41: 253–257.

    CAS  Google Scholar 

  56. Lecciones JA, Abejar NH, Dimaano EE, Bartolome R, Cinco S, Mariano N et al. A pilot double-blind, randomized, and placebo-controlled study of orally administered IFN-alpha in pediatric patients with measles. J Interferon Cytokine Res 1998; 18: 647–652.

    Article  CAS  PubMed  Google Scholar 

  57. Brandtzaeg P . The secretory immunoglobulin system: regulation and biological significance: focusing on human mammary glands. In: Davis MK, Isaacs CE, Hanson LA, Wright AL (eds). Integrating Population Outcomes, Biological Mechanisms and Research Methods in the Study of Human Milk and Lactation. Plenum: New York, 2002, pp 1–16.

    Google Scholar 

  58. Spencer J, MacDonald TT . Ontogeny of human mucosal immunity. In: MacDonald TT (ed). Ontogeny of the Immune System of the Gut. CRC Press: Boca Raton, FL, 1990, pp 23–50.

    Google Scholar 

  59. Stoll BJ, Lee FK, Hale E, Schwartz D, Holmes R, Ashby R et al. Immunoglobulin secretion by the normal and the infected newborn infant. J Pediatr 1993; 122: 780–786.

    Article  CAS  PubMed  Google Scholar 

  60. Ng PC, Li K, Wong RPO, Chui K, Wong E, Li G et al. Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections. Arch Dis Child Fetal Neonatal Ed 2003; 88: F209–F213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kliegman RM, Walker WA, Yolken RH . Necrotizing enterocolitis: research agenda for a disease of unknown etiology and pathogenesis. Clin Perinatol 1994; 21: 437–455.

    Article  Google Scholar 

  62. Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA . Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 2001; 49: 589–593.

    Article  CAS  PubMed  Google Scholar 

  63. Claud EC, Savidge T, Walker WA . Modulation of human intestinal epithelial cell IL-8 secretion by human milk factors. Pediatr Res 2003; 53: 419–425.

    Article  CAS  PubMed  Google Scholar 

  64. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R . Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118: 229–241.

    Article  CAS  PubMed  Google Scholar 

  65. Dvorak B, Halpern MD, Holubec H, Dvorakova K, Dominguez JA, Williams CS et al. Maternal milk reduces severity of necrotizing enterocolitis and increases intestinal IL-10 in a neonatal rat model. Pediatr Res 2003; 53: 426–433.

    Article  CAS  PubMed  Google Scholar 

  66. Dvorak B, Halpern MD, Holubec H, Williams CS, McWilliam DL, Dominguez JA . Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 2002; 282: G156–G164.

    Article  CAS  PubMed  Google Scholar 

  67. Caplan MS, Lickerman M, Adler L, Dietsch GN, Yu A . The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 1997; 42: 779–783.

    Article  CAS  PubMed  Google Scholar 

  68. Field CJ . The immunological components of human milk and their effect on immune development in infants. J Nutr 2005; 135: 1–4.

    Article  CAS  PubMed  Google Scholar 

  69. Hawkes JS, Bryan DL, Gibson RA . Cytokine production by human milk cells and peripheral mononuclear cells from the same mother. J Clin Immunol 2002; 22: 338–344.

    Article  CAS  PubMed  Google Scholar 

  70. Meki A-RMA, Saleem RTH, Al-Ghazali MH, Sayed AA . Interleukins-6, -8 and -10 and tumor necrosis factor alpha and its soluble receptor I in human milk at different periods of lactation. Nutr Res 2003; 23: 845–855.

    Article  CAS  Google Scholar 

  71. Blum JW, Baumrucker CR . Insulin-like growth factors (IGFs), IGF binding proteins and other endocrine factors in milk: role in the newborn. Adv Exp Med Biol 2008; 606: 397–422.

    Article  CAS  PubMed  Google Scholar 

  72. Elmlinger MW, Hochhaus F, Loui A, Frommer KW, Obladen M, Ranke MB . Insulin-like growth factors and binding proteins in early milk from mothers of preterm and term infants. Horm Res 2007; 68: 124–131.

    CAS  PubMed  Google Scholar 

  73. Kooijman R, Coppens A . Insulin-like growth factor -1 stimulates IL-10 production in human T cells. J Leukoc Biol 2004; 76: 862–867.

    Article  CAS  PubMed  Google Scholar 

  74. Baumrucker CR, Hadsell DL, Blum JW . Effects of dietary insulin-like growth factor 1 on growth and insulin-like growth factor receptors in neonatal calf intestine. J Anim Sci 1994; 72: 428–433.

    Article  CAS  PubMed  Google Scholar 

  75. Georgiev IP, Georgieva TM, Pfaffl M, Hammon HM, Blum JW . Insulin-like growth factor and insulin receptors in intestinal mucosa of neonatal calves. J Endocrinol 2003; 176: 121–132.

    Article  CAS  PubMed  Google Scholar 

  76. Bottcher MF, Jenmalm MC, Bjorksten B . Cytokine, chemokine and secretory IgA levels in human milk in relation to atopic disease and IgA production in infants. Pediatr Allergy Immunol 2003; 14: 35–41.

    Article  PubMed  Google Scholar 

  77. Ogawa J, Sasahara A, Yoshida T, Sira MM, Futatani T, Kanegane H et al. Role of transforming growth factor-beta in breast milk for initiation of IgA production in newborn infants. Early Hum Dev 2004; 77: 67–75.

    Article  CAS  PubMed  Google Scholar 

  78. Godding V, Sibille Y, Massion PP, Delos M, Sibille C, Thurion P et al. Secretory component production by human bronchial epithelial cells is upregulated by interferon gamma. Eur Respir J 1998; 11: 1043–1052.

    Article  CAS  PubMed  Google Scholar 

  79. Calhoun DA, Maheshwari A, Christensen RD . Recombinant granulocyte colony-stimulating factors administered enterally to neonates is not absorbed. Pediatrics 2003; 112: 421–423.

    Article  PubMed  Google Scholar 

  80. Gersting JA, Kotto-kome CA, Du Y, Christensen RD, Calhoun DA . Bioavailablity of granulocyte colony-stimulating factors administered enterally to suckling mice. Pharmacol Res 2003; 48: 643–647.

    Article  CAS  PubMed  Google Scholar 

  81. Kulkarni AB, Karlsson S . Transforming growth factor beta knockout mice: a mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol 1993; 143: 3–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ellis LA, Mastro AM, Picciano MF . Do milk-borne cytokines and hormones influence neonatal immune function? J Nutr 1997; 127: 985S–988S.

    Article  CAS  PubMed  Google Scholar 

  83. Hutchins TW, Henry JF, Yip TT, Hachey DL, Schanler RJ, Motil KJ et al. Origin of intact lactoferrin and its DNA-binding fragments in the urine of human milk-fed preterm infants. Evaluation by stable isotope enrichment. Pediatr Res 1991; 29: 243–250.

    Article  Google Scholar 

  84. Goldblum RM, Schanler RJ, Garza C, Goldman AS . Human milk feeding enhances the urinary excretion of immunological factors in low birth weight infants. Pediatr Res 1989; 25: 184–188.

    Article  CAS  PubMed  Google Scholar 

  85. Prentice A . Breastfeeding increased concentrations of IgA in infant's urine. Arch Dis Child 1987; 62: 792–795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schanler RJ, Goldblum RM, Garza C, Goldman AS . Enhanced fecal excretion of selected immune factors in very low birth weight infants fed fortified human milk. Pediatr Res 1986; 20: 711–715.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Velio Bocci (Professor of General Physiology, University of Sienna, Italy) for his invaluable assistance in preparing the article. Supported by NIH F31NR007584 and NR010009, and Medela Inc. (McHenry, IL, USA).

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Rodriguez, N., Meier, P., Groer, M. et al. Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives. J Perinatol 29, 1–7 (2009). https://doi.org/10.1038/jp.2008.130

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