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Lyophilized (freeze-dried) human milk for preterm infants: a scoping review

Journal of Perinatology (2024)Cite this article

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Abstract

Freeze-drying (FD), or lyophilization, is commonly used to preserve foods. FD offers potential to create a human milk-derived human milk fortifier, and an alternative to freeze-storing human milk. However, processing human milk is known to affect its components. This scoping review explores the effect of FD on the; macronutrient, micronutrient, vitamin, bioactive components, microbes and anti-microbial factors in human milk, and studies where lyophilized human milk has been given to newborn infants. 48 articles were identified after full text review. FD human milk reduces the fat globule size and as well as the quantity of enzymes, vitamin C and immunoglobulin. Common serum electrolyte disturbances have been reported when preterm infants’ are fed FD human milk however it appears a promising method to avoid exposure of preterm infants’ to cows’ milk. Due to limited data, further studies exploring the safety and efficacy of FD human milk in preterm infants are needed.

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References

  1. Varshney D, Singh M. Lyophilized biologics and vaccines—modality-based approches. Varshney D, Singh M, editors: Springer; 2015. 401 p.

  2. Adams GD, Cook I, Ward KR. The principles of freeze-drying. Cryopreservation and freeze-drying protocols. 2015:1257:121–43.

  3. Johnson S, Evans TA, Draper ES, Field DJ, Manktelow BN, Marlow N, et al. Neurodevelopmental outcomes following late and moderate prematurity: a population-based cohort study. Arch Dis Child Fetal Neonatal Ed. 2015;100:F301–8.

    Article  PubMed  Google Scholar 

  4. Eidelman AI. Breastfeeding and the use of human milk: an analysis of the American Academy of Pediatrics 2012 Breastfeeding Policy Statement. Breastfeed Med. 2012;7:323–4.

    Article  PubMed  Google Scholar 

  5. Spiegler J, Preuss M, Gebauer C, Bendiks M, Herting E, Gopel W, et al. Does breastmilk influence the development of bronchopulmonary dysplasia? J Pediatr. 2016;169:76–80 e4.

    Article  PubMed  Google Scholar 

  6. Gates A, Marin T, Leo G, Stansfield BK. Review of preterm human-milk nutrient composition. Nutr Clin Pract. 2021;36:1163–72.

    Article  PubMed  Google Scholar 

  7. Barresi AA, Pisano R, Fissore D, Rasetto V, Velardi SA, Vallan A, et al. Monitoring of the primary drying of a lyophilization process in vials. Chem Eng Process: Process Intensif. 2009;48:408–23.

    Article  CAS  Google Scholar 

  8. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol. 2005;8:19–32.

    Article  Google Scholar 

  9. Cavazos-Garduño A, Serrano-Niño JC, Solís-Pacheco JR, Gutierrez-Padilla JA, González-Reynoso O, Garcia HS, et al. Effect of pasteurization, freeze-drying and spray drying on the fat globule and lipid profile of human milk. J Food Nutr Res. 2016;4:296–302.

    Google Scholar 

  10. Manin L, Rydlewski A, Galuch M, Pizzo J, Zappielo C, Senes C, et al. Evaluation of the lipid quality of lyophilized pasteurized human milk for six months by GC-FID and ESI-MS. J Braz Chem Soc. 2019;30:1579–86.

  11. Bomfim VS, Jordao AA, Alves LG, Martinez FE, Camelo JS. Human milk enriched with human milk lyophilisate for feeding very low birth weight preterm infants: a preclinical experimental study focusing on fatty acid profile. Plos One. 2018;13:e0202794.

  12. Oliveira MM, Aragon DC, Bomfim VS, Trevilato TMB, Alves LG, Heck AR, et al. Development of a human milk concentrate with human milk lyophilizate for feeding very low birth weight preterm infants: A preclinical experimental study. PLoS One. 2019;14:e0210999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lucas A, Lucas PJ, Chavin SI, Lyster RLJ, Baum JD. A human milk formula. Early Hum Dev. 1980;4:15–21.

    Article  CAS  PubMed  Google Scholar 

  14. Neia V, Santos P, Tavares C, Paula M, Costa S, Zacarias J, et al. Lipid Profile of Human Milk in Different Lactation Stages Submitted to Pasteurization, Lyophilization and Spray-Drying Processes. J Braz Chem Soc. 2023;34:54–62.

  15. Friend BA, Shahani KM, Long CA, Agel EN. Evaluation of freeze-drying, pasteurization, high-temperature heating and storage on selected enzymes, B-vitamins and lipids of mature human milk. J Food Prot. 1983;46:330–4.

    Article  CAS  PubMed  Google Scholar 

  16. Blackshaw K, Wu J, Proschogo N, Davies J, Oldfield D, Schindeler A, et al. The effect of thermal pasteurization, freeze-drying, and gamma irradiation on donor human milk. Food Chem. 2022;373:131402.

    Article  CAS  PubMed  Google Scholar 

  17. Dill CW, Chen CT, Alford ES, Edwards RL, Richter RL, Garza C. Lipolytic activity during storage of human milk: accumulation of free fatty acids. J Food Prot. 1984;47:690–3.

    Article  CAS  PubMed  Google Scholar 

  18. Cortez MV, Soria EA. The effect of freeze-drying on the nutrient, polyphenol, and oxidant levels of breast milk. Breastfeed Med. 2016;11:551–4.

    Article  PubMed  Google Scholar 

  19. Grance TR, de Oliveira Serafin O, Thomaz DM, Palhares DB. Homologous fortifier for very low birth weight preterm infant feed. Rev Paul Pediatr. 2015;33:28–33.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dhar J, Davidson AGF, Martinez FE, Barr S, Desai ID, Nakai S. Ultrasonication, lyophilization, freezing and storage effects on fat loss during mechanical infusion of expressed human milk. J Food Sci. 1995;60:375–7.

    Article  CAS  Google Scholar 

  21. Hahn WH, Bae SP, Song S, Park S, Lee J, Seo JB, et al. The freeze-drying does not influence the proteomic profiles of human milk. J Matern Fetal Neonatal Med. 2020;33:2069–74.

    Article  CAS  PubMed  Google Scholar 

  22. Thomaz DM, Serafim PO, Palhares DB, Melnikov P, Venhofen L, Vargas MO. Comparison between homologous human milk supplements and a commercial supplement for very low birth weight infants. J Pediatr (Rio J). 2012;88:119–24.

    PubMed  Google Scholar 

  23. Thomaz DM, Serafin PO, Palhares DB, Tavares LV, Grance TR. Serum phenylalanine in preterm newborns fed different diets of human milk. J Pediatr (Rio J). 2014;90:518–22.

    Article  PubMed  Google Scholar 

  24. Hahn WH, Kim J, Song S, Park S, Kang NM. The human milk oligosaccharides are not affected by pasteurization and freeze-drying. J Matern Fetal Neonatal Med. 2019;32:985–91.

  25. Fusch S, Fusch G, Yousuf EI, Rochow M, So HY, Fusch C, et al. Individualized target fortification of breast milk: optimizing macronutrient content using different fortifiers and approaches. Front Nutr. 2021;8:652641.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Oliveira MM, Trevilato TMB, Segura-Munoz SI, Aragon DC, Alves LG, Nadal M, et al. Essential and toxic elements in human milk concentrate with human milk lyophilizate: a preclinical study. Environ Res. 2020;188:109733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barnett NW, Chen LS, Kirkbright GF. Determination of trace concentrations of lead and nickel in freeze-dried human milk by atomic absorption spectrometry and inductively-coupled plasma emission spectrometry. Anal Chim Acta. 1983;149:115–21.

    Article  CAS  Google Scholar 

  28. Martysiak-Żurowska D, Puta M, Rodzik A, Malinowska-Pańczyk E. The effect of lyophilization on selected biologically active components (vitamin C, catalase, lysozyme), total antioxidant capacity and lipid oxidation in human milk. Zywnosc Nauka Technologia Jakosc/Food Sci Technol Qual. 2017;112:121–8.

    Article  Google Scholar 

  29. Lozano B, Castellote AI, Montes R, Lopez-Sabater MC. Vitamins, fatty acids, and antioxidant capacity stability during storage of freeze-dried human milk. Int J Food Sci Nutr. 2014;65:703–7.

    Article  CAS  PubMed  Google Scholar 

  30. Sproat T, Payne RP, Embleton ND, Berrington J, Hambleton S. T cells in preterm infants and the influence of milk diet. Front Immunol. 2020;11:1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Carr LE, Virmani MD, Rosa F, Munblit D, Matazel KS, Elolimy AA, et al. Role of human milk bioactives on infants’ gut and immune health. Front Immunol. 2021;12:604080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jarzynka S, Strom K, Barbarska O, Pawlikowska E, Minkiewicz-Zochniak A, Rosiak E, et al. Combination of high-pressure processing and freeze-drying as the most effective techniques in maintaining biological values and microbiological safety of donor milk. Int J Environ Res Public Health. 2021;18:2147.

  33. Dill CW, Chen CT, Alford ES, Edwards RL, Richter RL, Garza C. Lipolytic activity during storage of human milk: stability of the bile salt-stimulated lipase. J Food Prot. 1983;46:994–6.

    Article  CAS  PubMed  Google Scholar 

  34. O’Connor CJ, Longbottom JR, Walde P. Inactivation of bile-salt stimulated human milk esterase: effect of storage and heat. J Pediatr Gastroenterol Nutr. 1986;5:630–7.

    Article  PubMed  Google Scholar 

  35. Castro-Albarrán J, Aguilar-Uscanga BR, Calon F, St-Amour I, Solís-Pacheco J, Saucier L, et al. Spray and freeze drying of human milk on the retention of immunoglobulins (IgA, IgG, IgM). Dry Technol. 2016;34:1801–9.

    Article  Google Scholar 

  36. Carbonare SB, Palmeira P, Silva MLM, Carneiro-Sampaio M. Effect of microwave radiation, pasteurization and lyophilization on the ability of human milk to inhibit Escherichia coli adherence to HEp-2 cells. J DIARRHOEAL Dis Res. 1996;14:90–4.

    CAS  PubMed  Google Scholar 

  37. Hahn WH, Bae SP, Lee H, Park J, Park S, Kang NM. The impact of freeze-drying on the glycoproteomic profiles of human milk. Anal Sci Technol. 2020;33:177–85.

    CAS  Google Scholar 

  38. Martysiak-Żurowska D, Rozek P, Puta M. The effect of freeze-drying and storage on lysosyme activity, lactoferrin content, superoxide dismutase activity, total antioxidant capacity and fatty acid profile of freeze-dried human milk. Dry Technol. 2022;40:615–25.

  39. Gila-Diaz A, Arribas SM, Algara A, Martin-Cabrejas MA, Lopez de Pablo AL, Saenz de Pipaon M, et al. A review of bioactive factors in human breastmilk: a focus on prematurity. Nutrients. 2019;11:1307.

  40. Neia VJC, Zacarias JMV, Alencar JBD, Santos PDSD, Tavares CBG, Paula MG, et al. Effect of lyophilization and spray-drying on cytokine levels and antioxidant capacity in human milk. Dry Technol. 2021;40:3149–59.

    Article  Google Scholar 

  41. Agel EN, Friend BA, Long CA, Shahani KM. Bacterial content of raw and processed human milk (1). J Food Prot. 1982;45:533–6.

    Article  CAS  PubMed  Google Scholar 

  42. Salcedo J, Gormaz M, Lopez-Mendoza MC, Nogarotto E, Silvestre D. Human milk bactericidal properties: effect of lyophilization and relation to maternal factors and milk components. J Pediatr Gastroenterol Nutr. 2015;60:527–32.

    Article  CAS  PubMed  Google Scholar 

  43. Blackshaw K, Wu J, Valtchev P, Lau E, Banati RB, Dehghani F, et al. The Effects of Thermal Pasteurisation, Freeze-Drying, and Gamma-Irradiation on the Antibacterial Properties of Donor Human Milk. Foods. 2021;10:2077.

  44. Boehm G, Senger H, Muller D, Beyreiss K, Raiha NC. Metabolic differences between AGA- and SGA-infants of very low birthweight. II. Relationship to protein intake. Acta Paediatr Scand. 1988;77:642–6.

    Article  CAS  PubMed  Google Scholar 

  45. Boehm G, Raiha NC. Postmenstrual age correlates to indices of protein metabolism in very low birth weight infants. J Pediatr Gastroenterol Nutr. 1993;16:306–10.

    CAS  PubMed  Google Scholar 

  46. Bechensteen AG, Haga P, Halvorsen S, Liestol K, Lindemann R, Whitelaw A, et al. Effect of low and moderate doses of recombinant human erythropoietin on the haematological response in premature infants on a high protein and iron intake. Eur J Pediatr. 1997;156:56–61.

    Article  CAS  PubMed  Google Scholar 

  47. Nogueira-Pileggi V, Achcar MC, Carmona F, Carnevale da Silva A, Aragon DC, da Veiga Ued F, et al. LioNeo project: a randomised double-blind clinical trial for nutrition of very-low-birth-weight infants. Br J Nutr. 2022;128:2490–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hagelberg S, Lindblad BS, Lundsjo A, Carlsson B, Fonden R, Fujita H, et al. The protein tolerance of very low birth weight infants fed human milk protein enriched mother’s milk. Acta Paediatr Scand. 1982;71:597–601.

    Article  CAS  PubMed  Google Scholar 

  49. Schanler RJ, Garza C. Plasma amino acid differences in very low birth weight infants fed either human milk or whey-dominant cow milk formula. Pediatr Res. 1987;21:301–5.

    Article  CAS  PubMed  Google Scholar 

  50. Schanler RJ, Garza C, O’Brian Smith E. Fortified mothers’ milk for very low birth weight infants: Results of macromineral balance studies. Fetal Neonatal Med. 1985;107:767–74.

    CAS  Google Scholar 

  51. Boehm G, Melichar V, Lorenz I, Muller D, Beyreiss K. Nutrition of newborns small for gestational age with human milk lyophilisate enriched human milk during the first week of life. Acta Paediatr Hungarica. 1985;26:261–9.

    CAS  Google Scholar 

  52. Voyer M, Senterre J, Rigo J, Charlas J, Satge P. Human milk lacto-engineering. Growth nitrogen metabolism, and energy balance in preterm infants. Acta Paediatr Scand. 1984;73:302–6.

    Article  CAS  PubMed  Google Scholar 

  53. Boehm G, Senger H, Muller D, Beyreiss K, Raiha NC. Metabolic differences between AGA-and SGA-infants of very low birthweight. III. Influence of postnatal age. Acta Paediatr Scand. 1989;78:677–81.

    Article  CAS  PubMed  Google Scholar 

  54. Boehm G, Gedlu E, Muller DM, Beyreiss K, Raiha NCR. Relationship between urea and ammonium excretion in the urine of very-low-birth-weight infants appropriate for gestational age. Biomed Biochim Acta. 1990;49:69–74.

    CAS  PubMed  Google Scholar 

  55. Boehm G, Geolu E, Muller MD, Beyreiss K, Raiha NCR. Postnatal development of urea and ammonia excretion in urine of very low birthweight infants small for gestational age. Acta Paediatr Hungarica. 1991;31:31–45.

    CAS  Google Scholar 

  56. Boehm G, Muller DM, Senger H, Borte M, Moro G. Nitrogen and fat balances in very low birth weight infants fed human milk fortified with human milk or bovine milk protein. Eur J Pediatr. 1993;152:236–9.

    Article  CAS  PubMed  Google Scholar 

  57. Boehm G, Müller MD, Senger H, Melichar V. Influence of postnatal age on nitrogen metabolism in very low birth weight infants appropriate for gestational age. Acta Paediatr Hungarica. 1990;30:423–33.

    CAS  Google Scholar 

  58. Boehm G, Melichar V, Müller DM, Mikova M. The application of redissolved human milk lyophilisate for nutrition of very low birth weight infants. Acta Paediatr Hungarica. 1987;28:267.

    CAS  Google Scholar 

  59. Book LS, Herbst JJ, Atherton SO, Jung AL. Necrotizing enterocolitis in fed an elemental formula low-birth-weight infants. J Pediatr. 1975;87:602–5.

    Article  CAS  PubMed  Google Scholar 

  60. Barness LA, Mauer AM, Holliday MA, Anderson AS, Dallman PR, Forbes GB, et al. Commentary on breast-feeding and infant formulas, including proposed standards for formulas. Pediatrics. 1976;57:278–85.

    Article  Google Scholar 

  61. Embleton ND, Moltu SJ, Lapillonne A, Van Den Akker CH, Carnielli V, Fusch C, et al. Enteral nutrition in preterm infants (2022): a position paper from the ESPGHAN committee on nutrition and invited experts. J Pediatr Gastroenterol Nutr. 2023;76:248–68.

  62. Kleinman RE, Greer FR, Nutrition AAoPCo. Pediatric nutrition: American Academy of Pediatrics Elk Grove Village, IL; 2014.

  63. Kumbhare SV, Jones WD, Fast S, Bonner C, Jong G, Van Domselaar G, et al. Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome. Cell Rep Med. 2022;3:100712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mizuno K, Shimizu T, Ida S, Ito S, Inokuchi M, Ohura T, et al. Policy statement of enteral nutrition for preterm and very low birthweight infants. Pediatr Int. 2020;62:124–7.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Castro Albarran J, Navarro Hernandez RE, Solis Pacheco JR, Salazar Quinones IC, Macias Lopez GG, Barrera de Leon JC. et al.[Impact of pasteurization/freeze-dryingon available immunoglobulin content of the mature human milk. Use in human milk banking of hospitals].Nutr Hosp.2017;34:899–906.

    CAS  PubMed  Google Scholar 

  66. 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;20:711–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are very grateful to Caitlin McClurg (University of Calgary Librarian) for performing the initial literature search.

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Authors and Affiliations

  1. Neonatal Gastroenterology and Nutrition Program, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Thomas D. R. Sproat, Anirban Ghosh & Belal N. Alshaikh

  2. Neonatal Unit, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

    Thomas D. R. Sproat

  3. Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada

    Belal N. Alshaikh

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BA & TDRS conceived and designed the work. TDRS/AG/BA reviewed the abstracts and full texts to identify suitable articles. TDRS charted and collated the data and drafted the initial manuscript. AG/BA reviewed and appraised the manuscript. All authors approved the final version.

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Correspondence to Thomas D. R. Sproat.

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Sproat, T.D.R., Ghosh, A. & Alshaikh, B.N. Lyophilized (freeze-dried) human milk for preterm infants: a scoping review. J Perinatol (2024). https://doi.org/10.1038/s41372-023-01861-8

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