Review Article| Volume 49, ISSUE 2, P447-460, June 2022

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Human Milk Fortification: A Practical Analysis of Current Evidence

Published:April 21, 2022DOI:


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        • Greer F.R.
        Feeding the premature infant in the 20th century.
        J Nutr. 2001; 131: 426s-430s
        • American Academy of Pediatrics Section on Breastfeeding
        Breastfeeding and the use of human milk.
        Pediatrics. 2012; 129: e827-e841
        • American Academy of Pediatrics, Committee on Nutrition
        Nutritional needs of low-birth-weight infants.
        Pediatrics. 1977; 60: 519-530
        • Ehrenkranz R.A.
        • Dusick A.M.
        • Vohr B.R.
        • et al.
        Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants.
        Pediatrics. 2006; 117: 1253-1261
        • Franz A.R.
        • Pohlandt F.
        • Bode H.
        • et al.
        Intrauterine, early neonatal, and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support.
        Pediatrics. 2009; 123: e101-e109
        • Ramel S.E.
        • Gray H.L.
        • Christiansen E.
        • et al.
        Greater early gains in fat-free mass, but not fat mass, are associated with improved neurodevelopment at 1 year corrected age for prematurity in very low birth weight preterm infants.
        J Pediatr. 2016; 173: 108-115
        • Pfister K.M.
        • Zhang L.
        • Miller N.C.
        • et al.
        Early body composition changes are associated with neurodevelopmental and metabolic outcomes at 4 years of age in very preterm infants.
        Pediatr Res. 2018; 84: 713-718
        • Meredith-Dennis L.
        • Xu G.
        • Goonatilleke E.
        • et al.
        Composition and variation of macronutrients, immune proteins, and human milk oligosaccharides in human milk from nonprofit and commercial milk banks.
        J Hum Lact. 2018; 34: 120-129
        • Gidrewicz D.A.
        • Fenton T.R.
        A systematic review and meta-analysis of the nutrient content of preterm and term breast milk.
        BMC Pediatr. 2014; 14: 216
        • Schanler R.J.
        Outcomes of human milk-fed premature infants.
        Semin Perinatol. 2011; 35: 29-33
        • American academy of pediatrics committe on nutrition
        • Section on breastfeeding
        • Committee on fetus and newborn
        Donor human milk for the high-risk infant: preparation, safety, and usage options in the United States.
        Pediatrics. 2017; 139: e20163440
        • Arslanoglu S.
        • Corpeleijn W.
        • Moro G.
        • et al.
        Donor human milk for preterm infants: current evidence and research directions.
        J Pediatr Gastroenterol Nutr. 2013; 57: 535-542
        • Quigley M.
        • Embleton N.D.
        • McGuire W.
        Formula versus donor breast milk for feeding preterm or low birth weight infants.
        Cochrane Database Syst Rev. 2019; 7: Cd002971
        • O'Connor D.L.
        • Gibbins S.
        • Kiss A.
        • et al.
        Effect of supplemental donor human milk compared with preterm formula on neurodevelopment of very low-birth-weight infants at 18 months: a randomized clinical trial.
        Jama. 2016; 316: 1897-1905
        • Lemons J.A.
        • Moye L.
        • Hall D.
        • et al.
        Differences in the composition of preterm and term human milk during early lactation.
        Pediatr Res. 1982; 16: 113-117
        • Atkinson S.A.
        • Anderson G.H.
        • Bryan M.H.
        Human milk: comparison of the nitrogen composition in milk from mothers of premature and full-term infants.
        Am J Clin Nutr. 1980; 33: 811-815
        • Radmacher P.G.
        • Adamkin D.H.
        Fortification of human milk for preterm infants.
        Semin Fetal neonatal Med. 2017; 22: 30-35
        • Meier P.
        • Patel A.
        • Esquerra-Zwiers A.
        Donor human milk update: evidence, mechanisms, and priorities for research and practice.
        J Pediatr. 2017; 180: 15-21
        • Colaizy T.T.
        Effects of milk banking procedures on nutritional and bioactive components of donor human milk.
        Semin Perinatol. 2021; 45: 151382
        • Perrin M.T.
        • Belfort M.B.
        • Hagadorn J.I.
        • et al.
        The nutritional composition and energy content of donor human milk: a systematic review.
        Adv Nutr (Bethesda, Md). 2020; 11: 960-970
        • Friend L.L.
        • Perrin M.T.
        Fat and protein variability in donor human milk and associations with milk banking processes.
        Breastfeed Med. 2020; 15: 370-376
        • Young B.E.
        • Murphy K.
        • Borman L.L.
        • et al.
        Milk bank pooling practices impact concentrations and variability of bioactive components of donor human milk.
        Front Nutr. 2020; 7: 579115
        • Brown J.V.
        • Embleton N.D.
        • Harding J.E.
        • et al.
        Multi-nutrient fortification of human milk for preterm infants.
        Cochrane Database Syst Rev. 2016; 5: Cd000343
        • Shah P.S.
        • Wong K.Y.
        • Merko S.
        • et al.
        Postnatal growth failure in preterm infants: ascertainment and relation to long-term outcome.
        J Perinatal Med. 2006; 34: 484-489
        • Belfort M.B.
        • Rifas-Shiman S.L.
        • Sullivan T.
        • et al.
        Infant growth before and after term: effects on neurodevelopment in preterm infants.
        Pediatrics. 2011; 128: e899-e906
        • Zozaya C.
        • Díaz C.
        • Saenz de Pipaón M.
        How should we define postnatal growth restriction in preterm infants?.
        Neonatology. 2018; 114: 177-180
        • Amissah E.A.
        • Brown J.
        • Harding J.E.
        Fat supplementation of human milk for promoting growth in preterm infants.
        Cochrane Database Syst Rev. 2020; 8: Cd000341
        • Amissah E.A.
        • Brown J.
        • Harding J.E.
        Carbohydrate supplementation of human milk to promote growth in preterm infants.
        Cochrane Database Syst Rev. 2020; 9: Cd000280
        • Amissah E.A.
        • Brown J.
        • Harding J.E.
        Protein supplementation of human milk for promoting growth in preterm infants.
        Cochrane Database Syst Rev. 2020; 9: Cd000433
        • Arslanoglu S.
        • Boquien C.Y.
        • King C.
        • et al.
        Fortification of human milk for preterm infants: update and recommendations of the european milk bank association (EMBA) working group on human milk fortification.
        Front Pediatr. 2019; 7: 76
        • Fabrizio V.
        • Trzaski J.M.
        • Brownell E.A.
        • et al.
        Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk.
        Cochrane Database Syst Rev. 2020; 11: Cd013465
        • Belfort M.B.
        • Woodward L.J.
        • Cherkerzian S.
        • et al.
        Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial.
        BMC Pediatr. 2021; 21: 167
        • de Halleux V.
        • Pieltain C.
        • Senterre T.
        • et al.
        Growth benefits of own mother's milk in preterm infants fed daily individualized fortified human milk.
        Nutrients. 2019; 11: 772
        • Rochow N.
        • Fusch G.
        • Zapanta B.
        • et al.
        Target fortification of breast milk: how often should milk analysis be done?.
        Nutrients. 2015; 7: 2297-2310
        • Fusch G.
        • Kwan C.
        • Kotrri G.
        • et al.
        Bed Side" human milk analysis in the neonatal intensive care unit: a systematic review.
        Clin Perinatol. 2017; 44: 209-267
        • Kwan C.
        • Fusch G.
        • Bahonjic A.
        • et al.
        Infrared analyzers for breast milk analysis: fat levels can influence the accuracy of protein measurements.
        Clin Chem Lab Med. 2017; 55: 1931-1935
        • Parat S.
        • Groh-Wargo S.
        • Merlino S.
        • et al.
        Validation of mid-infrared spectroscopy for macronutrient analysis of human milk.
        J Perinatol. 2017; 37: 822-826
        • Minarski M.
        • Maas C.
        • Engel C.
        • et al.
        Calculating protein content of expressed breast milk to optimize protein supplementation in very low birth weight infants with minimal effort-a secondary analysis.
        Nutrients. 2020; 12: 1231
        • Alyahya W.
        • Simpson J.
        • Garcia A.L.
        • et al.
        Early versus delayed fortification of human milk in preterm infants: a systematic review.
        Neonatology. 2020; 117: 24-32
        • Thanigainathan S.
        • Abiramalatha T.
        Early fortification of human milk versus late fortification to promote growth in preterm infants.
        Cochrane Database Syst Rev. 2020; 7: Cd013392
        • Basu S.
        • Upadhyay J.
        • Singh P.
        • et al.
        Early versus late fortification of breast milk in preterm infants: a systematic review and meta-analysis.
        Eur J Pediatr. 2020; 179: 1057-1068
        • Liotto N.
        • Amato O.
        • Piemontese P.
        • et al.
        Protein intakes during weaning from parenteral nutrition drive growth gain and body composition in very low birth weight preterm infants.
        Nutrients. 2020; 12: 1298
        • Bell K.A.
        • Matthews L.G.
        • Cherkerzian S.
        • et al.
        Associations of growth and body composition with brain size in preterm infants.
        J Pediatr. 2019; 214 (e22): 20-26
        • Ramel S.E.
        • Haapala J.
        • Super J.
        • et al.
        Nutrition, illness and body composition in very low birth weight preterm infants: implications for nutritional management and neurocognitive outcomes.
        Nutrients. 2020; 12: 145
        • Falciglia G.H.
        • Murthy K.
        • Holl J.L.
        • et al.
        Energy and protein intake during the transition from parenteral to enteral nutrition in infants of very low birth weight.
        J Pediatr. 2018; 202 (e31): 38-43
        • Brennan A.M.
        • Kiely M.E.
        • Fenton S.
        • et al.
        Standardized parenteral nutrition for the transition phase in preterm infants: a bag that fits.
        Nutrients. 2018; 10: 170
        • Miller M.
        • Vaidya R.
        • Rastogi D.
        • et al.
        From parenteral to enteral nutrition: a nutrition-based approach for evaluating postnatal growth failure in preterm infants.
        JPEN J Parenter enteral Nutr. 2014; 38: 489-497
        • Bell E.F.
        • Acarregui M.J.
        Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants.
        Cochrane Database Syst Rev. 2014; 2014: Cd000503
        • Abbas S.
        • Keir A.K.
        In preterm infants, does fluid restriction, as opposed to liberal fluid prescription, reduce the risk of important morbidities and mortality?.
        J paediatrics Child Health. 2019; 55: 860-866
        • Abiramalatha T.
        • Thomas N.
        • Thanigainathan S.
        High versus standard volume enteral feeds to promote growth in preterm or low birth weight infants.
        Cochrane Database Syst Rev. 2021; 3: Cd012413
        • Travers C.P.
        • Wang T.
        • Salas A.A.
        • et al.
        Higher- or usual-volume feedings in infants born very preterm: a randomized clinical trial.
        J Pediatr. 2020; 224 (e61): 66-71
        • Salas A.A.
        • Travers C.P.
        • Jerome M.L.
        • et al.
        Percent body fat content measured by plethysmography in infants randomized to high- or usual-volume feeding after very preterm birth.
        J Pediatr. 2021; 230 (e253): 251-254
        • Sullivan S.
        • Schanler R.J.
        • Kim J.H.
        • et al.
        An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products.
        J Pediatr. 2010; 156: 562-567 e561
        • Premkumar M.H.
        • Pammi M.
        • Suresh G.
        Human milk-derived fortifier versus bovine milk-derived fortifier for prevention of mortality and morbidity in preterm neonates.
        Cochrane Database Syst Rev. 2019; 2019
        • O'Connor D.L.
        • Kiss A.
        • Tomlinson C.
        • et al.
        Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial.
        Am J Clin Nutr. 2018; 108: 108-116
        • Lucas A.
        • Boscardin J.
        • Abrams S.A.
        Preterm infants fed cow's milk-derived fortifier had adverse outcomes despite a base diet of only mother's own milk.
        Breastfeed Med. 2020; 15: 297-303
        • Cristofalo E.A.
        • Schanler R.J.
        • Blanco C.L.
        • et al.
        Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants.
        J Pediatr. 2013; 163: 1592-1595
        • Centers for Disease Control and Prevention
        Enterobacter sakazakii infections associated with the use of powdered infant formula--Tennessee, 2001.
        MMWR Morbidity mortality weekly Rep. 2002; 51: 297-300
        • Jason J.
        Prevention of invasive Cronobacter infections in young infants fed powdered infant formulas.
        Pediatrics. 2012; 130: e1076-e1084
        • Chatterton D.E.
        • Nguyen D.N.
        • Bering S.B.
        • et al.
        Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns.
        Int J Biochem Cell Biol. 2013; 45: 1730-1747
        • Bæk O.
        • Brunse A.
        • Nguyen D.N.
        • et al.
        Diet modulates the high sensitivity to systemic infection in newborn preterm pigs.
        Front Immunol. 2020; 11: 1019
        • Bridges K.M.
        • Newkirk M.
        • Byham-Gray L.
        • et al.
        Comparative effectiveness of liquid human milk fortifiers: a systematic review and meta-analysis.
        Nutr Clin Pract. 2021; 36: 1144-1162
        • Schinkel E.R.
        • Nelson E.R.
        • Young B.E.
        • et al.
        Concentrating human milk: an innovative point-of-care device designed to increase human milk feeding options for preterm infants.
        J Perinatol. 2021; 41: 582-589
        • Bertino E.
        • Cavallarin L.
        • Cresi F.
        • et al.
        A novel donkey milk-derived human milk fortifier in feeding preterm infants: a randomized controlled trial.
        J Pediatr Gastroenterol Nutr. 2019; 68: 116-123
        • Cresi F.
        • Maggiora E.
        • Pirra A.
        • et al.
        Effects on gastroesophageal reflux of donkey milk-derived human milk fortifier versus standard fortifier in preterm newborns: additional data from the fortilat study.
        Nutrients. 2020; 12: 2142
        • Peila C.
        • Spada E.
        • Bertino E.
        • et al.
        The "Fortilat" randomized clinical trial follow-up: auxological outcome at 18 months of age.
        Nutrients. 2020; 12: 3730
        • Peila C.
        • Spada E.
        • Deantoni S.
        • et al.
        The "Fortilat" randomized clinical trial follow-up: neurodevelopmental outcome at 18 months of Age.
        Nutrients. 2020; 12: 3807
        • Juhl S.M.
        • Ye X.
        • Zhou P.
        • et al.
        Bovine colostrum for preterm infants in the first days of life: a randomized controlled pilot trial.
        J Pediatr Gastroenterol Nutr. 2018; 66: 471-478
        • Jiang P.P.
        • Muk T.
        • Krych L.
        • et al.
        Gut colonization in preterm infants supplemented with bovine colostrum in the first week of life: an explorative pilot study.
        JPEN J Parenter enteral Nutr. 2021; 46: 592-599
      1. Parker M. Human Milk feeding and fortification of human milk for premature infants. In: UptoDate, Post TW (ed), UpToDate, Waltham, MA. (Accessed on July 7th, 2021.)

        • American Academy of Pediatrics
        Current recommendations of advisable nutrient intakes for fully enterally fed VLBW infants.
        in: Kleinman R.E. Greer F.R. Pediatric nutrition. 8th edition. 2019
        • Koletzo B.
        • Poindexter B.B.
        • Uauy R.
        Nutrition in the preterm infant: scientific basis and practical guidelines.
        Digital Educational Publishing Inc, Cinncinati, OH2005
      2. Mead Johnson Nutrition. Enfamil® human milk fortifier powder.
        (Available at:) (Accessed June 15, 2021)
      3. Abbott. Similac® Human milk fortifier powder.
        (Available at:) (Accessed November 22, 2020)
      4. Mead Johnson Nutrition. Enfamil® liquid human milk fortifier standard protein.
        (Available at:) (Accessed June 15, 2021)
      5. Mead Johnson Nutrition. Enfamil® liquid human milk fortifier high protein.
        (Available at:) (Accessed June 15, 2021)
      6. Abbott. Similac® Human milk fortifier concentrated liquid.
        (Available at:) (Accessed June 15, 2021)
      7. Abbott. Similac® Human milk fortifier hydrolyzed protein concentrated liquid.
        (Available at:) (Accessed June 15, 2021)
      8. Prolacta® Bioscience. Preterm nutrition products.
        (Available at:) (Accessed June 15, 2021)
        • Moya F.
        • Sisk P.M.
        • Walsh K.R.
        • et al.
        A new liquid human milk fortifier and linear growth in preterm infants.
        Pediatrics. 2012; 130: e928-e935
        • Tillman S.
        • Brandon D.H.
        • Silva S.G.
        Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age.
        J Perinatol : official J Calif Perinatal Assoc. 2012; 32: 525-531
        • Kanmaz H.G.
        • Mutlu B.
        • Canpolat F.E.
        • et al.
        Human milk fortification with differing amounts of fortifier and its association with growth and metabolic responses in preterm infants.
        J Hum Lact. 2013; 29: 400-405
        • Kim J.H.
        • Chan G.
        • Schanler R.
        • et al.
        Growth and tolerance of preterm infants fed a new extensively hydrolyzed liquid human milk fortifier.
        J Pediatr Gastroenterol Nutr. 2015; 61: 665-671
        • Shah S.D.
        • Dereddy N.
        • Jones T.L.
        • et al.
        Early versus delayed human milk fortification in very low birth weight infants-a randomized controlled trial.
        J Pediatr. 2016; 174 (e121): 126-131