Modern Pediatrics. Ukraine. (2023). 3(131): 52-73. doi 10.15574/SP.2023.131.52
Kostiuk O. O.¹, Spatz D. L.^2,3, Shunko Ye. Ye.^1
1Shupyk National University of Healthcare of Ukraine, Kyiv
²Helen M. Shearer School of Nursing, University of Pennsylvania, USA
³Children's Hospital of Philadelphia, USA

For citation: Kostiuk OO, Spatz DL, Shunko YeYe. (2023). Comparative characterization the fortification of different types of nutrition for preterm and sick infants. What's the best? (Systematic review). Modern Pediatrics. Ukraine. 3(131): 52–73. doi 10.15574/SP.2023.131.52.
Article received: Jan 20, 2023. Accepted for publication: Apr 11, 2023.

Human milk is the preferred feeding for all infants, including those of very low birth weight and vulnerable groups. However, mother’s milk is generally likely has insufficient protein to promote appropriate growth. That's why fortification of human milk is required to meet nutrient requirements for growth and development for these preterm infants who are at high risk for growth faltering during the hospital stay. There are multiple strategies and products that may be employed to support desired growth rates.
Purpose – Conduct comparative analysis the current literature on the fortification own mothers’ milk and influence of this fortification on the outcomes for preterm and sick infant’s health.
Materials and methods. Search Strategy: A systematic search of the literature was conducted using search strategy was based on MeSH terms/subject headings and separate keywords. The study designs included were randomized or quasi-randomized controlled trials in the English, Ukrainian and Russian languages.
Study Selection: Published literature was searched from January 2010 up to July, 1, 2022 using five databases (PubMed, Ovid Medline, Web of Science, Ovid Embase, and the Cochrane Library). The search resulted in 75 articles, and an additional article was identified by an expert in the field; 20 were used for review.
Data Extraction: Data from the full-text articles was extracted into a Table. The manuscripts were organised in the table as follows: first Cochrane reviews and systematic reviews, followed by individual research studies that were not cited in any of the systematic reviews.
Results and conclusions. The primary outcomes of this review were influence of different types fortification of mother's milk and time of starting fortification in short term growth parameters (length, head growth, and weight gain), feeding intolerance (defined as clinical signs only and/or cessation of feeding), length of hospital stay (number of days that the baby remained in the neonatal unit), and post menstrual age (i.e., gestational age plus chronological age) at discharge. Secondary outcomes were narcotising enterocolitis  and sepsis. The study results suggested that early human milk fortification appears to positively affect growth for infants whose human milk feedings are fortified with a fortifier without adverse effects.
Implications for Practice: Adequate nutrition in the early weeks of life is rarely achieved in premature infants, resulting in extrauterine growth restriction. The use of fortified human milk produces adequate growth in premature infants and satisfies the specific nutritional requirements of these infants. The use of individualised fortification is recommended but with proper protocols.
No conflict of interests was declared by the authors.
Keywords: very low birth weight infants, mothers’ own milk, human milk, human, bovine milk-based fortifier, nutrition, prematurity, early, late, standard fortification, individualised fortification, neurodevelopment, growth, protein.
REFERENCES

1. Alan S, Atasay B, Cakir U, Yildiz D, Kilic A, Kahvecioglu D et al. (2013). An intention to achieve better postnatal in-hospital-growth for preterm infants: adjustable protein fortification of human milk. Early Hum Dev. 89: 1017-1023. https://doi.org/10.1016/j.earlhumdev.2013.08.015; PMid:24035039

2. Alizadeh TP, Sajjadian N, Asgharyan F M, Shariat M. (2017, Nov 27). Is early breast milk fortification more effective in preterm infants?: a clinical trial. J Perinat Med. 45 (8): 953-957. https://doi.org/10.1515/jpm-2015-0375; PMid:27676603

3. Alyahya W, Simpson J, Garcia AL, Mactier H, Edwards ChA. (2020). Early versus Delayed Fortification of Human Milk in Preterm Infants: A Systematic Review. Neonatology. 117(1): 24-32. https://doi.org/10.1159/000501279; PMid:31326969

4. Arslanoglu S, Bertino E, Coscia A, Tonetto P, Giuliani F, Moro GE. (2012). Update of adjustable fortification regimen for preterm infants: a new protocol. J Biol Regul Homeost Agents. 26; Suppl 3: 65-67.

5. Arslanoglu S, Boquien CY, King C et al. (2019). 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. 7: 76. Published 2019 Mar 22. https://doi.org/10.3389/fped.2019.00076; PMid:30968003 PMCid:PMC6439523

6. Arslanoglu S, Corpeleijn W, Moro G, Braegger C, Campoy C, Colomb V et al. (2013). ESPGHAN Committee on Nutrition. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr. 57: 535-542. https://doi.org/10.1097/MPG.0b013e3182a3af0a; PMid:24084373

7. Arslanoglu S, Moro GE, Ziegler EE, The WAPM Working Group On Nutrition. (2010). Optimization of human milk fortification for preterm infants: new concepts and recommendations. J Perinat Med. 38: 233-238. PMID: 20184400 https://doi.org/10.1515/jpm.2010.073

8. Arslanoglu S. (2015). IV. Individualized fortification of human milk: adjustable fortification. J Pediatr Gastroenterol Nutr. 61 (1): S4-5. https://doi.org/10.1097/01.mpg.0000471452.85920.4d; PMid:26296002

9. Ballard O, Morrow AL. (2013). Human milk composition. Pediatr Clin North Am. 60(1): 49-74. https://doi.org/10.1016/j.pcl.2012.10.002; PMid:23178060 PMCid:PMC3586783

10. Bertino E, Cavallarin L, Cresi F, Tonetto P, PeilaC, Ansaldi G et al. (2019). A Novel Donkey Milk-derived Human Milk Fortifier in Feeding Preterm Infants: A Randomized Controlled Trial. JPGN. 68: 116-123. https://doi.org/10.1097/MPG.0000000000002168; PMid:30320665 PMCid:PMC6314716

11. Bharwani SK, Green BF, Pezzullo JC, Bharwani SS, Dhanireddy R. (2016). Systematic review and meta-analysis of human milk intake and retinopathy of prematurity: a significant update. J Perinatol. 36: 913-920. https://doi.org/10.1038/jp.2016.98; PMid:27416321

12. Bhatia J. (2013). Human Milk and the Premature Infant. Ann Nutr Metab. 62; Suppl 3: 8-14. https://doi.org/10.1159/000351537; PMid:23970211

13. Biasini A, Monti F, Laguardia MC, Stella M, Marvulli L, Neri E. (2018). High protein intake in human/maternal milk fortification for ≤1250 gr infants: intrahospital growth and neurodevelopmental outcome at two years. Acta Biomed. 88: 470-476. doi: 10.23750/abm.v88i4.5316.

14. Brown JV, Lin L, Embleton ND, Harding JE, McGuire W. (2020). Multi-nutrient fortification of human milk for preterm infants. Cochrane Database of Systematic Reviews. 6: CD000343. https://doi.org/10.1002/14651858.CD000343; PMCid:PMC2326744

15. Buffin R, Decullier E, De Halleux V, Loys CM, Hays S, Studzinsky F et al. (2017). Assessment of human milk composition using mid-infrared analyzers requires calibration adjustment. J. Perinatol. 37: 552-557. https://doi.org/10.1038/jp.2016.230; PMid:28125098

16. Bulut O, Coban A, Uzunhan O, Ince Z. (2020). Effects of Targeted Versus Adjustable Protein Fortification of Breast Milk on Early Growth in Very Low-Birth-Weight Preterm Infants: A Randomized Clinical Trial. Nutr Clin Pract. 35(2): 335-343. https://doi.org/10.1002/ncp.10307; PMid:31025438

17. Burjonrappa SC, Crete E, Bouchard S. (2010). The role of amniotic fluid in influencing neonatal birth weight. J Perinatol. 30: 27-29. https://doi.org/10.1038/jp.2009.102; PMid:19626029

18. Colaizy TT, Carlson S, Saftlas AF, Morriss FH. (2012). Growth in VLBW infants fed predominantly fortified maternal and donor human milk diets: A retrospective cohort study. BMC Pediatr. 12: 124. https://doi.org/10.1186/1471-2431-12-124; PMid:22900590 PMCid:PMC3464178

19. Darrow CJ, Bai-Tong SS, Kang EM, Thompson CL, Walsh MC. (2020). Use of acidified versus non-acidified liquid human milk fortifier in very low birth weight infants: A retrospective comparison of clinical outcomes. J Neonatal Perinatal Med. 13(1): 71-79. https://doi.org/10.3233/NPM-180188; PMid:31771077

20. De Halleux V, Pieltain C, Senterre T et al. (2019). Growth Benefits of Own Mother's Milk in Preterm Infants Fed Daily Individualized Fortified Human Milk. Nutrients. 11(4): 772. Published 2019 Apr 3. https://doi.org/10.3390/nu11040772; PMid:30987136 PMCid:PMC6521225

21. De Halleux V, Pieltain C, Senterre T, Rigo J. (2017). Use of donor milk in the neonatal intensive care unit. Semin. Fetal. Neonatal Med. 22: 23-29. https://doi.org/10.1016/j.siny.2016.08.003; PMid:27649995

22. Dicky O, Ehlinger V, Montjaux N, Gremmo-Féger G, Sizun J, Rozé JC et al. (2017). Policy of feeding very preterm infants with their mother's own fresh expressed milk was associated with a reduced risk of bronchopulmonary dysplasia. Acta Paediatr. 106: 755-762. https://doi.org/10.1111/apa.13757; PMid:28128874

23. Eidelman AI. (2012). Breastfeeding and the use of human milk: an analysis of the American Academy of Pediatrics 2012 Breastfeeding Policy Statement. Breastfeeding Med. 7: 323e4. https://doi.org/10.1089/bfm.2012.0067; PMid:22946888

24. Ergenekon E, Soysal Ş, Hirfanoǧlu I, Baş V, Gücüyener K, Turan Ö et al. (2013). Short- and long-term effects of individualized enteral protein supplementation in preterm newborns. Turk J Pediatr. 55: 365-370.

25. Fabrizio V, Trzaski JM, Brownell EA, Esposito P, Lainwala S, Lussier MM, Hagadorn JI. (2020). Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. Cochrane Database of Systematic Reviews. 11: CD013465. https://doi.org/10.1002/14651858.CD013465; PMCid:PMC6827866

26. Fusch G, Kwan C, Kotrri G, Fusch C. (2017). "Bed Side" human milk analysis in the neonatal intensive care unit: a systematic review. Clin Perinatol. 44: 209-267. https://doi.org/10.1016/j.clp.2016.11.001; PMid:28159207

27. Garland M. (2020). Targeted Fortification of Donor Breast Milk in Preterm. Clinical Trials.gov Identifier: NCT04294368. https://beta.clinicaltrials.gov/study/NCT04294368.

28. Ginovart G, Gich I, Gutiérrez A, Verd S. (2017, Aug). A Fortified Donor Milk Policy is Associated With Improved In-Hospital Head Growth and Weight Gain in Very Low-Birth-Weight Infants. Advances in Neonatal Care. 17; 4: 250-257. https://doi.org/10.1097/ANC.0000000000000387; PMid:28749825

29. Gupta V, Rebekah G, Sudhakar Y, Santhanam S, Kumar M, Thomas N. (2020, Aug). A randomized controlled trial comparing the effect of fortification of human milk with an infant formula powder versus unfortified human milk on the growth of preterm very low birth weight infants. J Matern Fetal Neonatal Med. 33 (15): 2507-2515. https://doi.org/10.1080/14767058.2018.1554046; PMid:30486700

30. Hair AB, Blancо CL, Moreira AG, Hawthorne KM, Lee ML, Rechtman DJ, Abrams SA. (2014, Nov). Randomized Trial of Human Milk Cream as a Supplement to Standard Fortification of an Exclusive Human Milk-Based Diet in Infants 750-1250 g Birth Weight. The Journal of Paediatric. 165; 5: 915-920. https://doi.org/10.1016/j.jpeds.2014.07.005; PMid:25130571

31. Hay WW, Ziegler EE. (2016). Growth failure among preterm infants due to insufficient protein is not innocuous and must be prevented. J Perinatol. 36: 500-502. https://doi.org/10.1038/jp.2016.85; PMid:27339826

32. Hopperton KE, O'Connor DL, Bando N, Conway AM, Ng DNV, Kiss A et al. (2019). Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born <1250 g: 18-Month Neurodevelopment Follow-Up of a Randomized Clinical Trial. Curr Dev Nutr. 3: nzz129. NCT02137473. https://doi.org/10.1093/cdn/nzz129; PMid:32154499 PMCid:PMC7053578

33. Hustona RK, Leeb ML, Riderc ED, Stawarzd ML, Hedstrome DM, Pencef MM et al. (2019). Early fortification of enteral feedings for infants <1250 grams birth weight receiving a human milk diet including human milk based fortifier. J. of Neonatal-Perinatal Medicine. 13(2): 215-221. https://doi.org/10.3233/NPM-190300; PMid:31707377 PMCid:PMC7369034

34. Jensen GB, Ahlsson F, Domellöf M et al. (2021). Nordic study on human milk fortification in extremely preterm infants: a randomised controlled trial – the N-forte trial. BMJ Open. 11: e053400. https://doi.org/10.1136/bmjopen-2021-053400; PMid:34815288 PMCid:PMC8611420

35. Kemp JE, Wenhold FAM. (2016). Human milk fortification strategies for improved in-hospital growth of preterm infants. South African Journal of Clinical Nutrition. 29; 4: 157-164. https://doi.org/10.1080/16070658.2016.1217646

36. Khan Z, Morris N, Unterrainer H, Haiden N, Holasek SJ, Urlesberger B. (2018). Effect of standardized feeding protocol on nutrient supply and postnatal growth of preterm infants: A prospective study. J Neonatal Perinatal Med. 11(1): 11-19. https://doi.org/10.3233/NPM-18179; PMid:29689751

37. Kim JA, Chan CS, Vaucher YE et al. (2013). Challenges in the practice of human milk nutrition in the neonatal intensive care unit. Early Hum Dev. 89: S25-S38. https://doi.org/10.1016/j.earlhumdev.2013.08.002; PMid:23998449

38. Kleinman RE, Greer FR. (2013). Pediatric Nutrition. Handbook, ed 7. Elk Grove Village/IL, American Academy of Pediatrics.

39. Koletzko B, Poindexter B, Uauy R. (2014). Recommended nutrient intake levels for stable, fully enteral fed very low birth weight infants. World Rev Nutr Diet. 110: 297-299. https://doi.org/10.1159/isbn.978-3-318-02641-2

40. Kreins N, Buffin R, Michel-Molnar D, Chambon V, Pradat P, Picaud JC. (2018). Individualized fortification influences the osmolality of human milk. Frontiers Pediatr. 6: 322. https://doi.org/10.3389/fped.2018.00322; PMid:30430102 PMCid:PMC6220443

41. Kumar M, Upadhyay J, Basu S. (2021, Jan). Fortification of Human Milk with Infant Formula for Very Low Birth Weight Preterm Infants: A Systematic Review. Indian Pediatrics. 58: 253-258. https://doi.org/10.1007/s13312-021-2166-x; PMid:33408285

42. Kumar RK, Singhal A, Vaidya U, Banerjee S, Anwar F, Rao S. (2017). Optimizing nutrition in preterm low birth weight infant -Consensus Summary. Front Nutr. 26: 20. https://doi.org/10.3389/fnut.2017.00020; PMid:28603716 PMCid:PMC5445116

43. Madore LS, Bora S, Erdei C, Jumani T, Dengos AR, Sen S. (2017). Effects of Donor Breastmilk Feeding on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational Study. Clin. Ther. 39: 1210-1220. https://doi.org/10.1016/j.clinthera.2017.05.341; PMid:28576299

44. Maffei D, Schanler RJ. (2017). Human milk is the feeding strategy to prevent necrotizing colitis. Semin Perinatol. 41: 36-40. https://doi.org/10.1053/j.semperi.2016.09.016; PMid:27836421

45. Maly J, Burianova I, Vitkova V, Ticha E, Navratilova M, Cermakova E, PREMATURE MILK study group. (2019). Preterm human milk macronutrient concentration is independent of gestational age at birth. Arch Dis Child Fatal Neonatal Ed. 104: F50-56. https://doi.org/10.1136/archdischild-2016-312572; PMid:29353262

46. Mathes M, Maas C, Bleeker C, Vek J, Bernhard W, Peter A et al. (2018). Effect of increased enteral protein intake on plasma and urinary urea concentrations in preterm infants born at <32 weeks gestation and <1500 g birth weight enrolled in a randomized controlled trial – a secondary analysis. BMC Pediatr. 18: 154. https://doi.org/10.1186/s12887-018-1136-5; PMid:29739389 PMCid:PMC5941684

47. McLeod G, Sherriff J, Hartmann PE, Nathan E, Geddes D, Simmer K. (2016). Comparing different methods of human breast milk fortification using measured v. assumed macronutrient composition to target reference growth: A randomised controlled trial. Br. J. Nutr. 115: 431-439. https://doi.org/10.1017/S0007114515004614; PMid:26627899

48. Miller EM, Aiello MO, Fujita M, Hinde K, Milligan L, Quinn EA. (2013). Field and laboratory methods in human milk research. American Journal of Human Biology. 25: 1-11. https://doi.org/10.1002/ajhb.22334; PMid:23109280

49. Mimouni FB, Lubetzky R, Yochpaz S, Mandel D. (2017). Preterm human milk macronutrient and energy composition: a systematic review and metaanalysis. Clin Perinatol. 44: 165-172. https://doi.org/10.1016/j.clp.2016.11.010; PMid:28159203

50. Mimouni FB, Nathan N, Ziegler EE, Lubetzky R, Mandel D. (2017). The use of multinutrient human milk fortifiers in preterm infants: a systematic review of unanswered questions. Clin Perinatol. 44: 175-178. https://doi.org/10.1016/j.clp.2016.11.011; PMid:28159204

51. Moro GE, Arslanoglu S, Bertino E, Corvaglia L, Montirosso R, Picaud JC, Ziegler EE. (2015). XII. Human Milk in Feeding Premature Infants: Consensus Statement. Journal of Pediatric Gastroenterology and Nutrition. 61; Suppl 1: S16-S19. https://doi.org/10.1097/01.mpg.0000471460.08792.4d; PMid:26295999

52. Picaud JC, Houeto N, Buffin R, Loys CM, Godbert I, Haÿs S. (2016). Additional protein fortification is necessary in extremely low-birth-weight infants fed human milk. J Pediatr Gastroenterol Nutr. 63: 103-105. https://doi.org/10.1097/MPG.0000000000001142; PMid:26859094

53. Polberger S, Raiha NCR, Juvonen P, Moro GE, Minoli I, Warm A. (1999). Individualized protein fortification of human milk for preterm infants: comparison of ultrafiltrated human milk protein and a bovine whey fortifier. JPediatr Gastr Nutr. 29: 3328. https://doi.org/10.1097/00005176-199909000-00017; PMid:10468001

54. Premkumar MH, Pammi M, Suresh G. (2019). Human milk-derived fortifier versus bovine milk-derived fortifier for prevention of mortality and morbidity in preterm neonates. Cochrane Database of Systematic Reviews. 11: CD013145. https://doi.org/10.1002/14651858.CD013145.pub2; PMid:31697857 PMCid:PMC6837687

55. Radmacher PG, Adamkin DH. (2017). Fortification of human milk for preterm infants. Semin Fetal Neonatal Med. 22: 30-35. https://doi.org/10.1016/j.siny.2016.08.004; PMid:27593561

56. Rochow N, Fusch G, Choi A, Chessell L, Elliott L, McDonald K et al. (2013). Target fortification of breast milk with fat, protein, and carbohydrates for preterm infants. J. Pediatr. 163: 1001-1007. https://doi.org/10.1016/j.jpeds.2013.04.052; PMid:23769498

57. Schulz EV, Murphy HJ, Taylor SN. (2018). Sooner or later: does early human milk fortification improve outcomes? Journal of Perinatology. 38: 311-314. https://doi.org/10.1038/s41372-017-0013-7; PMid:29282352

58. Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ. (2016, Jul). Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial. J Pediatr. 174: 126-131.e1. https://doi.org/10.1016/j.jpeds.2016.03.056; PMid:27112041

59. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U et al. (2010, Apr). 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. 156 (4): 562-567.e1. https://doi.org/10.1016/j.jpeds.2009.10.040; PMid:20036378

60. Thanigainathan S, Abiramalatha T. (2020). Early fortification of human milk versus late fortification to promote growth in preterm infants. Cochrane Database of Systematic Reviews. 7: CD013392. https://doi.org/10.1002/14651858.CD013392

61. Thoene M, Hanson C, Lyden E, Dugick L, Ruybal L, Anderson-Berry A. (2014). Comparison of the effect of two human milk fortifiers on clinical outcomes in premature infants. Nutrients. 6(1): 261-275. Published 2014 Jan 3. https://doi.org/10.3390/nu6010261; PMid:24394538 PMCid:PMC3916860

62. Tillman S, Brandon DH, Silva SG. (2012, Jul). Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol. 32 (7): 525-531. https://doi.org/10.1038/jp.2011.140; PMid:21960127

63. WHO. (2013). Part I. Recommendations, rationale and evidence for nutrition actions; in World Health Organization: Essential Nutrition Actions: Improving Maternal, Newborn, Infant and Young Child Health and Nutrition. Geneva, WHO.

64. Young L, Embleton ND, McCormick FM, McGuire W. (2013). Multinutrient fortification of human breast milk for preterm infants following hospital discharge. Cochrane Database Syst Rev. 2: CD004866. Published 2013 Feb 28. https://doi.org/10.1002/14651858.CD004866.pub4

65. Ziegler EE. (2014). Human milk and human milk fortifiers. World Rev Nutr Diet. 110: 215-227.  https://doi.org/10.1159/000358470; PMid:24751632