Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Optimizing individual nutrition in preterm very low birth weight infants: double-blinded randomized controlled trial

Journal of Perinatology volume 40, pages 655–665 (2020)Cite this article

Subjects

Abstract

Objective

In preterm neonates fed human milk, fortification may be adjusted by (1) optimization, based on growth rate and serum nutrient analyses, or (2) individualization, based on serial milk nutrient analyses. The primary aim was to determine whether individualized plus optimized nutrition (experimental) improves velocity of weight gain and linear growth from birth to endpoint (36 weeks postmenstrual age or discharge) when compared with optimized nutrition alone (controls).

Study design

Double-blinded parallel group randomized trial in 120 neonates <29 weeks gestational age (GA) or <35 weeks and small for GA (birth weight < 10th centile).

Result

Weight-gain velocity (13.1 ± 2.1, n = 57 controls, vs. 13.0 ± 2.6 g kg−1 day−1, n = 59 experimental, P = 0.87), linear growth (0.9 ± 0.2, n = 55, vs. 0.9 ± 0.2 cm week−1, n = 52, P = 0.90) and frequency of weight/length disproportion (2% vs. 2%, P = 0.98) were similar in both groups.

Conclusions

Individualized plus optimized nutrition does not improve weight gain, linear growth, or weight/length disproportion at endpoint versus optimized nutrition alone.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Section on Breastfeeding. Breastfeeding and the use of breast milk. Pediatrics. 2012;129:e827–41.

    Article  Google Scholar 

  2. Arslanoglu S, Boquien CY, King C, Lamireau D, Tonetto P, Barnett D, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Libr. 2004;1:CD000343. Review. Update in: Cochrane Database Syst Rev. 2016;5:CD000343

    Google Scholar 

  4. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortification of human milk fed to preterm infants: does it make a difference? J Perinatol. 2006;26:614–21.

    Article  CAS  PubMed  Google Scholar 

  5. Alan S, Atasay B, Cakir U, Yildiz D, Kilic A, Kahvecioglu D, et al. An intention to achieve better postnatal in-hospital-growth for preterm infants: adjustable protein fortification of human milk. Early Hum Dev. 2013;89:1017–22.

    Article  CAS  PubMed  Google Scholar 

  6. Moro GE, Minoli I, Ostrom M, Jacobs JR, Picone TA, Räihä NC, et al. Fortification of human milk: evaluation of a novel fortification scheme and of a new fortifier. J Pediatr Gastroenterol Nutr. 1995;20:162–72.

    Article  CAS  PubMed  Google Scholar 

  7. Arslanoglu S, Moro GE, Ziegler EE, The Wapm Working Group On Nutrition. Optimization of human milk fortification for preterm infants: new concepts and recommendations. J Perinat Med. 2010;38:233–8.

    CAS  PubMed  Google Scholar 

  8. Brion LP, Rosenfeld CR, Heyne R, Brown LS, Lair C, Burchfield P. Adjustable feedings plus accurate serial length measurements decrease discharge weight-length disproportion in very preterm infants: quality improvement project. J Perinatol. 2019;39:1131–9. https://doi.org/10.1038/s41372-019-0521-8.

    Article  PubMed  Google Scholar 

  9. O’Neill EF, Radmacher PG, Sparks B, Adamkin DH. Creamatocrit analysis of human milk overestimates fat and energy content when compared to a human milk analyzer using mid-infrared spectroscopy. J Pediatr Gastroenterol Nutr. 2013;56:569–72.

    Article  CAS  PubMed  Google Scholar 

  10. Hair AB, Blanco CL, Moreira AG, Hawthorne KM, Lee ML, Rechtman DJ, et al. 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. J Pediatr. 2014;165:915–20.

    Article  CAS  PubMed  Google Scholar 

  11. Rochow N, Fusch G, Ali A, Bhatia A, Ahmad S, Nguyen A, et al. Target fortification of breast milk with protein, carbohydrate and fat for preterm infants improves growth outcomes: a double-blind randomized controlled trial. Pediatr Academic Societies. 2017;3120:3.

    Google Scholar 

  12. de Halleux V, Rigo J. Variability in human milk composition: benefit of individualized fortification in very-low-birth-weight infants. Am J Clin Nutr. 2013;98:529S–35S.

    Article  CAS  PubMed  Google Scholar 

  13. Corvaglia L, Aceti A, Paoletti V, e Mariani E, Patrono D, Ancora G, et al. Standard fortification of preterm human milk fails to meet recommended protein intake: bedside evaluation by near-infrared-reflectance-analysis. Early Hum Dev. 2010;86:237–40.

    Article  CAS  PubMed  Google Scholar 

  14. Corvaglia L, Battistini B, Paoletti V, Aceti A, Capretti MG, Faldella G. Near-infrared reflectance analysis to evaluate the nitrogen and fat content of human milk in neonatal intensive care units. Arch Dis Child Fetal Neonatal Ed. 2008;93:F372–F3275.

    Article  CAS  PubMed  Google Scholar 

  15. Aceti A, Corvaglia L, Paoletti V, Mariani E, Ancora G, Galletti S, et al. Protein content and fortification of human milk influence gastroesophageal reflux in preterm infants. J Pediatr Gastroenterol Nutr. 2009;49:613–8.

    Article  CAS  PubMed  Google Scholar 

  16. Di Natale C1, Coclite E, Di Ventura L, Di Fabio S. Fortification of maternal milk for preterm infants. J Matern Fetal Neonatal Med. 2011;24:41–3.

    Article  PubMed  Google Scholar 

  17. Polberger S, Lönnerdal B. Simple and rapid macronutrient analysis of human milk for individualized fortification: basis for improved nutritional management of very-low-birth-weight infants? J Pediatr Gastroenterol Nutr. 1993;17:283–90.

    Article  CAS  PubMed  Google Scholar 

  18. Polberger S, Räihä NC, Juvonen P, Moro GE, Minoli I, Warm A. Individualized protein fortification of human milk for preterm infants: comparison of ultra-filtrated human milk protein and a bovine whey fortifier. J Pediatr Gastroenterol Nutr. 1999;29:332–8.

    Article  CAS  PubMed  Google Scholar 

  19. Radmacher PG, Lewis SL, Adamkin DH. Individualizing fortification of human milk using real time human milk analysis. J Neonatal Perinat Med. 2013;1:319–23.

    Article  Google Scholar 

  20. Sauer CW, Kim JH. Human milk macronutrient analysis using point-of-care near-infrared spectrophotometry. J Perinatol. 2011;31:339–43.

    Article  CAS  PubMed  Google Scholar 

  21. Rochow N, Fusch G, Zapanta B, Ali A, Barui S, Fusch C. Target fortification of breast milk: how often should milk analysis be done? Nutrients. 2015;7:2297–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rochow N, Fusch G, Choi A, Chessell L, Elliott L, McDonald K, et al. Target fortification of breast milk with fat, protein, and carbohydrates for preterm infants. J Pediatr. 2013;163:1001–7.

    Article  CAS  PubMed  Google Scholar 

  23. Bulut O, Coban A, Uzunhan O, Ince Z. 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. 2019. https://doi.org/10.1002/ncp.10307.

  24. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth curves based on United States data. Pediatrics. 2010;125:e214–24.

    Article  PubMed  Google Scholar 

  25. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. ESPGHAN committee on nutrition. enteral nutrient supply for preterm infants: commentary from the european society of paediatric gastroenterology, hepatology and nutrition committee on nutrition. J Pediatr Gastroenterol Nutr. 2010;50:85–91.

    Article  CAS  PubMed  Google Scholar 

  26. Kleinman RE. Nutritional needs of the preterm infant. In: Pediatric nutrition handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009, p. 79–104.

  27. Koletzko B, Pointdexter B, Uauy R. Nutritional care of preterm infants. scientific basis and practice guidelines. World Review of Nutrition and Dietetics. Vol. 110. Karger, Basel, Switzerland: Karger; 2014.

  28. Pavageau L, Rosenfeld CR, Heyne R, Brown LS, Whitham J, Lair C, et al. Valid serial length measurements in preterm infants permit characterization of growth patterns. J Perinatol. 2018;38:1694–70.

    Article  PubMed  Google Scholar 

  29. Fusch G, Rochow N, Choi A, Fusch S, Poeschl S, Ubah AO, et al. Rapid measurement of macronutrients in breast milk: How reliable are infrared milk analyzers? Clin Nutr. 2015;34:465–76.

    Article  CAS  PubMed  Google Scholar 

  30. Wojcik KY1, Rechtman DJ, Lee ML, Montoya A, Medo ET. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc. 2009;109:137–40.

    Article  PubMed  Google Scholar 

  31. Patel AL, Engstrom JL, Meier PP, Jegier BJ, Kimura RE. Calculating postnatal growth velocity in very low birth weight (VLBW) premature infants. J Perinatol. 2009;29:618–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Olsen IE, Lawson ML, Ferguson AN, Cantrell R, Grabich SC, Zemel BS, et al. BMI curves for preterm infants. Pediatrics. 2015;135:e572–81.

    Article  PubMed  Google Scholar 

  33. Hummel P, Puchalski M, Creech SD, Weiss MG. Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain. J Perinatol. 2008;28:55–60.

    Article  CAS  PubMed  Google Scholar 

  34. Landau-Crangle E, Rochow N, Fenton TR, Liu K, Ali A, So HY, et al. Individualized postnatal growth trajectories for preterm infants. JPEN J Parenter Enter Nutr. 2018;42:1084–92. http://www.growthcalculator.org.

    Article  Google Scholar 

  35. Rochow N, Raja P, Liu K, Fenton T, Landau-Crangle E, Göttler S, et al. Physiological adjustment to postnatal growth trajectories in healthy preterm infants. Pediatr Res. 2016;79:870–9.

    Article  PubMed  Google Scholar 

  36. Kliegan RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr Probl Pediatr. 1987;17:213–88.

    Google Scholar 

  37. WHO Multicentre Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;450:76.

    Google Scholar 

  38. Grummer-Strawn LM, Reinold C, Krebs NF, Centers for Disease Control and Prevention (CDC). Use of World Health Organization and CDC growth charts for children aged 0–59 months in the United States. M M W R Recomm Rep. 2010;59:1–15.

    Google Scholar 

  39. Vaucher YE, Harrison GG, Udall TN, Morrow G III. Skinfold thickness in North American Infants 24-41 weeks gestation. Hum Biol. 1984;56:713–31.

    CAS  PubMed  Google Scholar 

  40. Abdel-Rahman SM, Paul IM, Delmore P, James L, Fearn L, Atz AM, et al. Best pharmaceuticals for children act – pediatric trials network. an anthropometric survey of US pre-term and full-term neonates. Ann Hum Biol. 2017;44:678–86.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Cooke RJ, Griffin I. Altered body composition in preterm infants at hospital discharge. Acta Paediatr. 2009;98:1269–73.

    Article  PubMed  Google Scholar 

  42. Stokes TA, Holston A, Olsen C, Choi Y, Curtis J, Higginson J, et al. Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages. J Pediatr. 2012;161:735–41.

    Article  PubMed  Google Scholar 

  43. Johnson MJ, Wootton SA, Leaf AA, Jackson AA. Preterm birth and body composition at term equivalent age: a systematic review and meta-analysis. Pediatrics. 2012;130:e640–49.

    Article  PubMed  Google Scholar 

  44. Rochow N, Yousuf E, So HS, Rochow E, Fusch G, Hutton E, et al. Trajectories of fat mass accretion among preterm compared to term infants during the first 6 months of postnatal life. E-PAS. 2019;3853:477.

    Google Scholar 

  45. Duncan AF, Heyne RJ, Morgan JS, Ahmad N, Rosenfeld CR. Elevated systolic blood pressure in preterm very-low birth-weight infants ≤3 years of life. Pediatr Nephrol. 2011;26:1115–21.

    Article  PubMed  Google Scholar 

  46. Frankfurt JA, Duncan AF, Heyne RJ, Rosenfeld CR. Renal function and systolic blood pressure in very-low-birthweight infants 1-3 years of age. Pediatr Nephrol. 2012;27:2285–91.

    Article  PubMed  Google Scholar 

  47. Duncan AF, Frankfurt JA, Heyne RJ, Rosenfeld CR. Biomarkers of adiposity are elevated in preterm very-low birth-weight infants at 1, 2 and 3 y of age. Pediatr Res. 2017;81:780–6.

    Article  CAS  PubMed  Google Scholar 

  48. Senterre T, Rigo J. Reduction in postnatal cumulative nutritional deficit and improvement of growth in extremely preterm infants. Acta Paediatr. 2012;101:e64–70.

    Article  PubMed  Google Scholar 

  49. de Halleux V, Pieltain C, Senterre T, Studzinski F, Kessen C, Rigo V, et al. Growth benefits of own mother’s milk in preterm infants fed daily individualized fortified human milk. Nutrients. 2019;11:E772. https://doi.org/10.3390/nu11040772.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by the Gerber Foundation ($300,000) and in part by the CCRAC Award from the Children’s Foundation ($100,000). Cost of breast milk analyses included $58,000 for the equipment (purchase and 3-year maintenance and supplies) and $201,000 for salaries and fringes for 0.5 FTE of a dietitian 0.33 FTE for a formula technician. Jülide Sisman, MD, MS and LSB, MS, conducted blinded meetings of the data safety committee every 6 months to review safety, adverse events, and futility. Susan Chacko, RN, Maria DeLeon, and RN were research coordinators for part of this study. Chen Du, RD, Elizabeth Brammer, RD and Audrey Edwards, RD, dietitians at Parkland Hospital, obtained anthropometric measurements for this study and participated in patient recruitment, assessments of growth and laboratory results and recommendations for nutritional interventions. Christopher Clark, IT specialist at Parkland Hospital, extracted data from EPIC at Parkland. LaShunda Wilson, Kennissia Collins, and Brandon Hadnot (formula technicians at Parkland Hospital) measured human milk samples in both groups and supplemented milk in the experimental group. Blair Holbein, PhD, DCS helped with IRB approval of the NIRS measurements. Dr Holbein is supported by NCATS “National Center for Advancing Translational Sciences of the NIH” UL1TR001105.

Preliminary results were submitted in abstract form:

• LPB, CRR, RH, LSB, CSL, and MC. Optimizing individual nutrition in preterm infants: randomized clinical trial (RCT). This abstract was presented at the Pediatric Academy Societies Meeting at Baltimore, MD, 4/29/19.

• LPB, CRR, RH, LSB, CSL, EP, TJ, MC, and PJB. Double-blinded randomized controlled trial (RCT) of Optimizing Individual Nutrition in Preterm (PT) very low birth weight infants: analysis of nutrient intake and growth patterns. Submitted for presentation at PAS, Philadelphia, PA, May 2020.

Funding

This study was supported by a National Grant from the Gerber Foundation (LPB), the George L. MacGregor Professorship (CRR) and the following grant: Children’s Medical Center Clinical Advisory Committee (CCRAC)—Senior Investigator Research Award—New Direction (LPB, 2015−17). The funding organizations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review and approval of the manuscript, and decision to submit the manuscript for publication.

Author contributions

LPB conceptualized and designed the study, developed the protocol and the database, collected and reviewed data from the medical records, participated in the interpretation of the data, wrote the first draft of the manuscript, critically reviewed the revisions, and approved the final manuscript as submitted. CRR and RH conceptualized and designed the study. Each participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted. LSB, MS, conceptualized and designed the study. He developed and ran the randomization algorithm and prepared three sets (one per stratum) of sequential cards with unique trial number. He merged into a single spreadsheet the randomized allocation data with data extracted from the medical records, conducted statistical analyses, prepared the CONSORT flow diagram, participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted. CSL obtained anthropometric measurements for this study and participated in patient recruitment, assessments of growth and laboratory results, and nutritional interventions. She participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted. EP participated in the organization of the trial, development of the methods and training of the personnel who ran the milk analyses. She organized and supervised patient allocation and milk analyses, supplementation, and documentation in a separate room, the infant nutrition center. She had no role in patient enrollment or patient care. She participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted. TJ obtained anthropometric measurements for this study and participated in patient recruitment, assessments of growth and laboratory results, and nutritional interventions. She participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted. MC was research coordinator for a large part of this study. She recruited and measured patients in the NICU and at follow-up. She extracted data from medical records into databases, critically reviewed the manuscript, and approved the final manuscript as submitted. PJB collected data on all infants, participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted.

Author information

Authors and Affiliations

  1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas, Southwestern Medical Center, Dallas, TX, USA

    Luc P. Brion, Charles R. Rosenfeld, Roy Heyne, Maria Caraig & Patti J. Burchfield

  2. Parkland Health & Hospital System, Dallas, TX, USA

    L. Steven Brown, Cheryl S. Lair, Elen Petrosyan & Theresa Jacob

Authors
  1. Luc P. Brion
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles R. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roy Heyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Steven Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheryl S. Lair
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elen Petrosyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Theresa Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria Caraig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patti J. Burchfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luc P. Brion.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brion, L.P., Rosenfeld, C.R., Heyne, R. et al. Optimizing individual nutrition in preterm very low birth weight infants: double-blinded randomized controlled trial. J Perinatol 40, 655–665 (2020). https://doi.org/10.1038/s41372-020-0609-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-020-0609-1

This article is cited by

Search

Advanced search

Quick links