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Follow-up of a randomized trial optimizing neonatal nutrition in preterm very low birthweight infants: growth, serum adipokines, renal function and blood pressure

Journal of Perinatology volume 44, pages 78–86 (2024)Cite this article

Subjects

Abstract

Objective

The primary objectives were to compare body mass index (BMI) Z-score (Z), systolic blood pressure (SBP), serum leptin:adiponectin (L:A) ratio and estimated glomerular filtration rate (eGFR) at ~3 years adjusted age between two arms of a randomized controlled trial (RCT) comparing two modes of human milk fortification for very low-birthweight infants in the neonatal intensive care unit.

Study design

Follow-up of RCT at 33–48 months.

Results

Follow-up data are available in 82/120 infants. Infants in the experimental arm have anthropometric data consistent with central obesity and higher serum L:A ratio (sensitivity analysis adjusting for sex and using all available data), but have similar eGFR and SBP at follow-up compared with controls. Serum L:A ratio is strongly correlated with anthropometric measurements suggesting central obesity.

Conclusions

Infants in the experimental arm have central obesity and higher serum L:A ratio compared with controls. Notably, serum L:A ratio is strongly correlated with weight gain.

Trial registration

This randomized controlled trial was registered at ClinicalTrials.gov NCT02372136.

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Fig. 1: Box plots of adipokines in control and experimental cohorts in the randomized trial.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Kumar VHS. Cardiovascular morbidities in adults born preterm: getting to the heart of the matter! Children. 2022;9:1843.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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 

  3. Beltowski J. Role of leptin in blood pressure regulation and arterial hypertension. J Hypertens. 2006;24:789–801.

    Article  CAS  PubMed  Google Scholar 

  4. Kim DH, Kim C, Ding EL, Townsend MK, Lipsitz LA. Adiponectin levels and the risk of hypertension. A systematic review and meta-analysis. Hypertension. 2013;62:27–32.

    Article  CAS  PubMed  Google Scholar 

  5. Diamond FB Jr, Cuthbertson D, Hanna S, Eichler D. Correlates of adiponectin and the leptin/adiponectin ratio in obese and non-obese children. J Pediatr Endocrinol Metab. 2004;17:1069–75.

    Article  CAS  PubMed  Google Scholar 

  6. Diamond F, Dharamraj C, Luther S, Eichler D. The leptin/adiponectin ratio in mid-infancy correlates with weight gain in healthy term infants, but is unrelated to serum insulin concentrations, body mass index, or skin fold thickness. J Pediatr Endocrinol Metab. 2008;21:1133–8.

    Article  CAS  Google Scholar 

  7. Santana-Meneses JF, Suano-Souza FI, Franco MDC, Fonseca FL, Strufaldi MWL. Leptin and adiponectin concentrations in infants with low birthweight: relationship with maternal health and postnatal growth. J Dev Orig Health Dis. 2022;13:338–44.

    Article  CAS  PubMed  Google Scholar 

  8. Tylutka A, Morawin B, Walas Ł, Michałek M, Gwara A, Zembron-Lacny A. Assessment of metabolic syndrome predictors in relation to inflammation and visceral fat tissue in older adults. Sci Rep. 2023;13:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kondo H, Abe I, Gotoh K, Fukui A, Takanari H, Ishii Y, et al. Interleukin 10 treatment ameliorates high-fat diet-induced inflammatory atrial remodeling and fibrillation. Circ Arrhythm Electrophysiol. 2018;11:e006040.

    Article  CAS  PubMed  Google Scholar 

  10. Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, et al. Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab. 2003;88:1055–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  12. 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 

  13. Wickland J, Brown LS, Blanco V, Heyne R, Turer C, Rosenfeld CR. Persistent high blood pressure and renal dysfunction in preterm infants during childhood. Pediatr Res. 2023;93:217–25.

    Article  CAS  PubMed  Google Scholar 

  14. Brion LP, Rosenfeld CR, Heyne R, Brown LS, Lair C, Burchfield P, et al. Adjustable feedings plus accurate serial length measurements decrease weight-length disproportion in very preterm infants. J Perinatol. 2019;39:1131–9. Corrected and republished from: J Perinatol. 2019; 39:1694.

    Article  PubMed  Google Scholar 

  15. Brion LP, Rosenfeld CR, Heyne R, Brown LS, Lair CS, Heyne E, et al. Association of age of initiation and type and of complementary foods with body mass index and weight-length at twelve months of age in preterm infants. J Perinatol. 2020;40:1394–404.

    Article  PubMed  Google Scholar 

  16. Simon L, Hadchouel A, Arnaud C, Frondas-Chauty A, Marret S, Flamant C, et al. Growth trajectory during the first 1000 days and later overweight in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2023;108:149–55.

  17. Brion LP, Rosenfeld CR, Heyne R, Brown LS, Lair CS, Petrosyan E, et al. Optimizing individual nutrition in preterm very low birthweight infants: double-blinded randomized controlled trial. J Perinatol. 2020;40:655–65.

    Article  PubMed  Google Scholar 

  18. Reis RD, Tolentino-Plata K, Caraig M, Heyne R, Rosenfeld CR, Brown LS, et al. Double-blinded randomized controlled trial of optimizing nutrition in preterm very low birthweight infants: Bayley scores at 18-38 months of age. J Perinatol. 2023;43:81–5.

    Article  CAS  PubMed  Google Scholar 

  19. Filler G, Lepage N. Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol. 2003;18:981–5.

    Article  PubMed  Google Scholar 

  20. 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 

  21. 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 

  22. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 2006;450:76–85.

    Article  Google Scholar 

  23. WHO Multicentre Growth Reference Study Group. WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization; 2006. https://www.who.int/publications/i/item/924154693X. Accessed 20 Jun 2023.

  24. Clark RH, Olsen IE, Spitzer AR. Assessment of neonatal growth in prematurely born infants. Clin Perinatol. 2014;41:295–307.

    Article  PubMed  Google Scholar 

  25. WHO Multicentre Growth Reference Study Group. WHO child growth standards: head circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and subscapular skinfold-for-age: methods and development. Geneva: World Health Organization; 2007. https://www.who.int/publications/i/item/9789241547185. Accessed 20 Jun 2023.

  26. Hampl SE, Hassink SG, Skinner AC, Armstrong SC, Barlow SE, Bolling CF, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151:e2022060640.

    Article  PubMed  Google Scholar 

  27. Schwartz GJ, Schneider MF, Maier PS, Moxey-Mims M, Dharnidharka VR, Warady BA, et al. Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Kidney Int. 2012;82:445–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Flynn, JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Subcommittee on screening and management of high blood pressure in children. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. Erratum in: Pediatrics. 2017 Nov 30;: Erratum in: Pediatrics. 2018 Sep;142.

  29. Erhardt E, Foraita R, Pigeot I, Barba G, Veidebaum T, Tornaritis M, et al. IDEFICS consortium. Reference values for leptin and adiponectin in children below the age of 10 based on the IDEFICS cohort. Int J Obes. 2014;38:S32–8.

    Article  CAS  Google Scholar 

  30. Li G, Taljaard M, Van den Heuvel ER, Levine MA, Cook DJ, Wells GA, et al. An introduction to multiplicity issues in clinical trials: the what, why, when and how. Int J Epidemiol. 2017;46:746–55.

    PubMed  Google Scholar 

  31. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ. 1998;316:1236–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu Y, Lin Q, Zhang Y, Deng H, Hu X, Yang X, et al. Mid-upper arm circumference as a simple tool for identifying central obesity and insulin resistance in type 2 diabetes. PLoS ONE. 2020;15:e0231308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. López-Jaramillo P, Gómez-Arbeláez D, López-López J, López-López C, Martínez-Ortega J, Gómez-Rodríguez A, et al. The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Horm Mol Biol Clin Investig. 2014;18:37–45.

    Article  PubMed  Google Scholar 

  34. Pan L, Li R, Park S, Galuska DA, Sherry B, Freedman DS. A longitudinal analysis of sugar-sweetened beverage intake in infancy and obesity at 6 years. Pediatrics. 2014;134:S29–35.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Heyman MB, Abrams SA. AAP section on gastroenterology, hepatology, and nutrition; AAP Committee on Nutrition. Fruit juice in infants, children, and adolescents: current recommendations. Pediatrics. 2017;139:e20170967.

    Article  PubMed  Google Scholar 

  36. Baldassarre ME, Giannì ML, Di Mauro A, Mosca F, Laforgia N. Complementary feeding in preterm infants: where do we stand? Nutrients. 2020;12:1259.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Vissers KM, Feskens EJ, van Goudoever JB, Janse AJ. The timing of initiating complementary feeding in preterm infants and its effect on overweight: a systematic review. Ann Nutr Metab. 2018;72:307–15.

    Article  CAS  PubMed  Google Scholar 

  38. Salvatori G, Martini L, The Study Group on Neonatal Nutrition and Gastroenterology-Italian Society of Neonatology OBO. Complementary feeding in the preterm infants: summary of available macronutrient intakes and requirements. Nutrients. 2020;12:3696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brenner BM, Garcia DL, Anderson S. Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens. 1988;11:335–47.

    Article  Google Scholar 

  40. Luyckx VA, Brenner BM. Low birthweight, nephron number, and kidney disease. Kidney Int Suppl. 2005;97:S68–77.

    Article  Google Scholar 

  41. Carmody JB, Charlton JR. Short-term gestation, long-term risk: prematurity and chronic kidney disease. Pediatrics 2013;131:1168–79.

    Article  PubMed  Google Scholar 

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Funding

Children’s Medical Center Clinical Advisory Committee (CCRAC) – Senior Investigator Research Award – Direction (L.P. Brion); National Grant from the Gerber Foundation (L.P. Brion); George L. MacGregor Professorship (C.R. Rosenfeld) UTSW consolidated account (R. Heyne) Crystal Charity Ball (CCB) UT Foundation (Lina Chalak). Funding/Financial Support: The RCT was supported by a National Grant from the Gerber Foundation (LP Brion), George L. MacGregor Professorship (CR Rosenfeld), a Children’s Medical Center Clinical Advisory Committee (CCRAC) – Senior Investigator Research Award – New Direction (LP Brion), a UTSW consolidated account (R. Heyne) and by the Crystal Charity Ball (CCB) UT Foundation (Lina Chalak). The follow-up was supported by the latter four sources. The study sponsors 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. One of the originally planned outcomes, body composition by Dexascan, was not performed for lack of funding.

Author information

Authors and Affiliations

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

    Jordan D. Reis, Roy Heyne, Charles R. Rosenfeld, Maria Caraig, P. J. Burchfield & Luc P. Brion

  2. Presently at Baylor-Scott & White Hospital System, Dallas, TX, USA

    Jordan D. Reis

  3. Parkland Hospital and Health System, Dallas, TX, USA

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

  4. Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    David B. Nelson

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Contributions

DJR, RH, CRR, and LPB conceptualized and designed the study. MC, RN was the research coordinator for the QI project. SB, MS conducted statistical analyses. Measurements of cystatin-C were obtained at the clinical laboratory at Children’s Medical Center. Measurements of adipokines and cytokines were obtained at UT Southwestern Medical Center. All authors participated in the interpretation of the data, critically reviewed the revisions, and approved the final manuscript as submitted.

Corresponding author

Correspondence to Luc P. Brion.

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Reis, J.D., Heyne, R., Rosenfeld, C.R. et al. Follow-up of a randomized trial optimizing neonatal nutrition in preterm very low birthweight infants: growth, serum adipokines, renal function and blood pressure. J Perinatol 44, 78–86 (2024). https://doi.org/10.1038/s41372-023-01821-2

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