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:

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 as early predictors of growth, body composition, and neurodevelopment in preterm infants

Journal of Perinatology (2024)Cite this article

Subjects

Abstract

Objective

To investigate the relationship between insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3) and long-term growth, body composition, and neurodevelopment in preterm infants.

Study design

Prospective data were collected from ≤32 weeks gestational age infant cohort (N = 50). IGF-1 and IGFBP-3 concentrations were measured at 1 week (early) and 35 weeks (late) post-menstrual age (PMA). Growth, body composition, and neurodevelopment outcomes were measured at 4 and 12 months PMA. Relationships were measured by linear regression analysis.

Results

Early IGFBP-3 concentration was positively associated with neurodevelopment at 12 months PMA. Early IGF-1 concentration was positively associated with weight at 4 months PMA, head circumference at 12 months PMA, and body mass index at 12 months PMA. Late IGFBP-3 concentration was positively associated with weight at 4 months PMA.

Conclusion

Further investigation of these associations may lead to novel biomarkers and/or treatments to optimize health outcomes in preterm infants.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: CONSORT flow diagram.

Similar content being viewed by others

Data availability

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

References

  1. Geng T, Wang M, Li X, Zhou T, Ma H, Fonseca VA, et al. Birth weight modifies the relation between adulthood levels of insulin-like growth factor-1 and type 2 diabetes: a prospective cohort study. BMJ Open Diabetes Res Care. 2021;9:e001885.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hellstrom A, Ley D, Hansen-Pupp I, Hallberg B, Lofqvist C, van Marter L, et al. Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development. Acta Paediatr. 2016;105:576–86.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hellstrom A, Sigurdsson J, Lofqvist C, Hellgren G, Kistner A. The IGF system and longitudinal growth in preterm infants in relation to gestational age, birth weight and gender. Growth Horm IGF Res. 2020;51:46–57.

    Article  PubMed  Google Scholar 

  4. Hellstrom W, Hortensius LM, Lofqvist C, Hellgren G, Tataranno ML, Ley D, et al. Postnatal serum IGF-1 levels associate with brain volumes at term in extremely preterm infants. Pediatr Res. 2022;93:666-74.

  5. Gonzalez Villamizar JD, Haapala JL, Scheurer JM, Rao R, Ramel SE. Relationships between Early Nutrition, Illness, and Later Outcomes among Infants Born Preterm with Hyperglycemia. J Pediatr. 2020;223:29–33.e2.

    Article  CAS  PubMed  Google Scholar 

  6. Ramel SE, Brown LD, Georgieff MK. The Impact of Neonatal Illness on Nutritional Requirements-One Size Does Not Fit All. Curr Pediatr Rep. 2014;2:248–54.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ramel SE, Demerath EW, Gray HL, Younge N, Boys C, Georgieff MK. The relationship of poor linear growth velocity with neonatal illness and two-year neurodevelopment in preterm infants. Neonatology. 2012;102:19–24.

    Article  PubMed  Google Scholar 

  8. Ramel SE, Haapala J, Super J, Boys C, Demerath EW. Nutrition, Illness and Body Composition in Very Low Birth Weight Preterm Infants: Implications for Nutritional Management and Neurocognitive Outcomes. Nutrients. 2020;12:145.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ingolfsland EC, Haapala JL, Buckley LA, Demarath EW, Guiang SF, Ramel SE. Late Growth and Changes in Body Composition Influence Odds of Developing Retinopathy of Prematurity among Preterm Infants. Nutrients. 2019;12:78.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mollers LS, Yousuf EI, Hamatschek C, Morrison KM, Hermanussen M, Fusch C, et al. Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome. Pediatr Res. 2022;91:1350–60.

  11. Kantake M, Ikeda N, Nakaoka H, Ohkawa N, Tanaka T, Miyabayashi K, et al. IGF1 gene is epigenetically activated in preterm infants with intrauterine growth restriction. Clin Epigenetics. 2020;12:108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pr Endocrinol Metab. 2007;3:302–10.

    Article  CAS  Google Scholar 

  13. Hellstrom A, Ley D, Hallberg B, Lofqvist C, Hansen-Pupp I, Ramenghi LA, et al. IGF-1 as a Drug for Preterm Infants: A Step-Wise Clinical Development. Curr Pharm Des. 2017;23:5964–70.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nagel EM, Gonzalez VJ, Bye JK, Super J, Demerath EW, Ramel SE. Enhanced Parenteral Nutrition Is Feasible and Safe in Very Low Birth Weight Preterm Infants: A Randomized Trial. Neonatology. 2023;120:242–49.

  15. Morris EE, Miller NC, Marka NA, Super JL, Nagel EM, Gonzalez JD, et al. Randomized Trial of Early Enhanced Parenteral Nutrition and Later Neurodevelopment in Preterm Infants. Nutrients. 2022;14:3890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Paulsen ME, Marka N, Nagel EM, Gonzalez Villamizar JD, Nathan BM, Ramel SE. An exploratory study of clinical factors associated with IGF-1 and IGFBP-3 in preterm infants. Pediatr Res. 2024. https://doi.org/10.1038/s41390-023-02970-y. [Epub ahead of print].

  17. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA. 2015;314:1039–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ellis KJ, Yao M, Shypailo RJ, Urlando A, Wong WW, Heird WC. Body-composition assessment in infancy: air-displacement plethysmography compared with a reference 4-compartment model. Am J Clin Nutr. 2007;85:90–5.

    Article  CAS  PubMed  Google Scholar 

  19. Fomon SJ, Haschke F, Ziegler EE, Nelson SE. Body composition of reference children from birth to age 10 years. Am J Clin Nutr. 1982;35:1169–75.

    Article  CAS  PubMed  Google Scholar 

  20. Simon L, Hanf M, Frondas-Chauty A, Darmaun D, Rouger V, Gascoin G, et al. Neonatal growth velocity of preterm infants: The weight Z-score change versus Patel exponential model. PLoS One. 2019;14:e0218746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pfister KM, Gray HL, Miller NC, Demerath EW, Georgieff MK, Ramel SE. Exploratory study of the relationship of fat-free mass to speed of brain processing in preterm infants. Pediatr Res. 2013;74:576–83.

    Article  CAS  PubMed  Google Scholar 

  22. Hickey MK, Miller NC, Haapala J, Demerath EW, Pfister KM, Georgieff MK, et al. Infants exposed to antibiotics after birth have altered recognition memory responses at one month of age. Pediatr Res. 2021;89:1500–7.

    Article  CAS  PubMed  Google Scholar 

  23. Hellstrom A, Engstrom E, Hard AL, Albertsson-Wikland K, Carlsson B, Niklasson A, et al. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003;112:1016–20.

    Article  PubMed  Google Scholar 

  24. Yumani DFJ, Calor AK, van Weissenbruch MM. The Course Of IGF-1 Levels and Nutrient Intake in Extremely and Very Preterm Infants During Hospitalisation. Nutrients. 2020;12:675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hansen-Pupp I, Hellstrom A, Hamdani M, Tocoian A, Kreher NC, Ley D, et al. Continuous longitudinal infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants: Evaluation of feasibility in a phase II study. Growth Horm IGF Res. 2017;36:44–51.

    Article  CAS  PubMed  Google Scholar 

  26. Ley D, Hallberg B, Hansen-Pupp I, Dani C, Ramenghi LA, Marlow N, et al. rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial. J Pediatr. 2019;206:56–65.e8.

    Article  CAS  PubMed  Google Scholar 

  27. Yumani DF, Lafeber HN, van Weissenbruch MM. Dietary proteins and IGF I levels in preterm infants: determinants of growth, body composition, and neurodevelopment. Pediatr Res. 2015;77:156–63.

    Article  CAS  PubMed  Google Scholar 

  28. Hansen-Pupp I, Hovel H, Hellstrom A, Hellstrom-Westas L, Lofqvist C, Larsson EM, et al. Postnatal decrease in circulating insulin-like growth factor-I and low brain volumes in very preterm infants. J Clin Endocrinol Metab. 2011;96:1129–35.

    Article  CAS  PubMed  Google Scholar 

  29. Euser AM, Finken MJ, Kharagjitsingh AV, Alizadeh BZ, Roep BO, Meulenbelt I, et al. IGF1 promoter polymorphism and cranial growth in individuals born very preterm. Horm Res Paediatr. 2011;76:27–34.

    Article  CAS  PubMed  Google Scholar 

  30. Hansen-Pupp I, Hovel H, Lofqvist C, Hellstrom-Westas L, Fellman V, Huppi PS, et al. Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants. Pediatr Res. 2013;74:564–9.

    Article  CAS  PubMed  Google Scholar 

  31. Okuma C, Hernandez MI, Rodriguez P, Flores R, Avila A, Cavada G, et al. Microstructural brain and multivoxel spectroscopy in very low birth weight infants related to insulin-like growth factor concentration and early growth. Horm Res Paediatr. 2013;79:197–207.

    Article  CAS  PubMed  Google Scholar 

  32. Diggikar S, Gurumoorthy P, Trif P, Mudura D, Nagesh NK, Galis R, et al. Retinopathy of prematurity and neurodevelopmental outcomes in preterm infants: A systematic review and meta-analysis. Front Pediatr. 2023;11:1055813.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kline JE, Illapani VSP, He L, Altaye M, Parikh NA. Retinopathy of Prematurity and Bronchopulmonary Dysplasia are Independent Antecedents of Cortical Maturational Abnormalities in Very Preterm Infants. Sci Rep. 2019;9:19679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stark A, Dammann C, Nielsen HC, Volpe MV. A Pathogenic Relationship of Bronchopulmonary Dysplasia and Retinopathy of Prematurity? A Review of Angiogenic Mediators in Both Diseases. Front Pediatr. 2018;6:125.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kramer BW, Niklas V, Abman S. Bronchopulmonary Dysplasia and Impaired Neurodevelopment-What May Be the Missing Link? Am J Perinatol. 2022;39:S14–S7.

    Article  PubMed  Google Scholar 

  36. Lin S, Fan LW, Rhodes PG, Cai Z. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol. 2009;217:361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Can E, Bulbul A, Uslu S, Bolat F, Comert S, Nuhoglu A. Early Aggressive Parenteral Nutrition Induced High Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) Levels Can Prevent Risk of Retinopathy of Prematurity. Iran J Pediatr. 2013;23:403–10.

    PubMed  PubMed Central  Google Scholar 

  38. Dai H, Goto YI, Itoh M. Insulin-Like Growth Factor Binding Protein-3 Deficiency Leads to Behavior Impairment with Monoaminergic and Synaptic Dysfunction. Am J Pathol. 2017;187:390–400.

    Article  CAS  PubMed  Google Scholar 

  39. Kalluri HS, Dempsey RJ. IGFBP-3 inhibits the proliferation of neural progenitor cells. Neurochem Res. 2011;36:406–11.

    Article  CAS  PubMed  Google Scholar 

  40. Beres AM. Time is of the Essence: A Review of Electroencephalography (EEG) and Event-Related Brain Potentials (ERPs) in Language Research. Appl Psychophysiol Biofeedback. 2017;42:247–55.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Colvin M, McGuire W, Fowlie PW. Neurodevelopmental outcomes after preterm birth. BMJ. 2004;329:1390–3.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hansen-Pupp I, Lofqvist C, Polberger S, Niklasson A, Fellman V, Hellstrom A, et al. Influence of insulin-like growth factor I and nutrition during phases of postnatal growth in very preterm infants. Pediatr Res. 2011;69:448–53.

    Article  CAS  PubMed  Google Scholar 

  43. Ohkawa N, Shoji H, Kitamura T, Suganuma H, Yoshikawa N, Suzuki M, et al. IGF-I, leptin and active ghrelin levels in very low birth weight infants during the first 8 weeks of life. Acta Paediatr. 2010;99:37–41.

    Article  CAS  PubMed  Google Scholar 

  44. Hikino S, Ihara K, Yamamoto J, Takahata Y, Nakayama H, Kinukawa N, et al. Physical growth and retinopathy in preterm infants: involvement of IGF-I and GH. Pediatr Res. 2001;50:732–6.

    Article  CAS  PubMed  Google Scholar 

  45. Kajantie E, Dunkel L, Rutanen EM, Seppala M, Koistinen R, Sarnesto A, et al. IGF-I, IGF binding protein (IGFBP)-3, phosphoisoforms of IGFBP-1, and postnatal growth in very low birth weight infants. J Clin Endocrinol Metab. 2002;87:2171–9.

    Article  CAS  PubMed  Google Scholar 

  46. Lo HC, Tsao LY, Hsu WY, Chi CY, Tsai FA. Changes in serum insulin-like growth factors, not leptin, are associated with postnatal weight gain in preterm neonates. JPEN J Parenter Enter Nutr. 2005;29:87–92.

    Article  CAS  Google Scholar 

  47. Kwinta P, Klimek M, Wojcik M, Grudzien A, Drozdz D, Pietrzyk JJ. Insulin-like growth factor-1 (IGF-1) serum concentration among 7-year-old extremely low birth weight children-an indicator of growth problems. J Pediatr Endocrinol Metab. 2011;24:651–7.

    Article  CAS  PubMed  Google Scholar 

  48. de Jong M, Cranendonk A, Twisk JW, van Weissenbruch MM. IGF-I and relation to growth in infancy and early childhood in very-low-birth-weight infants and term born infants. PLoS One. 2017;12:e0171650.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Patel L, Cavazzoni E, Whatmore AJ, Carney S, Wales JK, Clayton PE, et al. The contributions of plasma IGF-I, IGFBP-3 and leptin to growth in extremely premature infants during the first two years. Pediatr Res. 2007;61:99–104.

    Article  CAS  PubMed  Google Scholar 

  50. Gonzalez Villamizar JH, Haapala JL, Scheurer, JM, Rao, R, Ramel, SE. Relationships between early nutrition, illness, and later outcomes among infants born preterm with hyperglycemia. J Pediatrics. 2020;223:29–33.e2.

  51. Scheurer JM, Gray HL, Demerath EW, Rao R, Ramel SE. Diminished growth and lower adiposity in hyperglycemic very low birth weight neonates at 4 months corrected age. J Perinatol. 2016;36:145–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Jennifer Super, RD for her involvement in consultation regarding nutritional aspects of this work. We thank Jensina Ericksen, RN Jenna Wassenaar, and Neely Miller, MPH for their assistance with this study. We are also grateful to the participants and their parents for taking part in this study.

Funding

SR was supported by University of Minnesota Department of Pediatrics “R Award”; MEP was supported by NIH/NICHD grant K12HD055887, EMN was supported by NIH/NIDDK grant T32DK083250 and NIH/NICHD grant K99HD108276, NM and SL were supported by University of Minnesota CTSA UL1TR002494.

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

    Megan E. Paulsen, Juan David Gonzalez Villamizar & Sara Ramel

  2. Children’s Minnesota, Minneapolis, MN, USA

    Megan E. Paulsen & Juan David Gonzalez Villamizar

  3. Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, USA

    Megan E. Paulsen & Sara Ramel

  4. Biostatistical Design and Analysis Center, Clinical Translational Science Institute, University of Minnesota, Minneapolis, MN, USA

    Nicholas Marka & Scott Lunos

  5. University of Minnesota School of Public Health, Minneapolis, MN, USA

    Emily M. Nagel

  6. Division of Endocrinology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

    Brandon Nathan

Authors
  1. Megan E. Paulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas Marka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott Lunos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emily M. Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan David Gonzalez Villamizar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brandon Nathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sara Ramel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SER conceived and designed the study. EMN, JDGV and MEP performed data acquisition. NM and SL analyzed data. All authors interpreted data. MEP drafted the manuscript, tables, figures. All authors critically revised the manuscript, approve submission of manuscript for publication, and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Megan E. Paulsen.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paulsen, M.E., Marka, N., Lunos, S. et al. Insulin-like growth factor-1 and insulin-like growth factor binding protein-3 as early predictors of growth, body composition, and neurodevelopment in preterm infants. J Perinatol (2024). https://doi.org/10.1038/s41372-024-01933-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41372-024-01933-3

Search

Advanced search

Quick links