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.

  • Clinical Research Article
  • Published:

An exploratory study of clinical factors associated with IGF-1 and IGFBP-3 in preterm infants

Pediatric Research (2024)Cite this article

Abstract

Background

Despite advances in parenteral nutrition, postnatal growth failure in very low birthweight (VLBW) preterm infants is common and associated with chronic health problems. Insulin-like growth factor 1 (IGF-1) is positively associated with improved infant growth, but factors which promote IGF-1 levels in this population have not been clearly identified. The objective of this study was to explore early factors that influence IGF-1 in VLBW preterm infants.

Methods

VLBW infants were enrolled into a prospective, randomized controlled nutrition trial (N = 87). Outcome measures included IGF-1 and IGFBP-3 levels measured at 35 weeks PMA. Linear regression analyses tested the relationships between candidate clinical predictors and levels of IGF-1 and IGFBP-3.

Results

Higher protein intake, longer duration of parenteral nutrition, and lower IGFBP-3 levels at 1 week of life were associated with lower IGF-1 levels at 35 weeks PMA. Neither early markers of insulin resistance nor degree of illness were associated with IGF-1 levels at 35 weeks PMA.

Conclusion

Optimization of early nutrient intake, and attention to route of delivery, may have a lasting influence on IGF-1/IGFBP-3, and in turn, long-term health outcomes.

Impact

  • In very low birthweight preterm infants, early protein intake, duration of parenteral nutrition, and insulin-like growth factor binding protein 3 (IGFBP-3) levels at 1 week of life are positively associated with insulin-like growth factor 1 (IGF-1) levels at 35 weeks postmenstrual age.

  • Data from this study highlight the influence of early nutrition on components of the endocrine axis in preterm infants.

  • Strategies aimed at early initiation of enteral nutrition, as well as optimizing composition of parenteral nutrition, may bolster hormones involved in promoting preterm infant growth.

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.
Fig. 2: Early parenteral protein and IGFBP-3 levels are associated with Late IGF-1 levels.
Fig. 3: Early Markers Associated with IGF-1/IGFBP-3 at 35 weeks PMA.

Similar content being viewed by others

Data availability

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

References

  1. T. T. Colaizy, S. B. D., K. M. Mcnelis, B. B. Poindexter. in Avery’s Diseases of the Newborn (Christine A. Gleason, S. E. J. ed.) Ch. 68, 1009-1022 (Elsevier, 2018).

  2. Lee, S. M. et al. Prediction of postnatal growth failure among very low birth weight infants. Sci. Rep. 8, 3729 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lammertink, F., Vinkers, C. H., Tataranno, M. L. & Benders, M. Premature birth and developmental programming: mechanisms of resilience and vulnerability. Front. Psychiatry 11, 531571 (2020).

    Article  PubMed  Google Scholar 

  4. Gonzalez Villamizar, J. D., Haapala, J. L., Scheurer, J. M., Rao, R. & Ramel, S. E. Relationships between early nutrition, illness, and later outcomes among infants born preterm with hyperglycemia. J. Pediatr. 223, 29–33.e22 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Ramel, S. E., Brown, L. D. & Georgieff, M. K. The impact of neonatal illness on nutritional requirements-one size does not fit all. Curr. Pediatr. Rep. 2, 248–254 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  6. Ramel, S. E. et al. The relationship of poor linear growth velocity with neonatal illness and two-year neurodevelopment in preterm infants. Neonatology 102, 19–24 (2012).

    Article  PubMed  Google Scholar 

  7. Ramel, S. E., Haapala, J., Super, J., Boys, C. & Demerath, E. W. Nutrition, illness and body composition in very low birth weight preterm infants: implications for nutritional management and neurocognitive outcomes. Nutrients 12, 145 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  8. Kajantie, E. 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. 87, 2171–2179 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Hellstrom, A. et al. Insulin-Like Growth Factor 1 has multisystem effects on foetal and preterm infant development. Acta Paediatr. 105, 576–586 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  10. Gillman, M. W. et al. Meeting report on the 3rd International Congress on Developmental Origins of Health and Disease (Dohad). Pediatr. Res 61, 625–629 (2007).

    Article  PubMed  Google Scholar 

  11. Mollers, L. S. et al. Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome. Pediatr. Res. 91, 1350–1360 (2022).

  12. Patel, L. 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. 61, 99–104 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. 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. 51, 46–57 (2020).

    Article  PubMed  Google Scholar 

  14. Nagel, E. M. et al. Enhanced parenteral nutrition is feasible and safe in very low birth weight preterm infants: a randomized trial. Neonatology 120, 242–249 (2023).

  15. Morris, E. E. et al. Randomized trial of early enhanced parenteral nutrition and later neurodevelopment in preterm infants. Nutrients 14, 3890 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Baron, R. M. & Kenny, D. A. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J. Pers. Soc. Psychol. 51, 1173–1182 (1986).

    Article  CAS  PubMed  Google Scholar 

  17. Team, R. C. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, https://www.R-project.org/ (2022).

  18. Fu, T. T. et al. Correlation of Nicu anthropometry in extremely preterm infants with brain development and language scores at early school age. Sci. Rep. 13, 15273 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Miller, A. N. et al. Linear growth is associated with successful respiratory support weaning in infants with bronchopulmonary dysplasia. J. Perinatol. 42, 544–545 (2022).

    Article  Google Scholar 

  20. Geng, T. 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 9, e001885 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  21. Kantake, M. et al. Igf1 gene is epigenetically activated in preterm infants with intrauterine growth restriction. Clin. Epigenet. 12, 108 (2020).

    Article  CAS  Google Scholar 

  22. Hellstrom, W. et al. Postnatal serum Igf-1 levels associate with brain volumes at term in extremely preterm infants. Pediatr. Res. 93, 666–674 (2023).

  23. Chung, J. K. et al. Development and verification of a pharmacokinetic model to optimize physiologic replacement of Rhigf-1/Rhigfbp-3 in preterm infants. Pediatr. Res. 81, 504–510 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Hansen-Pupp, I. 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. 36, 44–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Hellstrom, A. et al. Igf-1 as a drug for preterm infants: a step-wise clinical development. Curr. Pharm. Des. 23, 5964–5970 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  26. Ley, D. et al. Rhigf-1/Rhigfbp-3 in preterm infants: a phase 2 randomized controlled trial. J. Pediatr. 206, 56–65.e58 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Yumani, D. F., Lafeber, H. N. & van Weissenbruch, M. M. Dietary proteins and Igf I levels in preterm infants: determinants of growth, body composition, and neurodevelopment. Pediatr. Res. 77, 156–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Meyers, J. M., Greecher, C. P., Shaffer, M. L. & Shenberger, J. S. Potential influence of total parenteral nutrition on body composition at discharge in preterm infants. J. Matern. Fetal Neonatal. Med. 26, 1548–1553 (2013).

    Article  PubMed  Google Scholar 

  29. Hansen-Pupp, I. et al. Influence of insulin-like growth factor I and nutrition during phases of postnatal growth in very preterm infants. Pediatr. Res. 69, 448–453 (2011).

    Article  CAS  Google Scholar 

  30. Engstrom, E., Niklasson, A., Wikland, K. A., Ewald, U. & Hellstrom, A. The role of maternal factors, postnatal nutrition, weight gain, and gender in regulation of serum Igf-I among preterm infants. Pediatr. Res. 57, 605–610 (2005).

    Article  PubMed  Google Scholar 

  31. Lafeber, H. N., van de Lagemaat, M., Rotteveel, J. & van Weissenbruch, M. Timing of nutritional interventions in very-low-birth-weight infants: optimal neurodevelopment compared with the onset of the metabolic syndrome. Am. J. Clin. Nutr. 98, 556S–560S (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Smith, W. J., Underwood, L. E. & Clemmons, D. R. Effects of caloric or protein restriction on insulin-like growth Factor-I (Igf-I) and Igf-binding proteins in children and adults. J. Clin. Endocrinol. Metab. 80, 443–449 (1995).

    CAS  PubMed  Google Scholar 

  33. Smith, W. J., Underwood, L. E., Keyes, L. & Clemmons, D. R. Use of insulin-like growth Factor I (Igf-I) and Igf-Binding protein measurements to monitor feeding of premature infants. J. Clin. Endocrinol. Metab. 82, 3982–3988 (1997).

    CAS  PubMed  Google Scholar 

  34. Counts, D. R., Gwirtsman, H., Carlsson, L. M., Lesem, M. & Cutler, G. B. Jr. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the Insulin-Like Growth Factors (Igfs), and the Igf-Binding proteins. J. Clin. Endocrinol. Metab. 75, 762–767 (1992).

    CAS  PubMed  Google Scholar 

  35. Reynolds, C. M., Gray, C., Li, M., Segovia, S. A. & Vickers, M. H. Early life nutrition and energy balance disorders in offspring in later life. Nutrients 7, 8090–8111 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Reynolds, C. M., Perry, J. K. & Vickers, M. H. Manipulation of the growth hormone-insulin-Like Growth Factor (Gh-Igf) axis: a treatment strategy to reverse the effects of early life developmental programming. Int J. Mol. Sci. 18, 1729 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  37. Eguchi, K. et al. Insulin-Like growth factor binding protein-3 suppresses osteoblast differentiation via bone morphogenetic Protein-2. Biochem. Biophys. Res. Commun. 507, 465–470 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Bloomfield, F. H. et al. Early amino acids in extremely preterm infants and neurodisability at 2 years. N. Engl. J. Med. 387, 1661–1672 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Hansen-Pupp, I. et al. Postnatal decrease in circulating insulin-like growth factor-I and low brain volumes in very preterm infants. J. Clin. Endocrinol. Metab. 96, 1129–1135 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Hansen-Pupp, I. et al. Circulatory insulin-like growth factor-i and brain volumes in relation to neurodevelopmental outcome in very preterm infants. Pediatr. Res. 74, 564–569 (2013).

Download references

Acknowledgements

We would like to thank Scott Lunos, MS for his involvement in the revision of this manuscript. We would like to thank Jennifer Super, RD for her involvement in consultation regarding nutritional aspects of this work. We are also grateful to the participants and their parents for taking part in this study.

Funding

Funding

University of Minnesota Department of Pediatrics “R Award” to S.E.R.; M.E.P. was supported by NIH/NICHD grant K12HD055887, E.M.N. was supported by NIH/NIDDK grant T32DK083250 and NIH/NICHD grant K99HD108276.

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 E. Ramel

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

    Megan E. Paulsen & Sara E. Ramel

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

    Nicholas Marka

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

    Emily M. Nagel

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

    Brandon M. 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. Emily M. Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan David Gonzalez Villamizar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brandon M. Nathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara E. Ramel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.E.R. conceived and designed the study. E.M.N., J.D.G.V. and M.E.P. performed data acquisition. N.M. analyzed data. All authors interpreted data. M.E.P. and N.M. drafted the manuscript, tables, and 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.

Consent statement

Parents of patients were required to provide informed consent to participate in this study.

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., Nagel, E.M. et al. 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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-023-02970-y

This article is cited by

Search

Advanced search

Quick links