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:

Perinatal blood biomarkers for the identification of brain injury in very low birth weight growth-restricted infants

Journal of Perinatology volume 41, pages 2252–2260 (2021)Cite this article

Subjects

Abstract

Objective

To determine if blood biomarkers measured at delivery and shortly after birth can identify growth-restricted infants at risk for developing severe brain injury.

Study design

In a cohort of very low birth weight neonates, fetal growth restricted (FGR) (birth weight <10%) were compared to non-FGR neonates, and within the FGR group those with brain injury were compared to those without. Biomarkers were measured in cord blood at delivery, and daily for the 1st 5 days of life.

Result

FGR was associated with significantly higher levels of interleukin (IL)-6, IL-8, IL-10, and lower levels of vascular endothelial growth factor (VEGF). FGR and brain injury were associated with significantly higher levels of IL-6, IL-8, IL-10, and glial fibrillary acidic protein (GFAP).

Conclusion

Interleukins may be involved in a common pathway contributing to both the development of growth restriction and brain injury, and GFAP may help identify brain injury within this growth-restricted group.

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

Similar content being viewed by others

References

  1. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8:110–24.

    Article  Google Scholar 

  2. Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed. 2008;93:F153–61.

    Article  CAS  Google Scholar 

  3. Malhotra A, Ditchfield M, Fahey MC, et al. Detection and assessment of brain injury in the growth-restricted fetus and neonate. Pediatr Res. 2017;82:184–93.

    Article  Google Scholar 

  4. Wei JC, Catalano R, Profit J, Gould JB, Lee HC. Impact of antenatal steroids on intraventricular hemorrhage in very-low-birth weight infants. J Perinatol. 2016;36:352–356.

    Article  CAS  Google Scholar 

  5. Pascal A, Govaert P, Oostra A, Naulaers G, Ortibus E, Van den Broeck C. Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review. Dev Med Child Neurol. 2018;60:342–55.

    Article  Google Scholar 

  6. Stewart A, Tekes A, Huisman TA, et al. Glial fibrillary acidic protein as a biomarker for periventricular white matter injury. Am J Obstet Gynecol. 2013;209:27.e1–27.e7.

    Article  CAS  Google Scholar 

  7. Dietrick B, Molloy E, Massaro AN, et al. Plasma and CSF candidate biomarkers of neonatal encephalopathy severity and neurodevelopmental outcomes. J Pediatr. 2020.

  8. Lausten-Thomsen U, Olsen M, Greisen G, Schmiegelow K. Inflammatory markers in umbilical cord blood from small-for-gestational-age newborns. Fetal Pediatr Pathol. 2014;33:114–118.

    Article  CAS  Google Scholar 

  9. Amarilyo G, Oren A, Mimouni FB, Ochshorn Y, Deutsch V, Mandel D. Increased cord serum inflammatory markers in small-for-gestational-age neonates. J Perinatol. 2011;31:30–32.

    Article  CAS  Google Scholar 

  10. Lindner U, Tutdibi E, Binot S, Monz D, Hilgendorff A, Gortner L. Levels of cytokines in umbilical cord blood in small for gestational age preterm infants. Klin Pediatr. 2013;225:70–74.

    Article  CAS  Google Scholar 

  11. Garcia JM, Stillings SA, Leclerc JL, et al. Role of interleukin-10 in acute brain injuries. Front Neurol. 2017;8:244.

    Article  Google Scholar 

  12. Massaro AN, Wu YW, Bammler TK, et al. Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2018;194:67–75.e1.

    Article  CAS  Google Scholar 

  13. O’Hare FM, Watson RW, O’Neill A, et al. Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy. Acta Paediatr. 2017;106:561–567.

    Article  Google Scholar 

  14. Poralla C, Hertfelder HJ, Oldenburg J, Muller A, Bartmann P, Heep A. Elevated interleukin-6 concentration and alterations of the coagulation system are associated with the development of intraventricular hemorrhage in extremely preterm infants. Neonatology. 2012;102:270–275.

    Article  CAS  Google Scholar 

  15. Lv H, Wang Q, Wu S, et al. Neonatal hypoxic-ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta. 2015;450:282–97.

    Article  CAS  Google Scholar 

  16. Sweetman DU, Onwuneme C, Watson WR, Murphy JF, Molloy EJ. Perinatal asphyxia and erythropoietin and VEGF: serial serum and cerebrospinal fluid responses. Neonatology. 2017;111:253–259.

    Article  CAS  Google Scholar 

  17. McElrath TF, Allred EN, Van Marter L, Fichorova RN, Leviton A.ELGAN Study Investigators Perinatal systemic inflammatory responses of growth-restricted preterm newborns. Acta Paediatr. 2013;102:e439–42.

    Article  CAS  Google Scholar 

  18. Ennen CS, Huisman TA, Savage WJ, et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. Am J Obstet Gynecol. 2011;205:251–e1-7.

    Article  CAS  Google Scholar 

  19. Chalak LF, Sanchez PJ, Adams-Huet B, Laptook AR, Heyne RJ, Rosenfeld CR. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr. 2014;164:468–74.e1.

    Article  CAS  Google Scholar 

  20. White CR, Doherty DA, Henderson JJ, Kohan R, Newnham JP, Pennell CE. Benefits of introducing universal umbilical cord blood gas and lactate analysis into an obstetric unit. Aust N Z J Obstet Gynaecol. 2010;50:318–28.

    Article  Google Scholar 

  21. Westgate J, Garibaldi JM, Greene KR. Umbilical cord blood gas analysis at delivery: a time for quality data. Br J Obstet Gynaecol. 1994;101:1054–63.

    Article  CAS  Google Scholar 

  22. American College of Obstetricians and Gynecologists, American Academy of Pediatricians. Criteria required to define an acute intrapartum hypoxic event as sufficient to cause cerebral palsy. In: Neonatal encephalopathy and cerebral palsy. Washington DC: ACOG; 2003:73–80.

  23. Riley RJ, Johnson JWC. Collecting and analyzing cord blood gases. Clin Obstet Gynecol. 1993;36:13–23.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funded by NICHD R01HD086058 “Adult Biomarkers in Neonatal Brain Injury and Development”.

Author information

Authors and Affiliations

  1. School of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Shanna L. Yue

  2. Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ahizechukwu C. Eke & Ernest M. Graham

  3. Biostatistics, Epidemiology and Data Management Core, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Dhananjay Vaidya

  4. Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Frances J. Northington

  5. Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Frances J. Northington & Ernest M. Graham

  6. Department of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Allen D. Everett

Authors
  1. Shanna L. Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahizechukwu C. Eke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dhananjay Vaidya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frances J. Northington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Allen D. Everett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ernest M. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ernest M. Graham.

Ethics declarations

Conflict of interest

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.

Disclosures

Under a license agreement between ImmunArray Ltd. and the Johns Hopkins University, the University and Dr. Everett are entitled to royalties on an invention described in this study and discussed in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

PRECIS

Biomarkers measured in cord blood at delivery and neonatal serum after birth may identify growth-restricted infants at risk for developing severe brain injury.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yue, S.L., Eke, A.C., Vaidya, D. et al. Perinatal blood biomarkers for the identification of brain injury in very low birth weight growth-restricted infants. J Perinatol 41, 2252–2260 (2021). https://doi.org/10.1038/s41372-021-01112-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-021-01112-8

Search

Advanced search

Quick links