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:

CSF neopterin and beta-2-microglobulin as inflammation biomarkers in newborns with hypoxic–ischemic encephalopathy

Abstract

Background

Inflammation plays a crucial role in the pathogenesis of hypoxic–ischemic encephalopathy (HIE). The aim of this study was to measure inflammation in HIE through an analysis of CSF neopterin and β2-microglobulin and to study the association with brain injury as shown by MRI findings and neurodevelopmental outcomes.

Methods

CSF biomarkers were measured in study patients at 12 and 72 h. Brain injury was evaluated by MRI, and neurodevelopmental outcomes were assessed at 2–3 years of life. An adverse outcome was defined as the presence of motor or cognitive impairment.

Results

Sixty-nine HIE infants were included. Median values of neopterin and β2-microglobulin paralleled the severity of HIE. Adverse outcomes were associated with early neopterin and β2-microglobulin values, late neopterin values, and the neopterin percentage change between the two samples. A cutoff value of 75% neopterin change predicted adverse outcomes with a specificity of 0.9 and a sensitivity of 0.75.

Conclusions

CSF neopterin and β2-microglobulin are elevated in HIE, indicating the activation of inflammation processes. Infants with adverse neurodevelopmental outcomes show higher levels of CSF neopterin and β2-microglobulin. The evolution of neopterin levels provides a better predictive capacity than a single determination.

Impact

  • Brain inflammation in newborns with HIE could be measurable through the analysis of CSF neopterin and β2-microglobulin, both of which are associated with neurodevelopmental outcomes.

  • Our study introduces two inflammatory biomarkers for infants with HIE that seem to show a more stable profile and are easier to interpret than cytokines.

  • CSF neopterin and β2-m may become clinical tools to monitor inflammation in HIE and might eventually be helpful in measuring the response to emerging therapies.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: Flowchart of patient inclusion.
Fig. 2: Cerebrospinal fluid levels of neopterin and β2-m and the percentage change between samples in HIE infants according to the clinical severity of encephalopathy in the first 6 h of life.

Similar content being viewed by others

References

  1. Tagin, M. A., Woolcott, C. G., Vincer, M. J., Whyte, R. K. & Stinson, D. A. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch. Pediatr. Adolesc. Med. 166, 558–566 (2012).

    Article  PubMed  Google Scholar 

  2. Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev. 1, CD003311 (2013).

    Google Scholar 

  3. Drury, P. P., Gunn, E. R., Bennet, L. & Gunn, A. J. Mechanisms of hypothermic neuroprotection. Clin. Perinatol. 41, 161–175 (2014).

    Article  PubMed  Google Scholar 

  4. Hagberg, H. et al. The role of inflammation in perinatal brain injury. Nat. Rev. Neurol. 11, 192–208 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davidson, J. O. et al. Perinatal brain injury: mechanisms and therapeutic approaches. Front. Biosci. 23, 2204–2226 (2018).

    Article  Google Scholar 

  6. Pang, R. et al. Elevated serum IL-10 is associated with severity of neonatal encephalopathy and adverse early childhood outcomes. Pediatr. Res. https://doi.org/10.1038/s41390-021-01438-1 (2021).

  7. Orrock, J. E. et al. Association of brain injury and neonatal cytokine response during therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy. Pediatr. Res. 79, 742–747 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Jenkins, D. D. et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J. Cereb. Blood Flow Metab. 32, 1888–1896 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martín-Ancel, A. et al. Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics 100, 789–794 (1997).

    Article  PubMed  Google Scholar 

  10. Sävman, K., Blennow, M., Gustafson, K., Tarkowski, E. & Hagberg, H. Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr. Res. 43, 746–751 (1998).

    Article  PubMed  Google Scholar 

  11. Ahearne, C. E., Chang, R. Y., Walsh, B. H., Boylan, G. B. & Murray, D. M. Cord blood IL-16 is associated with 3-year neurodevelopmental outcomes in perinatal asphyxia and hypoxic-ischaemic encephalopathy. Dev. Neurosci. 39, 59–65 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Hoffmann, G., Wirleitner, B. & Fuchs, D. Potential role of immune system activation-associated production of neopterin derivatives in humans. Inflamm. Res. 52, 313–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Furukawa, Y., Nishi, K., Kondo, T., Tanabe, K. & Mizuno, Y. Significance of CSF total neopterin and biopterin in inflammatory neurological diseases. J. Neurol. Sci. 111, 65–72 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Millner, M. M. et al. Neopterin concentrations in cerebrospinal fluid and serum as an aid in differentiating central nervous system and peripheral infections in children. Clin. Chem. 44, 161–167 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Dale, R. C., Brilot, F., Fagan, E. & Earl, J. Cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation. Dev. Med. Child Neurol. 51, 317–323 (2009).

    Article  PubMed  Google Scholar 

  16. Hagberg, L. et al. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS Res. Ther. 7, 15 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tiberti, N. et al. Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma brucei gambiense sleeping sickness. PLoS Negl. Trop. Dis. 7, e2088 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bernier, G. M. beta 2-Microglobulin: structure, function and significance. Vox Sang. 38, 323–327 (1980).

    CAS  PubMed  Google Scholar 

  19. Tagarro, A., García-Alix, A., Alarcón, A., Hernanz, A. & Quero, J. Congenital syphilis: beta2-microglobulin in cerebrospinal fluid and diagnosis of neurosyphilis in an affected newborn. J. Perinat. Med. 33, 79–82 (2005).

    Article  PubMed  Google Scholar 

  20. Alarcon, A. et al. Clinical, biochemical, and neuroimaging findings predict long-term neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection. J. Pediatr. 163, 828.e1–834.e1 (2013).

    Article  Google Scholar 

  21. Alarcon, A. et al. Beta2-microglobulin concentrations in cerebrospinal fluid correlate with neuroimaging findings in newborns with symptomatic congenital cytomegalovirus infection. Eur. J. Pediatr. 165, 636–645 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. García-Alix, A. et al. Cerebrospinal fluid beta 2-microglobulin in neonates with central nervous system infections. Eur. J. Pediatr. 154, 309–313 (1995).

    Article  PubMed  Google Scholar 

  23. Svatoňová, J., Bořecká, K., Adam, P. & Lánská, V. Beta2-microglobulin as a diagnostic marker in cerebrospinal fluid: a follow-up study. Dis. Markers 2014, 495402 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Garcia-Alix, A. et al. Development, reliability, and testing of a new rating scale for neonatal encephalopathy. J. Pediatr. 235, 83.e7–91.e7 (2021).

    Article  Google Scholar 

  25. Ormazabal, A. et al. HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins. J. Neurosci. Methods 142, 153–158 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Rutherford, M. et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 9, 39–45 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Martinez-Biarge, M. et al. Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology 76, 2055–2061 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Albers, C. A. & Grieve, A. J. Test review: Bayley, N. (2006). Bayley Scales of Infant and Toddler Development–Third Edition. San Antonio, TX: Harcourt Assessment. J. Psychoeduc. Assess. 25, 180–190 (2007).

  29. Surveillance of Cerebral Palsy in Europe. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Surveillance of Cerebral Palsy in Europe (SCPE). Dev. Med. Child Neurol. 42, 816–824 (2000).

    Article  Google Scholar 

  30. Palisano, R. et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev. Med. Child Neurol. 39, 214–223 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Freeman, S. WPPSI-III – Wechsler Preschool and Primary Scale of Intelligence, Third Edition in Encyclopedia of Autism Spectrum Disorders (ed. Volkmar, F. R.) 3400 (Springer New York, 2013).

  32. Grizzle, R. in Encyclopedia of Child Behavior and Development (eds Goldstein, S. & Naglieri, J. A.) 1553–1555 (Springer US, 2011).

  33. Brown, T. in Encyclopedia of Autism Spectrum Disorders (ed. Volkmar, F. R.) 1925–1939 (Springer New York, 2013).

  34. León-Lozano, M. Z. et al. Cerebrospinal fluid levels of neuron-specific enolase predict the severity of brain damage in newborns with neonatal hypoxic-ischemic encephalopathy treated with hypothermia. PLoS ONE 15, e0234082 (2020).

  35. Chalak, L. F. Inflammatory biomarkers of birth asphyxia. Clin. Perinatol. 43, 501–510 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wintermark, P., Boyd, T., Gregas, M. C., Labrecque, M. & Hansen, A. Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. Am. J. Obstet. Gynecol. 203, 579.e1–579.e9 (2010).

  37. Mir, I. N. et al. Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am. J. Obstet. Gynecol. 213, 849.e1–849.e7 (2015).

    Article  PubMed  Google Scholar 

  38. Osredkar, D. et al. Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic–ischemic brain injury. Resuscitation 85, 567–572 (2014).

    Article  PubMed  Google Scholar 

  39. Balada, R. et al. Enquiring beneath the surface: can a gene expression assay shed light into the heterogeneity among newborns with neonatal encephalopathy? Pediatr. Res. 88, 451–458 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Suzuki, S., Tanaka, K. & Suzuki, N. Ambivalent aspects of interleukin-6 in cerebral ischemia: Inflammatory versus neurotrophic aspects. J. Cereb. Blood Flow Metab. 29, 464–479 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Sweetman, D. U. et al. Neonatal encephalopathy is associated with altered IL-8 and GM-CSF which correlates with outcomes. Front. Pediatr. 8, 556216 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kleuskens, D. G. et al. Pathophysiology of cerebral hyperperfusion in term neonates with hypoxic-ischemic encephalopathy: a systematic review for future research. Front. Pediatr. 9, 631258 (2021).

  43. Wu, Y. W. et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics 137, e20160191 (2016).

  44. Robertson, N. J. et al. Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: a translational study. Neurobiol. Dis. 121, 240–251 (2019).

    Article  CAS  PubMed  Google Scholar 

  45. Hanson, A. L., Schunk, J. E., Corneli, H. M. & Soprano, J. V. A randomized controlled trial of positioning for lumbar puncture in young infants. Pediatr. Emerg. Care 32, 504–507 (2016).

    Article  PubMed  Google Scholar 

Download references

Funding

The authors declare financial support from the “Gerencia Regional de Salud de Castilla y León” (GRS 679/B/11).

Author information

Authors and Affiliations

Authors

Contributions

N.C. participated in the interpretation of data and the literature search and wrote the manuscript. A.G.-A. designed the study, participated in the acquisition and interpretation of data, and contributed to the drafting of the manuscript. J.A. participated in the acquisition and interpretation of data, reviewed the manuscript, and contributed to the drafting of the article. T.A., A.V., and C.S. participated in the acquisition of data and reviewed the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Alfredo Garcia-Alix.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Parental consent was obtained.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carreras, N., Arnaez, J., Valls, A. et al. CSF neopterin and beta-2-microglobulin as inflammation biomarkers in newborns with hypoxic–ischemic encephalopathy. Pediatr Res 93, 1328–1335 (2023). https://doi.org/10.1038/s41390-022-02011-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-022-02011-0

Search

Quick links