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  • Clinical Research Article
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Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants

Pediatric Research volume 93, pages 2014–2018 (2023)Cite this article

Abstract

Background

Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage.

Methods

We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups.

Results

Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time.

Conclusions

The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD.

Impact

  • Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage.

  • Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking.

  • NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.

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Fig. 1: Flowchart of inclusion process.
Fig. 2: Median NfL levels in infants with BPD and infants without BPD.

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Data availability

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

References

  1. Twilhaar, E. S. et al. Cognitive outcomes of children born extremely or very preterm since the 1990s and associated risk factors: a meta-analysis and meta-regression. JAMA Pediatr. 172, 361–367 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Natarajan, G. et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum. Dev. 88, 509–515 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Anderson, P. J. & Doyle, L. W. Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin. Perinatol. 30, 227–232 (2006).

    Article  PubMed  Google Scholar 

  4. DeMauro, S. B. Neurodevelopmental outcomes of infants with bronchopulmonary dysplasia. Pediatr. Pulmonol. 56, 3509–3517 (2021).

    Article  PubMed  Google Scholar 

  5. Bose, C. et al. Blood protein concentrations in the first two postnatal weeks that predict bronchopulmonary dysplasia among infants born before the 28th week of gestation. Pediatr. Res. 69, 347–353 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Leviton, A. et al. Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation. Pediatr. Res. 73, 362–370 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Leviton, A. et al. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early Hum. Dev. 87, 325–330 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Bose, C. L. et al. Systemic inflammation associated with mechanical ventilation among extremely preterm infants. Cytokine 61, 315–322 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Perrone, S., Tataranno, L. M., Stazzoni, G., Ramenghi, L. & Buonocore, G. Brain susceptibility to oxidative stress in the perinatal period. J. Matern. Fetal Neonatal Med. 28(Suppl. 1), 2291–2295 (2015).

    Article  PubMed  Google Scholar 

  10. Vliegenthart, R. J. S., van Kaam, A. H., Aarnoudse-Moens, C. S. H., van Wassenaer, A. G. & Onland, W. Duration of mechanical ventilation and neurodevelopment in preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 104, F631–F635 (2019).

    Article  PubMed  Google Scholar 

  11. Doyle, L. W., Cheong, J. L., Ehrenkranz, R. A. & Halliday, H. L. Early (<8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst. Rev. 10, CD001146 (2017).

    PubMed  Google Scholar 

  12. Burnett, A. C., Cheong, J. L. Y. & Doyle, L. W. Biological and social influences on the neurodevelopmental outcomes of preterm infants. Clin. Perinatol. 45, 485–500 (2018).

    Article  PubMed  Google Scholar 

  13. Kennedy, E., Poppe, T., Tottman, A. & Harding, J. Neurodevelopmental impairment is associated with altered white matter development in a cohort of school-aged children born very preterm. Neuroimage Clin. 31, 102730 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee, M. K., Xu, Z., Wong, P. C. & Cleveland, D. W. Neurofilaments are obligate heteropolymers in vivo. J. Cell Biol. 122, 1337–1350 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Nitz, E. et al. Serum neurofilament light chain in pediatric spinal muscular atrophy patients and healthy children. Ann. Clin. Transl. Neurol. 8, 2013–2024 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Olsson, B. et al. Nfl is a marker of treatment response in children with SMA treated with nusinersen. J. Neurol. 266, 2129–2136 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Alirezaei, Z. et al. Neurofilament light chain as a biomarker, and correlation with magnetic resonance imaging in diagnosis of CNS-related disorders. Mol. Neurobiol. 57, 469–491 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Sjobom, U. et al. Analysis of brain injury biomarker neurofilament light and neurodevelopmental outcomes and retinopathy of prematurity among preterm infants. JAMA Netw. Open 4, e214138 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Depoorter, A. et al. Neurofilament light chain: blood biomarker of neonatal neuronal injury. Front. Neurol. 9, 984 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Goeral, K. et al. Early life serum neurofilament dynamics predict neurodevelopmental outcome of preterm infants. J. Neurol. 268, 2570–2577 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Katz, T. A. et al. Severity of bronchopulmonary dysplasia and neurodevelopmental outcome at 2 and 5 years corrected age. J. Pediatr. 243, 40.e2–46.e2 (2021).

  22. Jobe, A. H. & Bancalari, E. Bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 163, 1723–1729 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Kuhle, J. et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: elisa, electrochemiluminescence immunoassay and Simoa. Clin. Chem. Lab. Med. 54, 1655–1661 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Beerepoot, S. et al. Neurofilament light chain and glial fibrillary acidic protein levels in metachromatic leukodystrophy. Brain 145, 105–118 (2021).

  25. Andreasson, U. et al. A practical guide to immunoassay method validation. Front. Neurol. 6, 179 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Stoll, B. J. et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126, 443–456 (2010).

    Article  PubMed  Google Scholar 

  27. Hoftiezer, L. et al. From population reference to national standard: new and improved birthweight charts. Am. J. Obstet. Gynecol. 220, 383 e381–383.e317 (2019).

    Article  Google Scholar 

  28. Pruessner, J. C., Kirschbaum, C., Meinlschmid, G. & Hellhammer, D. H. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28, 916–931 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Disanto, G. et al. Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann. Neurol. 81, 857–870 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rohrer, J. D. et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology 87, 1329–1336 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leigh, S. R. Brain growth, life history, and cognition in primate and human evolution. Am. J. Primatol. 62, 139–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Bouyssi-Kobar, M. et al. Third trimester brain growth in preterm infants compared with in utero healthy fetuses. Pediatrics 138, e20161640 (2016).

  33. Julious, S. A. Sample Sizes for Clinical Trials 317 (Chapman and Hall/CRC, 2010).

  34. Shein-Chung Chow, H. W. & Shao J. Sample Size Calculations in Clinical Research 480 (Chapman and Hall/CRC, 2007).

  35. David Machin, M. J. C., Tan, S. B. & Tan, S. H. Sample Size Tables for Clinical Studies 2nd edn (Wiley-Blackwell Science, 1997).

  36. Zar, J. H. Biostatistical Analysis 2nd edn (Practice-Hall, 1984).

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Funding

This research was supported by the Amsterdam Reproduction & Development Research Institute.

Author information

Authors and Affiliations

  1. Department of Pediatric Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, Boelelaan 1117, Amsterdam, the Netherlands

    Michelle Romijn, Emma M. Baas, Joost Rotteveel & Martijn J. J. Finken

  2. Department of Neonatology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands

    Michelle Romijn, Wes Onland & Anton H. van Kaam

  3. Amsterdam Reproduction & Development, Amsterdam, the Netherlands

    Michelle Romijn, Wes Onland, Joost Rotteveel, Anton H. van Kaam & Martijn J. J. Finken

  4. Department of Epidemiology and Data Science, Amsterdam UMC location Vrije Universiteit Amsterdam, Boelelaan 1117, Amsterdam, the Netherlands

    Birgit I. Lissenberg-Witte

  5. Emma Neuroscience Group, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands

    Marsh Königs

  6. Department of Pediatrics, Emma Children’s Hospital Amsterdam UMC Follow-Me program & Emma Neuroscience Group, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands

    Jaap Oosterlaan

  7. Neurochemistry Laboratory, Department of Clinical Chemistry Amsterdam Neuroscience, Amsterdam UMC location Vrije Universiteit Amsterdam, Boelelaan 1117, Amsterdam, the Netherlands

    Hans Heijst & Charlotte E. Teunissen

Authors
  1. Michelle Romijn
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Contributions

M.R. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, drafted and revised the article, and approved the final version to be published. E.M.B., B.I.L.-W., W.O., H.H., and M.J.J.F. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, revised it critically for important intellectual content, and approved the final version to be published. M.K., J.O., J.R., A.H.v.K., and C.E.T. made substantial contributions to interpretation of the data, revised the manuscript critically for important intellectual content, and approved the final version to be published.

Corresponding author

Correspondence to Michelle Romijn.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Written informed consent for participant and publication of the study results was obtained from all parents. The study was approved by the Medical Ethics Committee of the VU University Medical Center (protocol number 2019.371).

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Romijn, M., Baas, E.M., Lissenberg-Witte, B.I. et al. Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants. Pediatr Res 93, 2014–2018 (2023). https://doi.org/10.1038/s41390-022-02365-5

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