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Pro-inflammatory biomarkers and long term neurological outcomes in hypothermia plus melatonin treated asphyxiated newborns. A preliminary approach

Pediatric Research volume 97, pages 2217–2223 (2025)Cite this article

Abstract

Objective

To evaluate serum neuronal and inflammatory biomarkers in asphyxiated newborns treated with hypothermia alone or hypothermia plus melatonin, and whether biomarkers correlate with neurodevelopmental outcomes.

Design

A pilot multicentre, randomized, controlled, double blind clinical trial. 25 newborns were recruited. Neonatal neural biomarkers were measured in serum samples at hospital admission (T0), 24 h (T1), 72 hours (T2) and 7−10 days of age (T3). Neurodevelopmental scales were performed at 6 and 18 months. Treated patients received a daily dose of intravenous melatonin, for 3 days.

Results

In melatonin-treated group, lower plasma levels of GM-CSF, IL-2 and IL-13 at T1 were measured vs placebo-group. We also corroborated, at T2, lower concentrations of GM-CSF, as well as IL-7 and IL-13 at T3. Throughout the study period, we found a significant decrease in GM-CSF concentrations in the treatment group. We have also observed sustained decrease over time of GM-CSF and inflammatory cytokines IL-2, IL-7 and IL-13 correlates with better neurodevelopmental outcomes at 6 and 18 months.

Conclusions

In neonates affected by hypoxic-ischemic encephalopathy, the addition of iv melatonin to hypothermia therapy affects plasma biomarker concentration in the first week of life, with a high correlation with long-term neurological prognosis.

Impact

  • Several plasma cytokines act as inflammatory mediators and biomarkers of hypoxia-ischemia-acquired neonatal brain damage.

  • In animal research, melatonin has been shown to be a safe substance with proven anti-inflammatory and neuroprotective effects.

  • Findings from our clinical trial show that melatonin affects plasma inflammatory biomarker concentration within the first week of life. This effect may be related to long-term neurological prognosis.

  • To date, this is the only clinical trial in human infants including asphyxiated neonates treated with hypothermia and intravenous melatonin. Our study could help design future larger, well-designed clinical trials to clarify its effects in asphyxiated neonates.

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Fig. 1
Fig. 2: Correlations between the decrease in serum biomarkers level and the score on the Bayley III and Tardieu scales.

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Acknowledgements

Special thanks to all the healthcare professionals caring for neonates in the neonatal intensive care units of the hospitals participating in this clinical trial.

Funding

This research project was obtained in a public and competitive call for grant applications, financed through the national programme (Spanish Ministry of Health): Call for Grants for Independent Clinical Research, 2011. Reference Number EC11-222.

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Authors and Affiliations

  1. Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain

    Antonio Jerez Calero & Antonio Molina Carballo

  2. Department of Pediatrics, Faculty of Medicine. University of Granada, Granada, Spain

    Antonio Jerez Calero, Ángela Benítez Feliponi, Hatim Azaryah & Antonio Molina Carballo

  3. Department of Pediatrics, Clínico San Cecilio University Hospital, Granada, Spain

    Francisco Contreras Chova

  4. Department of Pediatrics, Virgen de las Nieves University Hospital, Granada, Spain

    Jose Antonio Hurtado Suazo & M. Fernanda Moreno Galdó

Authors
  1. Antonio Jerez Calero
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  2. Francisco Contreras Chova
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  3. Ángela Benítez Feliponi
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  4. Hatim Azaryah
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  6. M. Fernanda Moreno Galdó
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  7. Antonio Molina Carballo
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Contributions

A.J.C. and A.M.C. designed the study. A.J.C., F.C.C., J.A.H.S., and M.F.M.G. undertook the experimental work. H.A. performed the statistical analysis; A.B.F. participated in the neurological follow-up. A.J.C., F.C.C., and A.M.C. wrote the paper, which was edited and approved by all co-authors. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Antonio Jerez Calero.

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The authors declare no competing interests.

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All parents gave their written informed consent to enroll their newborns.

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Jerez Calero, A., Contreras Chova, F., Benítez Feliponi, Á. et al. Pro-inflammatory biomarkers and long term neurological outcomes in hypothermia plus melatonin treated asphyxiated newborns. A preliminary approach. Pediatr Res 97, 2217–2223 (2025). https://doi.org/10.1038/s41390-024-03742-y

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