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  • Clinical Research Article
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Plasma serotonergic biomarkers are associated with hypoxemia events in preterm neonates

Pediatric Research volume 94, pages 1436–1443 (2023)Cite this article

Abstract

Background

Hypoxemia is a physiological manifestation of immature respiratory control in preterm neonates, which is likely impacted by neurotransmitter imbalances. We investigated relationships between plasma levels of the neurotransmitter serotonin (5-HT), metabolites of tryptophan (TRP), and parameters of hypoxemia in preterm neonates.

Methods

TRP, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and kynurenic acid (KA) were analyzed in platelet-poor plasma at ~1 week and ~1 month of life from a prospective cohort of 168 preterm neonates <31 weeks gestational age (GA). Frequency of intermittent hypoxemia (IH) events and percent time hypoxemic (<80%) were analyzed in a 6 h window after the blood draw.

Results

At 1 week, infants with detectable plasma 5-HT had fewer IH events (OR (95% CI) = 0.52 (0.29, 0.31)) and less percent time <80% (OR (95% CI) = 0.54 (0.31, 0.95)) compared to infants with undetectable 5-HT. A similar relationship occurred at 1 month. At 1 week, infants with higher KA showed greater percent time <80% (OR (95% CI) = 1.90 (1.03, 3.50)). TRP, 5-HIAA or KA were not associated with IH frequency at either postnatal age. IH frequency and percent time <80% were positively associated with GA < 29 weeks.

Conclusions

Circulating neuromodulators 5-HT and KA might represent biomarkers of immature respiratory control contributing to hypoxemia in preterm neonates.

Impact

  • Hypoxemia events are frequent in preterm infants and are associated with poor outcomes.

  • Mechanisms driving hypoxemia such as immature respiratory control may include central and peripheral imbalances in modulatory neurotransmitters.

  • This study found associations between the plasma neuromodulators serotonin and kynurenic acid and parameters of hypoxemia in preterm neonates.

  • Imbalances in plasma biomarkers affecting respiratory control may help identify neonates at risk of short- and long-term adverse outcomes.

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Fig. 1: Preterm infants were screened for eligibility if they met the inclusion criteria of <306/7 weeks GA and <7 days postnatal age without major congenital anomalies.
Fig. 2: Graphical representation of associations between neuroactive biomarkers 5-HT and KA with hypoxemic parameters at 1 week of age.

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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.

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Acknowledgements

The authors wish to thank the participating families, the neonatal research staff, specifically Advanced Clinical Research Nurse Ms. Arlene Zadell, and our scientific collaborators at Institut des Biomolecules Max Mousseron, UMR 5247 CNRS, ENSCM, Universite de Montpellier, Montpellier, France, specifically Camille Oger, Jean-Marie Galano, and Thierry Durand.

Funding

This study was supported by grants from the National Institutes of Health [U01HL133643, U01HL133708 and UL1TR002548. A.S.I. acknowledges the support of RETICS from the Health Research Institute Carlos III, Spain (ISCIII) - European Regional Development Fund (FEDER) [RD16/0022/001], the PFIS grant from ISCIII (Ministry of Science and Innovation) [FI16/00380], and Margarita Salas grant [UP2021-044-MS21-084] from the Ministry of Universities of the Government of Spain, financed by the European Union, NextGeneration EU. M.V. acknowledges the support of RETICS [PN 2018-2021 (Spain)], ISCIII, Spain - Sub-Directorate General for Research Assessment and Promotion and FEDER [RD16/0022], and ISCIII (Ministry of Science and Innovation) [PI20/00964]. J.K. acknowledges the support of ISCIII, Spain and co-funded by the European Union [CPII21/00003].

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Authors and Affiliations

  1. Department of Pediatrics, University Hospitals Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, OH, USA

    Peter Mathew MacFarlane, Richard John Martin, Juliann Marie Di Fiore, Thomas Michael Raffay, Nori Minich & Anna Maria Hibbs

  2. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Curtis Tatsuoka & Zhengyi Chen

  3. Health and Biomedicine, Leitat Technological Center, Carrer de la Innovació, 2, 08225, Terrassa, Spain

    Guillermo Quintas

  4. Analytical Unit, Health Research Institute La Fe, Avda Fernando Abril Martorell 106, 46026, Valencia, Spain

    Guillermo Quintas

  5. Neonatal Research Unit, Health Research Institute La Fe (IISLAFE), University & Polytechnic Hospita La Fe (HULAFE), Valencia, Spain

    Ángel Sánchez-Illana, Julia Kuligowski, José David Piñeiro-Ramos & Maximo Vento

  6. Department of Analytical Chemistry, Chemistry Faculty, Universtitat de València, Burjassot, Spain

    Ángel Sánchez-Illana

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  1. Peter Mathew MacFarlane
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Contributions

P.M.M., A.M.H., T.M.R., J.M.D., M.V., and R.J.M. made substantial contributions to conception and study design, acquisition of data and analysis, and interpretation of data. G.Q., A.S.I., J.K., J.D.P.-R., C.T., Z.C., and N.M. made substantial contributions to data acquisition and analysis. All authors contributed to revising the article and gave critically important intellectual input. All authors gave final approval of the version to be published.

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Correspondence to Peter Mathew MacFarlane.

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MacFarlane, P.M., Martin, R.J., Di Fiore, J.M. et al. Plasma serotonergic biomarkers are associated with hypoxemia events in preterm neonates. Pediatr Res 94, 1436–1443 (2023). https://doi.org/10.1038/s41390-023-02620-3

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