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  • Clinical Research Article
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Longitudinal perturbations of plasma nuclear magnetic resonance profiles in neonatal encephalopathy

Pediatric Research volume 94, pages 331–340 (2023)Cite this article

Abstract

Background

Neonatal encephalopathy (NE) is a major cause of mortality and severe neurological disability in the neonatal period and beyond. We hypothesized that the degree of brain injury is reflected in the molecular composition of peripheral blood samples.

Methods

A sub-cohort of 28 newborns included in the HYPOTOP trial was studied. Brain injury was assessed by magnetic resonance imaging (MRI) once per patient and neurodevelopment at 24 months of age was evaluated using the Bayley III Scales of Infant and Toddler Development. The nuclear magnetic resonance (NMR) profile of 60 plasma samples collected before, during, and after cooling was recorded.

Results

In total, 249 molecular features were quantitated in plasma samples from newborns and postnatal age showed to affect detected NMR profiles. Lactate, beta-hydroxybutyrate, pyruvate, and three triglyceride biomarkers showed the ability to discern between different degrees of brain injury according to MRI scores. The prediction performance of lactate was superior as compared to other clinical and biochemical parameters.

Conclusions

This is the first longitudinal study of an ample compound panel recorded by NMR spectroscopy in plasma from NE infants. The serial determination of lactate confirms its solid position as reliable candidate biomarker for predicting the severity of brain injury.

Impact

  • The use of nuclear magnetic resonance (NMR) spectroscopy enables the simultaneous quantitation of 249 compounds in a small volume (i.e., 100 μL) of plasma.

  • Longitudinal perturbations of plasma NMR profiles were linked to magnetic resonance imaging (MRI) outcomes of infants with neonatal encephalopathy (NE).

  • Lactate, beta-hydroxybutyrate, pyruvate, and three triglyceride biomarkers showed the ability to discern between different degrees of brain injury according to MRI scores.

  • Lactate is a minimally invasive candidate biomarker for early staging of MRI brain injury in NE infants that might be readily implemented in clinical guidelines for NE outcome prediction.

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Fig. 1: Compound groups detected in plasma samples.
Fig. 2: PCA results from NMR data acquired from the analysis of 60 plasma samples from 28 newborns with NE.
Fig. 3: Between-group comparisons.
Fig. 4: Metabolite and lipoprotein concentrations over time observed in infants with normal (MRI score = 0) vs pathologic MRI (MRI scores = 1, 2, or 3) outcomes (top) and infants with non-severe (MRI scores = 0, 1, or 2) and severe (MRI score = 3) brain injury (bottom).
Fig. 5: Boxplots representing lactate concentrations [mM] in newborns with NE and normal (MRI score 0) and pathologic (MRI scores 1, 2, or 3) MRI outcomes in all study samples (left) and for sampling time points 24, 48, and 72 h (right).
Fig. 6: Lactate concentrations in plasma from newborns with NE for predicting MRI outcomes.

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Data availability

All data generated and analyzed during this study are included in this published article and its Supplementary Information files.

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Acknowledgements

The authors would like to express their gratitude to the parents and their newborns who participated in the study.

Funding

This work was supported by the Instituto Carlos III, Ministry of Economy and Competitiveness, Spain [grant numbers CM20/00187, CD19/00037, CPII21/00003, PI17/00127, EC11-046, and PI20/00964] (Co-funded by European Regional Development Fund “A way to make Europe”) and the HYPOTOP study group acknowledges RETICS funded by the PN 2018-2021 (Spain), ISCIII-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (FEDER), reference RD16/0022/001.

Author information

Author notes

  1. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain

    Mari Merce Cascant-Vilaplana, Inmaculada Lara-Cantón, Álvaro Solaz-García, Julia Kuligowski & Máximo Vento

  2. Division of Neonatology, University & Polytechnic Hospital La Fe, Valencia, Spain

    Antonio Núñez-Ramiro & Máximo Vento

  3. Division of Radiology and Imaging, University & Polytechnic Hospital La Fe, Valencia, Spain

    Roberto Llorens-Salvador

  4. Health and biomedicine, Leitat Technological Center, Valencia, Spain

    Guillermo Quintás

  5. Unidad Analítica, Health Research Institute La Fe, Valencia, Spain

    Guillermo Quintás

Authors
  1. Mari Merce Cascant-Vilaplana
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Consortia

the HYPOTOP study group

  • Mari Merce Cascant-Vilaplana
  • , Antonio Núñez-Ramiro
  • , Álvaro Solaz-García
  • , Roberto Llorens-Salvador
  • , Julia Kuligowski
  •  & Máximo Vento

Contributions

J.K. and M.V. were responsible for the conception and design of the study; M.M.C.-V., I.L.-C., A.N.-R., A.S.-G., and R.L.-S. acquired the data; J.K., G.Q., M.M.C.-V., I.L.-C., R.L.-S., and A.S.-G. analyzed and interpreted the data; J.K. drafted the article; G.Q., M.M.C.-V., and M.V. revised the manuscript critically and all authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Julia Kuligowski or Máximo Vento.

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Cascant-Vilaplana, M.M., Lara-Cantón, I., Núñez-Ramiro, A. et al. Longitudinal perturbations of plasma nuclear magnetic resonance profiles in neonatal encephalopathy. Pediatr Res 94, 331–340 (2023). https://doi.org/10.1038/s41390-023-02464-x

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