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Searching molecular biomarkers correlating with BSID-III at 24 months in infants with neonatal hypoxic-ischemic encephalopathy

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Abstract

An early prediction of outcomes of neonatal hypoxic-ischemic encephalopathy (NE) is of key importance in reducing neonatal mortality and morbidity. The objectives were (i) to analyze the characteristics of miRNA expression and metabolic patterns of neonates with NE and (ii) to assess their predictive performance for neurodevelopmental outcomes. Plasma samples from moderate/severe NE patients (N = 92) of the HYPOTOP study were collected before, during, and after therapeutic hypothermia (TH) and compared to a control group (healthy term infants). The expression of miRNAs and concentrations of metabolites (hypoxia-related and energy, steroid, and tryptophan metabolisms) were analyzed. Neurodevelopmental outcomes were evaluated at 24 months postnatal age using Bayley Scales of Infant Development, ed. III, BSID-III. Differences in miRNA and metabolic profiles were found between NE vs. control infants, abnormal (i.e., mildly and moderately abnormal and severe) vs. normal, and severe vs. non-severe (i.e., normal and mildly and moderately abnormal) BSID-III. 4-Androstene-3,17-dione, testosterone, betaine, xanthine, and lactate were suitable for BSID-III outcome prediction (receiver operating characteristic areas under the curve (AUCs) ≥ 0.6), as well as 68 miRNAs (AUCs of 0.5–0.9). Significant partial correlations of xanthine and betaine levels and the expression of several miRNAs with BSID-III sub-scales were found. 

Conclusion: We have identified metabolites/miRNAs that might be useful to support the prediction of middle-term neurodevelopmental outcomes of NE.

What is known and what is new:

• The early prediction of outcomes of neonatal hypoxic-ischemic encephalopathy (NE) is of key importance in reducing neonatal mortality and morbidity.

• Alterations of the metabolome and miRNAs had been observed in NE.

• We performed miRNA sequencing and quantified selected metabolites (i.e., lactate, pyruvate, ketone bodies, Krebs cycle intermediates, tryptophan pathway, hypoxia-related metabolites, and steroids) by GC- and LC–MS.

• Specific miRNAs and metabolites that allow prediction of middle-term neurodevelopmental outcomes of newborns with NE undergoing hypothermia treatment were identified.

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Data availability

All data generated during this study are included in supplementary information files of this published article.

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Acknowledgements

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

HYPOTOP study group

Ana Gimeno2, María Gormaz2, Raquel Escrig2, María Cernada2, Marta Aguar2, Antonio Núñez-Ramiro2, Isabel Benavente-Fernández7, Eva Valverde8, Malaika Cordeiro8, Dorotea Blanco9, Hector Boix10, Fernando Cabañas11, Mercedes Chaffanel12, Belén Fernández-Colomer13, Jose Ramón Fernández-Lorenzo14, Begoña Loureiro15, Maria Teresa Moral-Pumarega16, Antonio Pavón17, and Inés Tofé18

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

7Division of Neonatology, University Hospital Puerta del Mar, Cádiz, Spain

8Division of Neonatology, University Hospital La Paz, Madrid, Spain

9Division of Neonatology, University Hospital Gregorio Marañón, Madrid, Spain

10Department of Neonatology, University Hospital Vall d’Hebrón, Barcelona, Spain

11Division of Neonatology, University Hospital Quirónsalud Madrid, Madrid, Spain

12Division of Neonatology, Regional University Hospital Málaga, Málaga, Spain

13Division of Neonatology, Central University Hospital of Asturias, Oviedo, Spain

14Division of Neonatology, University Hospital Complex of Vigo, Vigo, Spain

15Division of Neonatology, University Hospital Cruces, Bilbao, Spain

16Division of Neonatology, University Hospital 12 de Octubre, Madrid, Spain

17Division of Neonatology, University Hospital Virgen del Rocío, Sevilla, Spain

18Division of Neonatology, University Hospital Reina Sofía, Córdoba, Spain

Funding

This work was supported by the Instituto de Salud Carlos III (ISCIII), Spain (grant numbers CM20/00187, CPII21/00003, EC11-046, and PI20/00964), and co-funded by the European Union. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “RD21/0012/0015” and co-funded by the European Union—NextGenerationEU.

Author information

Author notes

  1. Mari Merce Cascant-Vilaplana and Jose David Piñeiro-Ramos contributed equally to this work.

Authors and Affiliations

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

    Mari Merce Cascant-Vilaplana, Jose David Piñeiro-Ramos, Álvaro Soláz-García, Inmaculada Lara-Cantón, Nuria Boronat, Julia Kuligowski & Máximo Vento

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

    Álvaro Soláz-García, Isabel Izquierdo, Purificación Marin, Ester Torres-Martínez, Nuria Boronat & Máximo Vento

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

    Roberto Llorens

  4. The Bioinformatics Group, School of Water, Energy and Environment, Cranfield University, Bedford, UK

    Corentin Molitor & Fady Mohareb

  5. Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS-SAMID) (RD21/0012/0001), Instituto de Salud Carlos III, Madrid, Spain

    Nuria Boronat, Julia Kuligowski & Máximo Vento

  6. Health and Biomedicine, Leitat Technological Center, Valencia, Spain

    Guillermo Quintás

Authors
  1. Mari Merce Cascant-Vilaplana
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Consortia

the HYPOTOP study group

  • Ana Gimeno
  • , María Gormaz
  • , Raquel Escrig
  • , María Cernada
  • , Marta Aguar
  • , Antonio Núñez-Ramiro
  • , Isabel Benavente-Fernández
  • , Eva Valverde
  • , Malaika Cordeiro
  • , Dorotea Blanco
  • , Hector Boix
  • , Fernando Cabañas
  • , Mercedes Chaffanel
  • , Belén Fernández-Colomer
  • , Jose Ramón Fernández-Lorenzo
  • , Begoña Loureiro
  • , Maria Teresa Moral-Pumarega
  • , Antonio Pavón
  •  & Inés Tofé

Contributions

M.M.C.-V.: Methodology, Software, Validation, Formal analysis, Investigation, Data Curation, Writing—Original Draft, Writing—Review & Editing, Visualization. J.D.P.-R.: Methodology, Investigation, Data Curation, Writing—Review & Editing. ASG: Methodology, Investigation, Data Curation, Writing—Review & Editing. I.L.-C.: Methodology, Investigation, Data Curation, Writing—Review & Editing. Isabel Izquierdo: Methodology, Investigation, Resources, Writing—Review & Editing, Supervision. R.L.: Methodology, Formal analysis, Investigation, Data Curation, Writing—Review & Editing. P.M.: Methodology, Investigation, Writing—Review & Editing. E.T.: Methodology, Investigation, Writing—Review & Editing. C.M.: Methodology, Software, Formal analysis, Data Curation, Writing—Review & Editing. F.M.: Conceptualization, Software, Resources, Writing—Review & Editing, Supervision. N.B.: Methodology, Investigation, Data Curation, Writing—Review & Editing. G.Q.: Conceptualization, Software, Investigation, Data Curation, Writing—Review & Editing. J.K.: Conceptualization, Software, Formal analysis, Investigation, Resources, Data Curation, Writing—Original Draft, Writing—Review & Editing, Visualization, Supervision, Project administration. M.V.: Conceptualization, Resources, Writing—Review & Editing, Supervision, Project administration.

Corresponding author

Correspondence to Julia Kuligowski.

Ethics declarations

Consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. The Committee for Biomedical Research of the Health Research Institute La Fe (Valencia, Spain) approved the protocol for involving the recruitment of the control group of healthy term infants (2019/0312) and the multicenter clinical trial, registered under the acronym HYPOTOP (EudraCT 2011–005696-17) [13]. Written informed consent was obtained from parents or legal representatives.

Competing interests

The authors declare no competing interests.

Additional information

Communicated by Daniele De Luca

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Máximo Vento is the senior author to this work.

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Cascant-Vilaplana, M.M., Piñeiro-Ramos, J.D., Soláz-García, Á. et al. Searching molecular biomarkers correlating with BSID-III at 24 months in infants with neonatal hypoxic-ischemic encephalopathy. Eur J Pediatr (2024). https://doi.org/10.1007/s00431-024-05652-x

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