antioxidants Review Metabolomics to Diagnose Oxidative Stress in Perinatal Asphyxia: Towards a Non-Invasive Approach Anne Lee Solevåg 1, * , Svetlana N. Zykova 2 , Per Medbøe Thorsby 2 and Georg M. Schmölzer 3,4   Citation: Solevåg, A.L.; Zykova, S.N.; Thorsby, P.M.; Schmölzer, G.M. Metabolomics to Diagnose Oxidative Stress in Perinatal Asphyxia: Towards a Non-Invasive Approach. Antioxidants 2021, 10, 1753. https:// doi.org/10.3390/antiox10111753 Academic Editors: Julia Kuligowski and Máximo Vento Received: 1 October 2021 Accepted: 29 October 2021 Published: 2 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 The Department of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Nydalen, Norway 2 Biochemical Endocrinology and Metabolism Research Group, The Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, 0424 Nydalen, Norway; svezyk@ous-hf.no (S.N.Z.); pertho@ous-hf.no (P.M.T.) 3 Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, AB 23821, Canada; georg.schmoelzer@me.com 4 Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB 23821, Canada * Correspondence: a.l.solevag@medisin.uio.no; Tel.: +47-4146-9314 Abstract: There is a need for feasible and non-invasive diagnostics in perinatal asphyxia. Metabolomics is the study of small molecular weight products of cellular metabolism that may, directly and indirectly, reflect the level of oxidative stress. Saliva analysis is a novel approach that has a yet unexplored potential in metabolomics in perinatal asphyxia. The aim of this review was to give an overview of metabolomics studies of oxidative stress in perinatal asphyxia, particularly searching for studies analyzing non-invasively collected biofluids including saliva. We searched the databases PubMed/Medline and included 11 original human and 4 animal studies. In perinatal asphyxia, whole blood, plasma, and urine are the most frequently used biofluids used for metabolomics analyses. Although changes in oxidative stress-related salivary metabolites have been reported in adults, the utility of this approach in perinatal asphyxia has not yet been explored. Human and animal studies indicate that, in addition to antioxidant enzymes, succinate and hypoxanthine, as well acylcarnitines may have discriminatory diagnostic and prognostic properties in perinatal asphyxia. Researchers may utilize the accumulating evidence of discriminatory metabolic patterns in perinatal asphyxia to develop bedside methods to measure oxidative stress metabolites in perinatal asphyxia. Although only supported by indirect evidence, saliva might be a candidate biofluid for such point-of-care diagnostics. Keywords: asphyxia neonatorum; non-invasive diagnostics; metabolomics; oxidative stress; saliva 1. Introduction Failed placental gas exchange or deficient gas exchange in the lungs after birth may cause perinatal asphyxia with hypoxia and hypercapnia resulting in mixed metabolic and respiratory acidosis. Asphyxiated infants can present with severe cardiorespiratory compromise at birth and a need for cardiopulmonary resuscitation with supplementary oxygen. However, mild symptoms of asphyxia may also result in later morbidity and mortality in affected infants [1,2]. In perinatal asphyxia, balancing the harmful effects of iatrogenic hyperoxia (‘oxidative stress’) vs. anaerobic metabolism (continuing/prolonged hypoxia) is a complex task. Although humans have physiological and biochemical defense mechanisms to prevent hypoxia [3], defense mechanisms against hyperoxia are less developed in newborn infants, with the resulting oxidative stress potentially causing organ injury. During asphyxia and resuscitation, disrupted cellular homeostasis causes significant metabolic changes [4], and studies of the metabolome may provide a pathophysiological ‘snapshot’ of the condition. Metabolomics is the study of small molecular weight (<1500 Da) Antioxidants 2021, 10, 1753. https://doi.org/10.3390/antiox10111753 https://www.mdpi.com/journal/antioxidants