Early Prediction of Hypoxic-Ischemic Brain Injury by a New Panel of Biomarkers in a Population of Term Newborns

Hindawi Oxidative Medicine and Cellular Longevity Volume 2018, Article ID 7608108, 10 pages https://doi.org/10.1155/2018/7608108 Research Article Early Prediction of Hypoxic-Ischemic Brain Injury by a New Panel of Biomarkers in a Population of Term Newborns Simona Negro,1 Manon J. N. L. Benders ,2,3,4 Maria Luisa Tataranno,2 Caterina Coviello,5 Linda S. de Vries,2,4 Frank van Bel,2,4 Floris Groenendaal ,2,4 Mariangela Longini,1 Fabrizio Proietti ,1 Elisa Belvisi ,1 Giuseppe Buonocore ,1 and Serafina Perrone 1 1 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands 3 Centre for the Developing Brain, King’s College, London, UK 4 Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands 5 Division of Neonatology, Careggi University Hospital of Florence, Firenze, Italy 2 Correspondence should be addressed to Serafina Perrone; Received 30 January 2018; Revised 24 April 2018; Accepted 23 May 2018; Published 28 June 2018 Academic Editor: Jacek Zielonka Copyright © 2018 Simona Negro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This research paper is aimed at evaluating the predictive role of a default panel of oxidative stress (OS) biomarkers for the early identification of infants at high risk of HIE and their validation through the correlation with MRI findings. A multicenter prospective observational study was performed between March 2012 and April 2015 in two European tertiary NICUs. Eightyfour term infants at risk for HIE (pH < 7, BE < −13 mmol/L, and 5′ Apgar < 5) were enrolled. Three were excluded for chromosomal abnormalities and one due to lack of blood samples. The final population was divided according to the severity of perinatal hypoxia into 2 groups: mild/moderate HIE and severe HIE. Advanced oxidation protein products (AOPP), nonprotein-bound iron (NPBI), and F2-isoprostanes (F2-IsoPs) were measured in blood samples at P1 (4–6 hours), P2 (24–72 hours), and P3 (5 days), in both groups. MRIs were scored for the severity of brain injury, using a modified Barkovich score. The mean GA was 39.8 weeks (SD 1.4) and the mean birth weight 3538 grams (SD 660); 37 were females and 43 males. Significantly lower 5′ Apgar score, pH, and BE and higher Thompson score were found in group II compared to group I at birth. Group II showed significantly higher AOPP and NPBI levels than group I (mean (SD) AOPP: 15.7 (15.5) versus 34.1 (39.2), p = 0 033; NPBI 1.1 (2.5) versus 3.9 (4.4), p = 0 013) soon after birth (P1). No differences were observed in OS biomarker levels between the two groups at P2 and P3. A regression model, including adjustment for hypothermia treatment, gender, and time after birth, showed that AOPP levels and male gender were both risk factors for higher brain damage scores (AOPP: OR 3.6, 95% CI (1.1–12.2) and gender: OR 5.6, 95% CI (1.2–25.7), resp.). Newborns with severe asphyxia showed higher OS than those with mild asphyxia at birth. AOPP are significantly associated with the severity of brain injury assessed by MRI, especially in males. 1. Introduction Birth asphyxia is largely recognized as the most frequent cause of acute interruption of oxygen to the fetus and the most common cause of brain damage [1]. Currently, despite the advances offered by therapeutic hypothermia in terms of neuroprotection, the improvements on long-term neurological outcome remain modest [2–4]. Twenty to fifty percent of asphyxiated infants who develop HIE die in the neonatal period, and about twenty-five percent of survivors will develop neurological disabilities, such as cerebral palsy, cognitive deficits, learning disorders, sensory disruption, and neuropsychiatric problems [5]. Therefore, one of the most important goals in the approach to patients with HIE remains actually to determine the exact period in which the effects of potential damaging factors occur [1, 2, 5, 6]. Several methods are now available for detecting the type and timing of brain damage: conventional prenatal tests, such as fetal 2 cardiotocography; ultrasound; Doppler and amniotic fluid examination neuroimaging; aEEG; NIRS; and determination of numerous currently available biomarkers. Each provides information about different expressions of brain injury and has some limitations [1, 7]. MRI is the gold standard for the early evaluation of brain injury after HIE, including not only traditional neuroimaging methods but also advanced imaging techniques (DWI, 1H-MRS, and ASL) [8–11]. In this context, the use of specific biomarkers that will increase within the first hours of life in hypoxic-ischemic neonates may help in the early diagnosis of HIE and promptly identify neonates who may qualify for neuroprotection. Oxidative stress is involved in the mechanisms of hypoxic-ischemic and inflammatory brain injury, although the relationship between brain damage and OS is very complex and not entirely clear [12–15]. The pathophysiological process that leads to the development of brain lesions is in fact characterized by the combination of several mechanisms, either exogenous or endogenous (hypoxia, ischemia, ischemiareperfusion, hyperoxia, inflammation, and mitochondrial damage), whose effect on cell biology and on oxidative metabolism varies according to the severity and duration of the insult [16]. Furthermore, certain brain areas are particularly rich in iron, released by cells damaged during hypoxia, which may catalyze, through the Fenton reaction, the formation of hydroxyl radicals and nitroperoxide and so make the central nervous system more susceptible to the attack of the reactive species [17]. In addition, the brain of a full-term baby, being rich in polyunsaturated fatty acids and low in antioxidants, is particularly vulnerable to the free radical attack [18]. Increased oxidative stress in hypoxic fetuses and neonates has been detected by assaying several biomarkers: products of lipid peroxidation in expired air, serum malondialdehyde reaction, serum isoprostanes, serum total hydroperoxides, advanced oxidative protein products, and increased NPBI in serum [18–20]. Despite extensive research in the field over the last few years, no such biomarker has been validated in clinical practice so far. So the aim of our study was to evaluate the predictive role of a default panel of OS biomarkers for the early identification of infants at high risk of hypoxic-ischemic brain injury and their validation through the correlation with MRI. 2. Methods 2.1. Subjects. Eighty-four term subjects, born between March 2012 and April 2015, with clinical and biochemical signs of HIE, admitted to two European tertiary NICUs as part of a multicenter prospective observational study, were consecutively enrolled (...truncated)