Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy

Abstract

IMPORTANCE Neonatal hypoxic-ischemic encephalopathy (HIE) remains a significant cause of neurologic disability. Identifying infants suitable for therapeutic hypothermia (TH) within a narrow therapeutic time is difficult. No single robust biochemical marker is available to clinicians. OBJECTIVE To assess the ability of a panel of candidate microRNA (miRNA) to evaluate the development and severity of encephalopathy following perinatal asphyxia (PA). DESIGN, SETTING, AND PARTICIPANTS This validation study included 2 cohorts. For the discovery cohort, full-term infants with PA were enrolled at birth to the Biomarkers in Hypoxic-Ischemic Encephalopathy (BiHiVE1) study (2009-2011) in Cork, Ireland. Encephalopathy grade was defined using early electroencephalogram and Sarnat score (n = 68). The BiHiVE1 cohort also enrolled healthy control infants (n = 22). For the validation cohort, the BiHiVE2 multicenter study (2013-2015), based in Cork, Ireland (7500 live births per annum), and Karolinska Huddinge, Sweden (4400 live births per annum), recruited infants with PA along with healthy control infants to validate findings from BiHiVE1 using identical recruitment criteria (n = 80). The experimental design was formulated prior to recruitment, and analysis was conducted from June 2016 to March 2017. MAIN OUTCOMES AND MEASURES Alterations in umbilical cord whole-blood miRNA expression. RESULTS From 170 neonates, 160 were included in the final analysis. The BiHiVE1 cohort included 87 infants (21 control infants, 39 infants with PA, and 27 infants with HIE), and BiHiVE2 included 73 infants (control [n = 22], PA [n = 26], and HIE [n = 25]). The BiHiVE1 and BiHiVE2 had a median age of 40 weeks (interquartile range [IQR], 39-41 weeks) and 40 weeks (IQR, 39-41 weeks), respectively, and included 56 boys and 31 girls and 45 boys and 28 girls, respectively. In BiHiVE1, 12 candidate miRNAs were identified, and 7 of these miRNAs were chosen for validation in BiHiVE2. The BiHiVE2 cohort showed consistent alteration of 3 miRNAs; miR-374a-5p was decreased in infants diagnosed as having HIE compared with healthy control infants (median relative quantification, 0.38; IQR, 0.17-0.77 vs 0.95; IQR, 0.68-1.19; P = .009), miR-376c-3p was decreased in infants with PA compared with healthy control infants (median, 0.42; IQR, 0.21-0.61 vs 0.90; IQR, 0.70-1.30; P = .004), and mir-181b-5p was decreased in infants eligible for TH (median, 0.27; IQR, 0.14-1.41) vs 1.18; IQR, 0.70-2.05; P = .02). CONCLUSIONS AND RELEVANCE Altered miRNA expression was detected in umbilical cord blood of neonates with PA and HIE. These miRNA could assist diagnostic markers for early detection of HIE and PA at birth.

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

“…In the model of perinatal asphyxia used in our study, hypoxia/ischemia increased the expression of miR-181b, which is known to activate caspase-3-dependent apoptotic pathways and to inhibit the prosurvival PI3K/Akt signaling pathway [37]. This is in line with a report by O'Sullivan et al [38], who showed upregulation of miR-181b in umbilical cord blood of newborns suffering from perinatal asphyxia. Therefore, targeting miR-181b could be a protective strategy against ischemic insult, as evidenced by the application of an antagomir [39,40].…”

Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury

“…We consider miR-374a to be another promising bridging biomarker candidate for neonatal HIE, when considering this study alongside previous studies in umbilical cord blood of HIE neonates by our group and others [ 5 , 51 , 56 ]. It may be particularly useful in identification of moderate-severe cases.…”

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns—in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth

“…The role of miRNAs has been also reported in the context of neonatal diagnostics and the first description of miRNA profiling in UCB was reported in 2015 [29]. Recent studies have clearly shown that pathologies developing as a result of ischemia or asphyxia may alter the specific miRNA levels in UCB, suggesting their potential role in the early detection of such disorders [29,30]. PBMCs circulating in UCB might be a suitable alternative and valuable source of molecular biomarkers for neonatal diagnostics, thanks to the noninvasive and painless UCB collection at the time of child delivery.…”