Marc Paul O'Sullivan1,2,3, Ann Marie Looney1,2, Gerard M Moloney4, Mikael Finder5, Boubou Hallberg5, Gerard Clarke1,6,7, Geraldine B Boylan1,2, Deirdre M Murray1,2,3. 1. The Irish Centre for Fetal and Neonatal Translational Research, Cork, Ireland. 2. Department of Paediatrics and Child Health, University College Cork, Cork, Ireland. 3. National Children's Research Centre, Crumlin, Dublin, Ireland. 4. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. 5. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden. 6. Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland. 7. APC Microbiome Institute, Cork, Ireland.
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.
Importance: Neonatal hypoxic-ischemicencephalopathy (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-IschemicEncephalopathy (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.
Authors: Maria L V Dizon; Raye-Ann O deRegnier; Steven J Weiner; Michael W Varner; Dwight J Rouse; Maged M Costantine; Ronald J Wapner; John M Thorp; Sean C Blackwell; Nina K Ayala; Antonio F Saad; Steve N Caritis Journal: Dev Neurosci Date: 2022-06-15 Impact factor: 3.421
Authors: Ingran Lingam; Adnan Avdic-Belltheus; Christopher Meehan; Kathryn Martinello; Sara Ragab; Donald Peebles; Melinda Barkhuizen; Cally J Tann; Ilias Tachtsidis; Tim G A M Wolfs; Henrik Hagberg; Nigel Klein; Bobbi Fleiss; Pierre Gressens; Xavier Golay; Boris W Kramer; Nicola J Robertson Journal: Pediatr Res Date: 2020-06-10 Impact factor: 3.756
Authors: Catherine Mooney; Daragh O'Boyle; Mikael Finder; Boubou Hallberg; Brian H Walsh; David C Henshall; Geraldine B Boylan; Deirdre M Murray Journal: Heliyon Date: 2021-06-29
Authors: Sophie Casey; Kate Goasdoue; Stephanie M Miller; Gary P Brennan; Gary Cowin; Adam G O'Mahony; Christopher Burke; Boubou Hallberg; Geraldine B Boylan; Aideen M Sullivan; David C Henshall; Gerard W O'Keeffe; Catherine Mooney; Tracey Bjorkman; Deirdre M Murray Journal: Mol Neurobiol Date: 2020-07-27 Impact factor: 5.682
Authors: Aisling A Garvey; Andreea M Pavel; John M O'Toole; Brian H Walsh; Irina Korotchikova; Vicki Livingstone; Eugene M Dempsey; Deirdre M Murray; Geraldine B Boylan Journal: Pediatr Res Date: 2021-04-20 Impact factor: 3.756