Elsevier

The Journal of Pediatrics

Volume 167, Issue 2, August 2015, Pages 269-273.e2
The Journal of Pediatrics

Original Article
Downregulation of Umbilical Cord Blood Levels of miR-374a in Neonatal Hypoxic Ischemic Encephalopathy

https://doi.org/10.1016/j.jpeds.2015.04.060Get rights and content

Objective

To investigate the expression profile of microRNA (miRNA) in umbilical cord blood from infants with hypoxic ischemic encephalopathy (HIE).

Study design

Full-term infants with perinatal asphyxia were identified under strict enrollment criteria. Degree of encephalopathy was defined using both continuous multichannel electroencephalogram in the first 24 hours of life and modified Sarnat score. Seventy infants (18 controls, 33 with perinatal asphyxia without HIE, and 19 infants with HIE [further graded as 13 mild, 2 moderate, and 4 severe]) were included in the study. MiRNA expression profiles were determined using a microarray assay and confirmed using quantitative real-time polymerase chain reaction.

Results

Seventy miRNAs were differentially expressed between case and control groups. Of these hsa-miR-374a was the most significantly downregulated in infants with HIE vs controls. Validation of hsa-miR-374a expression using quantitative real-time polymerase chain reaction confirmed a significant reduction in expression among infants with HIE compared with those with perinatal asphyxia and healthy controls (mean relative quantification [SD] = 0.52 [0.37] vs 1.10 [1.52] vs 1.76 [1.69], P < .02).

Conclusions

We have shown a significant step-wise downregulation of hsa-miR-374a expression in cord blood of infants with perinatal asphyxia and subsequent HIE.

Section snippets

Methods

This study was approved by the Clinical Ethics Committee of the Cork Teaching Hospitals. All study subjects were enrolled in the ongoing Biomarkers of Hypoxic Ischemic Encephalopathy Study between May 2009 and June 2011 according to strict recruitment criteria: (1) gestation >36 weeks; and (2) 1 or more of the following: cord pH <7.1, 5-minute Apgar score ≤6, and intubation/cardiopulmonary resuscitation at birth. Parents of neonates meeting inclusion criteria were approached and written

Results

In total, 73 infants were recruited for this study. The initial exploratory study included 15 cases (8 perinatal asphyxia, 3 moderate HIE, and 4 severe HIE) and 9 controls. Following exploratory work, 3 samples had to be excluded from the final cohort because of an insufficient amount of sample. In the total cohort we performed qRT-PCR in 70 infants, consisting of 33 with perinatal asphyxia (no HIE), 19 with HIE, and 18 controls. In the HIE group, 6 had moderate-severe HIE (2 moderate and 4

Discussion

We have investigated miRNA expression in umbilical cord blood of infants with perinatal asphyxia and HIE. Seventy miRNA had altered expression between our control and HIE groups. The most significantly altered miRNA was hsa-miR-374a. The altered expression remained significant after validation using an alternate method of analysis (qRT-PCR) and in a larger cohort of infants. To our knowledge, hsa-miR-374a has not previously been linked to hypoxia or to HIE.

Alterations in hsa-miR-374a expression

References (26)

  • K.S. Tan et al.

    Expression profile of microRNAs in young stroke patients

    PLoS One

    (2009)
  • B.H. Walsh et al.

    Cord blood proteins and multichannel-electroencephalography in hypoxic-ischemic encephalopathy

    Pediatr Crit Care Med

    (2013)
  • J. Gosselin et al.

    The Amiel-Tison neurological assessment at term: conceptual and methodological continuity in the course of follow-up

    Ment Retard Dev Disabil Res Rev

    (2005)
  • Cited by (59)

    • Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology

      2021, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      MicroRNAs (miRNAs) are small non-coding RNA of 19–24 nucleotides, which have key gene regulatory activity in cell maintenance and homeostasis and rapid physiological and behavioral responses. Micro-RNAs have been studied in NE in cord blood and correlated with neonatal outcomes[78]. miR-223 downregulates NLRP3 to inhibit inflammation through caspase-1 and IL-1β, reduce brain edema and improve neurological functions[79].

    • Up-Regulation of Nfat5 mRNA and Fzd4 mRNA as a Marker of Poor Outcome in Neonatal Hypoxic-Ischemic Encephalopathy

      2021, Journal of Pediatrics
      Citation Excerpt :

      The patients for the second multicenter study—the validation cohort (ClinicalTrials.gov identifier NCT02019147)—were recruited between March 2013 and June 2015 at CUMH and Karolinska University Hospital Huddinge, which has roughly 4400 deliveries per annum. This study was designed to validate the findings of the BiHiVE1 discovery cohort and thus used identical recruitment criteria.11 Unlike BiHiVE1, BiHiVE2 recruited additional control infants; these were infants with an uneventful delivery, normal neonatal examination, and a 5-minute Apgar score >8.

    View all citing articles on Scopus

    A.L., D.M., and the Biomarkers of Hypoxic Ischemic Encephalopathy Study 2 are funded by the Health Research Board (HRB; CSA/2012/40). B.W. and the Biomarkers of Hypoxic Ischemic Encephalopathy Study are funded by Molecular Medicines Medicine Ireland. This research also was supported by a Science Foundation Ireland (SFI) Research Center Award (12/RC/2272). The Alimentary Pharmabiotic Center is funded by SFI, through the Irish Government's National Development Plan (SFI/12/RC/2273, 02/CE/B124 and 07/CE/B1368), and HRB (HRA_POR/2012/32; JFC, TGD). G.C. is supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Grant 20771). The authors declare no conflicts of interest.

    View full text