Identification of a Pool of miRNA to Improve Early Management of Perinatal Asphyxia and Hypoxic Ischemic Encephalopathy

August 3, 2023 updated by: Giuseppe De Bernardo, Ospedale Buon Consiglio Fatebenefratelli

Role of microRNAs as Diagnostic and Prognostic Biomarkers of Neonatal Perinatal Asphyxia and Hypoxic Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy is the most common cause of neurological damage in the neonatal period. It has an incidence of about 1.5-2.5% of livebirths in developed countries. It is associated with a high rate of mortality and morbidity. Major neurological outcomes such as cerebral palsy, mental retardation, learning disabilities, epilepsy occur in approximately 25% of survivors. The diagnostic and prognostic tools currently available for enrollment have limitations and additional reliable biomarkers are needed for all phases of clinical management. Sarnat staging has taken on a role in identifying those infants who may benefit from treatment of hypothermia, resulting in the need for neurological evaluation and staging within 6 hours of life. Therapeutic hypothermia is still the best therapeutic treatment.

A new tool in neuroscience research is represented by micro-ribonucleic acid (microRNA) profiling. The presence of microRNAs in blood, urine and saliva and the ability to measure their levels non-invasively has opened new doors in the search for peripheral biomarkers for the diagnosis and prognosis of neurodegenerative diseases and also as possible pharmacological targets.

The aim of the present study is to analyze a specific cluster of miRNAs selected from data obtained by macroarray (NGS Pannel) on the entire microRNAome in healthy newborns with normal cord arterial pH value (7.26-7.35) as control cases and in newborns with fetal metabolic acidosis with a pH threshold value lower than 7.12 of the blood gas analysis from cord arterial blood. This latter group will be further stratified into two groups, neonates who will practice therapeutic hypothermia according to current guidelines and a further group who will not practice therapeutic hypothermia. This study will make a further international contribution in evaluating and identifying the potential of microRNAs as diagnostic and prognostic biomarkers in perinatal asphyxia and hypoxic ischemic encephalopathy. Furthermore, the study aims to identify specific microRNA sequences as new possible markers to be used as an additional parameter for the enrollment of therapeutic hypothermia, especially in cases of mild hypoxic-ischemic encephalopathy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Hypoxic-ischemic encephalopathy is the most common cause of neurological damage in the neonatal period. It has an incidence of about 1.5-2.5% of livebirths in developed countries. It is associated with a high rate of mortality and morbidity. About 1 million newborns worldwide die of hypoxic-ischemic encephalopathy. In the neonatal period die between 20 and 50% of asphyxiated infants who develop hypoxic-ischemic encephalopathy. Major neurological outcomes such as cerebral palsy, mental retardation, learning disabilities, epilepsy occur in approximately 25% of survivors. Therapeutic hypothermia is still the best therapeutic treatment. The diagnostic and prognostic tools currently available for enrollment have limitations and additional reliable biomarkers are needed for all phases of clinical management. One of the difficulties in interpretation lies in the identification of mild-grade hypoxic-ischemic encephalopathy which appears to be operator dependent, as well as the timing of the diagnosis. Sarnat staging has taken on a role in identifying those infants who may benefit from treatment of hypothermia, resulting in the need for neurological evaluation and staging within 6 hours of life. This is a relatively short time frame in which it is plausible to think that mild hypoxic-ischemic encephalopathy could become moderate at 6 h. In fact, some studies have retrospectively demonstrated the outcome of infants with mild hypoxic-ischemic encephalopathy defined between 1 and 6 hours of birth showing worse neurodevelopmental outcomes than the data reported in the pre-hypothermia literature.

A new tool in neuroscience research is represented micro-ribonucleic acid (microRNA) profiling. Significant numbers of microRNAs have been observed outside cells including various body fluids. MicroRNAs have been detected in plasma, serum, milk, tears, saliva, urine, amniotic fluid, cerebrospinal fluid, and seminal fluid. Despite the instability of most RNA molecules in the extracellular environment, the presence and apparent stability of microRNAs has proven surprising. In particular, they were found to be very stable and resistant to RNases, freezing and pH variations. The presence of microRNAs in blood, urine and saliva and the ability to measure their levels non-invasively has opened new doors in the search for peripheral biomarkers for the diagnosis and prognosis of neurodegenerative diseases and also as possible pharmacological targets. In view of their usefulness, in recent years more and more different microRNAs have been analyzed as possible diagnostic and prognostic markers of perinatal asphyxia but specific sequences with high specificity and sensitivity have not yet been identified as markers of neonatal hypoxia and hypoxic ischemic encephalopathy with the need to perform further confirmatory studies. The aim of the present study is to analyze a specific cluster of miRNAs selected from data obtained by macroarray (NGS Pannel) on the entire microRNAome in healthy newborns with normal cord arterial pH value (7.26-7.35) as control cases and in newborns with fetal metabolic acidosis with a pH threshold value lower than 7.12 of the blood gas analysis from cord arterial blood. This latter group will be further stratified into two groups, neonates who will practice therapeutic hypothermia according to current guidelines and a further group who will not practice therapeutic hypothermia. This study will make a further international contribution in evaluating and identifying the potential of microRNAs as diagnostic and prognostic biomarkers in perinatal asphyxia and hypoxic ischemic encephalopathy. Furthermore, the study aims to identify specific microRNA sequences as new possible markers to be used as an additional parameter for the enrollment of therapeutic hypothermia, especially in cases of mild hypoxic-ischemic encephalopathy. Subsequently, this study will allow to evaluate their potential as new possible pharmacological targets in the pediatric field for hypoxic-ischemic encephalopathy in future preclinical studies as already reported in the literature in various preclinical studies, as therapeutic perspectives in ischemic stroke in adults.

Study Type

Observational

Enrollment (Estimated)

45

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Naples, Italy, 80131
        • Recruiting
        • Department of Neuroscience, Reproductive and Dentistry Sciences, University of Naples Federico II
        • Contact:
        • Principal Investigator:
          • Giuseppe Pignataro, Prof
        • Sub-Investigator:
          • Rohan Mahesh Patil, Ph.D.
      • Napoli, Italy, 80123
        • Recruiting
        • Department of Woman and Child, Buon Consiglio Fatebenefratelli Hospital
        • Contact:
        • Principal Investigator:
          • Giuseppe De Bernardo, MD
        • Sub-Investigator:
          • Giuseppe Buonocore, Prof
        • Sub-Investigator:
          • Matteo Miele, MD
        • Sub-Investigator:
          • Fabrizia Capasso, MD
        • Sub-Investigator:
          • Valentina Fattorusso, MD
        • Sub-Investigator:
          • Maurizio Giordano, Dr

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

Study Population

All patients transferred to the Buon Consiglio Fatebenefratelli hospital will be eligible

Description

Inclusion Criteria:

  • newborns with at least 35 weeks of gestational age
  • body weight of at least 1800 g

Exclusion Criteria:

  • Withdrawal of informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Group A
15 healthy newborns with umbilical cord arterial pH between 7.26 and 7.35
Diagnostic test: microRNA
Evaluation of microRNA levels
Group B
15 newborns with metabolic acidosis at birth with umbilical cord arterial pH at birth < 7.12 and who do not practice therapeutic hypothermia due to lack of enrollment criteria
Diagnostic test: microRNA
Evaluation of microRNA levels
Other: Metabolic acidosis
Metabolic acidosis at birth with umbilical cord arterial pH at birth < 7.12
Group C
15 newborns with metabolic acidosis at birth with umbilical cord arterial pH at birth < 7.12 and practicing therapeutic hypothermia in accordance with current guidelines
Diagnostic test: microRNA
Evaluation of microRNA levels
Other: Metabolic acidosis
Metabolic acidosis at birth with umbilical cord arterial pH at birth < 7.12
Other: Hypothermia
Therapeutic induced hypothermia refers to a lowering of the central body temperature for therapeutic purposes

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of microRNA levels
Time Frame: 60 minutes of life
Quantitative characterization of microRNAs (ng/uL) in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
60 minutes of life
Qualitative evaluation of microRNAs
Time Frame: 60 minutes of life
Characterization of the type of microRNAs in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
60 minutes of life
Evaluation of microRNA levels
Time Frame: 3 hours of life
Quantitative characterization of microRNAs (ng/uL) in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
3 hours of life
Qualitative evaluation of microRNAs
Time Frame: 3 hours of life
Characterization of the type of microRNAs in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
3 hours of life
Evaluation of microRNA levels
Time Frame: 72 hours of life
Quantitative characterization of microRNAs (ng/uL) in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
72 hours of life
Qualitative evaluation of microRNAs
Time Frame: 72 hours of life
Characterization of the type of microRNAs in healthy neonates and neonates with metabolic acidosis at birth with or without therapeutic hypothermia and who developed hypoxic ischemic encephalopathy
72 hours of life

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Predictive role of microRNAs
Time Frame: 60 minutes of life
To assess the role of microRNAs as marker of perinatal asphyxia
60 minutes of life
Predictive role of microRNAs
Time Frame: 60 minutes of life
To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
60 minutes of life
Predictive role of microRNAs
Time Frame: 3 hours of life
To assess the role of microRNAs as markers of perinatal asphyxia
3 hours of life
Predictive role of microRNAs
Time Frame: 3 hours of life
To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
3 hours of life
Predictive role of microRNAs
Time Frame: 72 hours of life
To assess the role of microRNAs as markers of perinatal asphyxia
72 hours of life
Predictive role of microRNAs
Time Frame: 72 hours of life
To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
72 hours of life

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ospedale Buon Consiglio Fatebenefratelli

Collaborators

Federico II University

Investigators

  • Principal Investigator: Giuseppe De Bernardo, Prof, Buon Consiglio Fatebenefratelli Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 18, 2023

Primary Completion (Estimated)

July 18, 2024

Study Completion (Estimated)

July 18, 2024

Study Registration Dates

First Submitted

July 8, 2023

First Submitted That Met QC Criteria

August 3, 2023

First Posted (Actual)

August 14, 2023

Study Record Updates

Last Update Posted (Actual)

August 14, 2023

Last Update Submitted That Met QC Criteria

August 3, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 495

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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