xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05986994</url>
    </required_header>
    <id_info>
      <org_study_id>495</org_study_id>
      <nct_id>NCT05986994</nct_id>
    </id_info>
    <brief_title>Identification of a Pool of miRNA to Improve Early Management of Perinatal Asphyxia and Hypoxic Ischemic Encephalopathy</brief_title>
    <official_title>Role of microRNAs as Diagnostic and Prognostic Biomarkers of Neonatal Perinatal Asphyxia and Hypoxic Ischemic Encephalopathy</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Ospedale Buon Consiglio Fatebenefratelli</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Federico II University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Ospedale Buon Consiglio Fatebenefratelli</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Hypoxic-ischemic encephalopathy is the most common cause of neurological damage in the&#xD;
        neonatal period. It has an incidence of about 1.5-2.5% of livebirths in developed countries.&#xD;
        It is associated with a high rate of mortality and morbidity. Major neurological outcomes&#xD;
        such as cerebral palsy, mental retardation, learning disabilities, epilepsy occur in&#xD;
        approximately 25% of survivors. The diagnostic and prognostic tools currently available for&#xD;
        enrollment have limitations and additional reliable biomarkers are needed for all phases of&#xD;
        clinical management. Sarnat staging has taken on a role in identifying those infants who may&#xD;
        benefit from treatment of hypothermia, resulting in the need for neurological evaluation and&#xD;
        staging within 6 hours of life. Therapeutic hypothermia is still the best therapeutic&#xD;
        treatment.&#xD;
  &#xD;
        A new tool in neuroscience research is represented by micro-ribonucleic acid (microRNA)&#xD;
        profiling. The presence of microRNAs in blood, urine and saliva and the ability to measure&#xD;
        their levels non-invasively has opened new doors in the search for peripheral biomarkers for&#xD;
        the diagnosis and prognosis of neurodegenerative diseases and also as possible&#xD;
        pharmacological targets.&#xD;
  &#xD;
        The aim of the present study is to analyze a specific cluster of miRNAs selected from data&#xD;
        obtained by macroarray (NGS Pannel) on the entire microRNAome in healthy newborns with normal&#xD;
        cord arterial pH value (7.26-7.35) as control cases and in newborns with fetal metabolic&#xD;
        acidosis with a pH threshold value lower than 7.12 of the blood gas analysis from cord&#xD;
        arterial blood. This latter group will be further stratified into two groups, neonates who&#xD;
        will practice therapeutic hypothermia according to current guidelines and a further group who&#xD;
        will not practice therapeutic hypothermia. This study will make a further international&#xD;
        contribution in evaluating and identifying the potential of microRNAs as diagnostic and&#xD;
        prognostic biomarkers in perinatal asphyxia and hypoxic ischemic encephalopathy. Furthermore,&#xD;
        the study aims to identify specific microRNA sequences as new possible markers to be used as&#xD;
        an additional parameter for the enrollment of therapeutic hypothermia, especially in cases of&#xD;
        mild hypoxic-ischemic encephalopathy.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hypoxic-ischemic encephalopathy is the most common cause of neurological damage in the&#xD;
        neonatal period. It has an incidence of about 1.5-2.5% of livebirths in developed countries.&#xD;
        It is associated with a high rate of mortality and morbidity. About 1 million newborns&#xD;
        worldwide die of hypoxic-ischemic encephalopathy. In the neonatal period die between 20 and&#xD;
        50% of asphyxiated infants who develop hypoxic-ischemic encephalopathy. Major neurological&#xD;
        outcomes such as cerebral palsy, mental retardation, learning disabilities, epilepsy occur in&#xD;
        approximately 25% of survivors. Therapeutic hypothermia is still the best therapeutic&#xD;
        treatment. The diagnostic and prognostic tools currently available for enrollment have&#xD;
        limitations and additional reliable biomarkers are needed for all phases of clinical&#xD;
        management. One of the difficulties in interpretation lies in the identification of&#xD;
        mild-grade hypoxic-ischemic encephalopathy which appears to be operator dependent, as well as&#xD;
        the timing of the diagnosis. Sarnat staging has taken on a role in identifying those infants&#xD;
        who may benefit from treatment of hypothermia, resulting in the need for neurological&#xD;
        evaluation and staging within 6 hours of life. This is a relatively short time frame in which&#xD;
        it is plausible to think that mild hypoxic-ischemic encephalopathy could become moderate at 6&#xD;
        h. In fact, some studies have retrospectively demonstrated the outcome of infants with mild&#xD;
        hypoxic-ischemic encephalopathy defined between 1 and 6 hours of birth showing worse&#xD;
        neurodevelopmental outcomes than the data reported in the pre-hypothermia literature.&#xD;
  &#xD;
        A new tool in neuroscience research is represented micro-ribonucleic acid (microRNA)&#xD;
        profiling. Significant numbers of microRNAs have been observed outside cells including&#xD;
        various body fluids. MicroRNAs have been detected in plasma, serum, milk, tears, saliva,&#xD;
        urine, amniotic fluid, cerebrospinal fluid, and seminal fluid. Despite the instability of&#xD;
        most RNA molecules in the extracellular environment, the presence and apparent stability of&#xD;
        microRNAs has proven surprising. In particular, they were found to be very stable and&#xD;
        resistant to RNases, freezing and pH variations. The presence of microRNAs in blood, urine&#xD;
        and saliva and the ability to measure their levels non-invasively has opened new doors in the&#xD;
        search for peripheral biomarkers for the diagnosis and prognosis of neurodegenerative&#xD;
        diseases and also as possible pharmacological targets. In view of their usefulness, in recent&#xD;
        years more and more different microRNAs have been analyzed as possible diagnostic and&#xD;
        prognostic markers of perinatal asphyxia but specific sequences with high specificity and&#xD;
        sensitivity have not yet been identified as markers of neonatal hypoxia and hypoxic ischemic&#xD;
        encephalopathy with the need to perform further confirmatory studies. The aim of the present&#xD;
        study is to analyze a specific cluster of miRNAs selected from data obtained by macroarray&#xD;
        (NGS Pannel) on the entire microRNAome in healthy newborns with normal cord arterial pH value&#xD;
        (7.26-7.35) as control cases and in newborns with fetal metabolic acidosis with a pH&#xD;
        threshold value lower than 7.12 of the blood gas analysis from cord arterial blood. This&#xD;
        latter group will be further stratified into two groups, neonates who will practice&#xD;
        therapeutic hypothermia according to current guidelines and a further group who will not&#xD;
        practice therapeutic hypothermia. This study will make a further international contribution&#xD;
        in evaluating and identifying the potential of microRNAs as diagnostic and prognostic&#xD;
        biomarkers in perinatal asphyxia and hypoxic ischemic encephalopathy. Furthermore, the study&#xD;
        aims to identify specific microRNA sequences as new possible markers to be used as an&#xD;
        additional parameter for the enrollment of therapeutic hypothermia, especially in cases of&#xD;
        mild hypoxic-ischemic encephalopathy. Subsequently, this study will allow to evaluate their&#xD;
        potential as new possible pharmacological targets in the pediatric field for hypoxic-ischemic&#xD;
        encephalopathy in future preclinical studies as already reported in the literature in various&#xD;
        preclinical studies, as therapeutic perspectives in ischemic stroke in adults.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">July 18, 2023</start_date>
    <completion_date type="Anticipated">July 18, 2024</completion_date>
    <primary_completion_date type="Anticipated">July 18, 2024</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Evaluation of microRNA levels</measure>
      <time_frame>60 minutes of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Qualitative evaluation of microRNAs</measure>
      <time_frame>60 minutes of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Evaluation of microRNA levels</measure>
      <time_frame>3 hours of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Qualitative evaluation of microRNAs</measure>
      <time_frame>3 hours of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Evaluation of microRNA levels</measure>
      <time_frame>72 hours of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Qualitative evaluation of microRNAs</measure>
      <time_frame>72 hours of life</time_frame>
      <description>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</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>60 minutes of life</time_frame>
      <description>To assess the role of microRNAs as marker of perinatal asphyxia</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>60 minutes of life</time_frame>
      <description>To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>3 hours of life</time_frame>
      <description>To assess the role of microRNAs as markers of perinatal asphyxia</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>3 hours of life</time_frame>
      <description>To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>72 hours of life</time_frame>
      <description>To assess the role of microRNAs as markers of perinatal asphyxia</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Predictive role of microRNAs</measure>
      <time_frame>72 hours of life</time_frame>
      <description>To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy</description>
    </secondary_outcome>
    <number_of_groups>3</number_of_groups>
    <enrollment type="Anticipated">45</enrollment>
    <condition>Hypoxic-Ischemic Encephalopathy</condition>
    <condition>Asphyxia Perinatal</condition>
    <arm_group>
      <arm_group_label>Group A</arm_group_label>
      <description>15 healthy newborns with umbilical cord arterial pH between 7.26 and 7.35</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group B</arm_group_label>
      <description>15 newborns with metabolic acidosis at birth with umbilical cord arterial pH at birth &lt; 7.12 and who do not practice therapeutic hypothermia due to lack of enrollment criteria</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Group C</arm_group_label>
      <description>15 newborns with metabolic acidosis at birth with umbilical cord arterial pH at birth &lt; 7.12 and practicing therapeutic hypothermia in accordance with current guidelines</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Metabolic acidosis</intervention_name>
      <description>Metabolic acidosis at birth with umbilical cord arterial pH at birth &lt; 7.12</description>
      <arm_group_label>Group B</arm_group_label>
      <arm_group_label>Group C</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>microRNA</intervention_name>
      <description>Evaluation of microRNA levels</description>
      <arm_group_label>Group A</arm_group_label>
      <arm_group_label>Group B</arm_group_label>
      <arm_group_label>Group C</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Hypothermia</intervention_name>
      <description>Therapeutic induced hypothermia refers to a lowering of the central body temperature for therapeutic purposes</description>
      <arm_group_label>Group C</arm_group_label>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          All patients transferred to the Buon Consiglio Fatebenefratelli hospital will be eligible&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  newborns with at least 35 weeks of gestational age&#xD;
  &#xD;
            -  body weight of at least 1800 g&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Withdrawal of informed consent&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>35 Weeks</minimum_age>
      <maximum_age>42 Weeks</maximum_age>
    </eligibility>
    <overall_official>
      <last_name>Giuseppe De Bernardo, Prof</last_name>
      <role>Principal Investigator</role>
      <affiliation>Buon Consiglio Fatebenefratelli Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Giuseppe De Bernardo, MD</last_name>
      <phone>3357441303</phone>
      <email>pinodebtin@gmail.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>Department of Neuroscience, Reproductive and Dentistry Sciences, University of Naples Federico II</name>
        <address>
          <city>Naples</city>
          <zip>80131</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Giuseppe Pignataro, Prof</last_name>
        <email>giuseppe.pignataro@unina.it</email>
      </contact>
      <investigator>
        <last_name>Giuseppe Pignataro, Prof</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Rohan Mahesh Patil, Ph.D.</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>Department of Woman and Child, Buon Consiglio Fatebenefratelli Hospital</name>
        <address>
          <city>Napoli</city>
          <zip>80123</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Giuseppe De Bernardo</last_name>
        <phone>3357441303</phone>
        <email>pinodebtin@gmail.com</email>
      </contact>
      <investigator>
        <last_name>Giuseppe De Bernardo, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Giuseppe Buonocore, Prof</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Matteo Miele, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Fabrizia Capasso, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Valentina Fattorusso, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Maurizio Giordano, Dr</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <results_reference>
      <citation>Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000 Apr;12(2):111-5. doi: 10.1097/00008480-200004000-00004.</citation>
      <PMID>10763759</PMID>
    </results_reference>
    <results_reference>
      <citation>Vinciguerra A, Cepparulo P, Anzilotti S, Cuomo O, Valsecchi V, Amoroso S, Annunziato L, Pignataro G. Remote postconditioning ameliorates stroke damage by preventing let-7a and miR-143 up-regulation. Theranostics. 2020 Oct 27;10(26):12174-12188. doi: 10.7150/thno.48135. eCollection 2020.</citation>
      <PMID>33204336</PMID>
    </results_reference>
    <results_reference>
      <citation>DE Bernardo G, Riccitelli M, Giordano M, Toni AL, Sordino D, Trevisanuto D, Buonocore G, Perrone S. Does high fidelity neonatal resuscitation simulation increase salivary cortisol levels of health care providers? Minerva Pediatr (Torino). 2021 Jun 21. doi: 10.23736/S2724-5276.21.05873-0. Online ahead of print.</citation>
      <PMID>34152109</PMID>
    </results_reference>
    <results_reference>
      <citation>Locci E, Bazzano G, Demontis R, Chighine A, Fanos V, d'Aloja E. Exploring Perinatal Asphyxia by Metabolomics. Metabolites. 2020 Apr 4;10(4):141. doi: 10.3390/metabo10040141.</citation>
      <PMID>32260446</PMID>
    </results_reference>
    <results_reference>
      <citation>Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146.</citation>
      <PMID>17695343</PMID>
    </results_reference>
    <results_reference>
      <citation>De Bernardo G, De Santis R, Giordano M, Sordino D, Buonocore G, Perrone S. Predict respiratory distress syndrome by umbilical cord blood gas analysis in newborns with reassuring Apgar score. Ital J Pediatr. 2020 Feb 12;46(1):20. doi: 10.1186/s13052-020-0786-8.</citation>
      <PMID>32050997</PMID>
    </results_reference>
    <results_reference>
      <citation>Hull J, Dodd KL. Falling incidence of hypoxic-ischaemic encephalopathy in term infants. Br J Obstet Gynaecol. 1992 May;99(5):386-91. doi: 10.1111/j.1471-0528.1992.tb13754.x.</citation>
      <PMID>1622910</PMID>
    </results_reference>
    <results_reference>
      <citation>Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review. Early Hum Dev. 2018 May;120:80-87. doi: 10.1016/j.earlhumdev.2018.02.007. Epub 2018 Feb 26.</citation>
      <PMID>29496329</PMID>
    </results_reference>
    <results_reference>
      <citation>O'Sullivan MP, Looney AM, Moloney GM, Finder M, Hallberg B, Clarke G, Boylan GB, Murray DM. Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy. JAMA Neurol. 2019 Mar 1;76(3):333-341. doi: 10.1001/jamaneurol.2018.4182.</citation>
      <PMID>30592487</PMID>
    </results_reference>
    <results_reference>
      <citation>Ponnusamy V, Yip PK. The role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy. Neuropharmacology. 2019 May 1;149:55-65. doi: 10.1016/j.neuropharm.2018.11.041. Epub 2019 Feb 1.</citation>
      <PMID>30716413</PMID>
    </results_reference>
    <results_reference>
      <citation>Walsh BH, Inder TE. MRI as a biomarker for mild neonatal encephalopathy. Early Hum Dev. 2018 May;120:75-79. doi: 10.1016/j.earlhumdev.2018.02.006. Epub 2018 Feb 17.</citation>
      <PMID>29463417</PMID>
    </results_reference>
    <results_reference>
      <citation>Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K. The microRNA spectrum in 12 body fluids. Clin Chem. 2010 Nov;56(11):1733-41. doi: 10.1373/clinchem.2010.147405. Epub 2010 Sep 16.</citation>
      <PMID>20847327</PMID>
    </results_reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 8, 2023</study_first_submitted>
    <study_first_submitted_qc>August 3, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 3, 2023</last_update_submitted>
    <last_update_submitted_qc>August 3, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Ospedale Buon Consiglio Fatebenefratelli</investigator_affiliation>
      <investigator_full_name>Giuseppe De Bernardo</investigator_full_name>
      <investigator_title>Chief Physician</investigator_title>
    </responsible_party>
    <keyword>newborn</keyword>
    <keyword>microRNA</keyword>
    <keyword>asphyxia</keyword>
    <keyword>encephalopathy</keyword>
    <keyword>hypothermia</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Brain Diseases</mesh_term>
      <mesh_term>Brain Ischemia</mesh_term>
      <mesh_term>Hypoxia-Ischemia, Brain</mesh_term>
      <mesh_term>Ischemia</mesh_term>
      <mesh_term>Hypoxia</mesh_term>
      <mesh_term>Asphyxia</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05986994
  org study id: 495
  nct id: NCT05986994
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  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.
  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.
  observational model: Cohort
  time perspective: Prospective
  measure: Evaluation of microRNA levels
  time frame: 60 minutes of life
  description: 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
  measure: Qualitative evaluation of microRNAs
  time frame: 60 minutes of life
  description: 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
  measure: Evaluation of microRNA levels
  time frame: 3 hours of life
  description: 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
  measure: Qualitative evaluation of microRNAs
  time frame: 3 hours of life
  description: 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
  measure: Evaluation of microRNA levels
  time frame: 72 hours of life
  description: 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
  measure: Qualitative evaluation of microRNAs
  time frame: 72 hours of life
  description: 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
  measure: Predictive role of microRNAs
  time frame: 60 minutes of life
  description: To assess the role of microRNAs as marker of perinatal asphyxia
  measure: Predictive role of microRNAs
  time frame: 60 minutes of life
  description: To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
  measure: Predictive role of microRNAs
  time frame: 3 hours of life
  description: To assess the role of microRNAs as markers of perinatal asphyxia
  measure: Predictive role of microRNAs
  time frame: 3 hours of life
  description: To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
  measure: Predictive role of microRNAs
  time frame: 72 hours of life
  description: To assess the role of microRNAs as markers of perinatal asphyxia
  measure: Predictive role of microRNAs
  time frame: 72 hours of life
  description: To assess the role of microRNAs as markers of mild hypoxic ischemic encephalopathy
  arm group label: Group A
  description: 15 healthy newborns with umbilical cord arterial pH between 7.26 and 7.35
  arm group label: Group B
  description: 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
  arm group label: Group C
  description: 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
  intervention type: Other
  intervention name: Metabolic acidosis
  description: Metabolic acidosis at birth with umbilical cord arterial pH at birth < 7.12
  arm group label: Group B
  arm group label: Group C
  intervention type: Diagnostic Test
  intervention name: microRNA
  description: Evaluation of microRNA levels
  arm group label: Group A
  arm group label: Group B
  arm group label: Group C
  intervention type: Other
  intervention name: Hypothermia
  description: Therapeutic induced hypothermia refers to a lowering of the central body temperature for therapeutic purposes
  arm group label: Group C
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 35 Weeks
  maximum age: 42 Weeks
  last name: Giuseppe De Bernardo, Prof
  role: Principal Investigator
  affiliation: Buon Consiglio Fatebenefratelli Hospital
  last name: Giuseppe De Bernardo, MD
  phone: 3357441303
  email: pinodebtin@gmail.com
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  investigator: 
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  country: Italy
  citation: Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000 Apr;12(2):111-5. doi: 10.1097/00008480-200004000-00004.
  PMID: 10763759
  citation: Vinciguerra A, Cepparulo P, Anzilotti S, Cuomo O, Valsecchi V, Amoroso S, Annunziato L, Pignataro G. Remote postconditioning ameliorates stroke damage by preventing let-7a and miR-143 up-regulation. Theranostics. 2020 Oct 27;10(26):12174-12188. doi: 10.7150/thno.48135. eCollection 2020.
  PMID: 33204336
  citation: DE Bernardo G, Riccitelli M, Giordano M, Toni AL, Sordino D, Trevisanuto D, Buonocore G, Perrone S. Does high fidelity neonatal resuscitation simulation increase salivary cortisol levels of health care providers? Minerva Pediatr (Torino). 2021 Jun 21. doi: 10.23736/S2724-5276.21.05873-0. Online ahead of print.
  PMID: 34152109
  citation: Locci E, Bazzano G, Demontis R, Chighine A, Fanos V, d'Aloja E. Exploring Perinatal Asphyxia by Metabolomics. Metabolites. 2020 Apr 4;10(4):141. doi: 10.3390/metabo10040141.
  PMID: 32260446
  citation: Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146.
  PMID: 17695343
  citation: De Bernardo G, De Santis R, Giordano M, Sordino D, Buonocore G, Perrone S. Predict respiratory distress syndrome by umbilical cord blood gas analysis in newborns with reassuring Apgar score. Ital J Pediatr. 2020 Feb 12;46(1):20. doi: 10.1186/s13052-020-0786-8.
  PMID: 32050997
  citation: Hull J, Dodd KL. Falling incidence of hypoxic-ischaemic encephalopathy in term infants. Br J Obstet Gynaecol. 1992 May;99(5):386-91. doi: 10.1111/j.1471-0528.1992.tb13754.x.
  PMID: 1622910
  citation: Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review. Early Hum Dev. 2018 May;120:80-87. doi: 10.1016/j.earlhumdev.2018.02.007. Epub 2018 Feb 26.
  PMID: 29496329
  citation: O'Sullivan MP, Looney AM, Moloney GM, Finder M, Hallberg B, Clarke G, Boylan GB, Murray DM. Validation of Altered Umbilical Cord Blood MicroRNA Expression in Neonatal Hypoxic-Ischemic Encephalopathy. JAMA Neurol. 2019 Mar 1;76(3):333-341. doi: 10.1001/jamaneurol.2018.4182.
  PMID: 30592487
  citation: Ponnusamy V, Yip PK. The role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy. Neuropharmacology. 2019 May 1;149:55-65. doi: 10.1016/j.neuropharm.2018.11.041. Epub 2019 Feb 1.
  PMID: 30716413
  citation: Walsh BH, Inder TE. MRI as a biomarker for mild neonatal encephalopathy. Early Hum Dev. 2018 May;120:75-79. doi: 10.1016/j.earlhumdev.2018.02.006. Epub 2018 Feb 17.
  PMID: 29463417
  citation: Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K. The microRNA spectrum in 12 body fluids. Clin Chem. 2010 Nov;56(11):1733-41. doi: 10.1373/clinchem.2010.147405. Epub 2010 Sep 16.
  PMID: 20847327
  responsible party type: Principal Investigator
  investigator affiliation: Ospedale Buon Consiglio Fatebenefratelli
  investigator full name: Giuseppe De Bernardo
  investigator title: Chief Physician
  mesh term: Brain Diseases
  mesh term: Brain Ischemia
  mesh term: Hypoxia-Ischemia, Brain
  mesh term: Ischemia
  mesh term: Hypoxia
  mesh term: Asphyxia
  sharing ipd: No