Follow-up of Inflammatory Responses and Multiorgan Outcomes FoLlowing Neonatal Brain injurY (FIREFLY)

March 23, 2021 updated by: Prof. Eleanor Molloy, University of Dublin, Trinity College

Babies who have brain injury also frequently have involvement of their kidneys, lung and heart. Although clinical care in the neonatal period is well defined there are few guidelines and evidence for developmental, heart and kidney followup in childhood. The investigators aim to develop and implement guidelines for health care workers and families on Followup after Neonatal Brain Injury.

Inflammation is an important factor in brain injury of newborns and also affects their heart lungs and other parts of their body. The investigators will use tests from the newborn period to predict outcome and help parents with planning health needs for their baby rather than waiting until any issues arise later on. By understanding inflammation the investigators can find methods to decrease the negative effects and improve outcomes in the future for babies and families.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

Neonatal brain injury is an important cause of neonatal death and disability such as cerebral palsy. Perinatal global hypoxic ischemic associated with Neonatal Encephalopathy (NE) results in multi-organ dysfunction which may persist in later childhood. In addition perinatal inflammation has been associated with neonatal brain injury and implicated in adult neuropsychiatric conditions.

The investigators aim to examine multi-organ dysfunction in early childhood in children who had NE by examining detailed cardiac, renal, neurological, haematological and neurodevelopmental outcomes. The investigators have previously defined detailed multi organ dysfunction (MOD) in this cohort in the neonatal period in infants with NE including organ outcomes as well as serum, urine and cerebrospinal fluid (CSF) biomarkers. They are now age-appropriate for detailed neurocognitive assessment and correlation with these biomarkers and the investigators plan to compare with age- matched controls. Immunological markers such as the inflammasome and microRNAs are altered in the neonatal period and may persist in early childhood. The investigators will modify negative inflammatory responses in vitro with specific antagonists as well as correlating these immune biomarkers with outcomes.

Quantifying multiorgan dysfunction in the neonatal period to ensure appropriate follow-up of all organs is merited. This would help in advanced clinical planning and long term follow up. In addition, understanding, the immune response in these children with NE and exploring systemic inflammation holds promise for future development of immunomodulatory adjunctive therapies and biomarkers to predict outcomes.

Study Type

Observational

Enrollment (Anticipated)

200

Contacts and Locations

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

Study Locations

  • Ireland
      • Dublin, Ireland
        • The Rotunda Hospital
      • Dublin, Ireland
        • The Coombe Women & Infants University Hospital
      • Dublin, Ireland
        • The National Maternity Hospital, or Holles Street Hospital
      • Dublin, Ireland
        • The Tallaght University Hospital
      • Dublin, Ireland
        • Trinity College Dublin, The University of Dublin

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

2 years to 3 years (Child)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Children at 2-3 years of age who were enrolled in the HRB-funded Neonatal Inflammation and Multiorgan dysfunction and Brain injUry reSearch group (NIMBUS) project. These babies had Neonatal Encephalopathy and required Therapeutic Hypothermia and are matched with controls.

Patients recruited as part of the NIMBUS study in 3 Dublin Maternity Hospitals: the National Maternity hospital (NMH), the Rotunda hospital & the Coombe Women's and Infant's University Hospital (CWIUH) with an average of 120 infants with Neonatal encephalopathy (NE) Grade I-III deliveries per annum. This study will enrol 100 infants with NE and 100 controls (recruited in Tallaght University Hospital). The controls include age-matched normal children born at term with a normal delivery and postnatal course.

Description

Inclusion Criteria:

  • Children at 2-3 years
  • With diagnosis of Neonatal Encephalopathy
  • Required Therapeutic Hypothermia

Exclusion Criteria:

-

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
Neonatal Encephalopathy (NE)
This study is a follow up of children at 2-3 years of age who were enrolled in the HRB-funded Neonatal Inflammation and Multiorgan dysfunction and Brain injUry reSearch group (NIMBUS) project. These babies had Neonatal Encephalopathy and required Therapeutic Hypothermia and are matched with controls. Detailed antenatal, birth, resuscitation, oxygen requirements throughout inpatient stay and detailed neonatal intensive care management were collected. In addition, details of Therapeutic Hypothermia treatment including initiation, duration and clinical examination, investigations including cranial USS, MRI, EEG and placental histology analysis performed as were recorded.
Other: Medical records and clinical measurements

Medical records and clinical measurements: Detailed antenatal, birth, resuscitation, oxygen requirements throughout inpatient stay and detailed neonatal intensive care management will be collected. Therapeutic Hypothermia treatment including initiation, duration and clinical examination, and investigations such as scans. In addition, clinical data will include medication, neurological (paediatric developmental psychologist assessment and Bayley Scales of Infant and Toddler Development) and multiorgan examination.

Questionnaires for caregivers to assess social-emotional and adaptive domains.

Tissue samples analysis and processing: Samples of blood, urine and saliva will be used for laboratory testing.

Biomarker correlation with Multiorgan outcomes using statistical analysis: Data collected from medical records, clinical measurements, questionnaires, and tissue processing will be analysed using SPSS software for statistical analysis and modelling.

Other Names:
  • Questionnaires for caregivers to assess social-emotional and adaptive domains
  • Tissue samples analysis and processing: blood, saliva and urine
Controls
The controls include age-matched normal children born at term with a normal delivery and postnatal course.
Other: Medical records and clinical measurements

Medical records and clinical measurements: Detailed antenatal, birth, resuscitation, oxygen requirements throughout inpatient stay and detailed neonatal intensive care management will be collected. Therapeutic Hypothermia treatment including initiation, duration and clinical examination, and investigations such as scans. In addition, clinical data will include medication, neurological (paediatric developmental psychologist assessment and Bayley Scales of Infant and Toddler Development) and multiorgan examination.

Questionnaires for caregivers to assess social-emotional and adaptive domains.

Tissue samples analysis and processing: Samples of blood, urine and saliva will be used for laboratory testing.

Biomarker correlation with Multiorgan outcomes using statistical analysis: Data collected from medical records, clinical measurements, questionnaires, and tissue processing will be analysed using SPSS software for statistical analysis and modelling.

Other Names:
  • Questionnaires for caregivers to assess social-emotional and adaptive domains
  • Tissue samples analysis and processing: blood, saliva and urine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with cardiovascular dysfunction in childhood
Time Frame: Children at 2-3 years of age
It will be determined by normal or abnormal echocardiography using Tissue doppler and functional imaging.
Children at 2-3 years of age
Number of participants with renal dysfunction in childhood
Time Frame: Children at 2-3 years of age
It will be assessed using renal scoring systems such as the Kidney disease Improving Global Outcomes (KDIGO) Acute Kidney injury score (scores 1 to 3, being 3 worse outcome) and measuring the concentration of urinary biomarkers (in mg/L) such as albumin, B2 microglobulin, Cystatin c, EGF, NGAL, OPN and UMOD. Deviations of the reference range values for the scores and urinary biomarkers will indicate renal dysfunction. Results will be reported as number of patients with renal dysfunction in childhood.
Children at 2-3 years of age
Number of participants with haematological anomalies persisting in childhood
Time Frame: Children at 2-3 years of age
Number of patients with signs of coagulopathy will be defined using three indicators: APTT/PT (units per seconds), fibrinogen (mg/dL) and Leukocyte/neutrophil (percentage and units per Liter). Deviations of the reference range values for the three indicators will point to haematological anomalies. Results will be reported as number of patients with signs of coagulopathy.
Children at 2-3 years of age
Number of participants with neurological outcomes
Time Frame: Children at 2-3 years of age
Presence or absence of seizures, motor and sensory dysfunction will be evaluated using Serial Cranial ultrasounds.
Children at 2-3 years of age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number and identity of miRNAs upregulated or downregulated in blood of participants.
Time Frame: Children at 2-3 years of age
Between 350 and 800 miRNAs will be assessed in serum from patients and controls.
Children at 2-3 years of age
Fold change of inflammasome components (NLRP3 and ASC) in RNA isolated from blood of participants.
Time Frame: Children at 2-3 years of age
Using RNA extracted from whole blood of patients and controls, the fold change RNA expression of inflammasome components (NLRP3 and ASC) will be evaluated.
Children at 2-3 years of age
Concentration level in pg/mL of multicytokines in serum of participants.
Time Frame: Children at 2-3 years of age
Multiplex cytokine analysis will be performed and reported in pg/mL in serum. Cytokines to be included: Interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL- 1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Tumour Necrosis Factor-alpha (TNF-α), Interferon-gamma (IFN-δ), Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), Erythropoietin, Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 and S100B.
Children at 2-3 years of age
Bayley Scales of Infant and Toddler development (BSID III) scores of participants.
Time Frame: Children at 2-3 years of age
Bayley Scales of Infant and Toddler development (BSID III) score is an assessment instrument designed to measure motor, cognitive, language, social-emotional, and adaptive behavior development in babies and young children. Composite scores are derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15, and range of 40 to 160. Scores lower than 85 indicating mild impairment, and lower than 70 indicating moderate or severe impairment. Scores equal or higher than 85 indicate normal development.
Children at 2-3 years of age

Collaborators and Investigators

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

Sponsor

University of Dublin, Trinity College

Collaborators

Health Research Board, Ireland

Investigators

  • Principal Investigator: Eleanor Molloy, Prof., Professor of Paediatrics & Child Health, Paediatrics

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)

August 4, 2020

Primary Completion (Anticipated)

June 30, 2022

Study Completion (Anticipated)

September 30, 2022

Study Registration Dates

First Submitted

March 2, 2021

First Submitted That Met QC Criteria

March 23, 2021

First Posted (Actual)

March 25, 2021

Study Record Updates

Last Update Posted (Actual)

March 25, 2021

Last Update Submitted That Met QC Criteria

March 23, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ILP-POR-2019-086

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will only be process within the research team associated to the project as per Ethical agreement with the corresponding ethical committees and explicit consent with parents/guardians of the patients.

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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