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

Sponsor

University of Dublin, Trinity College (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT04816331

Collaborator

Health Research Board, Ireland (Other)

200

Enrollment

Locations

25.9

Anticipated Duration (Months)

Patients Per Site

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Neonatal Encephalopathy	Other: Medical records and clinical measurements

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 Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

200 participants

Observational Model:

Case-Control

Time Perspective:

Cross-Sectional

Official Title:

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

Actual Study Start Date :

Aug 4, 2020

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	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

Arm

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

Other Names:

Questionnaires for caregivers to assess social-emotional and adaptive domains

Tissue samples analysis and processing: blood, saliva and urine

Outcome Measures

Primary Outcome Measures

Number of participants with cardiovascular dysfunction in childhood [Children at 2-3 years of age]
It will be determined by normal or abnormal echocardiography using Tissue doppler and functional imaging.
Number of participants with renal dysfunction in childhood [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.
Number of participants with haematological anomalies persisting in childhood [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.
Number of participants with neurological outcomes [Children at 2-3 years of age]
Presence or absence of seizures, motor and sensory dysfunction will be evaluated using Serial Cranial ultrasounds.

Secondary Outcome Measures

Number and identity of miRNAs upregulated or downregulated in blood of participants. [Children at 2-3 years of age]
Between 350 and 800 miRNAs will be assessed in serum from patients and controls.
Fold change of inflammasome components (NLRP3 and ASC) in RNA isolated from blood of participants. [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.
Concentration level in pg/mL of multicytokines in serum of participants. [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.
Bayley Scales of Infant and Toddler development (BSID III) scores of participants. [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 3 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	Country
1	The Coombe Women & Infants University Hospital	Dublin	Ireland
2	The National Maternity Hospital, or Holles Street Hospital	Dublin	Ireland
3	The Rotunda Hospital	Dublin	Ireland
4	The Tallaght University Hospital	Dublin	Ireland
5	Trinity College Dublin, The University of Dublin	Dublin	Ireland