The Long-term Consequences of Neonatal Encephalopathy in the Hypothermia Era

Child Development Clinical Trial

Official title:

The Long-term Consequences of Neonatal Encephalopathy in the Hypothermia Era: Protocol for a Follow-up Cohort Study at 9 Years of Age

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05756296
• Other study ID #: MP-37-2023-9320
• Status: Not yet recruiting
• Start date: November 1, 2023
• Est. completion date: December 31, 2028

Study information

• Verified date: October 2023
• Source: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Contact: Marie Brossard-Racine, PhD
• Phone: (514)934-1934
• Email: marie.brossardracine[@]mcgill.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this study is to characterize the ability and related brain profiles of children with Neonatal encephalopathy (NE) - Therapeutic hypothermia (TH) at 9 years old. The main questions it aims to answer are:

1. Compare executive function, attention, social cognition, behaviour, anxiety, self-esteem, and peer problems between children with NE-TH and matched peers without NE.

2. Compare brain volumes, cortical and subcortical morphology, white matter microstructure, and myelination between children with NE-TH and matched peers without NE.

3. Evaluate the associations of perinatal risk factors and structural brain integrity with neuropsychological deficits to inform about the potential aggravating and protective factors for neuropsychological functioning.

Participants will complete one study visit to perform standardized evaluations and a brain MRI. Parents of participants will be invited to complete a series of questionnaires during this study visit or at a moment of their choice virtually.

Description:

Rationale:

Therapeutic hypothermia (TH) became the standard of care treatment for neonates with moderate and severe neonatal encephalopathy (NE) in most industrialized countries about 10 years ago. Although TH is effective in reducing mortality and the incidence of severe developmental disabilities, various morbidities are still frequent in survivors. Moreover, because the focus of previous follow-up studies has been restricted to mortality rates and the most severe forms of morbidities, it is wrong to conclude that TH minimizes all developmental deficits. In fact, recent literature reports frequent cognitive and behavioural difficulties at school entry in children with NE-TH without severe disabilities. Although these difficulties can be less impressive than cerebral palsy and intellectual disability, their negative impacts on a child's self-determination and family well-being are not less important and their nature and extend need to be comprehensively assessed.

Aims and Hypotheses:

1. To compare higher-order cognitive, socialization, and psycho-emotional abilities using comprehensive standardized assessments of outcomes between 9-year-old children with NE-TH and age- and sex-matched peers without NE.

Hypothesis 1: Children with NE-TH will display lower IQ, executive functioning, attention, social cognition, and self-esteem, but more anxiety and behavioural and peer problems than age- and sex-matched peers without NE-TH.

2. To compare structural brain integrity using quantitative MRI between 9-year-old children with NE-TH and age- and sex-matched peers without NE.

Hypothesis 2: Children with NE-TH will present with smaller total and regional (basal ganglia, hippocampus, cerebellum) brain volumes, altered cortical and subcortical morphometry, and widespread white matter microstructural and myelination alterations when compared to age- and sex-matched peers without NE-TH.

3. To evaluate the relationships between cognitive, psycho-emotional and motor skills at 9 years and (1) individual and perinatal risk factors and (2) structural brain integrity at 9 years.

Hypothesis 3: A combination of individual (e.g., socio-economic), perinatal factors (e.g., neonatal brain injury) and markers of aberrant brain integrity (e.g., volume, microstructure) will be associated with domain-specific deficits at 9 years in children with NE-TH.

Population:

Children born between 2014 and 2018, who received whole-body cooling to an esophageal temperature of 33.5°C initiated within the first 6 hours of life, continued for 72 hours, and then they were slowly rewarmed for moderate or severe NE at one of the two centers will be approached. Eligibility for TH at our institutions followed those established in previous TH trials. Participants with a history of (1) congenital infections, (2) genetic or metabolic disorders, or (3) major brain malformations (e.g., lissencephaly), as well as (4) any contraindication for MRI (e.g., metal implant, claustrophobia), are ineligible.

For each of two same-sex and same-age NE-TH participants, a matched control for age (+/- 6 months of mean age) and sex will be recruited. Participants born at term (gestational age ≥37 weeks), without neonatal complication, will be considered as ineligible controls. Inclusion criteria for the controls include the same were similar to the NE-TH group, and a previous history of neurodevelopmental delay or disorder, or a traumatic brain injury were the specific exclusion cirteria for the comparison group.

Assessment procedure:

For this study, enrollees will complete one study visit to perform standardized evaluations and a brain MRI. Children will have the opportunity to familiarize themselves with the MRI environment on a mock scanner before the MRI and to watch a movie or listen to the music of their choice during the acquisition. Parents will be invited to complete a series of questionnaires during their child's testing or at a moment of their choice via a provided secure link. The visit will start with the outcome evaluations that are the most cognitively demanding and breaks will be provided as necessary. Outcome evaluations will be conducted by trained research staff or trainees blinded to the details of the child's neonatal and developmental history, and group allocation (i.e., NE-TH vs. control) to the extent possible. The choice of outcome measures has been made based on their clinical significance, psychometric properties, and availability in both French and English, considering the bilingual context of Quebec, Canada.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 198
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 11 Years

Eligibility

Inclusion Criteria:

• born between 2014 and 2018

• received whole-body cooling to an esophageal temperature of 33.5°C initiated within the first 6 hours of life, continued for 72 hours, and then they were slowly rewarmed received TH for moderate or severe NE

Exclusion Criteria:

Participants with a history of

• congenital infections

• genetic or metabolic disorders

• major brain malformations (e.g., lissencephaly) and

• any contraindication for MRI (e.g., metal implant, claustrophobia)

Related Conditions & MeSH terms

• Brain Diseases
• Brain Injuries
• Child Development
• Hypothermia
• Neonatal Encephalopathy
• Therapeutic Hypothermia

Intervention

Procedure:
• Therapeutic hypothermia
whole-body cooling to an esophageal temperature of 33.5°C initiated within the first 6 hours of life, continued for 72 hours, and then they were slowly rewarmed for moderate or severe NE

Locations

Country	Name	City	State
Canada	the Montreal Children's Hospital (MCH) of the McGill University Health Centre	Montreal	Quebec
Canada	Centre Hospitalier Universitaire Ste-Justine (CHUSJ).	Montréal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
McGill University Health Centre/Research Institute of the McGill University Health Centre	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

References & Publications (16)

Beck J, S., Beck A, T., Jolly J, B. . Beck Youth Inventories - Second Edition. San Antonio, TX: Peason; 2005

Conners CK. Conner Continuous Performance Test - 3rd Ed Pearson Publication Inc.; 2014.

Deli DC, Kaplan E, Kramer JH. Delis-Kaplan Executive Function System. Pearson Publication Inc; 2001

Gratz KL, Roemer L. Multidimensional Assessment of Emotion Regulation and Dysregulation: Development, Factor Structure, and Initial Validation of the Difficulties in Emotion Regulation Scale. Journal of Pyschopathology and Behavioral Assessment. 2004;26(1):41-54

Harrison P, Oakland T. Adaptive Behavior Assessment Systems 3rd Ed. Pearson Publication Inc; 2015.

Hunt C, Borgida E, Lavine H. Social Cognition. In: Encyclopedia of Human Behavior.2012:456-462

Korjman M, Kirk U, Kemp S. NEPSY Second Edition (NEPSY-II): A developmental NEuroPSYchological Assessment. Pearson Publication Inc; 2007

Levine DS. Neuroexecutive Function. In: Encyclopedia of Human Behavior.2012:701-706

March JS, Parker JD, Sullivan K, Stallings P, Conners CK. The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry. 1997 Apr;36(4):554-65. doi: 10.1097/00004583-199704000-00019. — View Citation

Rey A. L'examen psychologique dans les cas d'encéphalopathie traumatique. (Les problems.). [The psychological examination in cases of traumatic encepholopathy. Problems.]. Archives de Psychologie. 1941;28:215-285

Roid GH, Miller LJ. Leither Internaltional Performance Scale - Revised. Wod Dale, IL: Stoelting; 1997

Russel DJ, Rosenbaum P, Wright M, Avery LM. Gross Motor Function Measure (GMFM-66 & GMFM-88) User's Manual, 2nd Edition. 2nd ed: Mac Keith Press; 2013

Scarpina F, Tagini S. The Stroop Color and Word Test. Front Psychol. 2017 Apr 12;8:557. doi: 10.3389/fpsyg.2017.00557. eCollection 2017. — View Citation

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929. — View Citation

Spence SH. Spence Children's Anxiety Scale. Washington, DC: American Psychology Association; 1997

Thompson EJ, Beauchamp MH, Darling SJ, Hearps SJC, Brown A, Charalambous G, Crossley L, Darby D, Dooley JJ, Greenham M, Jaimangal M, McDonald S, Muscara F, Turkstra L, Anderson VA. Protocol for a prospective, school-based standardisation study of a digital social skills assessment tool for children: The Paediatric Evaluation of Emotions, Relationships, and Socialisation (PEERS) study. BMJ Open. 2018 Feb 8;8(2):e016633. doi: 10.1136/bmjopen-2017-016633. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Sex	determined by the physical appearance of genitalia recorded at birth	DAY 1
Other	Gender	self-reported by the child	DAY 1
Other	Socio-economic status	Maternal Education, employment, income and ethnicity	DAY 1
Other	Medical history of child	prenatal, perinatal, and postnatal factors extracted from existing clinical and research databases	DAY 1
Primary	Higher order cognitive abilities	Estimated IQ (Wechsler Abbreviated Scale of Intelligence 2nd ed. [WASI-2]), inhibition (Stroop test), planning (Tower - Delis-Kaplan Executive Function System [D-KEFS] and Rey-Osterrieth Complex Figure), impulsivity (Conner Continuous Performance Test - 3rd Ed [CPT-3]), working memory (Digit span), and word retrieval (verbal fluency - D-KEFS). Specific attentional skills; immediate (Digit Span) and sustained attention (CPT-3). Visual memory (Rey-Osterrieth Complex Figure). To characterize the ability to understand that others have thoughts, ideas, and feelings, and how emotion relates to social context, as well as the ability to recognize affect (Theory of Mind and Affect Recognition subtests).	DAY 1
Primary	Psycho-emotional abilities	Self-esteem (Self-Concept Inventory from the Beck Youth Inventories-II), children's anxiety and emotional regulation (Spence Children's Anxiety Scale, the Multidimensional Anxiety Scale for Children, and the Difficulties in Emotion Regulation Scales). Predominance of profiles (e.g., predominantly affective, cognitive, or generalized) will be examined following an in-depth interpretation of the cognitive and psycho-emotional outcomes.	DAY 1
Primary	Motor skills	Motor skills will be evaluated using the Movement Assessment Battery for Children-2nd Ed.in children without CP. In children with CP, motor skills will be evaluated with the Gross Motor Function Measure and subsequently be classified using the Gross Motor Function Classification System and the Manual Ability Classification System.Visual-motor integration will be assessed with the Berry-Buktenica Developmental Test of Visual-Motor Integration.	DAY 1
Primary	Functional profile	Adaptive Behaviour Assessment Systems 3rd Ed.	DAY 1
Primary	Brain profile	Quantitative MRI measuring structural brain integrity	DAY 1