Altered Cerebral Growth and Development in Infants With Congenital Heart Disease

Background: Congenital heart disease (CHD) is the most frequent inborn defect with an incidence of 1 in 100 newborns per year, i.e. 800 children born in Switzerland per year. 10% to 15% of cases are born with single ventricle (SV), the most complex type of CHF requiring immediate surgical intervention after birth. Infants with SV CHD are treated in three surgical staged procedures over the first three years of life. However, cerebral injuries occur in around 40% of those children and impact neurocognitive abilities. As more than 90% of all infants with CHD survive to adulthood, scientific concern is focussed on patient-individual course brain growth and development within the relative contribution of fetal, perinatal, cardiac and surgical risk factors. Therefore, serial cerebral MRI examinations are needed, starting (1) at the third trimester during fetal life proceeding to (2) pre- and postoperative time points at the stage I surgery after birth and (3) before stage II surgery at 4 months of age. We will compare the cerebral MRI findings with a healthy control population, recruited at the same time points, and correlate brain growth and development with the neurodevelopmental outcome assessed at one year of age. Three Pediatric Heart Centers in Switzerland and Germany will participate.

The overall aims are:

1. To analyse the patient-individual cerebral developmental trajectories, brain growth and determine the time course of brain abnormalities in infants with single ventricle CHD by serial cerebral MRI during fetal life, after birth and at an age of 4 months (primary endpoints).
2. To determine the neurodevelopmental outcome at one year of age using the Bayley III and will be correlated with the brain growth and brain development in the third trimester of fetal life and at the age of 4 months (secondary endpoints).
3. To analyse fetal, neonatal, surgery-related and intensive care associated factors determining the patient-individual course for altered cerebral growth and impaired neurodevelopmental outcome at one year of age.

Methodology: We will prospectively enroll fetuses and neonates with single ventricle CHD at the three Pediatric Heart Centers in Switzerland (Zurich, Bern) and Germany (Giessen). Advanced MR imaging will assess cerebral volumes, microstructural and hemodynamic changes at repeated time points during the third trimester of fetal life (32. week of gestation), the perioperative neonatal period before and after stage I surgery and before stage II surgery at 4 months of age. Biomechanical analysis of longitudinal changes of brain morphology will be applied to longitudinal fetal and neonatal MRI data. Outcome is determined with the Bayley-III at one year of age.

Significance: Using a population-based sample of children with single ventricle CHD, we will be able to determine cerebral growth from the third fetal trimester until the first 4 months after birth, when the brain is most rapidly growing. By performing serial brain imaging, the knowledge of etiological pattern affecting cerebral growth, development and brain injury will increase. Morphometric and biomechanical analysis of brain growth patterns will be performed that may capture fine-grained changes associated with CHD. By correlating these data with the neurodevelopmental outcome at one year of age it will be possible to identify specific risk constellations leading to impaired brain development and categories of brain injuries that confer a higher risk of adverse outcome. The better understanding of the pathophysiological mechanisms will serve as the basis for neuroprotective studies and pharmacological trials aiming to improve outcomes in children with CHD in the future.

Study Overview

• Status: Recruiting
• Conditions: Brain Injuries; Neurodevelopmental Disorders; Fetal Growth Retardation; Congenital Heart Disease

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Walter H Knirsch, MD; Phone Number: +41442667617; Email: walter.knirsch@kispi.uzh.ch

Study Locations

• Switzerland
  • Zurich, Switzerland, 8032
    • Recruiting
    • University Children's Hospital
    • Contact: Walter H Knirsch, MD; Phone Number: +41442667617; Email: walter.knirsch@kispi.uzh.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 months (Child)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Fetuses and neonates with complex type of CHD form the study population group. Healthy control population will also be recruited.

Description

Inclusion Criteria:

All fetuses and neonates with the diagnosis complex type of CHD undergoing open-heart surgery are prospectively enrolled

Exclusion Criteria:

a) Clinical evidence or suspicion of a congenital malformation or syndrome, b) brain malformation, c) congenital infection and d) preterms before 37 weeks. These criteria will exclude fetuses and newborns with other conditions that will impact neurodevelopmental outcome.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-individual cerebral developmental trajectories	Brain growth and brain development from third trimester of fetal life to 4 months after birth will be analysed	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopmental outcome at one year of age using the Bayley III	Bayley Scales Bayley scales of Infant Development will be used as a standardized method to assess cognitive and motor development in infants.	One year
Risk factor analysis	Risk factor analysis of fetal, neonatal, surgery-related and intensive care associated factors determining the patient-individual course for altered cerebral growth and impaired neurodevelopmental outcome at one year of age	One year

Collaborators and Investigators

• Sponsor: University Children's Hospital, Zurich
• Investigators: Principal Investigator: Walter H Knirsch, MD, University Children's Hospital, Pediatric Heart Center, Pediatric Cardiology

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 15, 2020
• First Submitted That Met QC Criteria: January 15, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: congenital heart disease; neurodevelopmental outcome; brain imaging
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Congenital Abnormalities; Craniocerebral Trauma; Trauma, Nervous System; Fetal Diseases; Pregnancy Complications; Cardiovascular Abnormalities; Growth Disorders; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Heart Diseases; Brain Injuries; Heart Defects, Congenital; Fetal Growth Retardation; Neurodevelopmental Disorders
• Other Study ID Numbers: Knirsch 01

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