Congenital heart disease (CHD) is known to negatively affect brain development. Individual clinical factors have been identified to contribute to this detrimental effect, however, the cumulative effect of these factors on brain development and neurodevelopmental outcomes are not fully understood. Our study utilized structural brain connectomics as an indicator of brain development to investigate the potential combined impact of clinical risk factors and family-environmental factors in adolescents with CHD. We developed a cumulative clinical risk (CCR) score by summing up binary risk factors (neonatal, cardiac, neurologic) based on clinically relevant thresholds and further investigated the role of family-environmental factors (parental education, parental mental health, and family function). Brain development in 53 adolescents with CHD who underwent infant open-heart surgery, and 75 healthy controls was studied by diffusion MRI connectomic analysis and neuropsychological assessments. The CCR score explains a great variability of the structural brain connectome. A higher CCR score was associated with lower network segregation, edge strength, and executive functioning. Edge strength was particularly reduced in an inter-frontal and fronto-parietal-thalamic network. There was no association with family-environmental factors. Poorer executive functioning was associated with lower network integration and segregation. Our results provide evidence for persisting alterations of network connectivity in adolescents with CHD ? particularly in those patients who face a cumulative exposure to multiple clinical risk over time. Quantifying the cumulative load of risk early in life, may help to better predict trajectories of brain development in order to identify and support the most vulnerable patients as early as possible.

The authors have declared no competing interest.

this is not a clinical trial/interventional study

https://bmjopen.bmj.com/content/9/10/e032363.abstract

This project was supported by the Swiss National Science Foundation (SNF 32003B_172914) and the University Research Priority Program (URPP) ?Adaptive Brain Circuits in Development and Learning (AdaBD)? of the University of Zurich. The sponsors had no influence on the study design, the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit the paper for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the ethics committee of the Canton of Zurich, Switzerland (KEK 2019?00035).

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De-identified data and statistical scripts supporting our findings can be shared specifically with other groups upon reasonable request. Patient data cannot be made openly available due to patient privacy reasons.