Structural covariance networks in the fetal brain reveal altered neurodevelopment for specific subtypes of congenital heart disease

Background Altered structural brain development has been identified in fetuses with Congenital Heart Disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. Methods We extracted structural covariance networks (SCNs) from the log Jacobian determinants of 429 in utero T2w MRI scans, (n = 67 controls, 362 CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery and CHD diagnosis were significant predictors of structural covariance. Results We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of SCNs, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra-axial CSF, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. Conclusions SCNs offer a sensitive, data-driven approach to explore whole-brain structural changes without anatomical priors. We used them to stratify a heterogenous CHD patient cohort, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Medical Research Council UK (MR/L011530/1 and MR/V002465/1) and a Wellcome Trust IEH Award (102431). This research was supported by core funding from the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z), and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: National Research Ethics Service West London committee provided ethical approval: (07/H0707/105; 14/LO/1806; 17/LO/0292). Informed written consent was obtained before fetal MRI. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Restrictions apply to the availability of these data, which were used under license for this study. Certain anonymised data are available upon request from the corresponding author.