Synopsis

Keywords: Fetal, Brain, Brain Volumes, Congenital Heart Disease

Total and regional brain volumes, derived from automatically segmented, motion-corrected, 3D fetal brain MR images were obtained in 45 healthy fetuses and 305 fetuses with isolated congenital heart disease (CHD) in the third trimester. Total brain tissue, cortical and deep grey matter, and white matter volumes are significantly lower in fetuses with CHD where cerebral oxygenation and substrate delivery are likely to be reduced. Brain volumes appear normal in fetuses with CHD but an otherwise expected normal cerebral oxygenation.

Introduction

Congenital heart disease (CHD) is common, affecting ~1% of live-births [1], and is associated with developmental impairments persisting into adulthood [2–4]. Exact mechanisms behind these impairments remain unclear but are likely to be multifactorial.

There is evidence that fetuses with CHD have impaired brain growth [5–10]. However, these studies are limited by small cohort sizes, or focus on specific diagnoses rather than underlying physiology. Furthermore, little work has been done involving CHD classed as ‘mild’. Receiving a CHD diagnosis of any kind is a source of parental anxiety, so investigating how less severe types of CHD impact brain development is warranted.

Fetal CHD can be grouped into three broad categories, as previously described [11–14]: (1) Normal expected cerebral oxygenation; (2) Mild-to-Moderately reduced cerebral oxygenation; (3) Severely reduced cerebral oxygenation.

We aimed to explore how expected cerebral oxygenation affects brain volumes in a large cohort of fetuses with CHD.

Methods

Women referred to our fetal cardiology service with a confirmed fetal diagnosis of CHD between 2014-2022, or women experiencing a low-risk pregnancy recruited to the iFIND project (https://www.ifindproject.com/) were included. Written, informed consent was obtained before MRI (NHS REC: 07/H0707/105&14/LO/1806). Twins, fetuses with confirmed genetic abnormalities, or with extracardiac or structural brain anomalies were excluded.

Images were acquired on a Philips Ingenia 1.5T MRI scanner. Fetal brain images were acquired using a T2-weighted single-shot fast-spin-echo sequence (TR=1500ms,TE=80ms,in-plane resolution=1.25mm²,slice thickness=2.5mm,slice gap=-1.25mm), optimised for fetal imaging [15]. Images were motion-corrected and reconstructed using an advanced slice-to-volume reconstruction (SVR) technique [16,17], before being up-sampled to 0.5mm³ isotropic resolution. Each SVR was independently assessed by two clinicians using a previously published scoring system [18]. Poor quality datasets were excluded (Figure 1).

Each brain SVR was segmented using an automated tool based on the developing Human Connectome Project segmentation protocol with 19 label ROIs (https://gin.g-node.org/kcl_cdb/fetal_brain_mri_atlas) and a 3D-UNet [19] convolutional neural network having undergone semi-supervised training in MONAI [20] (Figure 1). All segmentations were reviewed and confirmed to be acceptable for volumetry. Volumes were generated for cortical grey matter (cGM), white matter (WM), deep grey matter (dGM), cerebellum, brainstem, cerebrospinal fluid (CSF) and total brain tissue volume (TTV), calculated by summing cGM, WM, dGM, cerebellum and brainstem (Figure 2).

Each fetus with CHD was categorised into one of three groups, as described above, informed by the primary underlying CHD diagnosis and fetal echocardiographic and cardiac MR findings. Healthy control fetuses were assigned group (0).

An ANCOVA was performed to explore any effect of expected cerebral oxygenation on brain volumes, accounting for fetal sex and gestational age (GA) at scan. P-values, corrected for multiple-testing (pFDR) are reported.

Results

Data from 350 fetuses were included: 45 healthy controls and 305 with CHD (158 in group 1, 127 in group 2, 20 in group 3). There was a significant difference in GA at scan between groups (p_FDR<0.001), but not fetal sex (p=0.96). Histograms showing the distribution of GA at scan and CHD groups are in Figure 3.

After accounting for sex and scan GA, there was a significant difference in TTV, cGM, WM and dGM volumes (all p_FDR<0.004) between groups (Figure 4).

A post-hoc analysis comparing total and regional brain volumes between control fetuses and only CHD fetuses with expected normal cerebral oxygenation was performed. After accounting for sex and scan GA, no significant group difference was seen in any regions (pFDR>0.19). A further post-hoc analysis comparing brain volumes between only fetuses with CHD (Groups 1-3) was performed. After accounting for sex and scan GA, a significant difference in TTV, cGM, WM and dGM (p_FDR<0.002 for all) between groups was identified (Figure 5).

Discussion

This is one of the largest studies to date exploring brain volumes in fetuses with CHD. Expected cerebral oxygenation is significantly associated with total and regional brain volumes, with likely reduced cerebral oxygenation correlating with smaller volumes. Brain volumes in fetuses with TGA are most affected. WM appears to be the most strongly impacted region. This classification approach, based on expected cerebral oxygenation, is supported by recent advances allowing in-utero quantification of fetal arterial and venous oxygen saturations [12,21–23].

To our knowledge, this is the first large study exploring brain volumes in fetuses with mild CHD (i.e. associated with normal cerebral oxygenation). We identified no significant difference in brain volumes between these fetuses and healthy controls, supporting the hypothesis that cerebral oxygenation is a key mediator of fetal brain growth.

Our results align with existing studies that identify fetuses with TGA as having the smallest brain volumes [5], and in that dGM volumes are smaller in fetuses with severely reduced cerebral oxygenation [24]. They also complement work exploring associations between reduced cerebral oxygen delivery and brain volumes at earlier gestations [7,8] .

We focussed on a narrow GA range, as this is when most clinical fetal cardiac MRI’s are performed. We assumed linear trends in brain growth across gestation, which is not necessarily the case [24] but is appropriate for the narrow GA window used here. Future work should use direct measurements of fetal cerebral oxygenation where available, and investigate how brain volumes correlate with later neurodevelopmental outcomes.

Acknowledgements

We would like to thank the families who participated in this research. We also thank our research radiologists; our research radiographers, and our fetal scanning team. In addition, we thank the staff from the Evelina London Children’s Hospital Fetal and Paediatric Cardiology Departments and the Centre for the Developing Brain at King’s College London.

This research was funded by the Medical Research Council UK (MR/L011530/1; MR/V002465/1). This research was supported by by core funding from the Wellcome/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z], the Wellcome Engineering and Physical Sciences Research Council Centre for Medical Engineering at King's College London (WT 203148/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.

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