Title: Evaluation of state of the art ultrasound and novel three dimensional MRI for fetal facial and cranial examination of dysmorphic features; a pilot study
Funder: Health Education England

Abstract: Background: Genetic abnormalities affect 1/200 births and are the second leading cause of perinatal death, however, successful prenatal diagnosis varies widely (5-95%)1,2. Abnormal craniofacial development is implicated in more than 250 syndromes3, however two-dimensional (2D) antenatal ultrasound (US) is limited in recognising patterns of craniofacial dysmorphology resulting in poor detection rates4 and missed opportunities for early treatment or decision making. Three-dimensional (3D) ultrasound could improve anatomical visualisation, however its uptake is low due technical limitations and lack of expert consensus for its use82. Magnetic Resonance Imaging (MRI) is complementary to US, however fetal motion corrupts MRI data. Our open source slice-to-volume reconstruction (SVR) algorithm produces motion-corrected 3D volumetric datasets from 2D data improving the image quality5. Primarily used by our centre for the fetal brain, our recent pioneering work demonstrated MRI's ability to assess fetal heart anomalies better than 3D-US with novel 3D-MRI reconstructed volumes6,83.These approaches, if applied to characterise and quantify craniofacial morphology in-utero, will provide opportunities to overcome diagnostic challenges in high-risk cases. Research question: What is the additional benefit of 3D-US and novel motion-corrected fetal 3D-MRI for the investigation of craniofacial dysmorphic features compared to standard 2D imaging?Aim: To create an evidence-based fetal craniofacial examination using 3D-imaging techniques with both US and MRI, complementary to postnatal expert dysmorphology assessment.Methods (and timelines):Site: 4 years in a single tertiary centre: Months 1-18: Evaluation of novel motion-corrected fetal 3D-MRI compared to standard 2D-MRI in the assessment of craniofacial morphology. Design: Retrospective case-control and method comparison Sample: 120 fetal MRI cases scanned at 1.5T or 3T (60 high risk and 60 case-matched controls identified from an existing database) Procedure: 2D and then 3D-MRI images will be reported by an expert (JM), blinded to postnatal outcome and clinical imaging history. Morphological assessment and subjective quality scores and objective craniofacial measurements will be obtained. A 25% random sample will be also be reviewed by another fetal imaging expert. Analysis: Comparision of successful craniofacial assessments in 2D and 3D-MRI Comparision of image quality between MRI field strengths MRI anomaly findings compared with postnatal outcome Observer reliability and agreement Months 19 - 48: 3D-US and 3D-MRI compared to 2D-US in the assessment of fetal craniofacial morphology: A pilot study. Design: Prospective case-control and method comparison Sample: 50 (25 high-risk/25 healthy) Procedure: 2D-US, then 3D-US and MRI will be performed on the same day. Offline assessment of craniofacial anatomy and quality scores will be performed by 3 observers (radiographer (JM)/sonographer/MRI radiologist) blinded to previous results. Analysis: Evaluation of successful morphological assessments (3D-US and 3D-h;MRI compared to 2D-US) Imaging anomaly findings compared to postnatal outcomes Observer reliability and agreement Assessment of appropriate sample size and study set up for a larger future trialAnticipated Impact Implementation of US/MRI antenatal craniofacial imaging protocols Recommendations for fetal craniofacial imaging training Informed plan for future clinical audit/research Improved antenatal characterisation of craniofacial genotype-phenotype correlations to inform care decisionsDissemination 2 peer-review publications/2 conference abstracts A patient/public co-developed plain English summary (newsletters and social media) Educational/engagement events

Lay abstract: Aim This proposal aims to explore the ability of three-dimensional (3D) ultrasound (US) and fetal magnetic resonance imaging (MRI) to improve the assessment of fetal skull and face abnormalities associated with genetic problems or syndromes. BackgroundIn the UK, birth defects affect 1/49 births, with a quarter having an associated genetic abnormality as the underlying cause and many with changes in normal skull and facial development. These features are frequently undetected on conventional antenatal US because a number of factors reduce the scan quality, for example; skill/training of the operator, fetal position, amount of amniotic fluid in the womb, maternal size challenges visualising facial/skull characterisics from two-dimensional (2D) slicesMRI is less affected by these factors, can be challenging when there is fetal motion and is time-consuming. Although 3DUS has some of the same quality issues as 2DUS, it is a promising way to more clearly see the fetal facial/skull features but it is not widely used.Fetal MRI is more expensive than US, however, it is an emerging, detailed and safe technique for pregnancy. Our department has pioneered advanced MRI techniques which remove the detrimental appearance of fetal motion. This state-of-the-art image process converts 2D-MRI image data into 3D motion-corrected fetal images. We use these 3D-views for the fetal brain and, recently, in the fetal heart as a specialist approach to improve diagnosis. This work has led to a new local NHS service. Detecting anomalies before birth provides opportunities for early treatment or decision making that would otherwise be missed, thus improving individualised healthcare discussions, providing families with more appropriate counselling, medical treatments and surgical planning. Drawing on our technical work in US and MRI, I hypothesise that systematic fetal face and head assessment, could now provide clinicians with new insights in facial anomalies. Design and methods used The study has been divided into 2 parts: An MRI evaluation of the fetal face/skull in 60 pregnancies at high risk for abnormality and 60 healthy volunteers. The 2D-MRI scans have already been performed and they will be re-processed into easy-to-assess 3D volumes. The success of the 3D-MRI will be compared to standard 2D-MRI, with results compared to the postnatal outcomes in baby. Evaluation of the fetal face and skull anatomy with 3D-US and 3D-MRI; a pilot study. 50 research participants (half at high risk for fetal abnormality) will be offered a joint ultrasound and MRI on the same day (ideally). Experts will review the ability to see anatomy on 3D-US and new 3D-MRI techniques compared to standard 2D-US and compare the postnatal findings in baby. Additionally, guidance to support implementation into clinics and a future larger trial will be considered.Patient and public involvement (PPI) The School's imaging PPI group (where I have presented this topic) meets every three months and will be involved in the project planning/implementation and dissemination stages of the research cycle. I have a service user who has helped set these research priorities and assisted with design/PPI aspects. Along with another public stakeholder, she has agreed to be a patient representative on the Research Steering Group for the project. 3 dedicated craniofacial focus groups are planned so that the condition-specific patient perspective is integrated into the planning/ implementation/ dissemination and evaluation of the project. Dissemination In addition to scientific publications and conference presentations, a professional 'sketch note' artist will create eye-catching visuals from patient/public focus groups for dissemination. The focus groups will co-create a plain summary and a public dissemination plan (including charity newsletters, Twitter and the school's 'Imaging Blog'). Also, I will attend the 'Headlines' charity annual conference where I plan to get public feedback.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH