First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial

Congenital anomalies account for 15–20% of all fetal deaths and nearly 25% of all neonatal deaths in Europe [1]. Around 2% of all pregnancies are affected by a major anomaly that requires extensive postnatal support [2]. A correct prenatal diagnosis can direct future parents to the best possible care.

According to international and Dutch national guidelines, all pregnant women are offered a second trimester two-dimensional (2D) ultrasound scan to screen for fetal anomalies [3‐5]. Subsequently, future parents are counseled about the possible diagnosis, prognosis and treatment. However, by the end of the first trimester (< 14 weeks gestational age (GA)), a considerable amount of fetal anomalies can already be detected using 2D ultrasound [6, 7]. A systematic review, performed in a high risk population, showed that 61% of the (detectable) anomalies can already be identified by a first trimester anomaly scan [6]. A more recent prospective cohort study performed in The Netherlands even found a detection rate of 63% within a low risk population, which demonstrates the importance of performing a first trimester anomaly scan [8]. The observed high detection rate of major anomalies and ultrasonographic markers coincides with other advantages. Firstly, detection of an anomaly at an early stage in pregnancy provides additional time for counseling, advanced genetic testing, parental thought and reflection [9]. Secondly, a first trimester scan showing no abnormalities might provide parental reassurance, especially in a population at higher risk of fetal anomalies. Thirdly, if applicable, an early termination of pregnancy is considered a low risk procedure, in contrast to termination during advanced gestation, which shows a greater risk of maternal morbidity and mortality [10, 11]. When pregnant women opt for an early termination of pregnancy, methods available are considered less invasive when compared to termination at an advanced stage. Moreover, it has been shown that termination of pregnancy at a more advanced gestational age is associated with an increased risk of an adverse psychological outcome [12].

Finally, women with an increased BMI (i.e. > 30 kg/m²) could profit from a first trimester anomaly scan. It is known that the performance of the second trimester transabdominal ultrasound examination in women with an increased BMI is limited with regards to detection and completeness [13]. Incomplete ultrasound examination may lead to suboptimal care for these women. The efforts and costs greater when compared to women with a BMI < 30 kg/m². In the first trimester, transvaginal ultrasound may be used to overcome limited visibility in the women with an increased BMI.

From the above mentioned, we can conclude that postponing detection of anomalies to the second trimester of pregnancy can be regarded as a missed opportunity. This is the most compelling argument mentioned in international guidelines proposing a first trimester anomaly scan to be offered to all women, accompanied by adequate counseling of the potential benefits and limitations [14]. However, there is a lack of implementation of the guidelines’ advice in nationwide screening programs. The available literature concerning detection rates and feasibility of the first trimester anomaly scan include a low risk population and are retrospective in design [6]. Prospective or randomized trials for a high risk population are limited in number. In spite of this, some countries are offering a first trimester anomaly scan to their population [15].

Over the years several factors have contributed to the quality of first trimester 2D ultrasound imaging. The most important ones are the introduction of high frequency ultrasound probes and using the transvaginal approach. The addition of an application providing three-dimensional (3D) renderings have further enhanced first trimester ultrasound imaging by enabling improved visualization of fetal structures [16]. However, there are also limitations concerning 3D ultrasound examinations. The 3D datasets are presented as 3D reconstructions on 2D screens. Therefore, the third dimension, depth, cannot be used to its fullest since the images are being presented on 2D media. Improved visualization can be reached using Virtual Reality (VR) displays. VR enables true depth perception and provides 3D interaction. ‘Holograms’ of the 3D ultrasound scans can be created using the V-Scope software (Erasmus MC, Rotterdam, The Netherlands), allowing presentation of volumetric data in the best possible way [17, 18]. Following the acquisition of 3D data, using any 3D probe, application of V-scope imaging software enables 3D data to be displayed as ‘holograms’ on a 3D display, generating depth perception using 3D glasses. The difference between 2D, 3D and 3D VR is depicted in Fig. 1. These generated ‘holograms’, show easier to interpret images and provide detailed and relevant information about the fetal anatomy [19]. 3D VR might improve antenatal counseling of future parents.

The VR technology has already been used extensively to visualize 3D ultrasound datasets in the Barco I-Space system; which is a special room enabling VR [16]. To facilitate clinical use, a 3D VR Desktop system has been developed (Fig. 2 – photo published with consent of future parents and examiner). This system can be used in daily outpatient practice, offering the same functionality at a fraction of the cost [17, 18]. Baken et al. have compared 2D ultrasound, 3D ultrasound and 3D VR for detection of first trimester fetal anomalies [20]. This retrospective study showed that the general diagnostic performance between the different methods was comparable (sensitivity 3D: 52.2%, 3D VR 62.6%; specificity 3D: 99.7%, 3D VR 99.6%). 3D VR has shown to be of additional value in the detection of anomalies, especially with regards to limb defects, conjoined twins and aneuploidy [21, 22]. Besides improving visualization, V-Scope enables the measurement of regularly used biometric features (e.g. crown-rump length) and more recently developed biometric and volumetric features (e.g. embryonic volume) with high reproducibility [23‐27]. There is no difference with regards to the measurements performed in the I-Space or 3D VR Desktop system (excellent inter- and intra-observer class correlation (> 0.99)) [18].

In addition to the introduction of a first trimester anomaly scan in a high risk population, the use of VR as an additional technique is the subject of the current study. The diagnostic yield of the 3D VR will be compared with international guidelines and literature. Preferably, before implementing a new modality in daily clinical practice, cost-effectiveness should be considered [28]. Cost-effectiveness may be studied from several perspectives [29]. Ideally, this includes the societal perspective on medical costs, comprising both the direct (i.e. expenses associated with the disease and its complications) and indirect costs (e.g. effect of the illness for the patient on society, such as productivity loss). Therefore, we designed a randomized controlled trial to study the cost-effectiveness of the first trimester 3D VR ultrasound in a high risk population. Cost-effectiveness will be explored in terms of health-related quality of life and costs from a societal perspective. Also, the perspective of both patient and ultrasonographer on the new 3D VR modality will be surveyed.

This is the first randomized controlled trial designed to detect anomalies in the first trimester using 3D VR ultrasonography, with longitudinal follow-up in pregnancy. One previous study has shown a high sensitivity for the detection of structural anomalies in the first trimester using 3D VR and a trend towards improved detection rates [16]. 3D VR may especially improve the detection of surface anomalies in the first trimester [20]. Timely detection of major congenital malformations will provide women at risk with additional time to perform (genetic) testing as well as more time to consider continuation or termination of pregnancy. In current Dutch practice even women from the high risk population are only offered a second trimester anomaly scan. In the high risk group an additional first trimester ultrasound examination may be beneficial since there will be an increased prevalence of anomalies. Furthermore, the absence of a major anomaly following a first trimester 3D VR ultrasound examination could offer earlier reassurance and reduce anxiety in pregnant women. Overall, we hypothesize this will improve cost-effectiveness and patient quality of life.

This study has several strengths. The use of a standardized examination protocol will improve the detection of fetal anomalies. Recent studies have shown increased detection rate of anomalies when a standardized ultrasound protocol is used compared to a strategy that consists of a global fetal survey [6]. Also, transvaginal ultrasound or the combination of transvaginal and transabdominal ultrasound may increase the detection of anomalies in the first trimester compared to only using a transabdominal approach. This is especially true in case of maternal obesity. Detection of anomalies will be further improved by the limited filtering of the ultrasound data by the 3D VR system, which can enhance fetal surface details and thus improve the examination of limbs and face. This technique also provides recognizable and identifiable ‘holograms’ for the future parents.

Some challenges remain. The introduction of a first trimester ultrasound examination will necessitate an additional prenatal visit, as well as expertise and training of staff. This might increase healthcare costs. This study will add new understanding on maternal psychological functioning throughout pregnancy in relation to prenatal ultrasound. Ideally, we would use structured interviews. However, due to the size of the study this was not a possibility. Instead we chose to use validated questionnaires to investigate maternal stress and anxiety.

Some organ systems are not yet fully developed in the first trimester or are too small to be visualized in detail. As an example, one can state that it is not possible to detect all or a large proportion of fetal cardiac and brain anomalies in early pregnancy. Therefore, second trimester ultrasound examination cannot be omitted, and has to be used in addition to first trimester ultrasound.

From a clinician’s point of view, the first trimester ultrasound should be studied regarding its additional value of diagnostic performance. Rather than comparing first and second trimester ultrasound examination, the performance should be based on the combination of first and second trimester. We expect that first trimester detection will show an improvement in the clinical care of participants and lead to significant improvement in their quality of life. Furthermore, a second trimester ultrasound examination will show the development of a congenital anomaly over time. Parents’ decision for continuation of the pregnancy is likely to be affected by this. The second trimester ultrasound is indispensable, therefore we will study the combined first and second trimester ultrasound examination compared to the second trimester only.

This study will provide the highest level of evidence in the evaluation of first trimester 3D VR ultrasonograhpy in a high risk population concerning quality of life and cost-effectiveness. Only with a randomized controlled trial, like this study, the additional value of the 3D VR desktop can be examined in terms of improved diagnostic yield of regular first trimester 2D ultrasound and patients perspectives. If this new modality proves to be cost-effective or shows to improve quality of life, it should be offered in addition to the second trimester 2D ultrasound examination. The wider implications of the results will give policymakers and healthcare professionals an educated choice as whether to add first trimester ultrasound for detection of congenital anomalies in a high risk group as part of routine care.