Virtual Reality Use in Assisted Reproductive Technology

Study Overview
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Brief Summary
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The study will examine the effect of exposure to virtual reality on stress levels and pregnancy rates, in infertile women undergoing in vitro fertilization embryo transfer

Detailed Description
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In vitro fertilization (IVF) treatment involving ovarian stimulation, oocyte retrieval and embryo transfer (ET) is an effective treatment for various causes of infertility. Despite advances in ovarian stimulation regimens and laboratory conditions, many IVF cycles do not result in pregnancy, and repeated treatment cycles are required. According to the latest Assisted reproductive technology (ART) surveillance report in the United states, of 143,286 procedures that progressed to the ET stage, 50.9% resulted in a pregnancy and 41.4% in a live-birth. Achieving higher pregnancy and live birth rates remains a leading priority of IVF units worldwide. Both IVF practitioners and patients keep searching for new ways to improve reproductive outcomes. IVF is a multidimensional stressor. The treatment itself constitutes the primary stressor and is most likely to evoke anxiety. The highest anxiety scores were experienced before embryo transfer and were comparable to anxiety scores obtained from surgical female patients in the immediate preoperative period. Hence, it is not surprising that ET is defined by many investigators as a crucial event for determining IVF outcome, and many patients perceive it as the culmination of the IVF treatment. The stress this procedure may cause can result in a variety of autonomous nervous system expressions, altered uterine gene expression, resulting in decreased uterine receptivity, or an increase in uterine contraction frequency, which may be inversely correlated to embryo implantation and pregnancy rates in IVF. Several studies found that women who did not become pregnant with IVF, reported experiencing more stress during treatment than those who achieved pregnancy. Although the exact mechanism whereby stress interferes with reproductive processes is not fully understood, experimental evidence increasingly indicates that lower stress levels result in better fertility treatment outcome. The use of complementary medicine or adjuvant therapies to reduce psychological stress during ART therapy and improve IVF outcomes is increasing. Various alternative therapies have been proposed to improve reproductive outcomes during IVF treatment, such as acupuncture and Chinese herbal medicines. However, the impact of these therapies on IVF outcomes was inconclusive. The impact of medical clowning as a stress-reducing technique for 12-15 minutes after ET was found to increase the pregnancy rate - 36.4% in the intervention group compared with 20.2% in the control group. Other interventions, specifically prior or during the IVF-ET procedure itself have been studied in the context of improving cycle outcome and/or reducing anxiety levels. In order to assess anxiety levels before and after interventions, most of these studies included the validated State-Trait Anxiety Inventory (STAI) questionnaire, which is a self-assessment questionnaire, consisting of 40 items rated on 4-point Likert scale. The scale consists of two sub-dimensions: the state anxiety has 20 items and is used to determine what is felt at a specific moment under certain conditions, and the trait anxiety has 20 items and is used to determine what has been felt in the last seven days. Higher scores are positively correlated with higher levels of anxiety. Other studies assessing stress related to ET procedure used salivary a-amylase (SAA). SAA measurement presents a non-invasive and a highly reliable indicator of sympathetic-adrenal medullary activity can be used as a physiologic indicator of the acute stress response. The impact of hypnosis during ET on the outcome of IVF was studied in 89 patients, compared with controls. The results suggested that the use of hypnosis during ET may significantly improve the IVF-ET cycle outcome in terms of increased implantation rates (IR) and clinical pregnancy rates (CPR). Harp therapy during ET of 90 IVF patients was found to significantly decrease levels of anxiety post transfer and having a positive effect on acute levels of stress, compared with controls. However, CPR was comparable between the harp group and the control group. Another study assessed the effectiveness of a deep relaxation massage therapy prior to frozen ET in 56 IVF patients. In patients using the massage therapy prior to ET, statistically significant increases in pregnancy and live birth rates were observed when compared with the control group (58.9% vs 41.7%, and 32.0% vs 20.3%, respectively). The researchers hypothesized these improvements were most likely due to a relaxing effect on patients and reduction in stress, leading to a reduction in uterine contractions. A recent randomized controlled trial assessed the effect of music therapy in women undergoing IVF-ET. They examined the effect of music therapy before and after ET, on the anxiety levels and pregnancy rates in 89 IVF patients. The mean state anxiety scores decreased in both groups, however these changes did not reach statistical significance. CPR were comparable between the groups. Virtual reality (VR) is a therapeutic approach which has been gaining attention over the past two decades for both medical and psychiatric purposes. VR is an advanced technological system that allows users to be transported into a 'virtual world'. Users are engaged in a fully immersive VR experience through a combination of technologies, including a head-mounted display, headphones with sound/music and noise reduction, and another device for manipulation/navigation of the virtual environment. Multimodal stimuli contribute to a sense of actual presence/immersion in the virtual world, thus making the VR experience distinct from a passive visual or auditory stimuli. Being a safe, non-invasive and easy to use technique, VR therapy has been explored for numerous health applications, showing positive outcomes in clinical conditions such as anxiety disorders, addictions, phobias, posttraumatic stress disorder, eating disorders, stroke rehabilitation, and pain management. A recent systematic review including 11 VR studies and 467 patients, concluded that VR's immersive, entertaining effects are useful for redirecting the patient's attention away from painful treatment experiences and reducing anxiety, discomfort, or unpleasantness. Other studies also showed a significant decrease in pain perception and state anxiety scores when treated with VR, as indicated by anxiety questionnaires, pulse rate reduction, and electroencephalogram (EEG) changes when treated with VR as compared with controls, all supporting the therapeutic potential of VR for anxiety management and stress reduction. A study presented at the 2018 anesthesia congress in Europe (Unpublished data) compared the effect of two different VR sessions (distraction and hypnosis) before sedation, on the anxiety level and the following cycle outcomes in 100 IVF patients. The preliminary results of the study showed a reduction in the anxiety scores in both groups, however the differences between the groups did not reach statistical significance. The aim of this study is to examine the effects of VR technology on the most stressful event during IVF-the transfer of embryos into the uterus. The investigators will use the STAI questionnaire to assess levels of anxiety experienced during the ET procedure, in participants exposed to VR session before the ET, compared with participants who are not exposed. The investigators hypothesize that the use of this unique technology before the procedure may reduce stress levels and consequently improve implantation and pregnancy rates. According to a recent literature review, there are no published studies examining the effect of VR prior to ET on IVF outcomes.

Official Title
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The Use of Virtual Reality Technology in Infertile Women Undergoing in Vitro Fertilization-embryo Transfer: A Randomized Controlled Trial

Conditions
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IVF Outcomes, Stress Levels

Intervention / Treatment
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* Device: Virtual reality


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 21-45-year-old female patients, if using own ovum. Patients above this age range may be approached for study if using a donated ovum, as long as egg age (age of donor at ovum pick up) falls in 21-45 age range. Undergoing frozen ET procedures, and approached for study on Day 2 - Day 4 of ET transfer cycle. Ability to provide written consent to use VR technology before the ET procedure Exclusion Criteria: Contraindication to use VR technology (Epilepsy/previous seizure, claustrophobia, current migraine, heart disease, visual and/or auditory deficits/use of medical devices such as cardiac pacemaker or hearing aids) Anxiety disorder and/or Regular use of anti-anxiety medications Major uterine anomalies and/or uterine fibroids distorting the cavity

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 54 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>Patients who will be randomized to the control group will be waiting for the ET procedure without any intervention and without any deviation from the standard of care | |
| Experimental: Study group<br>Exposure to virtual reality environment exposure | Device: Virtual reality<br>* Patients randomized to the study group, will be provided with the VR headset and sensors. The VR exposure will take place before the ET procedure, during their routine pre-transfer waiting period, in a private room. The patient will be able to choose between three different calming VR environments (3 scenes: beach sunset, palm tree patio or redwood forest) and will be exposed to the chosen VR environment for a continuous duration of 15-30 minutes. The VR exposure will be passive, and the patient can control her observation inside the environment by herself, simply by moving her head. During this period, at any time and for any reason, the patient can discontinue the use of the VR session simply by self-removing the helmet<br>* Other names: Immersive environment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate (CPR) | The difference in CPR (determined by sonographic evidence of a gestational sac and fetal heart rate at 6 weeks' gestation by transvaginal ultrasound) between the study and the control group. An increase of 15% in the clinical pregnancy rate in the study group will be considered as significant. | Assessed 4 weeks after ET (= 6 weeks of gestation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stress levels - STAI questionnaires | Will be assessed using the STAI questionnaire (scored 20-80 points). We are expecting a 25% decrease in the STAI scores in the study group to be significant, based on clinical experience with similar patient population | Questionnaires will be filled out in 3 different time points during the study: 1) Day 1 of recruitment, before beginning the medications for endometrial preparation 2) ET day, 30-60 minutes before ET 3) ET day, 5-10 minutes after ET procedure | 
| Salivary alpha amylase (SAA) levels | Salivary samples will be collected and analyzed. A 30% decrease in the SAA levels in the study group vs control will be considered significant, based on a previous study | Samples will be collected in 3 different time points during the study: 1) Day 1 of recruitment, before beginning the medications for endometrial preparation 2) ET day, 30-60 minutes before ET 3) ET day, 5-10 minutes after ET procedure | 
| Sympathetic autonomous nervous system expressions | Heart rate & blood pressure measurements. These 2 sympathetic nervous system variables were selected as physical parameters which may indicate anxiety. A significant change between the groups will be based on clinical experience with similar patient populations. An estimated one-third (33%) of the patients would experience elevated blood pressure and/or heart rate readings in the moderate-to-severe range during the standard procedure. VR exposure therapy is expected to reduce this proportion to 20%. | Measurements will be taken in 3 different time points during the study: 1) Day 1 of recruitment, before beginning the medications for endometrial preparation 2) 30-60 minutes before ET 3) ET day, 5-10 minutes after ET procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Virtual reality, In vitro fertilization, Embryo transfer