Clinical trial NCT02413697: Three-dimensional Versus Two-dimensional Ultrasound Guided Embryo Transfer in Women Undergoing ART Treatment
Official title: A Randomised Control Trial of Three-dimensional Versus Two-dimensional Ultrasound Guided Embryo Transfer in Women Undergoing Artificial Reproductive Technology Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infertility
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2015-04-10
Enrollment: 481
Sex: FEMALE
Minimum age (years): 24
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Objectives: To assess whether embryo transfer guided by three-dimensional ultrasound (3DUS) produces a significantly higher clinical pregnancy rate than embryo transfer guided by two-dimensional ultrasound (2DUS).

Hypothesis: 3DUS guided embryo transfer will produce a significantly higher clinical pregnancy rate compared with 2DUS guided embryo transfer. Design and subjects: Prospective randomised control trial (RCT) at the Prince of Wales Hospital. Inclusion criteria include women undergoing embryo transfer in fresh and frozen cycles. Exclusion criteria include women aged \>42 years and women whose endometrial cavity cannot be visualised adequately via US. Power calculations indicate that 232 patients per arm are required to demonstrate an increase of 12% in clinical pregnancy rates.

Study instruments: US examinations will be performed using a General Electric(GE) Voluson series US machine with a standard 3D transvaginal probe. For embryo transfer, the Cooks Guardia Access EchoTip catheter will be used.

Interventions: 3D versus 2DUS for guidance during embryo transfer. Main outcome measures: clinical pregnancy. Secondary outcome measures: implantation rate, multiple pregnancy, miscarriage, ectopic pregnancy and live birth rates.

Data analysis: Data processing and analysis will be performed using the Statistical Packages of Social Sciences for Windows (SPSS, Inc). Descriptive and comparative statistical methods will be used to analyse the primary outcomes. P-values of \<0.05 will be considered significant.

Expected results: The study arm undergoing 3DUS guided embryo transfer are expected to have an improved clinical pregnancy rate compared with the control arm undergoing 2DUS guided embryo transfer.

Detailed description: INTRODUCTION

The role and use of 2DUS in gynaecology is undisputed as it forms an integral part of diagnosing pathologies of the uterus, tubes and ovaries. In reproductive medicine, it is of particular significance as it is additionally the most widespread tool available to monitor endometrial thickness, follicular status and growth, allow guided retrieval of oocytes from the ovary and also guided transfer of fertilised embryos into the uterus \[1\]. These are undoubtedly some of the most critical procedures/steps of ART.

The development of 3DUS has brought somewhat of a breakthrough in the field as now 3D volumes of images can be acquired and analysed live or retrospectively. From a practical perspective, the scanning procedure does not differ from the routine 2D US and the acquisition of a 3D volume requires only a few seconds. Analysis of these volumes allows reconstruction of planes which are not always possible with 2DUS (such as the 3D coronal plane of the uterus). As a result, 3DUS is now considered to be the most accurate non-invasive modality to diagnose uterine anomalies \[2, 3\]. Furthermore, 3DUS allows accurate volume calculations of structures such as the endometrium and follicles. These new possibilities, coupled with advanced software now also allows for automated measurements of these variables, which may improve accuracy, reduce interobserver variability and increase efficiency of an ART unit \[4\].

Several publications now in the literature support that 3DUS may play a major role in ART in the future \[5-8\]. Areas which 3D US may provide additional information are:

* Assessment of ovarian blood flow, follicular volume and growth \[9\]
* Assessment of endometrial and subendometrial blood flow and volume \[10, 11\]
* Assessment of precise catheter placement during embryo transfers \[12\] The latter is perhaps the area which has been the least investigated so far, despite embryo transfer being arguably the step of highest importance throughout the entire ART process. Two preliminary studies have shown that 3DUS guided embryo transfer significantly improves catheter placement compared with 2DUS \[13\] and can allow for correction of up to 20% of mal-positioned catheters where 2DUS alone has been used \[14\]. The largest series to date, has demonstrated that by use of 3DUS, the placement of embryos can be performed in the so called maximum implantation potential point, which is where the trajectories of the fallopian tubes meet in the centre of the uterine cavity, where the endometrial thickness and blood flow is thought to be greatest \[12\]. However, to our knowledge, there has been no randomised controlled trial (RCT) in the literature to systematically test 3DUS versus 2DUS guided embryo transfer with respect to pregnancy outcomes. If 3DUS guided embryo transfer is confirmed to produce a higher pregnancy rate than 2DUS guided embryo transfer, it will have significant impact on the daily clinical practice of ART units worldwide.

AIMS AND HYPOTHESES

Aims To determine if 3DUS guided embryo transfer should routinely replace 2DUS guided embryo transfer.

Hypotheses 3DUS guided embryo transfer produces a higher clinical pregnancy rate compared with 2DUS guided embryo transfer

PLAN OF INVESTIGATION

Subject recruitment Women with infertility will be recruited from the Assisted Reproductive Technology Unit of the department of Obstetrics and Gynaecological, Prince of Wales Hospital. They will be given information leaflets at the beginning of their treatment cycle, and further counselled on the day of oocyte retrieval or on the day of commencement of progesterone therapy. This will allow sufficient time to consider participation in the trial and confirm their consent on the day of embryo transfer. The investigators anticipate that over 80% of subjects undergoing embryo transfer will participate.

Study design A prospective single-blinded randomized controlled trial.

Inclusion criteria:

* Women undergoing embryo transfer in either fresh or frozen cycles.
* Women whose endometrial cavity can be visualised adequately via US Exclusion criteria
* Women aged \>42 years
* Women whose endometrial cavity cannot be visualised adequately via US, such as:

Large fibroids Adenomyosis BMI\>35 Significant uterine retroflexion/retroversion

Power calculation The largest published series to date using 3DUS guided embryo transfers demonstrates a clinical pregnancy rate of 37% for women with an average age of 38 \[12\]. Our unit in 2013 achieved a clinical pregnancy rate of 25% for women in a similar age group. Assuming that 3DUS guided embryo transfer will enable our unit to increase the clinical pregnancy rate from 25% to 37 % (an increase of 12%), a power calculation using alpha of 0.05, beta of 0.2 and power of 0.80, indicates that 232 patients per arm are required. To account for a small amount of drop-outs 480 subjects in total will be recruited.

Methods 232 women per arm will be recruited as part of this prospective randomized controlled trial. The inclusion criteria will be patients with reproductive failure undergoing IVF/ICSI embryo transfer. The exclusion criteria will be (i) women aged \>42 years; (ii) women whose endometrial cavity cannot be visualised adequately via US, such as large fibroids, adenomyosis; (iii) BMI\>35, and (iv) significant uterine retroflexion/retroversion. At the time of embryo transfer, patients will be assigned to either of two groups: a) the 2DUS group where they will have their embryo transferred under the guidance of 2DUS, or b) the 3DUS group, where they will have their embryo transferred under the guidance of 3DUS.

Randomisation Patients will be randomised into the 3D or 2DUS groups with a 1 to 1 ratio using a computer-generated randomisation list with blocks of 10 in sealed envelopes pre-prepared by an impartial research nurse, to ensure equal distribution of subject assignment.

Procedure The use of 2DUS guidance for embryo transfer is universally standard practice. All ultrasound examinations will be performed using the GE Voluson series ultrasound machines, with a standard 3D transvaginal probe (model RIC5-9-D; 6.6 MHz central image frequency). The examination with 3DUS will be identical to the routine 2D examination including an acquisition of a 3D volume which takes a few seconds. The 3D facility is engaged by switching into the "3D" mode. A mobile sector appears and the operator identifies the "region of interest." The acquisition is then commenced and the transducer crystal then rotates through approximately 90° for less than 10 seconds. The images are shown instantly to the operator and can be stored digitally onto the hard disc attached to ultrasonography machine for subsequent analysis. For the purpose of homogeneity and to reduce operator bias, the principal applicant (SS) will perform all 3DUS examinations.

For the purpose of homogeneity and to reduce operator bias, the principal investigator (SS) will perform all 3DUS examinations. In the 3D group, the catheter position will be corrected according to the coronal plane view of the uterus on 3DUS, aiming for the maximum implantation potential point, along the midline of the uterine cavity, as previously described in the literature \[12\]. In the 2D group, the catheter position will be guided in the longitudinal plane by 2DUS, according to current clinical practice. The patients will be blinded to which technique is used during the embryo transfer, but will be shown a 2D/3D image of the embryo flash after the transfer is complete and after the catheter has been removed.

Outcome measures The primary outcome measure will be the clinical pregnancy rate, defined as the presence of at least one gestational sac at 6 weeks gestation. The secondary outcome measures will include implantation rate, multiple pregnancy, miscarriage, ectopic pregnancy, and live birth rates. Miscarriage will be defined as biochemical if there is no US evidence of pregnancy and clinical if there is US evidence of pregnancy. Live birth will be considered as a baby born live after 24 weeks gestation.

Data processing and analysis The researchers will ensure the confidentiality of sensitive data by minimizing the number of personnel who handles subject data. The computer data will be encrypted as required to maximize security. All paper documents will be locked in filing cabinets, and only authorized personnel could access this information.

Data processing for statistical analysis will be performed using the Statistical Packages of Social Sciences for Windows (SPSS, Inc). Data will be presented by percentage, mean and standard deviation, median and range where appropriate. Comparisons between groups will be carried out by Student T test for continuous variables, ANOVA for mean value comparisons, Chi-square/Fisher's exact test for categorical data. Stepwise logistic regression analysis may be performed as part of systematic analysis for primary outcomes. P-values of \<0.05 will be considered significant.

Monitoring and interim analysis As the study is perceived to be safe and poses no additional hazard, a Data Monitoring Committee and interim analysis is not considered necessary, in accordance with the most current Food and Drug Administration (FDA) recommendation \[15\].

Ethical considerations US is a safe and non-invasive examination. There are no known adverse effects of routine ultrasound to the mother or the embryo. No extra pain or discomfort is associated with the 3DUS versus 2DUS and the time difference in performing the exam is minimal. Application for ethics approval has already been submitted in December 2014 and is pending final approval.

Consent All subjects will be given detailed written explanation of the study and sufficient time to consider their participation. A written consent form will be signed by the patient and retained in our confidential records.

Eligibility criteria: Inclusion Criteria:

* Women undergoing embryo transfer in either fresh or frozen cycles.
* Women whose endometrial cavity can be visualised adequately via US

Exclusion Criteria:

* Women aged \>42 years
* Women whose endometrial cavity cannot be visualised adequately via US, such as large fibroids, adenomyosis, BMI\>35, significant uterine retroflexion/retroversion

Primary outcomes:
measure: Clinical pregnancy
timeFrame: 12 months
Secondary outcomes:
measure: Implantation
timeFrame: 12 months
measure: Multiple pregnancy
timeFrame: 12 months
measure: Miscarriage
timeFrame: 12 months
measure: Ectopic pregnancy
timeFrame: 12 months
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: The Chinese University of Hong Kong
state: Shatin
Study officials:
affiliation: Chinese University of Hong Kong
name: Sotirios Saravelos, MBBS
role: PRINCIPAL_INVESTIGATOR
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