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Rationale: A rising number of adenomyosis cases are being diagnosed in women in the age group of 30 to 40 years. This is due to a combination of better diagnostic imaging techniques and a higher number of women delaying the fulfilment of their fertility aspirations. The association between adenomyosis and pregnancy outcomes in women with subfertility has not been adequately explained by existing evidence due to lack of data on the association between the severity of adenomyosis, disease location, presence of symptoms and coexisting gynaecological conditions and pregnancy loss in women undergoing fertility treatment. There is a need to improve our understanding of prognostic features which would be beneficial in counselling women with adenomyosis undergoing fertility treatment and inform future management options. The investigators propose a research body of work aimed at improving our understanding of adenomyosis and its association with pregnancy loss. Objective: The aim of the study is to determine the association between adenomyosis and pregnancy loss in women undergoing assisted reproductive technology (ART) treatment. Study design: Prospective multicentre cohort study. The cohort will comprise of women with adenomyosis undergoing ART treatment and the control group will include women with normal uterus on baseline ultrasound scan undergoing ART treatment during the study duration. Settings: The study will be conducted at all main CARE fertility units, one of the largest providers of fertility treatment in the United Kingdom. Participant population with exposure and sample size: The cohort group will comprise of women diagnosed with adenomyosis on pre-treatment baseline ultrasound scan before ART treatment who satisfy the eligibility criteria and consent to participate in the study. The total sample size for this study will be 750 participants with 375 women in each arm. Recruitment will take place over the course of 18 months. Diagnostic tool for detection of exposure: The diagnosis of adenomyosis will be made using transvaginal ultrasound scan (TVS) (2D and 3D Ultrasound and applying Morphological Uterus Sonographic Assessment (MUSA) criteria. Schematic mapping system of adenomyosis severity proposed by Lazzeri and colleagues will be used to grade the severity of adenomyosis. Eligibility: Inclusion criteria: All women aged >18 years and ≤42 years undergoing IVF/ICSI cycle. Exclusion criteria: Women with coexisting fibroid uterus, endometrioma confirmed on USS or known laparoscopic diagnosis of endometriosis (with histological confirmation), untreated hydrosalpinx, uterine malformation, previous myomectomy, previous surgery for adenomyosis or inconclusive USS. Recruitment: All women undergoing pre-treatment pelvic ultrasound scans before ART treatment will be screened for adenomyosis at the participating centres. Women who meet the eligibility criteria will be provided with an information leaflet about the study. They will be enrolled in the study after informed consent is obtained. The severity of adenomyosis will be subsequently evaluated using stored 2D and 3D ultrasound scan (USS) images. Several demographic, clinical and treatment characteristics will be recorded for each participant. Control: To ensure adequate comparability of the cohort, women with normal uterus on baseline ultrasound scan during the study duration will be used as control and will be matched for the following variables: age, embryo quality, type of ART cycle (donor or self and IVF or ICSI) and number of embryos transferred. The eligibility criteria will be applicable to the controls as well. Outcome measures: Primary outcome: Pregnancy loss up to 24 weeks out of all pregnancies achieved. The pregnancy loss will include biochemical pregnancy loss, miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy. This will be reported per embryo transfer and per woman. Secondary outcomes:1. Implantation rate per embryo transfer (number of gestational sacs divided by number of embryos transferred) and per woman; 2. Biochemical pregnancy rate per embryo transfer (positive pregnancy test following embryo transfer) and per woman; 3. Clinical pregnancy rate per embryo transfer (presence of at least one intrauterine gestational sac on ultrasound) and per woman; 4. Ongoing pregnancy rate per woman (defined as a live pregnancy at 12 weeks onwards); 5. Live birth rate after 34 weeks per woman. Subgroup analysis: We will carry out subgroup analysis according to specific patient characteristics. These analyses will include, but not necessarily be limited to women with the following characteristics:1. Varying severity of adenomyosis; 2. Presence /absence of symptoms of adenomyosis; 3. Frozen vs. Fresh embryo transfer; 4. Short vs. long vs. ultralong ovarian stimulation protocol; 5. Recurrent miscarriages; 6. Other associations that may become apparent in post-hoc analyses.
Full description
The study investigators propose a prospective observational study to determine the association between adenomyosis and pregnancy loss in women undergoing ART treatment using a consistent classification system for adenomyosis diagnosed on ultrasound scan. This will be supplemented with subgroup analyses such as the following: presence vs absence of adenomyosis symptoms; frozen and fresh embryo transfer cycles; and varying severity of adenomyosis. These subgroup analyses will help determine the influence of these factors on the association between adenomyosis and pregnancy outcomes.
AIMS AND OBJECTIVES
AIM OF THE STUDY: To investigate the association between adenomyosis and pregnancy outcomes in women undergoing ART treatment.
PRIMARY OBJECTIVES: To compare the incidence of pregnancy loss in women with and without adenomyosis undergoing ART treatment. The pregnancy loss will include biochemical pregnancy loss, miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy.
SECONDARY OBJECTIVES:
STUDY DESIGN AND SETTING
STUDY DESIGN: Prospective multicentre cohort study SETTING The study will be conducted at all main CARE fertility units, one of the largest providers of fertility treatment, in the United Kingdom.
PARTICIPANT POPULATION
DIAGNOSTIC TOOL FOR DETECTION OF EXPOSURE
Diagnostic tool: The pooled sensitivity and specificity of TVUS for the diagnosis of adenomyosis for all combined imaging characteristics is 83.8% and 63.9% for 2D and 88.9% and 56.0% for 3D, respectively. The diagnosis of adenomyosis in the study participants will be made using transvaginal ultrasound scan; 2D and 3D Ultrasound with a 4-9 MHz trans-vaginal probe on Voluson S8.
Pre-implementation meeting: Preliminary meetings to discuss the sonographic appearance and diagnostic criteria for adenomyosis will be organised with the clinicians and nurse sonographers participating in the study. An operations manual will be disseminated to the participating centres to assure a uniform and standardised approach is followed for the diagnosis of adenomyosis.
Timing of the diagnosis: At the time of baseline pre-treatment scan
Image: Images will be printed or stored as 2D and 3D images. Where possible 2D video clips and 3D volumes will be stored as well
Reliability assessment: Intra-observer reliability will be assessed using test-retest measure
Diagnostic criteria: The Morphological Uterus Sonographic Assessment (MUSA) criteria will be used to describe the ultrasound features of adenomyosis. The MUSA criteria outlines the ultrasound features of myometrium and myometrial lesions using standardised terms, definitions and measurements. The MUSA criteria for diagnosis of adenomyosis on ultrasound is based on consensus opinion of a panel of clinicians with expertise in gynaecological ultrasonography, fertility treatment, hysteroscopy, general gynaecology and clinical research. A diagnosis of adenomyosis is made if any morphological features of adenomyosis are present. This stems from data demonstrating a strong correlation between the presence of at least one sonographic feature of adenomyosis with histopathological findings of adenomyosis. All the images stored will be re-reviewed by a 2nd clinician specialising in gynaecological ultrasound. Where the two practitioners do not reach a consensus on the diagnosis of adenomyosis, arbitration will be undertaken by a senior third clinician. If there is no consensus reached, the case will be excluded. The following MUSA criteria would be used for diagnosis of adenomyosis
Classification of severity: A schematic mapping system of adenomyosis severity will be used for determining the severity of uterine adenomyosis. This has been chosen due to reproducibility, substantial to almost perfect interobserver agreement rate and clinical correlation with symptom severity. A score ranging from to 1 to 4 is attributed to each grade, and the sum of the score numbers is used to calculate the extension of the disease: mild (range, 1-3), moderate (4-6), and severe (>7). The investigators will also classify the extent of affected myometrial as a percentage: Mild (<25%), Moderate (25-50%), Severe (>50%). Stored 2D and 3D USS images of patients diagnosed with adenomyosis on USS will be reviewed by two clinicians to determine the severity score.
CONSENT Written informed voluntary consent will be obtained by the investigator for each potential participant meeting the diagnostic and eligibility criteria. Responsibility for taking consent will be either of a clinician or nurse as delegated by the Principal Investigator. To facilitate the consent process, each participant will be provided with a Participant Information Sheet (PIS). Adequate explanation about the purpose of the study, the exposure and possible benefits of the study will be discussed with each participant. The voluntary nature of the participation will be discussed. Participants will be informed that they may decline participation or withdraw from the study at any time without giving any reason. This will not affect their medical care or legal rights. Time will be given to the participants to read the PIS and to discuss their participation with others outside of the site research team. The participants will have the opportunity to ask questions before signing the latest version of the Informed Consent Form (ICF).
After the participant has signed and dated the consent form, the investigator or delegate will also sign and date the ICF. The consent signing will be done online where possible. There will be triplicates of the ICF; one copy will be given to the participant; a second copy will be filed in the woman's medical notes; and the original will be placed in the Investigator Site File (ISF). The participant will have the opportunity to ask questions about the study throughout the study duration. The record of the details of informed consent discussions will be made in the participant's medical notes. This will include the name of the study, date of discussion, summary of discussion, version number of the PIS given to participant and version number of ICF signed and date consent received.
RECRUITMENT AND ENROLMENT
All women undergoing pelvic pre-treatment ultrasound scans before fertility treatment will be screened for adenomyosis at the participating centres by the clinicians and nurses experienced in performing ultrasound scan. The clinicians and nurses will be performing the baseline scan as per the standard protocol and therefore blinding to the baseline characteristics of the women will not be possible. All the stored ultrasound images of adenomyotic and normal uterus will be reviewed by a 2nd clinician who will be blinded to the baseline characteristics of the women to avoid identification and recruitment bias. Women who meet the eligibility criteria will be provided with a PIS describing the study. They will be enrolled in the study after informed consent is obtained. The demographic, clinical and treatment characteristics which will be recorded and used for data analysis are outlined as below:
MANAGEMENT OF IVF/ICSI CYCLE FOR PARTICIPANT POPULATION Women recruited for the study will be offered ART treatment according to a standardised clinical protocol at CARE fertility. The starting dose of gonadotrophins and the type of protocol for stimulation will be based on patient's age, body mass index (BMI), AMH and the number of basal antral follicles. Transvaginal ultrasound and oestradiol measurements will be used to monitor follicular growth, and the doses of gonadotrophin will be adjusted accordingly. Trigger in form of HCG/ GnRH agonist will be given once at least two follicles are observed to be greater than 17 mm in diameter on ultrasound examination and oocyte retrieval will be carried out 36 h after injection of trigger. Embryo transfer will be carried out on day 2, day 3 or day 5 depending on the number of good quality embryo and the number of embryos transferred will be 1 or 2 depending on the age of the patient and the quality of embryo.
Since this study also includes frozen embryo transfer cycles, endometrial preparation will be as per FET protocols according to local practice (natural, stimulated, modified natural with HCG trigger, or hormone replacement therapy [HRT] cycles). All embryo transfers will be performed under transabdominal USS guidance using soft Wallace catheter. This will be followed by luteal phase support with progesterone (vaginal capsules at a dose of 400 mg twice daily or combined vaginal and subcutaneous progesterone at a dose of 25 mg once daily) until 8-12 completed weeks of gestation.
OUTCOME All women will be followed up for primary and secondary outcomes. The CARE Fertility electronic patient database will be used to record the outcome data and collated for subsequent analyses.
DATA HANDLING AND RECORD KEEPING Data will be stored in the CARE Fertility electronic patient record system in accordance with the Data Protection Act 2018. Patient data will be anonymised for the purposes of statistical analysis.
QUALITY CONTROL AND QUALITY ASSURANCE Principles of Good Clinical Practice will be followed throughout the study duration.
ADVERSE EVENT REPORTING Considering the observational nature of the study and no additional step involved in the study design other than baseline USS, there are no safety considerations involved.
STATISTICS
The cohort group will comprise of women with USS diagnosis of adenomyosis and the control group will comprise of women with normal uterus on USS. The cohort and the control group will be matched for the following variables: age, embryo quality, type of ART cycle (donor or self and IVF or ICSI) and number of embryos transferred. Pregnancy outcomes will be reported as dichotomous variables. Generalised linear models will be used to determine the strength of the association between adenomyosis and pregnancy outcomes and will be reported as point estimates (e.g. risk ratios, odds ratios, risk differences) with 95% confidence interval. Generalised linear models with a binomial distribution with appropriate link functions will be used to calculate the adjusted relative risk and the mean differences, accounting for the following variables: BMI, ovarian reserve, previous IVF cycles, stimulation protocol, endometrial preparation and endometrial thickness prior to transfer. Statistical confidence will be determined by using the p value. Statistical analysis will be conducted using Stata 17.0.
• SUBGROUP ANALYSIS
A subgroup analysis for the primary outcome will also be conducted for women with:
varying severity of adenomyosis
presence /absence of symptoms of adenomyosis
frozen vs fresh embryo transfer
short vs. long vs. ultralong ovarian stimulation protocol
recurrent miscarriages: loss of two or more pregnancies prior to 24 weeks of gestation as defined in the ESHRE guideline on recurrent pregnancy loss, 2018.
other associations that may become apparent in post-hoc analyses. The subgroup characteristics will be described in detail and statistical analysis that has been outlined for the primary outcome will be followed for subgroup analysis
The investigators aim to collect the baseline characteristics and follow-up parameters on all the participant and control populations in the best possible way. In first instance for prevention of missing data, the missing data will be flagged up in the data entry stage and investigators will try their best to collect this information from the database and patient follow up. The following methods of analyses will be used to handle missing data:
CONFIDENTIALITY AND DATA PROTECTION A unique trial identification number will be used for identification of study participants. All the personal data used in the study will be processed in accordance with the Data protection Act 2018 and will be regarded as strictly confidential.
CONFLICTS OF INTEREST There are no conflicts of interest associated with this study.
AMENDMENTS Any amendments to the study protocol or documentation will be initiated by the Chief Investigator. All substantial amendments will be submitted to IRB for approval followed by implementation of the changes in all sites involved in the study. Amendments will be documented in the 'Protocol Amendment' section of the study protocol.
END OF PROJECT DEFINITION Patient recruitment will occur over the course of 18 months. In order to follow up the patients for the outcome of live birth rate, data analysis, manuscript writing, and publication will take place over the subsequent 12 months.
September 2022: Amendments to the protocol: Some of the methodological aspects of the AdAPT-ART study to ensure timely delivery of the study to a full sample size. These amendments have been approved by the ethics committee and are as follows:
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September 2022: Amendments to the protocol: Some of the methodological aspects of the AdAPT-ART study have been revisited to ensure timely delivery of the study to a full sample size and to make the recruitment smooth. These amendments have been approved by the local ethics committee.
Amendment to the eligibility criteria: Inclusion:
Rationale: Adenomyosis with coexisting endometriosis is common and is an important group to look at in terms of outcome of pregnancy loss.
828 participants in 2 patient groups
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Central trial contact
Ishita Mishra, MBBS, MS, MRCOG
Data sourced from clinicaltrials.gov
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