Modified Downregulation for Women With Adenomyosis of the Uterus Prior to Frozen-thawed Embryo Transfer.

Objectives:

The primary objective is to determine whether modified downregulation before embryo transfer improves the chance of clinical pregnancy after embryo transfer in women with moderate/severe adenomyosis of the uterus. A secondary objective is to evaluate the impact of IVF on adenomyosis-related symptom presence, severity and progression.

Type of trial:

A randomised, controlled, multi-site trial in women with moderate/severe adenomyosis of the uterus undergoing frozen-thawed embryo transfer.

Trial design and methods:

This will be a prospective, randomised controlled study of patients undergoing assisted conception.

Prior to assisted conception all patients are referred for a diagnostic scan. The scan is done in a systematic fashion starting from the uterus in longitudinal plane and measurement of the endometrial thickness. The probe is then rotated to the transverse plane and the uterus scanned from the cervix to the fundus with any uterine pathologies noted and measured in 3 orthogonal planes. A 3D ultrasound volume is then be obtained and saved starting with the uterus in longitudinal view making sure to include all uterine tissue in the 3D volume sweep. Any congenital or acquired uterine anomalies are diagnosed according to published diagnostic criteria. Adenomyosis is diagnosed according to the diagnostic criteria outlined by Exacoustos et al and Naftalin et al and graded for severity according to the number of adenomyosis features present (assign a score of 1 for each of: i) asymmetrical myometrial thickening, ii) parallel shadowing, iii) myometrial cysts, iv) disrupted endometrial myometrial junction, v) endometrial striae, vi) endometrial islands, vii) adenomyoma).

The operator then sweeps to the adnexae, starting from the left, identifies and measures the ovaries in 3 orthogonal planes and documents the antral follicle count. Each ovary is examined for the presence of cysts as well as for mobility and tenderness by gentle pressure with the ultrasound probe. Once the ovaries have been assessed the operator examines the pouch of Douglas for the presence of free fluid as well as any evidence of endometriosis such as obliteration and/or endometriotic nodules as previously described by Holland et al. Videosonography for a period of 5 mins will be performed. Once the ultrasound scan is concluded all information is added to the clinical database.

Patients found to have moderate or severe adenomyosis (4 or more features of adenomyosis as defined by Mavrelos et al) on this scan will be approached by a member of the research team. The researcher will describe the project and provide a copy of the patient information leaflet. Patients will then be invited to return to the unit at a designated time for a scan by a member of the research team. On return to the unit the researcher will repeat the scan to confirm eligibility.

After the scan and once eligibility is confirmed patients will be asked to confirm if they want to participate in the trial. If they agree they will be asked to sign a consent form.

Participating patients will then be followed through the process of assisted conception.

Consenting patients will be randomized to one of two protocols (A vs. B) for frozen thawed embryo transfer.

Protocol A (standard) - start Norethisterone on day 14 of downregulation cycle and continue for 11 days. Start Buserelin 0.5ml on day 21 of downregulation cycle and reduce to 0.2ml on day 1 of bleed. Baseline scan on day 1 - 5 of bleed and start Progynova 2mg TDS PO. Serial scanning from day 10 until endometrial thickness more than 8mm. Once endometrial thickness more than 8mm start cyclogest 400mg BD PV/PR and lubion 25mg BD and proceed to embryo transfer on appropriate day for embryo age.

Protocol B (modified) - Baseline scan on day 1-5 of bleed and administer Triptorelin acetate 3.75 mg. 28 days later administer 1.875 mg Triptorelin acetate and 21 days later start Progynova 2 mg TDS PO. Serial scanning from day 10 of Progynova until endometrial thickness more than 8mm. Once endometrial thickness more than 8mm start Cyclogest 400mg BD PV/PR and Lubion 25mg BD and proceed to embryo transfer on appropriate day for embryo age.

Patients will be offered the opportunity to complete an adenomyosis symptom assessment questionnaire at the start of their treatment, and again two months after completion of treatment.

Trial duration per participant:

8-12 weeks

Estimated total duration:

3 years.

Planned trial sites:

Multi-site.

Total number of participants planned:

162.

Sample size estimation:

The investigators recently reported that the clinical pregnancy rate in women with moderate to severe adenomyosis is 22.9% vs. 42.7% in women with mild disease. They speculate that the modified protocol will improve the chance of clinical pregnancy to be equivalent to those with mild disease.

162 patients are required to have an 80% chance of detecting an increase in the clinical pregnancy rate from 22.9% in the control group to 42.7% in the experimental group, as significant at the 5% level (α = 0.05, β = 0.20). The trial is powered at 80%.

Statistical methodology and analysis:

The investigators will first perform univariate analysis to explore significant differences in the demographic characteristics (age, duration of subfertility), and clinical factors known to impact the outcome of assisted conception (number of oocytes retrieved, number and quality of embryos transferred) between women randomized to standard and modified FTET protocol.

In the second stage analysis the investigators will perform univariate analysis to compare the primary outcome (clinical pregnancy rate after FTET) between woman randomized to the standard and modified clinical protocol. The investigators will perform univariate analysis to compare secondary outcomes (livebirth, pregnancy loss (biochemical pregnancy, miscarriage, ectopic pregnancy, stillbirth, termination of pregnancy), gestational age at delivery, birth weight, neonatal mortality, major congenital anomaly, serious medication reaction, number of frozen embryos available for transfer, number of days to achieve optimal endometrial thickness). They will perform a sub-analysis for women with co-existing endometriosis. All models will be estimated in the Stat 12 statistical software.