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:
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.
