Natural Versus Artificial Cycle for Frozen-Thawed Embryo Transfer

Study Overview
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Brief Summary
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This study evaluates clinical pregnancy rates, obstetrical outcome parameters, costs and patient preferences in natural cycle versus artificial cycle frozen embryo transfers (FET).

Detailed Description
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Transfer of cryopreserved embryos can be performed in a natural cycle (NC-FET) or in an artificially prepared cycle (AC-FET). Both cycle regimens have their advantages and disadvantages. So far, most comparative studies have failed to identify the optimal protocol for FET. In this study patients undergoing FET will be randomized between an endometrial preparation by a natural cycle or by an artificial cycle (by oestradiol validate and micronized progesterone).

Official Title
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Frozen-thawed Embryo Transfer in a Natural Versus Artificial Cycle: a Randomized Clinical Trial

Conditions
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Embryo Transfer

Intervention / Treatment
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* Drug: Natural cycle
* Drug: Estradiol Valerate
* Drug: Micronized progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women undergoing FET after a first, second or third fresh IVF/ICSI cycle Single embryo transfer (SET) or Double embryo transfer (DET) Female age between 18-45 year Women having a natural ovulatory cycle (24-35 days) Normal uterine cavity (fundal indentation at the cavity <10mm) Written informed consent Exclusion Criteria: Use of donor gametes BMI > or equal to 35 kg / m2 Any contra-indication to estrogen or progesterone supplementation (e.g. history of thrombosis, prior or current hormone-sensitive malignancy…)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter prospective randomized clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Natural cycle<br>no medication | Drug: Natural cycle<br>* no medication<br>|
| Active Comparator: Artificial cycle<br>Oestradiol valerate (Progynova, Bayer, Germany) 6mg daily will be given from day 2 of the cycle. The dose of Progynova is increased to 8mg daily if the endometrial thickness is less than 7mm after 7-10 days of Progynova use. Progynova will be discontinued the day of the pregnancy test in case of a negative result. In case of a pregnancy, Progynova will be continued until 12 weeks or until diagnosis of a non-viable pregnancy. Micronized progesterone (Utrogestan, Besins, Belgium) 200 mg vaginally three times daily is started as soon as the endometrial thickness is 7 mm. Utrogestan will be discontinued the day of the pregnancy test in case of a negative result. In case of a pregnancy, Utrogestan will be continued until 12 weeks or until diagnosis of a non-viable pregnancy. | Drug: Estradiol Valerate<br>* Oestradiol valerate (Progynova, Bayer, Germany) 6mg daily will be given from day 2 of the cycle. The dose of Progynova is increased to 8mg daily if the endometrial thickness is less than 7mm after 7-10 days of Progynova use. Progynova will be discontinued the day of the pregnancy test in case of a negative result. In case of a pregnancy, Progynova will be continued until 12 weeks or until diagnosis of a non-viable pregnancy.<br>* Other names: Artificial cycle;Drug: Micronized progesterone<br>* Micronized progesterone (Utrogestan, Besins, Belgium) 200 mg vaginally three times daily is started as soon as the endometrial thickness is 7 mm. Utrogestan will be discontinued the day of the pregnancy test in case of a negative result. In case of a pregnancy, Utrogestan will be continued until 12 weeks or until diagnosis of a non-viable pregnancy.<br>* Other names: Artificial cycle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate with fetal heart beat | Clinical pregnancy rate with fetal heart beat diagnosed by ultrasound no later than the gestational age of 9 weeks | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical pregnancy rate |  | 9 weeks | 
| Miscarriage rate |  | 12 weeks | 
| Ectopic pregnancy rate |  | 9 weeks | 
| Live birth rate |  | 41 weeks | 
| Multiple pregnancy rate |  | 9 weeks | 
| Adverse events | tombo-embolic events, serious side-effects (car leaflet) which require cancellation of treatment | 12 weeks | 
| Cycle cancellation rate |  | 4 weeks | 
| Endometrial thickness |  | 3 weeks | 
| Endometrial pattern | Sonographic aspect of the endometrium (triple-line, no triple-line) | 3 weeks | 
| number of center visits to monitor FET cycle |  | From date of randomization until the date of the embryo transfer or until cancellation (estimated period of time up to 4 weeks) | 
| cost analysis per treatment cycle |  | From date of randomization until the date of the embryo transfer or until cancellation (estimated period of time up to 4 weeks) | 
| patient satisfaction | To evaluate the effect of the different regimens on patients wellbeing/distress, Patient Reported Experience Measures (PREMS) from validated questionnaires will be used. Twenty-two questions from the Benyamini questionnaire will be used (Benyamini et al. 2005) and 10 questions from the subscales 'environment' (α=0.81) and 'tolerability' (α=0.75) of the FertilQol questionnaire (Pedro et al 2013). On the day of embryo transfer, the treating gynecologist will hand out the questionnaire to the patient. The patient will return the filled-in questionnaire on the day of the pregnancy test, before she knows the result of the pregnancy test. | 12 weeks |