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Freeze-all  (progesterone)

Go to the Freeze-all website

The freeze-all strategy in IVF: who benefits?


Objective
Primary Objective: To test the hypothesis that in women undergoing IVF/ICSI a freeze-all strategy results in higher ongoing pregnancy rates compared to IVF/ICSI with fresh embryo transfer.
Secondary Objectives:
  • The success rate in the freeze-all strategy is associated with the progesterone level in serum.
  • The freeze-all strategy is more cost-effective compared to a fresh embryo transfer.

Study design
Multicentre, marker RCT with a cost-effectiveness analysis.

Study population
Subfertile women between 18 and 43 years of age undergoing IVF/ICSI.

Intervention
Postpone the first embryo transfer to the next menstrual cycle. Therefore we freeze all embryos at day 3 or 4 and transfer them in unstimulated cycles. In both study arms markers for endometrium receptivity will be collected for marker analysis.
  • Serum progesterone: One blood sample (4,5 ml) on the day of ovulation trigger.
  • Endometrium:  Transvaginal ultrasound on day of ovulation trigger and day of embryo transfer

Outcome measures
  • Primary outcome is ongoing pregnancy rate per woman. Ongoing pregnancy is   defined as a positive heartbeat at 12 weeks gestation.
  • Progesterone serum level at day of ovulation trigger. 


Power/data analysis
The study will be a marker based superiority study with a sample size calculated by 1000 simulations. We assume an ongoing pregnancy rate of 14% following a fresh embryo transfer in women with high progesterone levels, an ongoing pregnancy rate of 30% following the fresh embryo transfer in women with low progesterone levels, and 30% ongoing pregnancy rate following frozen-thawed embryo transfer in high or low progesterone. The estimated distribution of progesterone used for the sample size calculation was a normal distribution with a mean of 2.5 mmol/L and a standard deviation of 1.1 mmol/L. We set the alpha for the overall treatment success (hypothesis 1) at an alpha of 3%; the interaction of treatment success with progesterone (hypothesis 2) at an alpha of 2%. With this we keep the alpha level constant at 5%. Under these assumptions a sample size of 855 women is needed to keep the power for either of the hypotheses to be significant at 80%. Since we anticipate a 5% lost to follow up, 900 women need to be randomized

Economic evaluation
The economic evaluation will be designed from a healthcare and from a societal perspective. The economic evaluation will be designed as a cost-effectiveness analysis. The time horizon will be from randomisation until positive pregnancy test leading to the ongoing pregnancy. If no ongoing pregnancy occurs, costs from randomisation until the last thawed embryo transfer of that cycle is conducted will be calculated. Cost-effectiveness of each strategy (freeze-all strategy or a fresh embryo transfer) will be presented as cost per ongoing pregnancy and costs per live birth as well as average costs per woman. Longer-term costs, i.e. costs of delivery and perinatal costs, will be determined if sufficient funds are available.

Time schedule
A total of 48 months will be needed.

Projectleaders
Dr. F. Mol
Dept. Obstetrics/Gynaecology
AMC Amsterdam
E: f.mol@amc.uva.nl

Methodology
dr. M. van Wely
Dept. Obstetrics/Gynaecology
AMC Amsterdam 
E: m.vanwely@amc.uva.nl
 
Subsidy
ZonMw 

Contact (researcher)
R.P. Berkhout
PhD student
Centre for Reproductive Medicine
Academic Medical Centre, the Netherlands
E. r.p.berkhout@amc.uva.nl
T: +31 20 5665810