The increasing use of FET emphasizes the importance of preparing and timing the endometrium in FET cycles, however there is no consensus on luteal phase progesterone supplementation in mNC-FET and the optimal day of blastocyst warming and transfer. The aim of this multicenter RCT is to assess the effect of progesterone supplementation in hCG-triggered mNC-FET and the effect of embryo thawing and transfer at hCG+6 or hCG+7 days, respectively. In total 604 patients will be included with n=151 in each of the four study arms. The primary outcome is live birth rate per transfer (LBR) and the goal is to show a 10% increase in LBR after progesterone supplementation and to assess whether blastocyst warming+transfer 6 days after hCG trigger is superior to 7 days after hCG trigger in mNC-FET.
Single embryo transfer and freezing of surplus embryos has lowered twin birth rates after in vitro fertilization (IVF) to a level of less than 5% in Denmark. However, several treatments with repeated frozen embryo transfers (FET) before a viable pregnancy is confirmed are burdensome to the patients. New freezing techniques has optimized the quality of the embryo transferred in FET cycles, but optimization of the endometrium in the luteal phase is still lacking behind. In a mNC-FET, which is the routine in many clinics, ovulation is induced with an hCG injection when the leading follicle is ≥17 mm. The hCG trigger is important for controlling the time of ovulation, but triggering an unhealthy follicle at an inappropriate time may cause luteal phase insufficiency and thus suboptimal function of the endometrium. Danish public fertility clinics are not routinely using progesterone supplementation in mNC-FET, but there may be a rationale to do so, and some implantations may be rescued. In this study we will compare live birth rates in mNC-FET with and without progesterone supplementation in the luteal phase, and further we will explore the optimal timing of blastocyst warming and transfer by comparing embryo transfer at hCG trigger +6 days versus +7 days. This is a superiority study with the aim to detect an increase in live birth rates of 10%. Hence, this adequately powered RCT may make a major contribution to knowledge on mNC-FET to the benefits of patients. We will include 604 patients divided 1:1 (302:302) in each arm +/- progesterone and these will further be divided 1:1 in blastocyst warming and transfer +6 and +7 days after hCG injection. The primary endpoint is live birth rate per transfer.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
679
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Four parallel groups of patients undergoing fertility treatment (modified natural cycle frozen embryo transfer) will be compared using/not using vaginal progesterone (Lutinus) and subject to blastocyst warming and transfer 6/7 days after hCG trigger.
Fertility Clinic, Rigshospitalet, Copenhagen University Hospital
Copenhagen, Denmark
Live birth rates per transfer
Comparison of live birth rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Registered at the one-year follow-up after a positive pregnancy test.
Chemical pregnancy rates per transfer
Comparison of chemical pregnancy rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured 16 days after ovulation trigger (hCG+16).
Clinical pregnancy rates per transfer
Comparison of clinical pregnancy rates (ultrasound) between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or seven after hCG trigger.
Time frame: Ultrasound performed at 7-8 weeks of gestation.
Abortion rates per transfer
Comparison of abortion rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Registered at the one-year follow-up after a positive pregnancy test.
ASAT (U/L)
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
Time frame: Measured at baseline.
ALAT (U/L)
ALAT measured by blood sample to ensure normal liver parameters before administration of progesterone.
Time frame: Measured at baseline.
AMH (pol/L)
Comparison of AMH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline.
Estradiole (mmol/L)
Comparison of estradiole measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
FSH (IU/L)
Comparison of FSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
LH (IU/L)
Comparison of LH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
Progesterone (nmol/L)
Comparison of progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
OH-progesterone (nmol/L)
Comparison OH-progesterone measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at ovulation trigger day (hCG+0), at transfer day (hCG+6/7) and at hCG+11.
beta-hCG
Comparison of beta-hCG measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at transfer day (hCG+6/7), hCG+11 and hCG+16.
TSH (*10^3 IU/L)
Comparison of TSH measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline, at ovulation trigger day (hCG+0), at transfer day (hCG+6/7), at hCG+11, at hCG+14 and at hCG+19.
Thyroglobulin antibodies (arb.units/L)
Comparison of thyroglobulin antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline.
Thyroid peroxidase anitbodies (arb.units/L)
Comparison of thyroid peroxidase antibodies measured by blood samples between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Measured at baseline.
Obstetric complication rates
Comparison of obstetric complication rates between patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Registered at the one-year follow-up after a positive pregnancy test.
Neonatal complication rates
Comparison of neonatal complication rates for children of patients receiving and not receiving Lutinus, with blastocyst warming and transfer day 6 or 7 after hCG trigger.
Time frame: Registered at the one-year follow-up after a positive pregnancy test.
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