Effect of Intervention on Progesterone Levels Before Euploid Embryo Transfer in Pregnancy Outcomes.

Study Overview
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Brief Summary
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Transferring an euploid embryo avoids one of the main reasons of miscarriage and implantation failure (1), overcoming confounding factors such as embryo ploidy or maternal age. Frozen Euploid Embryo Transfer (FEET) is routinely performed under standard hormone replacement therapy (HRT) and could be considered the best model for evaluating the impact of the endometrial preparation in clinical pregnancy rate and also in miscarriage rate. Recently several authors have paid attention to serum progesterone (P) as a possible factor influencing Frozen Embryo Transfer (FET) outcomes. P plays an important role in endometrial gland formation, embryonic implantation and pregnancy maintenance. Labarta et al. (2) described in blastocyst FET performed under HRT that serum P <9.2 ng/mL measured on the transfer day is associated to significantly lower ongoing pregnancy rate (OR 0.297, 95% CI:0.113-0.779). Recently the investigators have analyzed 244 FEET performed under HRT in a retrospective study (3). Preimplantation genetic testing for aneuploidies (PGT-A) was carried out as previously described (4). Embryos that reached the blastocyst stage were biopsied and frozen immediately afterwards using the vitrification method (5). Euploid embryos were transferred in a subsequent cycle under HRT. Serum P was analyzed the day previous to FEET. Patients with serum P <10.6 ng/mL had significantly higher miscarriage rate (26.6% vs 9.5%, p=0.007) and lower live birth rate (47.5% vs 62.3 %, p= 0.029) than those with serum P >10.6 ng/mL. The investigators also observed that patients with serum P >13.1 ng/mL had the lowest miscarriage rate (9.1%) and the highest live birth rate (65.6%). The worst outcomes were observed when serum P was <8.06 ng /mL (41% live birth rate and 32.4% miscarriage rate). As miscarriage was higher among FEET cycles with serum P <10.6 ng/ml, the investigators hypothesize that altering the progesterone supplementation scheme could potentially reduce miscarriage rates and increase live birth rate. The purpose of this study is to modify the standard progesterone supplementation in FEET under HRT (vaginal micronized progesterone 200 mg every 8 hours) (6) according to serum P measured not only on the day prior to transfer but also on Beta subunit of Human Chorionic Gonadotropin (β-hCG) analysis day, and to probe if this intervention reduces miscarriage rate and increases pregnancy outcome.

Official Title
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Effect of Intervention on Progesterone Levels Before Euploid Embryo Transfer in Pregnancy Outcomes

Conditions
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Infertility, Progesterone, Frozen Embryo Transfer, Euploid Embryo Transfer, Pregnancy Outcome, Artificial Cycle, Ongoing Pregnancy

Intervention / Treatment
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* Drug: Low Progesterone
* Drug: Normal Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: FEET of at least one single embryo HRT Endometrial thickness >= 6 mm measured day 4 of progesterone supplementation Exclusion Criteria: Patients with mosaic embryos. Uterine abnormality. Natural cycle protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Normal Progesterone group<br>Progesterone level >10.64 ng/mL on day 4 of progesterone supplementation | Drug: Normal Progesterone<br>* Same Progesterone supplementation (vaginal micronized P 200mg/200mg/200mg) Warming and transfer on D5 Beta-hCG and P analysis is performed on the 14th day of P supplementation (D14). In case of positive Beta-hCG analysis: If P is >10.64 ng /mL: the same P supplementation is continued. If P is <10.64 ng /mL: an additional dosage of vaginal micronized P (200 mg) is added at night<br>|
| Experimental: Low Progesterone group<br>Progesterone level <10.64 ng/mL on day 4 of progesterone supplementation | Drug: Low Progesterone<br>* Additional daily dosage of subcutaneous progesterone (Psc) 25 mg/day at night since D4 (vaginal micronized P 200mg/200mg/200mg + Psc 25 mg/night) New Progesterone analysis on D5 before warming the embryo. Group 2a (Canceled Group, P on D5 <10.64 ng/mL): cancel PGT-FET. Scheduling a new procedure under different P supplementation. Group 2b (Restored Progesterone Group, P on D5 >10.64 ng/mL): continue HRT as previously described (vaginal micronized P 200mg/200mg/200mg + Psc 25 mg/night). Warming and transfer the same day (D5) Beta-hCG and P analysis is performed on the 14th day of P supplementation (D14). In case of positive Beta-hCG analysis: If P is >10.64 ng /mL: the same P supplementation is continued. If P is <10.64 ng /mL: an additional dosage of vaginal micronized P (200 mg) is added at night<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy Rate (OPR) | Ongoing Pregnancy Rate (OPR) beyond pregnancy week 12 in FEET according to serum P level and interventions on D4 and D5 | 12 weeks after transfer procedure | 
| Miscarriage Rate (MR) | Miscarriage Rate (MR) in FEET according to serum P level and interventions on D4 and D5. | 12 weeks after transfer procedure | 
| Concentration of serum P level | P level | D4, D5 and D14 of P supplementation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of cancellation due to lack of response in case of additional Psc dose on D4. |  | Day 5 of progesterone supplementation | 
| Rate of rescued cycles in case of additional Psc dose |  | Day 5 of progesterone supplementation | 
| Ongoing Pregnancy Rate and Live Birth Rate according to serum P level and interventions n D14 |  | On day 14 of progesterone supplementation | 
| Live birth Rate (LBR) | Live birth Rate (LBR) in FEET according to serum P level and interventions on D4 and D5 and D14. | 40 weeks after transfer procedure |