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

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

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.

Study Overview

• Status: Completed
• Conditions: Infertility; Frozen Embryo Transfer; Pregnancy Outcome; Progesterone; Euploid Embryo Transfer; Artificial Cycle; Ongoing Pregnancy
• Intervention / Treatment: Drug: Normal Progesterone; Drug: Low Progesterone

• Study Type: Interventional
• Enrollment (Actual): 598
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08028
    • Departamento Ginecología, Obstetricia y Reproducción . Hospital Universitari Dexeus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Normal Progesterone group; Progesterone level >10.64 ng/mL on day 4 of progesterone supplementation	Drug: Normal Progesterone; 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
Experimental: Low Progesterone group; Progesterone level <10.64 ng/mL on day 4 of progesterone supplementation	Drug: Low Progesterone; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut Universitari Dexeus
• Collaborators: Fundación Santiago Dexeus Font; Dexeus Clinic Woman
• Investigators: Study Chair: Bueaventura Coroleu, PhD, Hospital Universitari Dexeus. Departamento de Ginecología, Obstetricia y Reproducción

Publications and helpful links

General Publications

• Rubio C, Bellver J, Rodrigo L, Castillon G, Guillen A, Vidal C, Giles J, Ferrando M, Cabanillas S, Remohi J, Pellicer A, Simon C. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017 May;107(5):1122-1129. doi: 10.1016/j.fertnstert.2017.03.011. Epub 2017 Apr 19.
• Labarta E, Mariani G, Holtmann N, Celada P, Remohi J, Bosch E. Corrigendum: Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Hum Reprod. 2018 Jan 1;33(1):178. doi: 10.1093/humrep/dex353. No abstract available.
• Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Alvarez M, Parriego M, Barri PN, Polyzos N, Coroleu B. Low serum progesterone the day prior to frozen embryo transfer of euploid embryos is associated with significant reduction in live birth rates. Gynecol Endocrinol. 2019 May;35(5):439-442. doi: 10.1080/09513590.2018.1534952. Epub 2018 Dec 26.
• Coll L, Parriego M, Boada M, Devesa M, Arroyo G, Rodriguez I, Coroleu B, Vidal F, Veiga A. Transition from blastomere to trophectoderm biopsy: comparing two preimplantation genetic testing for aneuploidies strategies. Zygote. 2018 Jun;26(3):191-198. doi: 10.1017/S0967199418000084. Epub 2018 May 25.
• Sole M, Santalo J, Boada M, Clua E, Rodriguez I, Martinez F, Coroleu B, Barri PN, Veiga A. How does vitrification affect oocyte viability in oocyte donation cycles? A prospective study to compare outcomes achieved with fresh versus vitrified sibling oocytes. Hum Reprod. 2013 Aug;28(8):2087-92. doi: 10.1093/humrep/det242. Epub 2013 Jun 5.
• Martinez F, Boada M, Coroleu B, Clua E, Parera N, Rodriguez I, Barri PN. A prospective trial comparing oocyte donor ovarian response and recipient pregnancy rates between suppression with gonadotrophin-releasing hormone agonist (GnRHa) alone and dual suppression with a contraceptive vaginal ring and GnRH. Hum Reprod. 2006 Aug;21(8):2121-5. doi: 10.1093/humrep/del121. Epub 2006 Apr 21.
• Alvarez M, Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Gonzalez-Foruria I, Rodriguez I, Parriego M, Polyzos NP, Coroleu B. Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Hum Reprod. 2021 May 17;36(6):1552-1560. doi: 10.1093/humrep/deab031.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2018
• Primary Completion (Actual): February 28, 2020
• Study Completion (Actual): February 28, 2020

Study Registration Dates

• First Submitted: November 9, 2018
• First Submitted That Met QC Criteria: November 9, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 29, 2020
• Last Update Submitted That Met QC Criteria: July 28, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: FSD-PRG-2018-09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No