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

Infertility Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03740568
• Other study ID #: FSD-PRG-2018-09
• Status: Completed
• Phase: N/A
• Start date: November 15, 2018
• Est. completion date: February 28, 2020

Study information

• Verified date: July 2020
• Source: Institut Universitari Dexeus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 598
• Est. completion date: February 28, 2020
• Est. primary completion date: February 28, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Artificial Cycle
• Euploid Embryo Transfer
• Frozen Embryo Transfer
• Infertility
• Ongoing Pregnancy
• Pregnancy Outcome
• Progesterone

Intervention

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
• 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

Locations

Country	Name	City	State
Spain	Departamento Ginecología, Obstetricia y Reproducción . Hospital Universitari Dexeus	Barcelona

Sponsors (3)

Lead Sponsor	Collaborator
Institut Universitari Dexeus	Dexeus Clinic Woman, Fundación Santiago Dexeus Font

Country where clinical trial is conducted

Spain, 

References & Publications (6)

Coll L, Parriego M, Boada M, Devesa M, Arroyo G, Rodríguez 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. — View Citation

Gaggiotti-Marre S, Martinez F, Coll L, Garcia S, Álvarez 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. — View Citation

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. — View Citation

Martínez F, Boada M, Coroleu B, Clua E, Parera N, Rodríguez 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. Epub 2006 Apr 21. — View Citation

Rubio C, Bellver J, Rodrigo L, Castillón G, Guillén A, Vidal C, Giles J, Ferrando M, Cabanillas S, Remohí J, Pellicer A, Simón 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. — View Citation

Solé M, Santaló J, Boada M, Clua E, Rodríguez I, Martínez 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Miscarriage Rate (MR)	Miscarriage Rate (MR) in FEET according to serum P level and interventions on D4 and D5.	12 weeks after transfer procedure
Primary	Concentration of serum P level	P level	D4, D5 and D14 of P supplementation
Secondary	Rate of cancellation due to lack of response in case of additional Psc dose on D4.		Day 5 of progesterone supplementation
Secondary	Rate of rescued cycles in case of additional Psc dose		Day 5 of progesterone supplementation
Secondary	Ongoing Pregnancy Rate and Live Birth Rate according to serum P level and interventions n D14		On day 14 of progesterone supplementation
Secondary	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

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