Clinical trial NCT05838105: Two Different Types of Luteal Phase Support in Natural Cycle Frozen Embryo Transfer and Its Effect on Pregnancy Rates
Official title: Prospective Randomized Control Study of Two Different Types of Luteal Phase Support in Natural Cycle Frozen Embryo Transfer and Its Effect on Pregnancy Rates
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Luteal Phase Support
Lead sponsor: Shaare Zedek Medical Center
Sponsor class: OTHER
First posted: 2023-05-01
Enrollment: 144
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All patients will be randomly divided into two groups, each will receive a different luteal treatment:

1. Study group - patients will receive luteal support with GNRH agonist and HCG according to departmental protocol (described later).
2. Control group - patients will receive luteal support with vaginal progesterone.
Primary purpose: TREATMENT

Brief summary: The aim of the study is to compare the pregnancy rate between women treated with Gonadotropin Releasing Hormone (GnRH) agonist together with Human Chorionic Gonadotropin (HCG) and standard luteal support with progesterone following transfer of frozen embryos in in-vitro-fertilization (IVF) natural cycles.

Detailed description: The rate of frozen embryos transfer (FET) has increased in recent years due to a higher tendency of single embryo transfer, use of preimplantation genetic testing, and prevention of ovarian hyperstimulation.

There are different methods to prepare the endometrium for FET:

1. Natural cycle (NC) - natural preparation of the body for implantation without the need for medicinal intervention.
2. Modified natural cycle (mNC) - Inducing ovulation by administration of Human Chorionic Gonadotropin (HCG) trigger.
3. Medical - preparation of endometrium with hormones (estrogen and progesterone).

Following embryo transfer, luteal phase support should be considered. Administration of treatment depends on the type of cycle chosen (either natural or medicated). Treatment options include progesterone, HCG and Gonadotropin Releasing Hormone (GnRH) analog - either one of them or combined. Different protocols (dosages and duration of use) with different pregnancy outcomes were explore before with inconclusive results. We wish to investigate administration of GnRH agonist+HCG vs. progesterone.

Patients included in the study will be women undergoing natural cycle FET at the IVF center in Shaare Zedek, Jerusalem, Israel. All patients will be randomly divided into two groups, each will receive a different luteal treatment support as will be detailed later. Patients demographic data and pregnancy outcomes will be collected.

Based on the clinical pregnancy rate in the prospective study by Bjuresten, et al \[Fertil Steril, 2011\], where a clinical pregnancy rate of 32% was found among women treated with progesterone for luteal support, and given an alpha of 5% and a power of 80%, 144 women (72 women in each group) are required in order to demonstrate a clinical pregnancy rate of 55% in the study group.

Comparison of categorical variables will be carried out using the the chi-squared test. Comparison of continuous variables will be performed using the Students t-Test or Mann-Whitney U method depending on the variable distribution (normal vs. non-normal distribution, respectively). A multivariate regression will also be conducted in order to determine which variables are significantly and independently related. Statistical significance will be defined when P values are less than 0.05

Eligibility criteria: Inclusion Criteria:

* Normo-ovulatory women
* Women undergoing frozen embryos transfer in a natural cycle
* Age 18-45
* BMI 18-35

Exclusion Criteria:

* Women undergoing medicated frozen embryos transfer
* Women with a BMI over 35 or under 18.
* Women with hydrosalpinges
* Women with defects or uterine malformations (congenital) or acquired such as myomas
* Egg donation and surrogacy
* Use of preimplantation genetic testing

Primary outcomes:
measure: Clinical pregnancy rate
timeFrame: up to two month after embryo transfer
Secondary outcomes:
measure: Overall pregnancy rate
timeFrame: up to two month after embryo transfer
measure: Implantation rate
timeFrame: up to two month after embryo transfer
measure: Ectopic pregnancy rate
timeFrame: up to two month after embryo transfer
measure: Miscarriage rate
timeFrame: up to 20 weeks after embryo transfer
measure: Live birth rate
timeFrame: up to 42 weeks after embryo transfer
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Shaare Zedek medical center
Study officials:
affiliation: Sharee Zedek Medical Center, Israel
name: Keren Rotshenker Olshnika, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update. 2013 Sep-Oct;19(5):458-70. doi: 10.1093/humupd/dmt030. Epub 2013 Jul 2.
citation: Le Lannou D, Griveau JF, Laurent MC, Gueho A, Veron E, Morcel K. Contribution of embryo cryopreservation to elective single embryo transfer in IVF-ICSI. Reprod Biomed Online. 2006 Sep;13(3):368-75. doi: 10.1016/s1472-6483(10)61441-1.
citation: Loutradi KE, Kolibianakis EM, Venetis CA, Papanikolaou EG, Pados G, Bontis I, Tarlatzis BC. Cryopreservation of human embryos by vitrification or slow freezing: a systematic review and meta-analysis. Fertil Steril. 2008 Jul;90(1):186-93. doi: 10.1016/j.fertnstert.2007.06.010. Epub 2007 Nov 5.
citation: Weissman A, Horowitz E, Ravhon A, Steinfeld Z, Mutzafi R, Golan A, Levran D. Spontaneous ovulation versus HCG triggering for timing natural-cycle frozen-thawed embryo transfer: a randomized study. Reprod Biomed Online. 2011 Oct;23(4):484-9. doi: 10.1016/j.rbmo.2011.06.004. Epub 2011 Jun 15.
citation: Mackens S, Stubbe A, Santos-Ribeiro S, Van Landuyt L, Racca A, Roelens C, Camus M, De Vos M, van de Vijver A, Tournaye H, Blockeel C. To trigger or not to trigger ovulation in a natural cycle for frozen embryo transfer: a randomized controlled trial. Hum Reprod. 2020 May 1;35(5):1073-1081. doi: 10.1093/humrep/deaa026.
citation: Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev. 2017 Jul 5;7(7):CD003414. doi: 10.1002/14651858.CD003414.pub3.
citation: Montagut M, Santos-Ribeiro S, De Vos M, Polyzos NP, Drakopoulos P, Mackens S, van de Vijver A, van Landuyt L, Verheyen G, Tournaye H, Blockeel C. Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues. Hum Reprod. 2016 Dec;31(12):2803-2810. doi: 10.1093/humrep/dew263. Epub 2016 Oct 25.
citation: Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril. 2010 Nov;94(6):2054-8. doi: 10.1016/j.fertnstert.2009.11.036. Epub 2010 Jan 25.