Assessing the Convenience of Natural Proliferative Phase Frozen Embryo Transfer

Assessing the Convenience of Natural Proliferative Phase Frozen Embryo Transfer: an Ambispective Cohort Study

This study will assess the convenience of the natural proliferative phase frozen embryo transfer (NPP-FET) in terms of number of number of appointments needed before cycle scheduling.

Study Overview

• Status: Recruiting
• Conditions: Frozen Embryo Transfer
• Intervention / Treatment: Procedure: Natural proliferative phase frozen embryo transfer

Detailed Description

Frozen embryo transfer (FET) is increasingly used nowadays in Assisted Reproductive Techniques (ART) clinics. Several factors account for this uprising. Among them, the concept of ovarian hyperstimulation syndrome (OHSS)-free clinic, the increasing use of preimplantation genetic testing (PGT), the improved vitrification systems, and the growing evidence regarding similar, or even better, pregnancy rates when FET are compared to fresh embryo transfers.

In the last few years, research has focused on the selection of the best protocol for endometrial preparation in patients undergoing FET cycles. Despite the accumulating evidence suggesting similar reproductive outcomes following both artificial cycle (AC-FET) and natural cycle (NC-FET) protocols, AC-FET is frequently adopted in ART centers due to its convenience in terms of cycle scheduling. However, a role for the corpus luteum in the maternal vasodilatory changes of early pregnancy has recently been associated with a decreased risk of pre-eclampsia. In fact, several large cohort studies have reported a higher risk of hypertensive diseases of pregnancy, macrosomia, post-term delivery and cesarean section following AC-FET.

The NPP-FET protocol is a strategy that potentially allows for cycle scheduling while maintaining the benefits of the natural cycle in terms of pregnancy outcomes. The main goal of the present study is to analyze its convenience in terms of the number of appointments needed before FET scheduling by comparing it with the NC-FET protocol. Additionally, the investigators aim to compare the reproductive outcomes between the two strategies and to analyze whether NPP-FET patients undergo ovulation.

Briefly, the study group will prospectively recruit ovulatory patients who will perform vaginal ultrasound monitoring will be performed on cycle day 8-12, depending on the length of the patients' menstrual cycle. When the endometrial thickness is at least 7 mm and the dominant follicle is at least 13 mm, vaginal micronized progesterone will be initiated at 400mg every 12 hours. One embryo will be transferred on the fifth day of progesterone supplementation under ultrasound guidance. The control group will include a retrospective cohort of ovulatory patients who underwent NC-FET.

• Study Type: Observational
• Enrollment (Estimated): 530

Contacts and Locations

• Study Contact: Name: Ana R Neves, MD; Phone Number: 00351 915227816; Email: anaraquel.lneves@gmail.com

Study Locations

• Portugal
  • Lisboa, Portugal
    • Recruiting
    • Instituto Valenciano de Infertilidade
    • Contact: Samuel Santos-Ribeiro, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study group will include a prospectively recruited cohort of ovulatory patients undergoing their first or second FET attempt following oocyte donation in a natural proliferative phase protocol. The control group will include a retrospective cohort of ovulatory patients undergoing a natural cycle frozen embryo transfer following oocyte donation.

Description

Inclusion Criteria:

• Endometrial thickness ≥ 7 mm on the day of starting progesterone-based luteal phase support (LPS)
• Serum progesterone levels <1.5 ng/ml on the day of starting progesterone-based LPS
• LPS with micronized progesterone 400mg b.i.d.
• Regular cycles (>24 days, ≤ 38 days)
• IVF/ICSI with donated oocytes
• Single blastocyst stage embryo transfer
• First or second embryo transfer from the same cohort

Exclusion Criteria:

• Use of exogenous ovarian stimulation during FET
• Untreated hydrosalpinx, polyp, submucous myomas or severe adenomyosis
• Recurrent pregnancy loss (≥ 3 previous pregnancy losses)
• Recurrent implantation failure with embryos from oocyte donation (≥ 3 previous failed embryo transfers)
• Personalized initiation of exogenous progesterone according to a previous endometrial receptivity assay test

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Natural proliferative phase frozen embryo transfer (NPP-FET); When the endometrial thickness is at least 7 mm, vaginal micronized progesterone will be initiated at 400mg every 12 hours, as per standard clinical practice, when the dominant follicle is at least 13 mm, serum estradiol (E2) levels are >80 pg/ml, and serum progesterone levels are <1.5ng/ml. One embryo will be transferred on the fifth day of progesterone supplementation under ultrasound guidance. Progesterone will be continued until the 11th week of pregnancy.	Procedure: Natural proliferative phase frozen embryo transfer; When endometrial thickness is above 7 mm, vaginal micronized progesterone will be administered 400mg 12/12h when the dominant follicle is at least 13 mm, serum estradiol (E2) levels are >80 pg/ml, and serum progesterone levels are <1.5ng/ml. Embryo transfer will be performed on the fifth day of progesterone.
Natural cycle frozen embryo transfer (NC-FET); When the mean dominant follicle diameter was at least 17 mm and the endometrial thickness was at least 7 mm, serum E2, progesterone and luteinizing hormone (LH) were evaluated. If a spontaneously LH peak was detected (E2>80 pg/ml, LH peak >18 mIU/mL with progesterone level <1.5 ng/mL), vaginal micronized progesterone was started from the evening of ovulation at a dose of 200 mg every 12 hours. Conversely, whenever a LH peak was not detected (E2>80 pg/ml, LH <18mIU/ml and progesterone <1,5 ng/ml), r-hCG 250µg (Ovitrelle®) was administered subcutaneously, followed, 48 hours later, by daily administration of 200 mg micronized vaginal progesterone every 12 hours. One embryo was transferred 7 days after r-hCG administration or 6 days after LH peak detection. Progesterone was continued until the 8th week of pregnancy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of appointments needed before cycle scheduling	Number of visits for cycle monitoring until embryo transfer scheduling	Up to three weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cycle duration until embryo transfer (days)	Number of days since the first day of menstrual bleeding until the day of embryo transfer	Up to four weeks
Proportion of patients with low progesterone values on the day of embryo transfer	Percentage of patients with low serum progesterone levels on the day of embryo transfer	One day
Human corionic gonadotropin (hCG) positive rate	Proportion of patients with a positive hCG test	10-14 days after ET
Miscarriage rate	Proportion of patients with spontaneous loss of an intra-uterine pregnancy prior to 22 completed weeks of gestational age	Up to 20 weeks after ET
Ongoing pregnancy rate	Proportion of patients with a pregnancy beyond the 11th week	9-11 weeks after ET
Live birth rate	Proportion of patients with a live birth	40 weeks after ET

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Relaxin-2 levels	Serum Relaxin-2 levels (colateral study)	5 weeks
Serum Luteinizing Hormone (LH) levels	Serum LH levels (colateral study)	5 days

Collaborators and Investigators

• Sponsor: Instituto Valenciano de Infertilidade de Lisboa
• Collaborators: Gedeon Richter Ltd.
• Investigators: Principal Investigator: Ana R Neves, MP, Instutito Valenciano de Infertilidade de Lisboa (IVI-RMA Lisboa)

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2024
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: February 17, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pregnancy; Progesterone; Endometrial preparation; Natural cycle
• Other Study ID Numbers: 2301-LIS-007-AN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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