Immediate Versus Delayed Natural Cycle Frozen Embryo Transfers (FET)

February 8, 2025 updated by: Antalya IVF

Comparison of Immediate with Delayed Natural Cycle Frozen Embryo Transfers from Freeze-all-IVF Cycles: a Randomized Control Trial of First Frozen Embryo Transfers

Introduction:

Based on recent studies the suggestion is that natural cycle frozen embryo transfers (NC FET) should preferably be used, with evidence suggesting that artificial cycle FET (AC FET) is subject to increased risks of adverse obstetric and perinatal outcomes and possibly lower live birth rates. There, however, is limited evidence on the most efficient and effective timing of NC FET following oocyte retrieval.

Objective: In this non-inferiority randomised controlled trial, the effect on reproductive outcomes of NC FET performed immediately following the oocyte retrieval cycle (i.e., after one menstruation) will be investigated.

Materials and Methods: At a single IVF centre, patients will be recruited from infertile patients presenting for freeze-all-IVF treatments. Patients aged 18 to 30 years will be enrolled, if they had ≤2 previous embryo transfers and had ≥1 blastocyst cryopreserved in their freeze-all cycles. Enrolled patients (N = 800) will be randomised (1:1) to either the immediate group (i.e., FET performed in the menstrual cycle immediately following the oocyte retrieval cycle) or the delayed group (i.e., FET performed in the menstrual cycle following two menstruations). All FET will be performed in NC. The primary outcome measure will be clinical pregnancy, defined as the visual confirmation by transvaginal ultrasound scan of a gestational sac with normal heartbeat at >5 weeks of gestation. The analyses will be performed according to per-procedure principles.

Results: The ovarian, endometrial and time to transfer outcomes of the immediate group will be compared with those of the delayed group. The clinical pregnancy rate of the immediate group will be compared with that of the delayed group.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Introduction The increasing success of frozen embryo transfers (FET) in assisted reproductive technology (ART), and, therefore, the increasing use of FET to overcome standard IVF complications (i.e., adverse ovarian stimulation iatrogenesis and intra-cycle discovery of intrauterine abnormalities) and to facilitate the use of modified IVF treatment (i.e., pre-implantation genetic testing and luteal ovarian stimulation) has highlighted disadvantages inherent to FET. The major concern is the evidence that FET pregnancies are subject to adverse obstetric and perinatal outcomes such as placental and hypertensive complications, large for gestational age infants, increased pregnancy loss, increased preterm delivery. Moreover, the presumed benefits of more physiological endometria in FET demands further research into the origins of the adverse obstetric and perinatal outcomes and the elimination of their causes.

Endometrial preparation methods in FET can be divided into two major groups, artificial (AC) and natural cycle (NC) methods. While the initial studies comparing endometrial preparation methods for FET and confirmed by study reviews and meta-analyses, showed that no one method was superior in terms of reproductive outcomes, recent studies have shown that the NC cycle method results in reduced adverse obstetric and perinatal outcome rates and increased live birth rates. There is increasing evidence and understanding that using the AC method significantly increases the risks of adverse obstetric and perinatal outcomes because of the absence of a functional corpus luteum (CL). In addition to the production of hormones (i.e., estrogen and progesterone), CL also produces vasoactive molecules (i.e., relaxin, vascular endothelial growth factor) essential for optimal vascular developments in early pregnancy (i.e., implantation and placentation). Based on recent studies the suggestion, therefore, is that clinicians should preferably use NC FET. Further research, however, may be required to confirm the most optimal endometrial preparation and timing (i.e., embryo and endometrial synchrony) method for FET, because suggested preference is still being based on poor-quality evidence.

There is limited evidence on the most efficient and effective timing of NC FET following oocyte retrieval (i.e., the cycle subject to ovarian stimulation), as nearly all previous studies included the investigation of mostly AC FET. These studies, at most, confirmed that reproductive outcomes were not disadvantaged if FET were performed immediately following the oocyte retrieval cycle. Therefore, suggesting that ovarian stimulation (i.e., supraphysiological hormone levels) had no spill-over effects on endometrial and ovarian function in subsequent menstrual cycles, even in the cycle immediately following oocyte retrieval. Not having an extended delay to FET is considered by most patients to be less stressful and by clinicians to be more efficient. In this non-inferiority randomised controlled trial, the effect on reproductive outcomes of NC FET performed in menstrual cycles immediately following the oocyte retrieval cycle will be investigated.

Study Type

Observational

Enrollment (Actual)

818

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Turkey
      • Antalya, Turkey, 07080
        • Antalya IVF

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Study participants will be recruited from (unselected) infertile patients presenting for freeze-all-IVF treatment at the IVF centre from the start date of enrollment.

Description

Inclusion Criteria:

  • Patients with female age 18≤40 years.
  • Patients who provide written informed consent to participate in the trial and for the use of their anonymized data in research.
  • Patients with <2 previous IVF treatments.
  • Patients with ≥1 blastocyst cryopreserved.

Exclusion Criteria:

  • Patients with female age >40 years
  • Patients with female BMI ≥30 kg/m2.
  • Female patients with insulin dependent diabetes or non-insulin dependent diabetes mellitus and female patients with gastrointestinal, cardiovascular, pulmonary, liver or kidney disease.
  • Female patients with any contraindications or allergies to the drugs used in routine freeze-all-IVF.
  • Patients with untreated intrauterine anomalies and tubal pathology.
  • Patients undergoing PGT-A (aneuploidy) or PGT-M (monogenic disorders)
  • Patients with no blastocysts cryopreserved.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Immediate
NC endometrial preparation will start immediately after blastocyst cryopreservation confirmation.
Procedure: natural cycle endometrial preparation
Cycles will be monitored from either day-10 or-12, according to patient's menstrual cycle length, with serial analysis of blood serum LH and progesterone levels and assessment of dominant follicle growth. In a spontaneous cycle, ovulation will be determined by a LH surge (>20 IU/L) and a corresponding rise in progesterone (>0.8 ng/ml). In a triggered cycle, ovulation will be determined by the administration of an hCG trigger when the dominate follicle reached >16 mm (and LH was <20 IU/L).
Delayed
NC endometrial preparation will start on day 1 of the patient's 2nd menstruation after the oocyte retrieval cycle menstruation or in a subsequent cycle.
Procedure: natural cycle endometrial preparation
Cycles will be monitored from either day-10 or-12, according to patient's menstrual cycle length, with serial analysis of blood serum LH and progesterone levels and assessment of dominant follicle growth. In a spontaneous cycle, ovulation will be determined by a LH surge (>20 IU/L) and a corresponding rise in progesterone (>0.8 ng/ml). In a triggered cycle, ovulation will be determined by the administration of an hCG trigger when the dominate follicle reached >16 mm (and LH was <20 IU/L).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical pregnancy from frozen embryo transfers
Time Frame: Transvaginal ultrasound examination will be performed after 5 weeks of gestation (>5.5 weeks)
Clinical pregnancy rate will be defined as a pregnancy cycle with a normal gestational sac and fetal heartbeat confirmed by ultrasound at >5.5 weeks of gestation.
Transvaginal ultrasound examination will be performed after 5 weeks of gestation (>5.5 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pregnancy from frozen embryo transfers
Time Frame: Blood serum pregnancy tests will be performed 9 days after blastocyst transfer
Pregnancy will be defined as a cycle with an arbitrary serum βHCG level of >5 mIU/mL, measured 9 days after blastocyst transfer.
Blood serum pregnancy tests will be performed 9 days after blastocyst transfer
Early pregnancy loss of frozen embryo transfer pregnancies
Time Frame: Serial transvaginal ultrasound scans will be performed to 12 weeks of gestation
Early pregnancy loss will be defined as a pregnancy lost before 10 weeks of gestation.
Serial transvaginal ultrasound scans will be performed to 12 weeks of gestation
Ongoing pregnancy from frozen embryo transfers
Time Frame: Transvaginal ultrasound scan will be performed after 12 weeks of gestation
Ongoing pregnancy will be defined as a clinical pregnancy developing normally past 12 weeks of gestation.
Transvaginal ultrasound scan will be performed after 12 weeks of gestation

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Antalya IVF

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 4, 2022

Primary Completion (Actual)

February 8, 2025

Study Completion (Actual)

February 8, 2025

Study Registration Dates

First Submitted

January 18, 2022

First Submitted That Met QC Criteria

January 18, 2022

First Posted (Actual)

January 31, 2022

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 8, 2025

Last Verified

February 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • timetoFETJan2022

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The

IPD Sharing Time Frame

To be published immediately after publication acceptance

IPD Sharing Access Criteria

Open access at the Mendeley Data registry at the URLs provided

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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