Study Comparing Outcomes Between Conventional IVF and a "Freeze-all"-Strategy in Assisted Reproductive Technology

A Multicentre Randomized Controlled Trial of a "Freeze All and Transfer Later" Versus a Conventional "Fresh Embryo Transfer" Strategy for Assisted Reproductive Technology (ART) in Women With a Regular Menstrual Cycle

The purpose of this study is to compare conventional fresh embryo transfer with a "freeze all and transfer later strategy" in assisted reproductive technology in terms of ongoing pregnancy rates, live birth rates as well as perinatal outcomes.

Study Overview

• Status: Unknown
• Conditions: Infertility
• Intervention / Treatment: Procedure: Freeze all

Detailed Description

The study is a multicentre randomized controlled double-blinded trial with the purpose to investigate if pregnancy- and live birth rates can be improved by a "freeze all and transfer later"-strategy with transfer of the best quality, frozen, thawed embryo in a subsequent natural cycle compared with conventional fresh embryo transfer with transfer of the embryo in the stimulated cycle.

In total 5 clinics in Denmark and Sweden will be participating in the recruitment of patients for the study.

The patients will be screened and randomized computerized on cycle day 2 or 3 and allocated to one of the two study arms:

I: hCG (human chorion gonadotrophin) arm with traditional hCG triggering and fresh blastocyst transfer II: GnRH (gonadotropin-releasing hormone)- agonist triggering arm with blastocyst cryopreservation and subsequent transfer in a subsequent natural cycle.

The randomization will be done after the decision of gonadotrophin (rFSH/hMG) starting dose, and both doctor and patient will be blinded to the randomization until the day of hCG/agonist trigger. Both groups will be stimulated in a short GnRH antagonist protocol. The ovarian stimulation The gonadotrophin stimulation is performed according to the general standards in each of the clinics and can be altered according to the ovarian response with a maximum of 300 IU.

Blood samples are collected at baseline before the first gonadotrophin injection and at day of hCG injection and further blood samples in the luteal phase will be collected for a small subgroup of patients. All blood samples will be kept at the Biobank for the study at Hvidovre Hospital.

Women in both arms will furthermore be requested to fill out a physical discomfort and a quality of life questionnaire at two different visits. Additionally the men will be asked to fill out quality of life questionnaires.

Comprehensive sonography will be performed at the start of ovulation with details on each ovary. Ultrasound examination is performed on cycle day 2-3, at stimulation day 6 and thereafter every 2-3 days until ovulation is inducted.

On the day of oocyte retrieval the randomization is unblinded. The oocytes are fertilized by either IVF or ICSI and cultured individually according to the normal procedures in the clinics.

If the patient is allocated to the "Fresh embryo transfer"-group the best quality blastocyst will be transferred on day five after oocyte pick-up, if a blastocyst is developed. Surplus good quality blastocysts are vitrified on day five or six.

For patients in the "Freeze all" group all embryos of good quality are vitrified at the blastocyst stage day 5 in the stimulated cycle according to the criteria for freezing blastocysts in each clinic. The highest quality embryo is selected and marked and will be the first one to be thawed after at least one mentrual cycle that is considered as a wash out period. Embryo transfer is performed 6-7 days after hCG injection in the blastocyst transfer cycle in this group.

A serum beta-hCG test is performed 11 days after blastocyst transfer, and clinical pregnancy is confirmed by transvaginal ultrasound 3 to 4 weeks after a positive serum-hCG test.

A follow-up of all pregnancies will be performed within three months after delivery or termination of pregnancy on predefined information sheets. All pregnancies resulting from blastocysts retrieved and thawed according to this study protocol will be followed from study inclusion and one year onwards.

All data will be collected in a single database and all participants will be anonymized by way of an identificationcode. The biobank will be closed and all samples destroyed after 5 years of the conclusion of the study at the latest.

The study is a superiority study with 424 (212 in each arm) patients required to have an 80 % chance of detecting, as significant at the 5 % level, a decrease in the primary outcome measure from 30 % in the control group to 43 % in the experimental group.

• Study Type: Interventional
• Enrollment (Anticipated): 424
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • Rigshospitalet
    • Contact: Sacha Stormlund, MD; Email: sacha.stormlund.01@regionh.dk
  • Hvidovre, Denmark
    • Recruiting
    • University Hospital Hvidovre
    • Contact: Sacha Stormlund, MD; Email: sacha.stormlund.01@regionh.dk
    • Contact: Anja Pinborg, MD, DMSc; Email: anja.bisgaard.pinborg@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• AMH (Anti-Müllerian hormone) > 6.28 pmol/L (Roche Elecsys assay)
• Female age 18 years to less than 40 years
• 1, 2 or 3 IVF/ICSI cycle with oocyte aspiration
• Regular menstrual cycle between 24 and 35 days
• BMI between 18 and 35
• Two ovaries
• Can and will sign informed consent

Exclusion Criteria:

• Women who do not fulfil the inclusion criteria
• Endometriosis stage III to IV
• Ovarian cysts with diameter > 30 mm at day of start of stimulation
• Submucosal fibroids
• Women with severe co-morbidity (IDDM, NIDDM, gastrointestinal, cardiovascular, pulmonary, liver or kidney disease)
• Dysregulation of thyroid disease
• Not danish or English speaking women
• Contraindications or allergies to use of Gonadotrophins or GnRH antagonists
• TESA (testicular sperm aspiration)
• OD (oocyte donation)
• Previous inclusion in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Freeze all; Transfer of a frozen, thawed blastocyst in a subsequent natural menstrual cycle	Procedure: Freeze all; Freezing of all blastocyst stage embryos with thawing and transfer in a subsequent natural cycle
No Intervention: Fresh embryo transfer; Standard procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy rates	Outcome measured per transfer of the first blastocyst, per oocyte pick-up, per start of ovarian stimulation and per randomized patient.	Two years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rates	Outcome measured after the first blastocyst transfer calculated per randomized patient, per started ovarian stimulation, per oocyte pick-up and per transfer	Two years
Cumulative live birth rates	Measured after one stimulated cycle with oocyte retrieval and after use of all frozen blastocysts or after at least 1 year of follow-up	Two years
Number of cycles with no embryo transfer		Two years
Time-to-pregnancy	From start of ovarian stimulation to positive hCG	Two years
Time-to-delivery		Three years
Preterm birth		Three years
Low birth weight		Three years
Small-for-gestational age (SGA)		Three years
Large-for-gestational age (LGA)		Three years
Perinatal mortality		Three years
Preeclampsia		Three years
Placental rupture		Three years
Positive hCG 11 days post embryo transfer		Three years
Miscarriages, biochemical pregnancies, ectopic pregnancies		Three years
Quality of life for female and partner		Two years
Cost-effectiveness		Three years

Collaborators and Investigators

• Sponsor: Anja Bisgaard Pinborg
• Collaborators: Rigshospitalet, Denmark; Sahlgrenska University Hospital, Sweden; Herlev Hospital; Holbaek Sygehus; Skane University Hospital; Regional Hospital Skive; Dexeus University Hospital Barcelona
• Investigators: Study Director: Anja Bisgaard Pinborg, MD, DMSc, Fertility Clinic, Obstetrical and Gynecological department, Hvidovre Hospital

Publications and helpful links

General Publications

• Zaat T, Zagers M, Mol F, Goddijn M, van Wely M, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev. 2021 Feb 4;2(2):CD011184. doi: 10.1002/14651858.CD011184.pub3.
• Alexopoulou E, Stormlund S, Lossl K, Praetorius L, Sopa N, Bogstad JW, Mikkelsen AL, Forman J, la Cour Freiesleben N, Vikkelso Jeppesen J, Bergh C, Al Humaidan PSH, Grondahl ML, Zedeler A, Pinborg AB. Embryo Morphokinetics and Blastocyst Development After GnRH Agonist versus hCG Triggering in Normo-ovulatory Women: a Secondary Analysis of a Multicenter Randomized Controlled Trial. Reprod Sci. 2021 Oct;28(10):2972-2981. doi: 10.1007/s43032-021-00564-9. Epub 2021 Apr 13.
• Stormlund S, Sopa N, Zedeler A, Bogstad J, Praetorius L, Nielsen HS, Kitlinski ML, Skouby SO, Mikkelsen AL, Spangmose AL, Jeppesen JV, Khatibi A, la Cour Freiesleben N, Ziebe S, Polyzos NP, Bergh C, Humaidan P, Andersen AN, Lossl K, Pinborg A. Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial. BMJ. 2020 Aug 5;370:m2519. doi: 10.1136/bmj.m2519.
• Stormlund S, Lossl K, Zedeler A, Bogstad J, Praetorius L, Nielsen HS, Bungum M, Skouby SO, Mikkelsen AL, Andersen AN, Bergh C, Humaidan P, Pinborg A. Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial. BMJ Open. 2017 Jul 31;7(7):e016106. doi: 10.1136/bmjopen-2017-016106.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): January 1, 2019
• Study Completion (Anticipated): September 1, 2019

Study Registration Dates

• First Submitted: April 18, 2016
• First Submitted That Met QC Criteria: April 18, 2016
• First Posted (Estimate): April 21, 2016

Study Record Updates

• Last Update Posted (Actual): April 2, 2019
• Last Update Submitted That Met QC Criteria: April 1, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: In vitro fertilisation; Assisted reproduction; Frozen embryo transfer (FET)
• Additional Relevant MeSH Terms: Infertility
• Other Study ID Numbers: 1600-1116

Plan for Individual participant data (IPD)

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