Progesterone as Luteal Support in Frozen IVF Natural Cycles (ProFET)

Vaginal Progesterone as Luteal Support for Improvement of Live Birth in Frozen/Thawed In-vitro Fertilization Natural Cycles; a Multicenter, Open, Randomized Trial

The ProFET study aims to investigate if luteal phase support by vaginal progesterone, is superior to no luteal phase support, in terms of live birth rate per woman after a frozen embryo transfer (FET), in a natural cycle (NC) after in-vitro fertilization (IVF), and if 7 weeks of treatment is superior to 3 weeks duration.

Vaginal progesterone supplementation is routine treatment after IVF with fresh embryo transfer, but it is uncertain whether vaginal progesterone after frozen embryo transfer in natural cycles is efficacious in terms of increasing the chance of a live birth. The ProFET study is a multicenter, open randomized, controlled trial planning to include 1800 women, intended to undergo a FET in a natural cycle. Primary objectives are to investigate if luteal phase support by vaginal progesterone, is superior to no luteal phase support, in terms of live birth rate per woman after a frozen embryo transfer, in a natural cycle and if 7 weeks of treatment is superior to 3 weeks duration. Secondary objectives are to compare groups regarding pregnancy outcomes including biochemical pregnancy, clinical, ongoing and term pregnancy rates, as well as rates of miscarriage, termination of pregnancy, and ectopic pregnancy. Secondary objectives are also perinatal and obstetrics outcomes, self-reported side effects, adverse events and cost effectiveness. The investigators will also analyze the effect of S-Progesterone level before FET on the chance of achieving live birth and secondary pregnancy outcomes.

Two main arms, of which the experimental arm is split in two arms with different duration of treatment

At day LH+3 patients will start treatment with vaginal progesterone tablet at 100mg three times daily for three weeks.

At day LH+3 patients will start treatment with vaginal progesterone tablet at 100mg three times daily for seven weeks.

A child born alive. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix.

An intrauterine pregnancy with one or more fetuses with heartbeats measured in gestational week 7+5 to 9+0 with vaginal ultrasound.

The spontaneous loss of an intra-uterine pregnancy prior to 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix.

A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization, or histopathology.

Defined as the termination of a clinical pregnancy, by deliberate interference that takes place before 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix.

The gestational age at FET is calculated by adding the number of culture days to ovulation (ovulation=day 14). Gestational age at delivery is then calculated by adding the number of days since FET.

The death of a fetus prior to the complete expulsion or extraction from its mother, after and including 22 completed weeks of gestational age. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix.

Fetal or neonatal death occurring during late pregnancy (at 22 completed weeks of gestational age and later), during childbirth, or up to seven days after birth. Also, the outcome will be reported according to Core Outcome Measure for Infertility Trials (Duffy et al., 2020) in a separate appendix.

Congenital birth defects were defined according the International Statistical Classification of Diseases and Related Health Problems (ICD-10). And further defined according to the EUROCAT classification system.

Hypertensive disorders of pregnancy defined as high blood pressure disorders including preeclampsia, gestational hypertension and chronic hypertension.

Defined as the premature separation of a normally located placenta from the uterine wall that occurs before delivery of the fetus.

Defined as a cumulative blood loss of greater than 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process.

Defined as formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel.

Defined as female deaths from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes) during pregnancy and childbirth.

Side effects reported according to study specific questionnaire. Questions are answered with yes or no. If yes, symptoms are described, but not by using a scale.

Any untoward medical occurrence in symptom or disease temporally associated with the use of the medicinal (investigational) product, whether or not related to the medicinal product.

Comparison between groups regarding the total costs for the intervention divided by treatment efficacy (live birth).

Inclusion Criteria: Planned for a FET-NC with a blastocyst BMI >18.5 <35 Regular menstrual cycles 24-35 days Given informed consent Understand written and spoken Swedish, English or Arabic Exclusion Criteria: Oocyte donor cycles, preimplantation genetic testing (PGT) cycles. Uterine malformation, submucous myoma and endometrial polyps. Hypersensitivity against study medication. Other contraindications according to www.fass.se Development of serious disease contraindicating ART or pregnancy. Participation or recent participation in a clinical study with an investigational product (past 30 days). Previous participation in this study.

Duffy JMN, AlAhwany H, Bhattacharya S, Collura B, Curtis C, Evers JLH, Farquharson RG, Franik S, Giudice LC, Khalaf Y, Knijnenburg JML, Leeners B, Legro RS, Lensen S, Vazquez-Niebla JC, Mavrelos D, Mol BWJ, Niederberger C, Ng EHY, Otter AS, Puscasiu L, Rautakallio-Hokkanen S, Repping S, Sarris I, Simpson JL, Strandell A, Strawbridge C, Torrance HL, Vail A, van Wely M, Vercoe MA, Vuong NL, Wang AY, Wang R, Wilkinson J, Youssef MA, Farquhar CM; Core Outcome Measure for Infertility Trials (COMMIT) initiative. Developing a core outcome set for future infertility research: an international consensus development studydagger double dagger. Hum Reprod. 2020 Dec 1;35(12):2725-2734. doi: 10.1093/humrep/deaa241.

Stadelmann C, Bergh C, Brannstrom M, Olsen KH, Khatibi A, Kitlinski M, Liffner S, Lundborg E, Rodriguez-Wallberg KA, Strandell A, Westlander G, Widlund G, Magnusson A. Vaginal progesterone as luteal phase support in natural cycle frozen-thawed embryo transfer (ProFET): protocol for a multicentre, open-label, randomised controlled trial. BMJ Open. 2022 Jul 8;12(7):e062400. doi: 10.1136/bmjopen-2022-062400.