IVM Versus IVF in High Antral Follicle Count Patients

Study Overview
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Brief Summary
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In vitro maturation (IVM) is postulated to be an alternative to conventional in vitro fertilization (IVF) to avoid ovarian hyperstimulation syndrome. This has particular potential in women with Polycystic Ovarian Syndrome (PCOS), who are at increased risk for the ovarian hyperstimulation syndrome. However, no randomized controlled trials on the comparison of IVM and conventional IVF in women with PCOS have been reported with respect to pregnancy rate and hyper-stimulation. Investigators aim to compare the effectiveness and safety of IVM with controlled ovarian hyperstimulation/IVF in women with high antral follicle count.

Detailed Description
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Women with PCOS and PCOM or high AFC: ≥24 Antral Follicles in Both Ovaries will be given the information about the study during the first consultation which is at least 2 weeks before having periods. On the second day of periods, women will be screened for eligibility by the treating clinicians. Women who met the inclusion criteria will be invited to participate in the study. Women will be randomized (1:1) to IVM or IVF- GnRH agonist triggering cycle using block randomization by an independent study coordinator via telephone, using a computer-generated random list (block size 2, 4, 6 or 8). Group 1: IVM Patients with a normal cycle length (>/=35 days) will receive injected highly purified human menopausal gonadotropin (hp-hMG; Menopur, Ferring) 150 IU/day starting on day two or three of the spontaneous menstrual cycle. Oocyte retrieval will be performed 42 hours after the last hp-hMG injection. Women who do not have a normal cycle length (>35 days; 4-9 menstrual cycles in a year or amenorrhea) will take an oral contraceptive for 2 weeks, then receive hp-hMG 150 IU/day (hp-hMG; Menopur, Ferring injection for 2 days starting 5 days later. In all patients, ultrasound will be performed on the second day of gonadotrophin injection and OPU is scheduled for 42 hours after the last gonadotrophin injection. After oocyte pick-up, all oocytes will be placed in pre-maturation medium (CAPA Pre-maturation in Medicult IVM medium, Origio, Denmark) for 24 hours, then transferred to maturation culture (Medicult IVM system with phenol red, Origio, Denmark) for 30 hours. Group 2: IVF All women in this group will undergo COH using a hp-hMG/GnRH antagonist protocol, with an hp-hMG dose of 150-225 IU/day (Menopur, Ferring), depending on age and body mass index. Follicular development will be monitored using ultrasound scanning, and estradiol and progesterone levels. When at least two leading follicles reach 17 mm in diameter, GnRH agonist (GnRHa) triggering with triptorelin 0.2 mg (Diphereline, Ipsen Beaufour) will be administered, and oocyte retrieval performed 36 hours later. Laboratory procedures For both groups, insemination will be performed using intra-cytoplasmic sperm injection (3-4 hours after oocyte retrieval or maturation check); only matured oocytes will be inseminated. Fertilization check will be performed under an inverted microscope at 16-18 hours after insemination. Embryo evaluation will be performed at 68 ±1 hours after fertilization using the Istanbul consensus. Freeze-all and Frozen embryo transfer In both groups, all embryos will be frozen on day 3. Frozen transfer of a maximum of 2 embryos will be performed in a subsequent cycle using HRT for endometrial preparation. In the following cycle, the endometrium will be prepared using oral estradiol valerate (Valiera®; Laboratories Recalcine) 8 mg/day starting from the second or third day of the menstrual cycle. Endometrial thickness will be monitored from day six onwards, and vaginal progesterone (Cyclogest®; Actavis) 800 mg/day will be started when endometrial thickness reached 8 mm or more. A maximum of 2 embryos will be thawed on the day of embryo transfer, three days after the start of progesterone. Two hours after thawing, surviving embryos will be transferred into the uterus under ultrasound guidance. When women had more than two embryos frozen, the procedure will be repeated in subsequent cycles if they fail the first transfer.

Official Title
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The Effectiveness and Safety of in Vitro Maturation of Oocytes Versus in Vitro Fertilization in Women With High Antral Follicle Count (AFC): a Randomised Controlled Trial

Conditions
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IVM, PCOS, IVF

Intervention / Treatment
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* Procedure: IVM
* Procedure: IVF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with high AFC (≥24 Antral Follicles in Both Ovaries), including PCOS plus PCO or high AFC Having indications for ART Having ≤ 2 IVM/IVF attempts Permanent resident in Vietnam Agree to have all embryos frozen on day 3 Agree to have ≤ 2 embryos transferred in a subsequent frozen transfer Not participating in another IVF study at the same time Exclusion Criteria: Oocyte donation cycles Pre-implantation genetic diagnosis (PGD) cycles

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IVM (in vitro maturation)<br>Receiving FSH (Menopur, Ferring) for 2 days on day 2/3 of the menstrual cycle (spontaneous/ OCP administration) and an ultrasound scan will be performed subsequently. Oocytes retrieval will be performed 42 hours after the last injection. Pre-maturation will last for 24-30 hours. ICSI will be used for insemination. Freeze-only on day 3 and frozen embryo transfer will be performed on the subsequent cycle using HRT protocol with a maximum of 2 embryos transferred | Procedure: IVM<br>* Patients in IVM group will receive FSH (Menopur, Ferring) for 2 days on day 2/3 of the menstrual cycle (spontaneous/ OCP administration) and the ultrasound scan will be performed subsequently. Oocytes retrieval will be performed 42 hours after the last injection. Pre-maturation will last for 24-30 hours. ICSI will be used for insemination. Freeze-only on day 3 and frozen embryo transfer will be performed on the subsequent cycle using HRT protocol with a maximum of 2 embryos transferred.<br>|
| Active Comparator: IVF (in vitro fertilization)<br>Undergoing controlled ovarian hyperstimulation for in vitro Fertilization (IVF) with recombinant FSH (Menopur, Ferring) in GnRH antagonist protocol, treatment monitoring using ultrasound scans and blood tests. GnRH agonist triggering will be used for final oocytes maturation. ICSI will be used for insemination. Freeze-only on day 3 and frozen embryo transfer will be performed on the subsequent cycle using HRT protocol with a maximum of 2 embryos transferred. | Procedure: IVF<br>* Patients in IVF arm will undergo controlled ovarian hyperstimulation with recombinant FSH (Menopur, Ferring) in GnRH antagonist protocol, treatment monitoring using ultrasound scans and blood tests. GnRH agonist will be used for final oocytes maturation. ICSI will be used for insemination. Freeze-only on day 3 and frozen embryo transfer will be performed on the subsequent cycle using HRT protocol with a maximum of 2 embryos transferred.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth after the first embryo transfer of the started treatment cycle | Live birth is defined as the birth of at least one newborn after 24 weeks' gestation that exhibits any sign of life (twins will be a single count). To allow assessment of the timing of live birth, the rate of ongoing pregnancy at 12 weeks will be used in calculations, conditional on the fact that this ongoing pregnancy results in live birth. | 12 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive pregnancy test | Serum human chorionic gonadotropin level greater than 5 mIU/mL | at 2 weeks after the embryo placement after the completion of the first transfer | 
| Clinical pregnancy | at least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity | 5 weeks after embryo placement after the completion of the first transfer | 
| Ongoing pregnancy | Pregnancy with detectable heart rate at 12 weeks' gestation or beyond | at 10 weeks or beyond after the embryo placement after the completion of the first transfer | 
| Implantation rate | as the number of gestational sacs per number of embryos transferred | 3 weeks after embryo transferred after the completion of the first transfer | 
| Number of top quality embryos | Top quality embryos are defined followed Istanbul consensus | 3 days after oocytes pick-up day in IVF or 5 days in IVM | 
| Number of freezable embryos | Number of frozen embryos | 3 days after oocytes pick-up day in IVF or 5 days in IVM after the completion of the first transfer | 
| Time from randomisation to ongoing pregnancy | Time from randomization to ongoing pregnancy after the completion | 12 weeks of gestation after the completion of the first transfer | 
| Cumulative ongoing pregnancy at 6 months | After 6 months, most patients doing IVM have finished all their frozen embryos. If they still fail, they usually change to IVF. We lose the comparison; therefore, we consider this time point for analyzing the cumulative ongoing pregnancy rate. | at 6 months after randomization | 
| Cumulative ongoing pregnancy at 12 months | After 12 months, most patients doing IVF have finished all their frozen embryos; therefore, we consider this time point for analyzing the cumulative ongoing pregnancy rate. | at 12 months after randomization |