IVM Versus IVF in High Antral Follicle Count Patients

IVF Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03405701
• Other study ID #: CS/MD/17/11
• Status: Completed
• Phase: N/A
• Start date: January 25, 2018
• Est. completion date: December 3, 2019

Study information

• Verified date: November 2018
• Source: M? Ð?c Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 546
• Est. completion date: December 3, 2019
• Est. primary completion date: November 30, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• IVF
• IVM
• PCOS

Intervention

Procedure:
• IVM
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.
• IVF
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.

Locations

Country	Name	City	State
Vietnam	M? Ð?c Hospital	Ho Chi Minh City	Tan Binh

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

Country where clinical trial is conducted

Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ovarian hyperstimulation syndrome (OHSS)	Routine assessments for OHSS were performed on day 3 post oocyte retrieval in both groups. At other times, OHSS was evaluated if symptoms were reported by the patient. OHSS was classified using the flow diagram developed by Humaidan and colleagues for use in clinical trial settings	at 03 days after oocytes pick-up and 14 days after embryo transfer
Other	Ectopic pregnancy	a pregnancy in which implantation takes place outside the uterine cavity after the completion of the first transfer	at 12 weeks of gestation after the completion of the first transfer
Other	Ectopic pregnancy	A pregnancy in which implantation takes place outside the uterine cavity	at 6 months after randomisation
Other	Ectopic pregnancy	A pregnancy in which implantation takes place outside the uterine cavity	at 12 months after randomisation
Other	Miscarriage	pregnancy loss at < 12 weeks	at 24 weeks of gestation after the completion of the first transfer
Other	Miscarriage	pregnancy loss at < 12 weeks	At 6 months after randomisation
Other	Miscarriage	pregnancy loss at < 12 weeks	at 12 months after randomisation
Other	Hypertensive disorders of pregnancy	Pregnancy-induced hypertension, pre-eclampsia and eclampsia	at 20 weeks of gestation or beyond after the completion of the first transfer
Other	Hypertensive disorders of pregnancy	Pregnancy-induced hypertension, pre-eclampsia and eclampsia	at 20 weeks of gestation or beyond at 6 months after randomisation
Other	Hypertensive disorders of pregnancy	Pregnancy-induced hypertension, pre-eclampsia and eclampsia	at 20 weeks of gestation or beyond at 12 months after randomisation
Other	Gestational diabetes mellitus	using a 75g oral glucose tolerance test	at 24 weeks of gestation after the completion of the first transfer
Other	Gestational diabetes mellitus	using a 75g oral glucose tolerance test	at 24 weeks of gestation at 6 months after randomisation
Other	Gestational diabetes mellitus	using a 75g oral glucose tolerance test	at 24 weeks of gestation at 12 months after randomisation
Other	Preterm delivery	Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
Other	Preterm delivery	Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
Other	Preterm delivery	Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
Other	Multiple pregnancy	Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)	after the completion of the first transfer
Other	Multiple pregnancy	Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)	at 6 months after randomisation
Other	Multiple pregnancy	Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)	at 12 months after randomisation
Other	Multiple delivery	Birth of more than one baby beyond 24 weeks	22 weeks of gestation or beyond after the completion of the first transfer
Other	Multiple delivery	Birth of more than one baby beyond 24 weeks	22 weeks of gestation or beyond at 6 months after randomisation
Other	Multiple delivery	Birth of more than one baby beyond 24 weeks	22 weeks of gestation or beyond at 12 months after randomisation
Other	Antepartum haemorrhage	Including placenta previa, placenta accreta and unexplained	After the completion of the first transfer
Other	Antepartum haemorrhage	Including placenta previa, placenta accreta and unexplained	At 6 months after randomisation
Other	Antepartum haemorrhage	Including placenta previa, placenta accreta and unexplained	At 12 months after randomisation
Other	Spontaneous preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
Other	Spontaneous preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
Other	Spontaneous preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
Other	Iatrogenic preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer
Other	Iatrogenic preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation
Other	Iatrogenic preterm birth	Defined as delivery at <24, <28, <32, <37 completed weeks	at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation
Other	Birth weight	Weight of singletons and twins	at the time of delivery
Other	Large for gestational age	birth weight >90th percentile	at the time of delivery after the completion of the first transfer
Other	Large for gestational age	birth weight >90th percentile	at the time of delivery at 6 months after randomisation
Other	Large for gestational age	birth weight >90th percentile	at the time of delivery at 12 months after randomisation
Other	Small for gestational age	birth weight < 10th percentile	at the time of delivery after the completion of the first transfer
Other	Small for gestational age	birth weight < 10th percentile	at the time of delivery at 6 months after randomisation
Other	Small for gestational age	birth weight < 10th percentile	at the time of delivery at 12 months after randomisation
Other	Low birth weight	Weight < 2500 gm at birth	at birth after the completion of the first transfer
Other	Low birth weight	Weight < 2500 gm at birth	at 6 months after randomisation
Other	Low birth weight	Weight < 2500 gm at birth	at 12 months after randomisation
Other	Very low birth weight	Weight < 1500 gm at birth	at birth after the completion of the first transfer
Other	Very low birth weight	Weight < 1500 gm at birth	at 6 months after randomisation
Other	Very low birth weight	Weight < 1500 gm at birth	at 12 months after randomisation
Other	High birth weight	Weight >4000 gm at birth	at birth after the completion of the first transfer
Other	High birth weight	Weight >4000 gm at birth	at 6 months after randomisation
Other	High birth weight	Weight >4000 gm at birth	at 12 months after randomisation
Other	Very high birth weight	Weight >4500 gm at birth	at birth after the completion of the first transfer
Other	Very high birth weight	Weight >4500 gm at birth	at 6 months after randomisation
Other	Very high birth weight	Weight >4500 gm at birth	at 12 months after randomisation
Other	Congenital anomaly	Any congenital anomaly will be included	At 6 months after randomisation
Other	Congenital anomaly	Any congenital anomaly will be included	At birth after the completion of the first transfer
Other	Congenital anomaly	Any congenital anomaly will be included	At 12 months after randomisation
Other	Admission to NICU	The admittance of the newborn to NICU	7 days after delivery after the completion of the first transfer
Other	Admission to NICU	The admittance of the newborn to NICU	At 6 months after randomisation
Other	Admission to NICU	The admittance of the newborn to NICU	At 12 months after randomisation
Other	Genetic and epigenetic analysis of newborn	Maternal whole blood; newborn's materials including cord blood, neonatal buccal smear, and placental tissue will be collected	1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery)
Other	Cost-effectiveness	Including direct and indirect costs; costs related to complications treatment. Cost data will be collected for a supplementary analysis and will be reported in a separated paper.	Two year after randomization
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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