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NCT Number: NCT03405701

IVM Versus IVF in High Antral Follicle Count Patients

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.

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Key information

Conditions

PCOS IVF IVM

Age range

18 year–40 year

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

Mỹ Đức Hospital

Ho Chi Minh City, Tan Binh, Vietnam

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

IVM

Procedure

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

Procedure

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.

Primary outcomes

  1. Live birth after the first embryo transfer of the started treatment cycle

    Time frame: 12 weeks of gestation

    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.

Secondary outcomes

  1. Positive pregnancy test

    Time frame: at 2 weeks after the embryo placement after the completion of the first transfer

    Serum human chorionic gonadotropin level greater than 5 mIU/mL

  2. Clinical pregnancy

    Time frame: 5 weeks after embryo placement after the completion of the first transfer

    at least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity

  3. Ongoing pregnancy

    Time frame: at 10 weeks or beyond after the embryo placement after the completion of the first transfer

    Pregnancy with detectable heart rate at 12 weeks' gestation or beyond

  4. Implantation rate

    Time frame: 3 weeks after embryo transferred after the completion of the first transfer

    as the number of gestational sacs per number of embryos transferred

  5. Number of top quality embryos

    Time frame: 3 days after oocytes pick-up day in IVF or 5 days in IVM

    Top quality embryos are defined followed Istanbul consensus

  6. Number of freezable embryos

    Time frame: 3 days after oocytes pick-up day in IVF or 5 days in IVM after the completion of the first transfer

    Number of frozen embryos

  7. Time from randomisation to ongoing pregnancy

    Time frame: 12 weeks of gestation after the completion of the first transfer

    Time from randomization to ongoing pregnancy after the completion

  8. Cumulative ongoing pregnancy at 6 months

    Time frame: at 6 months after randomization

    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.

  9. Cumulative ongoing pregnancy at 12 months

    Time frame: at 12 months after randomization

    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.

Other outcomes

  1. Ovarian hyperstimulation syndrome (OHSS)

    Time frame: at 03 days after oocytes pick-up and 14 days after embryo transfer

    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

  2. Ectopic pregnancy

    Time frame: at 12 weeks of gestation after the completion of the first transfer

    a pregnancy in which implantation takes place outside the uterine cavity after the completion of the first transfer

  3. Ectopic pregnancy

    Time frame: at 6 months after randomisation

    A pregnancy in which implantation takes place outside the uterine cavity

  4. Ectopic pregnancy

    Time frame: at 12 months after randomisation

    A pregnancy in which implantation takes place outside the uterine cavity

  5. Miscarriage

    Time frame: at 24 weeks of gestation after the completion of the first transfer

    pregnancy loss at < 12 weeks

  6. Miscarriage

    Time frame: At 6 months after randomisation

    pregnancy loss at < 12 weeks

  7. Miscarriage

    Time frame: at 12 months after randomisation

    pregnancy loss at < 12 weeks

  8. Hypertensive disorders of pregnancy

    Time frame: at 20 weeks of gestation or beyond after the completion of the first transfer

    Pregnancy-induced hypertension, pre-eclampsia and eclampsia

  9. Hypertensive disorders of pregnancy

    Time frame: at 20 weeks of gestation or beyond at 6 months after randomisation

    Pregnancy-induced hypertension, pre-eclampsia and eclampsia

  10. Hypertensive disorders of pregnancy

    Time frame: at 20 weeks of gestation or beyond at 12 months after randomisation

    Pregnancy-induced hypertension, pre-eclampsia and eclampsia

  11. Gestational diabetes mellitus

    Time frame: at 24 weeks of gestation after the completion of the first transfer

    using a 75g oral glucose tolerance test

  12. Gestational diabetes mellitus

    Time frame: at 24 weeks of gestation at 6 months after randomisation

    using a 75g oral glucose tolerance test

  13. Gestational diabetes mellitus

    Time frame: at 24 weeks of gestation at 12 months after randomisation

    using a 75g oral glucose tolerance test

  14. Preterm delivery

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer

    Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks

  15. Preterm delivery

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation

    Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks

  16. Preterm delivery

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation

    Multiple definitions, defined as delivery at <24, <28, <32, <37 completed weeks

  17. Multiple pregnancy

    Time frame: after the completion of the first transfer

    Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)

  18. Multiple pregnancy

    Time frame: at 6 months after randomisation

    Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)

  19. Multiple pregnancy

    Time frame: at 12 months after randomisation

    Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)

  20. Multiple delivery

    Time frame: 22 weeks of gestation or beyond after the completion of the first transfer

    Birth of more than one baby beyond 24 weeks

  21. Multiple delivery

    Time frame: 22 weeks of gestation or beyond at 6 months after randomisation

    Birth of more than one baby beyond 24 weeks

  22. Multiple delivery

    Time frame: 22 weeks of gestation or beyond at 12 months after randomisation

    Birth of more than one baby beyond 24 weeks

  23. Antepartum haemorrhage

    Time frame: After the completion of the first transfer

    Including placenta previa, placenta accreta and unexplained

  24. Antepartum haemorrhage

    Time frame: At 6 months after randomisation

    Including placenta previa, placenta accreta and unexplained

  25. Antepartum haemorrhage

    Time frame: At 12 months after randomisation

    Including placenta previa, placenta accreta and unexplained

  26. Spontaneous preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer

    Defined as delivery at <24, <28, <32, <37 completed weeks

  27. Spontaneous preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation

    Defined as delivery at <24, <28, <32, <37 completed weeks

  28. Spontaneous preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation

    Defined as delivery at <24, <28, <32, <37 completed weeks

  29. Iatrogenic preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation after the completion of the first transfer

    Defined as delivery at <24, <28, <32, <37 completed weeks

  30. Iatrogenic preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 6 months after randomisation

    Defined as delivery at <24, <28, <32, <37 completed weeks

  31. Iatrogenic preterm birth

    Time frame: at 24, 28, 32 weeks and 37 weeks of gestation at 12 months after randomisation

    Defined as delivery at <24, <28, <32, <37 completed weeks

  32. Birth weight

    Time frame: at the time of delivery

    Weight of singletons and twins

  33. Large for gestational age

    Time frame: at the time of delivery after the completion of the first transfer

    birth weight >90th percentile

  34. Large for gestational age

    Time frame: at the time of delivery at 6 months after randomisation

    birth weight >90th percentile

  35. Large for gestational age

    Time frame: at the time of delivery at 12 months after randomisation

    birth weight >90th percentile

  36. Small for gestational age

    Time frame: at the time of delivery after the completion of the first transfer

    birth weight < 10th percentile

  37. Small for gestational age

    Time frame: at the time of delivery at 6 months after randomisation

    birth weight < 10th percentile

  38. Small for gestational age

    Time frame: at the time of delivery at 12 months after randomisation

    birth weight < 10th percentile

  39. Low birth weight

    Time frame: at birth after the completion of the first transfer

    Weight < 2500 gm at birth

  40. Low birth weight

    Time frame: at 6 months after randomisation

    Weight < 2500 gm at birth

  41. Low birth weight

    Time frame: at 12 months after randomisation

    Weight < 2500 gm at birth

  42. Very low birth weight

    Time frame: at birth after the completion of the first transfer

    Weight < 1500 gm at birth

  43. Very low birth weight

    Time frame: at 6 months after randomisation

    Weight < 1500 gm at birth

  44. Very low birth weight

    Time frame: at 12 months after randomisation

    Weight < 1500 gm at birth

  45. High birth weight

    Time frame: at birth after the completion of the first transfer

    Weight >4000 gm at birth

  46. High birth weight

    Time frame: at 6 months after randomisation

    Weight >4000 gm at birth

  47. High birth weight

    Time frame: at 12 months after randomisation

    Weight >4000 gm at birth

  48. Very high birth weight

    Time frame: at birth after the completion of the first transfer

    Weight >4500 gm at birth

  49. Very high birth weight

    Time frame: at 6 months after randomisation

    Weight >4500 gm at birth

  50. Very high birth weight

    Time frame: at 12 months after randomisation

    Weight >4500 gm at birth

  51. Congenital anomaly

    Time frame: At 6 months after randomisation

    Any congenital anomaly will be included

  52. Congenital anomaly

    Time frame: At birth after the completion of the first transfer

    Any congenital anomaly will be included

  53. Congenital anomaly

    Time frame: At 12 months after randomisation

    Any congenital anomaly will be included

  54. Admission to NICU

    Time frame: 7 days after delivery after the completion of the first transfer

    The admittance of the newborn to NICU

  55. Admission to NICU

    Time frame: At 6 months after randomisation

    The admittance of the newborn to NICU

  56. Admission to NICU

    Time frame: At 12 months after randomisation

    The admittance of the newborn to NICU

  57. Genetic and epigenetic analysis of newborn

    Time frame: 1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery)

    Maternal whole blood; newborn's materials including cord blood, neonatal buccal smear, and placental tissue will be collected

  58. Cost-effectiveness

    Time frame: Two year after randomization

    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.

Sponsors and collaborators

Lead sponsor

Mỹ Đức Hospital

Other

Registry information

Official study 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

Important dates

Study start
2018
Primary completion
2019
Study completion
2019
First posted
Jan 23, 2018
Registry last updated
Dec 4, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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