ICSI Versus Conventional IVF in Non-male Factor Couples

Study Overview
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Brief Summary
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Conventionally, ICSI was initially developed and has been shown to be an effective treatment for male factor infertility. It is increasingly being used for patients without a male factor diagnosis, despite the lack of clinical evidence to support its use. Moreover, ICSI is an invasive and expensive procedure. This multi-center, randomized, controlled, parallel-group trial will be conducted to compare the effectiveness of ICSI versus conventional IVF in infertile couples scheduled for IVF treatment, in whom the male partner has normal sperm.

Detailed Description
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All patients undergoing IVF/ICSI will be treated with a GnRH antagonist protocol. Recombinant FSH (Puregon, MSD) will be given on day 2 or day 3 of menstrual cycle for 5 days. The starting dose is individualized for each patient based on the following criteria: AMH <0.7 ng/mL, dose 300 IU/day; AMH 0.7-2.1 ng/mL, dose 200 IU/day; AMH >2.1 ng/mL, dose 150 IU/day. After that, investigators can titrate the dose based on their clinical judgment. Follicular development will be monitored by ultrasound scanning and measurement of estradiol and progesterone levels, starting on day 5 of stimulation. Scanning and hormonal measurement will be repeated every 2 to 3 days, depending on the size of follicles. An antagonist is routinely used on day 5 until the day of triggering. Criteria for triggering, by hCG (Ovitrelle 250 mg, Merck, Germany) will be the presence of at least three leading follicles of 17 mm. In women with excessive follicular response (≥15 follicles ≥12 mm), 0,2 mg Triptorelin (Diphereline, Ipsen Beaufour, France) will be used when there are at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering. Randomization and allocation of participants to study groups will be performed on the day of egg pick up, after having obtained the semen from the husband. Eligible participants that have provided informed consent will be randomised to either ICSI or conventional IVF. In ICSI group, insemination will be performed by using ICSI, 3 - 4 hours after oocyte retrieval. OCCs will be stripped by using hyaluronidase. Only matured oocytes will be inseminated. In conventional IVF group, insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours, at a concentration of 100,000 motile sperm/ml. Inseminated OCCs will be cultured overnight in culture medium. In both groups, fertilization check will be performed under inverted microscope at period of 16-18 hours after insemination. On day 3, embryo evaluation will be performed at fixed time point 66±2 hours after fertilization, using the Istanbul consensus. Embryo transfer will be performed on day 3 under ultrasound guidance. A maximum of 2 embryos will be transferred into the uterus. The remaining grade 1 and 2 embryos will be frozen. Luteal-phase support will be done with estradiol (Valiera 2mg) 8mg/day and vaginal progesterone 800mg/day (Cyclogest 400mg) until 7th week of gestation. If there are contra-indications for fresh embryo transfer, a freeze-all strategy will be applied, using Cryotech technique. Indications for freeze-all include: risk of ovarian hyperstimulation syndrome (OHSS), premature progesterone rise (≥1.5 ng/ml), thin endometrium (<7 mm), fluid in cavity on day of embryo transfer, endometrial polyp, hydrosalpinx that have not removed before oocyte retrieval. In the next cycle, endometrium will be prepared by using estradiol (Valiera 2 mg, 8 mg/day) orally, starting from day 2-3 of menstrual cycle. When the endometrium thickness reaches 8 mm or more, patients will start using progesterone vaginally (Cyclogest 400 mg, 800 mg/day). Embryo transfer will be performed 3 days after using progesterone. On the day of embryo transfer, embryos will be thawed. In the frozen/thawed cycle, the best embryos will be utilized first, as in fresh transfer. Two hours after thawing, a maximum of 2 surviving embryos will be transferred into the uterus under ultrasound guidance. Luteal phase support will be provided with estradiol (Valiera 2mg) 8mg/day and vaginal progesterone 800 mg/day (Cyclogest 400 mg) until the seventh week of gestation. In both groups, clinicians who perform embryo transfer, either fresh or frozen cycles, will be blinded to the intervention. A serum hCG will be measured 2 weeks after embryo transferred, and if positive, an ultrasound scan of the uterus will be performed at gestational weeks 7 and 12. At 11 - 12 weeks of gestation, participants will be referred to the Outpatient clininc, O&G Department, My Duc hospital or An Sinh hospital for prenatal care until giving birth.

Official Title
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The Effectiveness of Intracytoplasmic Sperm Injection Versus Conventional in Vitro Fertilization in Couples With Non-male Factor Infertility: a Randomized Controlled Trial

Conditions
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Infertility

Intervention / Treatment
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* Procedure: ICSI
* Procedure: IVF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Having ≤ 2 IVF/ICSI cycles Total sperm count and motility are normal (WHO, 2010) Antagonist protocol Agree to have ≤ 2 embryos transferred Not participating in another IVF study at the same time Exclusion Criteria: In-vitro maturation (IVM) cycles Using frozen semen Poor fertilization in previous cycle (≤ 25%)

Ages Eligible for Study
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Minimum Age: 18 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: Intracytoplasmic Sperm Injection (ICSI)<br>All patients will be treated with a GnRH antagonist protocol. hCG (Ovitrelle 250 mg) will be used in the presence of at least three leading follicles of 17 mm. In women with ≥15 follicles ≥12 mm, 0,2 mg Triptorelin (Diphereline) will be used when there is at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering. Insemination will be performed by using ICSI, 3 - 4 hours after oocyte retrieval. OCCs will be stripped by using hyaluronidase. Only matured oocytes will be inseminated. Fertilization check will be performed at period of 16-18 hours after insemination. Embryo transfer will be performed on day 3 under ultrasound guidance. A maximum of 2 embryos will be transferred into the uterus. The remaining grade 1 and 2 embryos will be frozen. | Procedure: ICSI<br>* In ICSI group, insemination will be performed by using ICSI, 3 - 4 hours after oocyte retrieval. OCCs will be stripped by using hyaluronidase. Only matured oocytes will be inseminated.<br>|
| Active Comparator: In Vitro Fertilization (IVF)<br>All patients will be treated with a GnRH antagonist protocol. hCG (Ovitrelle 250 mg) will be used in the presence of at least three leading follicles of 17 mm. In women with ≥15 follicles ≥12 mm, 0,2 mg Triptorelin (Diphereline) will be used when there is at least two leading follicles of 17 mm. Oocyte retrieval will be performed 36 hours after triggering. Insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours (100,000 motile sperm/ml). Inseminated OCCs will be cultured overnight in culture medium. Fertilization check will be performed at period of 16-18 hours after insemination. Embryo transfer will be performed on day 3. A maximum of 2 embryos will be transferred. The remaining grade 1-2 embryos will be frozen. | Procedure: IVF<br>* In IVF group, insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours, at a concentration of 100,000 motile sperm/ml. Inseminated OCCs will be cultured overnight in culture medium.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy resulting in 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 (twin will be a single count). For the timing of this occur, ongoing pregnancy will be used, conditional on the fact that this ongoing pregnancy results in live birth. | At 12 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fertilization rate per oocyte inseminated/injected | Fertilization is defined as the appearance of 2 PN | At 16-18 hours after injected or 17-19 hours after inseminated | 
| Fertilization rate per oocyte retrieved | Fertilization is defined as the appearance of 2 PN | At 16-18 hours after injected or 17-19 hours after inseminated | 
| Abnormal fertilization rate | Abnormal fertilization is defined as the appearance of 1PN or ≥3 PN | At 16-18 hours after injected or 17-19 hours after inseminated | 
| Total fertilization failure rate | Total fertilization is defined as the absence of any zygotes with 2PN | At 16-18 hours after injected or 17-19 hours after inseminated | 
| Number of embryos on day 3 | Number of embryos on day 3 | 3 days after oocytes pick-up day in IVF/ICSI | 
| Number of good quality embryo on day 3 | Numbers of embryos on day 3 with good quality | 3 days after oocytes pick-up day in IVF/ICSI | 
| Number of embryo freezing on day 3 | Number of embryos freezing on day 3 | 3 days after oocytes pick-up day in IVF/ICSI | 
| Positive pregnancy test | Positive pregnancy test is defined as a serum human chorionic gonadotropin level greater than 25 mIU/mL after the completion of the first transfer | 14 days after embryo transfer | 
| Clinical pregnancy | Clinical pregnancy is defined as the presence of at least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity, after the completion of the first transfer | At 7 weeks' gestation | 
| Implantation rate | Implantation rate is defined as the number of gestational sacs per number of embryos transferred after the completion of the first transfer | At 3 weeks after embryo transferred | 
| Ongoing pregnancy | Ongoing pregnancy is defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond, after the completion of the first transfer | At 12 weeks' gestation | 
| Cumulative ongoing pregnancy | Ongoing pregnancy is defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond, after transfer of all embryos from the started treatment cycle. | At 12 weeks' gestation 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. | 
| Ongoing pregnancy resulting in live birth obtained from all embryos from the first 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 (twin will be a single count). | 12 weeks of gestation at 12 months after randomization | 
| Time from randomization to ongoing pregnancy | Time from randomization to ongoing pregnancy after the completion of the first transfer | 12 weeks of gestation after the completion of first transfer | 
| Ovarian hyperstimulation syndrome (OHSS) | Symptoms of OHSS | At 10 days after hCG injection and 14 days after embryo transfer | 
| Ectopic pregnancy | A pregnancy in which implantation takes place outside the uterine cavity after completion of the first transfer | At 12 weeks of gestation after the completion of the first transfer | 
| Ectopic pregnancy | A pregnancy in which implantation takes place outside the uterine cavity after transfer of all embryos from the started treatment cycle. | At 12 weeks of gestation at 12 months after randomization. | 
| Miscarriage | The loss of a clinical pregnancy at 24 weeks of gestation after the completion of the first transfer | At 24 weeks of gestation after the completion of the first transfer | 
| Miscarriage | The loss of a clinical pregnancy at 24 weeks of gestation after the completion transfer of all embryos from the started treatment cycle | At 24 weeks of gestation at 12 months after the randomization. | 
| Multiple pregnancy | Multiple pregnancy is explained as two or more gestational sacs or positive heart beats by transvaginal sonography, after the completion of the first transfer | 7 weeks' gestation after the completion of the first transfer | 
| Multiple pregnancy | Multiple pregnancy is explained as two or more gestational sacs or positive heart beats by transvaginal sonography, after the completion transfer of all embryos from the started treatment cycle | 7 weeks' gestation at 12 months after randomization | 
| Multiple delivery | Multiple delivery is defined as birth of more than one baby beyond 24 weeks, after the completion of the first transfer | At birth, after the completion of the first transfer | 
| Multiple delivery | Multiple delivery is defined as birth of more than one baby beyond 24 weeks, after the completion transfer of all embryos from the started treatment cycle | At birth at 12 months after randomization | 
| Gestational diabetes mellitus | Development of diabetes during pregnancy | At 24 weeks of gestation after the completion of the first transfer | 
| Gestational diabetes mellitus | Development of diabetes during pregnancy | At 24 weeks of gestation at 12 months after randomization | 
| Hypertensive disorders of pregnancy | Hypertensive disorders of pregnancy will include pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia) | From 20 weeks of gestation up to at birth after the completion of the first transfer | 
| Hypertensive disorders of pregnancy | Hypertensive disorders of pregnancy will include pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia) | From 20 weeks of gestation up to at birth at 12 months after randomization | 
| Antepartum haemorrhage | Including placenta previa, placenta accreta and unexplained | From 20 weeks of gestation up to at birth, after the completion of the first transfer | 
| Antepartum haemorrhage | Including placenta previa, placenta accreta and unexplained | From 20 weeks of gestation up to at birth, at 12 months after randomization | 
| Gestational age at delivery | Gestational age at delivery | At birth, after the completion of the first transfer | 
| Gestational age at delivery | Gestational age at delivery | At birth, at 12 months after randomization | 
| Preterm delivery | Preterm delivery is defined as any delivery at <24, <28, <32, <37 completed weeks' gestation | At birth, after the completion of the first transfer | 
| Preterm delivery | Preterm delivery is defined as any delivery at <24, <28, <32, <37 completed weeks' gestation | At birth, at 12 months after randomization | 
| Spontaneous preterm birth | Spontaneous preterm birth is defined as delivery spontaneously at <24, <28, <32, <37 completed weeks | At birth, after the completion of the first transfer | 
| Spontaneous preterm birth | Spontaneous preterm birth is defined as delivery spontaneously at <24, <28, <32, <37 completed weeks | At birth, at 12 months after randomization | 
| Iatrogenic preterm birth | Iatrogenic preterm birth is defined as delivery non-spontaneously at <24, <28, <32, <37 completed weeks | At birth, after the completion of the first transfer | 
| Iatrogenic preterm birth | Iatrogenic preterm birth is defined as delivery non-spontaneously at <24, <28, <32, <37 completed weeks | At birth, at 12 months after randomization | 
| Birth weight | Weight of newborn | At birth, after the completion of the first transfer | 
| Birth weight | Weight of newborn | At birth, at 12 months after randomization | 
| Low birth weight | Low birth weight is defined as <2500 gm | At birth, after the completion of the first transfer | 
| Low birth weight | Low birth weight is defined as <2500 gm | At birth, at 12 months after randomization | 
| Very low birth weight | Very low birth weight is defined as <1500 gm | At birth, after the completion of the first transfer | 
| Very low birth weight | Very low birth weight is defined as <1500 gm | At birth, at 12 months after randomization | 
| High birth weight | High birth weight is defined as >4000 gm | At birth, after the completion of the first transfer | 
| High birth weight | High birth weight is defined as >4000 gm | At birth, at 12 months after randomization | 
| Very high birth weight | Very high birth weight is defined as >4500 gm | At birth, after the completion of the first transfer | 
| Very high birth weight | Very high birth weight is defined as >4500 gm | At birth, at 12 months after randomization | 
| Large for gestational age | Large for gestational age is defined as birth weight >90th percentile | At birth, after the completion of the first transfer | 
| Large for gestational age | Large for gestational age is defined as birth weight >90th percentile | At birth, at 12 months after randomization | 
| Small for gestational age | Small for gestational age is defined as birth weight <10th percentile | At birth, after the completion of the first transfer | 
| Small for gestational age | Small for gestational age is defined as birth weight <10th percentile | At birth, at 12 months after randomization | 
| Congenital anomaly diagnosed at birth | Any congenital anomaly will be included | At birth, after the completion of the first transfer | 
| Congenital anomaly diagnosed at birth | Any congenital anomaly will be included | At birth, at 12 months after randomization | 
| Admission to NICU | The admittance of the newborn to NICU | 7 days after delivery after the completion of the first transfer | 
| Admission to NICU | The admittance of the newborn to NICU | 7 days after delivery, at 12 months after randomization | 
| Genetic and epigenetic analysis of newborn | Maternal whole blood; newborn's materials including cord blood, neonatal buccal smear, and placental tissue will be collected. Data will be collected for a supplementary analysis and will be reported in a separated paper. | 1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICSI, Conventional IVF, Non-male factor