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

Brief Summary

Detailed Description

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.

Primary Outcomes

Secondary Outcomes

• Positive pregnancy test(14 days after embryo transfer)
• Clinical pregnancy(At 7 weeks' gestation)
• Multiple pregnancy(7 weeks' gestation at 12 months after randomization)
• Fertilization rate per oocyte retrieved(At 16-18 hours after injected or 17-19 hours after inseminated)
• Number of good quality embryo on day 3(3 days after oocytes pick-up day in IVF/ICSI)
• Fertilization rate per oocyte inseminated/injected(At 16-18 hours after injected or 17-19 hours after inseminated)
• Birth weight(At birth, at 12 months after randomization)
• Implantation rate(At 3 weeks after embryo transferred)
• Time from randomization to ongoing pregnancy(12 weeks of gestation after the completion of first transfer)
• Hypertensive disorders of pregnancy(From 20 weeks of gestation up to at birth at 12 months after randomization)
• Antepartum haemorrhage(From 20 weeks of gestation up to at birth, at 12 months after randomization)
• High birth weight(At birth, at 12 months after randomization)
• Number of embryo freezing on day 3(3 days after oocytes pick-up day in IVF/ICSI)
• Ongoing pregnancy resulting in live birth obtained from all embryos from the first started treatment cycle(12 weeks of gestation at 12 months after randomization)
• Ovarian hyperstimulation syndrome (OHSS)(At 10 days after hCG injection and 14 days after embryo transfer)
• Abnormal fertilization rate(At 16-18 hours after injected or 17-19 hours after inseminated)
• Total fertilization failure rate(At 16-18 hours after injected or 17-19 hours after inseminated)
• Number of embryos on day 3(3 days after oocytes pick-up day in IVF/ICSI)
• Ongoing pregnancy(At 12 weeks' gestation)
• Cumulative ongoing pregnancy(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.)
• Ectopic pregnancy(At 12 weeks of gestation at 12 months after randomization.)
• Miscarriage(At 24 weeks of gestation at 12 months after the randomization.)
• Gestational age at delivery(At birth, at 12 months after randomization)
• Iatrogenic preterm birth(At birth, at 12 months after randomization)
• Multiple delivery(At birth at 12 months after randomization)
• Small for gestational age(At birth, at 12 months after randomization)
• Gestational diabetes mellitus(At 24 weeks of gestation at 12 months after randomization)
• Preterm delivery(At birth, at 12 months after randomization)
• Low birth weight(At birth, at 12 months after randomization)
• Very low birth weight(At birth, at 12 months after randomization)
• Admission to NICU(7 days after delivery, at 12 months after randomization)
• Cost-effectiveness(Two year after randomization)
• Spontaneous preterm birth(At birth, at 12 months after randomization)
• Very high birth weight(At birth, at 12 months after randomization)
• Congenital anomaly diagnosed at birth(At birth, at 12 months after randomization)
• Genetic and epigenetic analysis of newborn(1 day (Prior to the initiation of IVF/IVM) and 1 day ( at the time of delivery))
• Large for gestational age(At birth, at 12 months after randomization)