ICSI Versus Conventional IVF in Couples With Non-severe Male Infertility

A multicenter, large-scale, randomized controlled clinical trial will enroll 2,346 couples with non-severe male infertility undergoing their first or second cycle of IVF or ICSI. The study will recruit participants from 6 Reproductive Medical Centers across mainland China.The participation in this study will be approximately 2 years with a total of 7 visits from controlled ovarian hyperstimulation, pregnancy to delivery. On the day of oocyte retrieval, eligible participants will be allocated to two groups at a ratio of 1:1- ICSI protocol, and conventional IVF protocol. All participants will be randomized through stratified block randomization according to the study sites.

• ICSI (Other): All patients will receive controlled ovarian hyperstimulation (COH) treatment, which is performed by standard routines at each study center. The COH treatment includes either gonadotrophin-releasing hormone agonist (GnRH-a) protocol or gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol.Oocyte retrieval is scheduled for 36 (±2) after hCG injection.The retrieved cumulus oocyte complexes (COC) will be allocated to undergo routine ICSI procedure according to the result of randomization in each study site.
• Conventional IVF (Other): All patients will receive controlled ovarian hyperstimulation (COH) treatment, which is performed by standard routines at each study center. The COH treatment includes either gonadotrophin-releasing hormone agonist (GnRH-a) protocol or gonadotrophin-releasing hormone antagonist (GnRH-ant) protocol.Oocyte retrieval is scheduled for 36 (±2) after hCG injection.The retrieved cumulus oocyte complexes (COC) will be allocated to undergo conventional IVF procedure according to the result of randomization in each study site.

Primary outcomes

• Ongoing pregnancy leading to live birth after the first cycle with embryo transfer [After 22 weeks of gestation]: A delivery of one or more living infants (≥22 weeks gestation or birth weight more than 1,000g).

Secondary outcomes

• Fertilization [16-20 hours after oocyte retrieval]: Number of zygotes with 2 PN (per oocyte retrieved and per women randomized).
• Total fertilization failure [72 hours after oocyte retrieval]: No oocyte formed 2 PN in this given cycle.
• Available embryo [72 hours after oocyte retrieval]: Number of embryos ≥4 cells and ≤30% fragmentation on day 3 observation.
• Good quality embryo [72 hours after oocyte retrieval]: Number of embryos with ≥6 cells and ≤30% fragmentation developed from 2PN embryos on day 3 observation.
• Implantation [28 days after embryo transfer]: Number of gestational sacs observed per embryo transferred.
• Clinical pregnancy [7 weeks after embryo transfer]: One or more observed gestational sac or definitive clinical signs of pregnancy under ultrasonography at 7 weeks after embryo transfer (including clinically documented ectopic pregnancy).
• Multiple pregnancy [7 weeks after embryo transfer]: Pregnancy with two or more gestational sacs or positive heart beats at 7 weeks of gestation.
• Ongoing pregnancy [12 weeks after embryo transfer]: Presence of a gestational sac and fetal heartbeat after 12 weeks of gestation.
• Moderate/severe ovarian hyperstimulation syndrome (OHSS) [From date of controlled ovarian hyperstimulation until the date of oocyte retrieval, assessed about 14-16 days.]: exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations. It is classified as mild, moderate, or severe according to the degree of abdominal distention, ovarian Enlargement, and respiratory, hemodynamic, and metabolic complications.
• Miscarriage [22 weeks of gestation]: Spontaneous loss of an intra-uterine pregnancy prior to 22 completed weeks of gestational age.
• Ectopic pregnancy [7 weeks of gestation]: Implantation takes place outside the uterine cavity, confirmed by sonography or laparoscopy.
• Gestational diabetes mellitus (GDM) [24-37 weeks of pregnancy]
• Hypertensive disorders of pregnancy [28-37 weeks of pregnancy]: Comprising pregnancy induced hypertension (PIH); pre-eclampsia (PET) and eclampsia.
• Antepartum haemorrhage [28-37 weeks of pregnancy]: Including placenta previa, placenta accreta and unexplained.
• Preterm birth [28-37 weeks of pregnancy]: Birth of a fetus delivered after 28 and before 37 completed weeks of gestational age in participants confirmed ongoing pregnancy.
• Birth weight [Within 2 weeks after live birth]: Including low birth weight (defined as weight < 2500 gm at birth), very low birth weight (defined as < 1500 gm at birth), high birth weight (defined as >4000 gm at birth) and very high birth weight (defined as >4500 gm at birth).
• Large for gestational age [Within 2 weeks after live birth]: Birth weight >90th centile for gestation, based on standardised ethnicity based charts.
• Small for gestational age [Within 2 weeks after live birth]: Less than 10th centile for gestational age at delivery based on standardised ethnicity based charts.
• Congenital anomaly [Within 2 weeks after live birth]: Any congenital anomaly will be included.
• Perinatal mortality [Within 6 weeks after live birth]: Fetal or neonatal death occurring during late pregnancy (at 28 completed weeks of gestational age and later), during childbirth, or up to seven completed days after birth.
• Neonatal mortality [Within 6 weeks after live birth]: death of a live born baby within 28 days of birth

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Infertile couples scheduled for their first or second IVF/ICSI cycle.
* Men with non-severe male infertility: Sperm concentration 5,000,000-15,000,000/ml or sperm with progressive motility (type A+B) 10-32%.
* Women received either gonadotrophin-releasing hormone agonist protocol or gonadotrophin-releasing hormone antagonist protocol as their controlled ovarian hyperstimulation treatment.
* Informed consent obtained.

Exclusion Criteria:

* Couple with contraindication for IVF or ICSI.
* Couples receiving donor sperm or donor eggs.
* Couples undergoing PGD and PGS.
* Sperm concentration with progressive motility used for insemination <100,000/ml on the day of oocyte retrieval.
* Women with 0 oocytes after oocyte retrieval.
* Using frozen semen.
* Poor fertilization in previous cycle (≤ 25%).

• Results publication: Wang Y, Wang R, Lian Y, Yang R, Gao J, Liu J, Tang L, Liang X, Cao Y, Li W, Jin L, Zhu Y, Zhao J, Hao G, Wang H, Mol BW, Li R, Qiao J. Evaluating the potential for sperm DNA fragmentation testing to guide the use of ICSI for couples with non-severe male infertility. Hum Reprod Open. 2026 Mar 7;2026(2):hoag011. doi: 10.1093/hropen/hoag011. eCollection 2026. PMID 41836350
• Results publication: Wang Y, Li R, Yang R, Zheng D, Zeng L, Lian Y, Zhu Y, Zhao J, Liang X, Li W, Liu J, Tang L, Cao Y, Hao G, Wang H, Zhang H, Wang R, Mol BW, Huang H, Qiao J. Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial. Lancet. 2024 Mar 9;403(10430):924-934. doi: 10.1016/S0140-6736(23)02416-9. Epub 2024 Feb 5. PMID 38330980
• Results publication: Zheng D, Zeng L, Yang R, Lian Y, Zhu YM, Liang X, Tang L, Wang H, Cao Y, Hao G, Liu J, Zhao J, Wang R, Mol BW, Li R, Huang HF, Qiao J. Intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilisation (IVF) in couples with non-severe male infertility (NSMI-ICSI): protocol for a multicentre randomised controlled trial. BMJ Open. 2019 Sep 30;9(9):e030366. doi: 10.1136/bmjopen-2019-030366. PMID 31575574

• Jie Qiao, M.D., Study director, Peking University Third Hospital