ICSI Versus Conventional IVF in Couples With Unexplained Infertility (ICSI/IVF-UI)

Intracytoplasmic Sperm Injection (ICSI) Versus Conventional in Vitro Fertilization (IVF) in Couples With Unexplained Infertility: a Multicenter, Open-label, Parallel-group, Randomized Controlled Trial

This multicenter, open-label, parallel-group, randomized controlled trial aims to compare the live birth rate, fertilization outcomes, other pregnancy outcomes and safety between ICSI and conventional IVF among couples with unexplained infertility in China.

Study Overview

• Status: Not yet recruiting
• Conditions: Unexplained Infertility
• Intervention / Treatment: Procedure: ICSI; Procedure: IVF

Detailed Description

A multicenter, large-scale, randomized controlled clinical trial will enroll 848 couples with unexplained infertility undergoing their first 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 1 years with a total of 9 visits from controlled ovarian hyperstimulation, pregnancy to delivery. On the day of oocyte retrieval, eligible participants will be allocated to either the ICSI group or the IVF group in a 1:1 ratio. All participants will be randomized through block randomization, and each center will enroll participants using a competitive enrollment method.

• Study Type: Interventional
• Enrollment (Estimated): 848
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Min Jin, PhD; Phone Number: +86-15925602121; Email: min_jin@zju.edu.cn

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Beijing Obstetrics and Gynecology Hospital, Capital Medical University
      • Contact: Xiaokui Yang; Phone Number: +86-010-52276699; Email: yangxiaokui@ccmu.edu.cn
  • Hubei
    • Huangshi, Hubei, China, 435000
      • Huangshi Central Hospital
      • Contact: Junling Wang; Phone Number: +86-0714-3189999; Email: wangjunling225969@163.com
    • Wuhan, Hubei, China, 430060
      • Renmin Hospital of Wuhan University
      • Contact: Qingzhen Xie; Phone Number: +86-027-88041911; Email: rm001138@whu.edu.cn
    • Xiangyang, Hubei, China, 441021
      • Xiangyang Central Hospital
      • Contact: Xuezhou Yang; Phone Number: +86-0710-3520081; Email: dryangxz@163.com
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310052
      • Second Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Min Jin; Phone Number: +86-15925602121; Email: min_jin@zju.edu.cn
    • Jiaxing, Zhejiang, China, 314051
      • Jiaxing Maternity and Child Health Care Hospital
      • Contact: Weiping Fu; Phone Number: +86-0573-82066132; Email: fuweiping2816@163.com
    • Ningbo, Zhejiang, China, 315012
      • Ningbo Women & Children's Hospital
      • Contact: Liming Zhou; Phone Number: +86-0574-87083300; Email: zhou.li.ming@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 20-38 years
2. 18.5 < BMI < 24kg/m2

3. Couples diagnosed with primary unexplained infertility:

   • Regular menses or confirmed ovulation;

     • Normal ovarian reserve;

       • Patent fallopian tubes;

         • Normal uterus and cervix;

           • Normal endocrine profile;

             • Semen analysis meeting WHO 6th edition criteria

               • Normal karyotypes in both partners, no family history of genetic disorders
4. First IVF/ICSI cycle
5. Received GnRH agonist protocol or GnRH antagonist protocol
6. Willing to provide informed consent and comply with follow-up

Exclusion Criteria:

1. Preimplantation genetic testing (PGT) cycles
2. In vitro maturation (IVM) cycles
3. Using donor sperm/oocyte
4. Using frozen sperm/oocyte
5. <5 oocytes retrieved
6. Abnormal semen parameters on the day of oocyte retrieval
7. High risk of tubal pathology or endometriosis without laparoscopic exclusion
8. Untreated or poorly controlled endocrine disorders
9. Abnormal immune related examinations
10. Major organ/system disorders (cardiac, hepatic, renal, oncologic, hematologic, psychiatric, etc.)
11. Concurrent participation in other clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intracytoplasmic Sperm Injection (ICSI); All patients will receive controlled ovarian hyperstimulation (COH) treatment, which is performed by standard routines at each study center. The COH treatment includes either GnRH agonist protocol or GnRH antagonist protocol. Oocyte retrieval is scheduled for 36 (±2) hours after hCG injection. The retrieved cumulus oocyte complexes (COCs) will be allocated to undergo ICSI procedure according to the result of randomization. The first embryo transfer is performed using fresh embryo transfer (if without contraindication), limited to transferring 1-2 cleavage embryos or 1 blastocyst. The remaining available embryos will be frozen.	Procedure: ICSI; Insemination will be performed by using ICSI, 2 hours after oocyte retrieval. COCs will be stripped by using hyaluronidase. Only matured oocytes (MII stage) will be injected. Fertilization check will be performed at period of 16-18 hours after injection. Other standard assisted reproductive treatments are similar and parallel between two groups.
Active Comparator: Conventional in vitro fertilization (c-IVF); All patients will receive controlled ovarian hyperstimulation (COH) treatment, which is performed by standard routines at each study center. The COH treatment includes either GnRH agonist protocol or GnRH antagonist protocol. Oocyte retrieval is scheduled for 36 (±2) hours after hCG injection. The retrieved cumulus oocyte complexes (COCs) will be allocated to undergo conventional IVF procedure according to the result of randomization. The first embryo transfer is performed using fresh embryo transfer (if without contraindication), limited to transferring 1-2 cleavage embryos or 1 blastocyst. If the embryos in the IVF group are fertilized through different methods (some with late-RICSI), the first embryo transfer is limited to embryos fertilized through conventional IVF. The remaining available embryos will be frozen.	Procedure: IVF; Insemination will be performed by using conventional IVF, 2-4 hours after oocyte retrieval. Collected COCs will be inseminated (1-5×105 sperm/ml) and cultured overnight in culture medium. Fertilization check will be performed at period of 16-18 hours after insemination. If the IVF group experiences total fertilization failure or a fertilization rate of less than 25%, late rescue ICSI (Late-RICSI) will be performed on all MII stage oocytes using semen retained on the day of egg retrieval. The injection method is same as standard ICSI. Other standard assisted reproductive treatments are similar and parallel between two groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate after the first embryo transfer 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).	At birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age at delivery		At birth
Cumulative ongoing pregnancy rate within one year	Achieving ongoing pregnancy within 12 months after randomization, regardless of the number of embryo transfers performed (limited to embryos obtained in the current study). Ongoing pregnancy refers to the presence of a gestational sac and fetal heart beat after 12 weeks of gestation.	At 12 weeks of gestation; At 12 months after randomization
Number of retrieved oocyte	Number of oocyte obtained on the day of oocyte retrieval	2 hours after oocyte retrieval
MII rate	[Only in ICSI group] The proportion of MII oocytes to the total number of retrieved oocytes.	2 hours after oocyte retrieval
Fertilization rate per oocyte inseminated/injected	The proportion of fertilized oocytes to inseminated oocytes (IVF group) / injected oocytes (ICSI group).	At 16-18 hours after insemination or injection
Fertilization rate per oocyte retrieved	The proportion of fertilized oocytes to the total number of retrieved oocytes.	At 16-18 hours after insemination or injection
Normal fertilization rate	Normal fertilization is defined as the appearance of 2PN	At 16-18 hours after insemination or injection
Abnormal fertilization rate	Abnormal fertilization is defined as the appearance of 1PN or ≥3PN	At 16-18 hours after insemination or injection
Degeneration rate of ICSI oocytes	[Only in ICSI group] The proportion of oocytes that undergo degeneration assessed on Day 2 among all oocytes receiving ICSI.	At 16-18 hours after injection
Cleavage rate	The proportion of normal cleavage observed on Day 2 in normally fertilized oocytes	At 16-18 hours after insemination or injection
Day 2 embryo formation rate	The proportion of 4-cell stage embryos formed on Day 2 compared to normal fertilized oocytes.	2 days after oocyte retrieval
Day 3 embryo formation rate	The proportion of 8-cell stage embryos formed on Day 3 compared to normal fertilized oocytes.	3 days after oocyte retrieval
Good quality embryo rate on Day 3	The proportion of I-II grade embryos with 6-10 cells on Day 3 compared to normal fertilized oocytes, according to Peter's scoring criteria.	3 days after oocyte retrieval
Blastocyst formation rate	The proportion of the number of blastocysts formed to the number of embryos undergoing blastocyst culture.	6 days after oocyte retrieval
Good quality blastocyst formation rate	The proportion of the number of blastocysts classified as 3BB or higher grade (according to Gardner scoring system) to the number of embryos undergoing blastocyst culture.	6 days after oocyte retrieval
Good quality blastocyst rate	The proportion of good quality blastocysts to the total number of blastocysts.	6 days after oocyte retrieval
Number of available blastocyst	Number of blastocysts of BC, CB grade and above, according to the Gardner scoring system.	6 days after oocyte retrieval
Number of available embryo	The total number of embryos that can be utilized for transplantation or cryopreservation.	6 days after oocyte retrieval
Total fertilization failure rate	Total fertilisation failure rate is defined as the absence of any zygotes with 2PN	At 16-18 hours after insemination or injection
Cycle cancellation rate	The proportion of cycles with total fertilization failure or no available embryo to all oocyte retrieval cycles.	6 days after oocyte retrieval
Moderate/severe ovarian hyperstimulation syndrome (OHSS)	The exaggerated systemic response to ovarian stimulation. It is classified into mild, moderate, and severe based on the degree of bloating, ovarian volume enlargement, and respiratory, hemodynamic, and metabolic complications.	At 10days after trigger; At 14 days after embryo transfer
Positive pregnancy rate	Positive pregnancy test is defined as a serum human chorionic gonadotropin level greater than 10mIU/mL after embryo transfer.	10-14 days after embryo transfer; At 12 months after randomization
Clinical pregnancy rate	Clinical pregnancy is defined as ultrasound detection of at least one gestational sac or other clear pregnancy manifestations under ultrasound (including clear ectopic pregnancy).	30 days after embryo transfer
Implantation rate	Implantation rate is defined as the number of gestational sacs per number of embryos transferred.	30 days after embryo transfer; At 12 months after randomization
Ongoing pregnancy rate	Ongoing pregnancy refers to the presence of a gestational sac and fetal heart beat after 12 weeks of gestation.	At 12 weeks of gestation; At 12 months after randomization
Ectopic pregnancy	Ectopic pregnancy is defined as the presence of the gestational sac outside the uterine cavity detected by ultrasound.	30 days after embryo transfer; At 12 months after randomization
Multiple pregnancy rate	Multiple pregnancy is defined as the detection of two or more gestational sacs or positive heart beats by ultrasound.	30 days after oocyte retrieval; At 12 months after randomization
Miscarriage rate	Miscarriage refers to the loss of an intra-uterine pregnancy before 24 weeks of gestation.	At 24 weeks of gestation; At 12 months after randomization
Gestational diabetes mellitus	Abnormal OGTT test	At 24-28 weeks of gestation
Hypertensive disorders of pregnancy	The hypertensive disorders of pregnancy include gestational hypertension, chronic hypertension, pre-eclampsia, chronic hypertension with preeclampsia, eclampsia and HELLP syndrome.	From 20 weeks of gestation up to at birth
Antepartum haemorrhage	Vaginal bleeding caused by placenta previa, placental implantation, or unknown reasons in mid or late pregnancy.	From 20 weeks of gestation up to at birth
Thrombotic diseases	If the participant experiences clinical symptoms such as lower limb pain, chest pain, hemoptysis, etc., and there is a high suspicion of thrombotic disease in clinical practice, confirmation will be made through examinations such as vascular ultrasound and CT angiography.	From 20 weeks of gestation up to 4-6 weeks after birth
Preterm birth	Pregnancy terminates after 28 weeks and before 37 weeks of gestation.	At birth
Spontaneous preterm birth	Termination of pregnancy due to premature rupture of membranes or spontaneous uterine contractions between 28 to 37 weeks of gestation.	At birth
Iatrogenic preterm birth	Termination of pregnancy due to iatrogenic factors between 28 to 37 weeks of gestation.	At birth
Birth weight	Weight of newborn, classified as very low birth weight (<1500g), low birth weight (1500-2500g), macrosomia (>4000g).	At birth
Small for gestational age	Birth weight below the 10th percentile for gestational age.	At birth
Large for gestational age	Birth weight above the 90th percentile for gestational age.	At birth
Birth defect / Congenital anomaly	Any birth defect or congenital anomaly will be included.	At birth; At 4-6 weeks after birth
NICU admission	The admittance of the newborn to NICU.	At 4-6 weeks after birth
Perinatal mortality	Fetal or neonatal death occurring after 28 weeks of gestation, during delivery, or within 7 days after birth.	At 4-6 weeks after birth
Neonatal mortality	Death of a live born baby within 28 days of birth.	At 4-6 weeks after birth

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: Renmin Hospital of Wuhan University; Jiaxing Maternity and Child Health Care Hospital; Beijing Obstetrics and Gynecology Hospital; Xiangyang Central Hospital; Ningbo Women & Children's Hospital; Huangshi Central Hospital
• Investigators: Principal Investigator: Min Jin, PhD, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): July 30, 2028
• Study Completion (Estimated): July 30, 2028

Study Registration Dates

• First Submitted: August 27, 2025
• First Submitted That Met QC Criteria: December 7, 2025
• First Posted (Actual): December 19, 2025

Study Record Updates

• Last Update Posted (Actual): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 7, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Intracytoplasmic sperm injection; Unexplained infertility; Conventional in vitro fertilization
• Additional Relevant MeSH Terms: Investigative Techniques; Therapeutics; Fertilization in Vitro; Reproductive Techniques, Assisted; Reproductive Techniques; Sperm Injections, Intracytoplasmic
• Other Study ID Numbers: 2025-0689

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No