Cumulative Live Birth Rates After Cleavage-stage Versus Blastocyst-stage Embryo Transfer (CLBR-CBSET)

Cumulative Live Birth Rates After Cleavage-stage Versus Blastocyst-stage Embryo Transfer: A Multicenter, Prospective, Randomized Controlled Trial

The aim of this RCT is to compare differences in the efficacy and safety between cleavage-stage embryo transfer and blastocyst-stage embryo transfer in IVF/ICSI treatment cycle, taking into account of subsequent vitrified embryo transfers. Subjects with 3 or more transferrable cleavage embryos will be randomized to the cleavage-stage or blastocyst-stage embryos transfer group. The primary outcome is cumulative live birth rate (CLBR) per patient until the first live birth from one initiated oocyte retrieval cycle, calculated using outcomes from the first three embryo transfers within 1 year after randomization.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Procedure: blastocyst-stage embryo transfer; Procedure: cleavage-stage embryo transfer

Detailed Description

This is a multicenter, randomized clinical trial comparing the efficacy and safety between cleavage-stage embryo transfer and blastocyst-stage embryo transfer in IVF/ICSI treatment cycle, taking into account of subsequent vitrified embryo transfers.Randomization will be performed on day 2/3 after oocyte retrieval, when at least 3 embryos are achieved. Patients in group A will have 1 cleavage-stage embryo transferred. Patients in group B will have 1 blastocyst-stage embryo transferred. The outcomes from all the embryo transfers within 1 year after randomization will be followed up. If a pregnancy/live birth is not achieved, single embryo transfer is required for the first 3 embryo transfers within 1 year after randomization. For embryo transfers beyond the third within the 1 year, patient's treatment must follow their randomized allocation, and SET is no longer mandatory. The follow-up period is 2 years from the day of randomization.Due to the COVID-19 pandemic, the participants who were unable to undergo the embryo transfers in 1 year of randomization will have 3 months extension for frozen embryo transfer. The follow-up for these participants will be extended for 3 months as well.

• Study Type: Interventional
• Enrollment (Actual): 992
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of Anhui Medical University
  • Dongbei
    • Shenyang, Dongbei, China
      • Shengjing Hospital of China Medical University
  • Guangdong
    • Guangzhou, Guangdong, China
      • The Third Affiliated Hospital of Guangzhou Medical University
  • Guangxi
    • Nanning, Guangxi, China
      • Guangxi Maternal and Child Health Hospital
  • Henan
    • Zhengzhou, Henan, China
      • Henan Provincial People's Hospital
    • Zhengzhou, Henan, China
      • The Third Affiliated Hospital of Zhengzhou University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Clinical Center of Reproductive Medicine at the First Affiliated Hospital of Nanjing Medical University
  • Ningxia
    • Yinchuan, Ningxia, China
      • General Hospital of Ningxia Medical University
  • Shandong
    • Jinan, Shandong, China
      • Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University
  • Shanghai
    • Shanghai, Shanghai, China
      • Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine
  • Suzhou
    • Suzhou, Suzhou, China
      • Suzhou Municipal Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion criteria:

1. Women aged ≥20 and ≤40 years.
2. Women with the number of transferrable cleavage embryos ≥ 3;
3. Women undergoing their first or second cycle of IVF or ICSI.

Exclusion criteria

1. Women who have been diagnosed with uterine abnormalities (confirmed by three-dimensional ultrasonography or hysteroscopy), including malformed uterus (uterus unicornis, septate uterus or duplex uterus), submucous myoma, or intrauterine adhesion
2. Women who plan to undergo In Vitro Maturation (IVM);
3. Women who plan to undergo Preimplantation Genetic Diagnosis (PGD) /Preimplantation Genetic Screening (PGS).
4. Women who have Women who have hydrosalpinx visible on ultrasound.
5. Women who have experienced recurrent spontaneous abortions, defined as 2 or more previous pregnancy losses.
6. Women who have been developed a "freeze-all" treatment plan for purpose of subsequent surgery, such as salpingectomy due to hydrosalpinx after oocytes retrieval.
7. Women with contraindications to assisted reproductive technology and/or pregnancy, such as uncontrolled hypertension, symptomatic heart diseases, uncontrolled diabetes, undiagnosed liver disease or dysfunction (based on serum liver enzyme test results), undiagnosed renal disease or abnormal renal function, severe anemia, history of deep venous thrombosis, pulmonary embolus or cerebrovascular accident, history of or suspicious for cancer, undiagnosed vaginal bleeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: blastocyst-stage embryo transfer group; For subjects assigned to blastocyst-stage (D5/D6) embryo transfer group, all embryos will be cultured to D5 or D6. 1 blastocysts of the best quality will be transferred in fresh cycle on D5 or D6 after oocyte retrieval (D5 embryo will be the prior choice). The surplus embryos, if any, will be vitrified for future FET in case the fresh cycle does not result in a live birth. If a patient is at a high risk of OHSS, all embryos on D5 or D6 can be cryopreserved with vitrification for patient's safety. The FET cycle will be initiated on the second menstrual cycle after oocyte retrieval.	Procedure: blastocyst-stage embryo transfer; All the participants will receive a long GnRH-agonist, ultra-long GnRH-agonist, short GnRH-agonist or GnRH antagonist protocol in combination with recombinant FSH. HCG will be administered for final oocyte maturation. Patients will have a single blastocyst-stage embryos transferred. The outcomes of all the embryo transfers within 1 year after randomization will be followed up. Single embryo transfer (SET) is required for the first 3 embryo transfers within 1 year after randomization. For embryo transfers beyond the third within the 1 year, patients' treatment must follow their randomized allocation, and SET is no longer mandatory. Luteal phase support will be administered before embryo transfer. If pregnancy is confirmed, luteal phase support will be continued until 10 weeks of gestation. The follow up will be continued until 6 weeks after delivery.
EXPERIMENTAL: cleavage-stage embryo transfer group; For subjects assigned to the cleavage-stage (D2/3) embryo transfer group, 1 cleavage embryos of the best quality will be transferred in fresh cycle on Day 2/3 after oocyte retrieval. The surplus embryos, if any, will be vitrified for future FET if the fresh cycle does not result in a live birth. If a patient is at a high risk of OHSS, all embryos on Day 2/3 are allowed to be cryopreserved with vitrification for patient's safety. The FET cycle will be initiated on the second menstrual cycle after oocyte retrieval.	Procedure: cleavage-stage embryo transfer; All the participants will receive a long GnRH-agonist, ultra-long GnRH-agonist, short GnRH-agonist or GnRH antagonist protocol in combination with recombinant FSH. HCG will be administered for final oocyte maturation. Patients will have a single cleavage-stage embryos transferred. The outcomes of all the embryo transfers within 1 year after randomization will be followed up. Single embryo transfer (SET) is required for the first 3 embryo transfers within 1 year after randomization. For embryo transfers beyond the third within the 1 year, patients' treatment must follow their randomized allocation, and SET is no longer mandatory. Luteal phase support will be administered before embryo transfer. If pregnancy is confirmed, luteal phase support will be continued until 10 weeks of gestation. The follow up will be continued until 6 weeks after delivery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative live birth rate	Cumulative live birth rate (CLBR) is defined the first live birth per patient from one initiated oocyte retrieval cycle(Calculated using outcomes from the first three embryo transfers within 1 year after randomization). Live birth is defined as delivery of any neonate ≥24 weeks gestation with heart beat and breath.	30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
biochemical pregnancy rate	Biochemical pregnancy is defined as a serum β-HCG level of at least 25 IU/L 14 days after embryo transfer.	30 months
clinical pregnancy rate	Clinical pregnancy is defined by the presence of intrauterine gestation sacs at 30-35 days after embryo transfer.	30 months
ongoing pregnancy rate	Ongoing pregnancy is defined as a viable pregnancy at 12 weeks gestation.	30 months
Pregnancy loss rate	Pregnancy loss is defined as a pregnancy that results in a spontaneous abortion or therapeutic abortion that occurred throughout pregnancy.	30 months
moderate or severe OHSS rate	Number of patients with moderate or severe OHSS/ number of COS cycles.	12 months
ectopic pregnancy	diagnosed by ultrasound examination or laparoscopic surgery visualizing more than or equal to 1 gestational sacs outside the uterus or by abnormally increasing serum hCG level without sonographic visualization and the absence of chorionic villi inside the uterus after uterine curettage, which was treated by methotrexate.	24 months
sex ratio	the ratio of males to females in the newborns	30 months
multiple pregnancy	Number of multiple pregnancies / number of clinical pregnancies.	30 months
incidence of obstetric and perinatal complications	Number of pregnancies with complications / number of pregnancies; ;number of live births with neonatal complications / number of live births	30 months
congenital anomalies	structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or later in life.	30 months
implantation rate	the number of gestational sacs detected with sonography at 6 weeks of pregnancy/the number of embryos transferred	30 months
Birth weight	Weight of newborns at delivery	30 months

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: The First Affiliated Hospital of Anhui Medical University; RenJi Hospital; The Third Affiliated Hospital of Guangzhou Medical University; Shengjing Hospital; Shandong Provincial Hospital; Henan Provincial People's Hospital; General Hospital of Ningxia Medical University; Suzhou Municipal Hospital; Third Affiliated Hospital of Zhengzhou University; Guangxi Maternal and Child Health Hospital
• Investigators: Principal Investigator: Jiayin Liu, MD &PhD, The First Affiliated Hospital with Nanjing Medical University; Principal Investigator: Zi-Jiang Chen, MD &PhD, Center for Reproductive Medicine, affiliated to Shandong University

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 29, 2018
• Primary Completion (ACTUAL): September 6, 2021
• Study Completion (ACTUAL): February 18, 2022

Study Registration Dates

• First Submitted: May 9, 2017
• First Submitted That Met QC Criteria: May 11, 2017
• First Posted (ACTUAL): May 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 9, 2022
• Last Update Submitted That Met QC Criteria: June 8, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: blastocyst transfer; Cumulative live birth rates; cleavage-stage embryo transfer
• Additional Relevant MeSH Terms: Infertility
• Other Study ID Numbers: CLBR-CBSET

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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