Cumulative Live Birth Rate With eSET After Preimplantation Genetic Screening Versus Conventional In-vitro Fertilization (CESE-PGS)

Cumulative Live Birth Rate With eSET After In-vitro Fertilization With Preim-plantation Genetic Screening by Next Generation Sequencing Versus Conventional In-vitro Fertilization: A Pragmatic Randomized Controlled Clinical Trial

The purpose of this randomized clinical trial is to compare the efficacy and safety with transfer of embryos selected by next generation sequencing (NGS) versus conventional morphological criteria. Subjects with 3 or more blastocysts on day 5 of embryo culture will be randomized to the PGS or IVF group. A Freeze-all strategy and a single frozen blastocyst transfer will be performed in both PGS and IVF groups. The primary outcome is the cumulative live birth after transfers of up to 3 single blastocycsts in both groups.

Study Overview

• Status: Unknown
• Conditions: Infertility
• Intervention / Treatment: Procedure: blastocyst morphologic score; Procedure: blastocyst biopsy and sequencing; Procedure: freeze-all and single thawed blastocyst transfer

Detailed Description

This is a multicenter, randomized clinical trial comparing the efficacy and safety with transfer of embryos selected by next generation sequence (NGS) and morphologic criteria versus by morphological criteria alone. Subjects who obtain 3 or more good-quality blastocysts will be randomized to PGS or IVF group. All embryos will be frozen and a single thawed blastocyst will be transferred in both PGS and IVF group. Subjects in the PGS group will have 3 blastocysts sequenced and euploid embryos will be subsequently transferred. Subjects in the IVF group will have blastocysts selected by morphology assessment. The cumulative live birth rate will be counted after transfers of all euploid embryo in the PGS group and 3 blastocysts in the IVF group within 1 year after randomization.

• Study Type: Interventional
• Enrollment (Anticipated): 1215
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zi-Jiang Chen, Professor; Phone Number: +0086 531 85651190; Email: chenzijiang@vip.163.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Shandong University
      • Contact: Zi-Jiang Chen, Professor; Phone Number: +0086 531 85651190; Email: chenzijiang@vip.163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 37 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Women who are participating in their first cycle of IVF or ICSI
2. Women ages 20 to 37 years.
3. Women who obtain 3 or more good-quality blastocysts defined as morphological score of inner cell mass B or A, trophectoderm C or better, and grade 4 or better on day 5 of embryo culture will be randomized.

Exclusion Criteria:

1. Women with a uterine cavity abnormality, such as a uterine congenital malformation (uterus uni-cornate, bicornate, or duplex); untreated uterine septum, adenomyosis, submucous myoma, or endo-metrial polyp(s); or with history of intrauterine adhesions.
2. Women with untreated hydrosalpinx;
3. Women who are indicated and planned to undergo PGD, for example, parental abnormal karyo-type or diagnosed with monogenic disease;
4. Women who use donated oocytes or sperm to achieve pregnancy;
5. Women with contraindication for assisted reproductive technology or for pregnancy, such as poorly controlled Type I or Type II diabetes; undiagnosed liver disease or dysfunction (based on se-rum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hyper-tension, known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma; undiagnosed vaginal bleeding.

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: PGS group; Subjects in the PGS group will have blastocyst biopsy and sequencing done with 3 good-quality embryos on Day 5. Principle of freeze-all and single thawed blastocyst transfer will be applied. The transfer order of euploid embryos will be determined by blastocyst morphologic score. The outcome of all euploids transfers within 1 year after randomization will be followed up. During study, every subject will have at most one live birth.	Procedure: blastocyst morphologic score; Blastocysts will be scored by Gardner morphologic criteria.; Procedure: blastocyst biopsy and sequencing; Three blastocysts will be biopsied on trophectoderm, sequenced with next-generation sequencing (NGS). Euploidy will transferred one by one according to morphologic score.; Procedure: freeze-all and single thawed blastocyst transfer; All blastocysts will be vitrified in fresh cycle. Single blastocyst will be thawed and transferred.
Active Comparator: IVF group; Subjects in the IVF group will also comply with the principle of freeze-all and single thawed blastocyst transfer. The order of transfer will be determined by blastocyst morphologic score. The outcome of up to 3 transfers within 1 year after randomization will be followed up. During study, every subject will have at most one live birth.	Procedure: blastocyst morphologic score; Blastocysts will be scored by Gardner morphologic criteria.; Procedure: freeze-all and single thawed blastocyst transfer; All blastocysts will be vitrified in fresh cycle. Single blastocyst will be thawed and transferred.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative live birth rate	Live birth is defined as the delivery of any viable infant at 28 weeks or more of gestation after our interventions, and cumulative live birth rate is calculated by dividing the number of women achieving live birth after transfers of all study-specific embryos (up to 3 transfers of single blastocycst within 1 year after randomization), by the total number of women randomized to the specific group.	22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multiple pregnancy rate	Number of multiple pregnancies / number of clinical pregnancies over (up to) 3 transfers within 1 year.	22 months
Duration of pregnancy	The time from the first day of last menstrual period to the day of delivery.	22 months
Birth weight	Weight of newborns at delivery.	22 months
Number of embryo transfers to achieve live birth	Number of embryo transfers the patients have gone through to achieve live birth.	22 months
Rate of Good Birth Outcomes	Number of good birth outcomes / number of clinical pregnancies over (up to) 3 transfers within 1 year.Good Birth Outcome is defined as live birth of an infant born at ≥ 37 weeks, with a birth weight between 2500 and 4000g and without a major congenital anomaly.	22 months
Cumulative pregnancy rate	Number of women with clinical pregnancies over (up to) 3 transfers within 1 year / number of women randomized to the specific group. Clinical pregnancy will be diagnosed with detection of an intrauterine gestational sac.	14 months
Cumulative pregnancy loss rate	Number of pregnancy losses / number of clinical pregnancies over (up to) 3 transfers within 1 year.Pregnancy loss refers to a complete spontaneous abortion or a nonviable pregnancy before 28 weeks of gestation.	19 months
Cumulative incidence of maternal and neonatal complications during whole gestation and prenatal stage	Number of pregnancies with complications / number of pregnancies over (up to) 3 transfers within 1 year;number of live births with neonatal complications / number of live births over (up to)3 transfers within 1 year.	22 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy loss rate after the first transfer	Number of pregnancy losses / number of clinical pregnancies after the first transfer .	9 months
Clinical pregnancy rate after the first transfer	Number of women with clinical pregnancies after the first transfer / number of women randomized to the specific group.	4 months
Live birth rate after the first transfer	Number of women with live births after the first transfer / number of women randomized to the specific group.	12 months

Collaborators and Investigators

• Sponsor: Chen Zi-Jiang
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital of Anhui Medical University; Peking University Third Hospital; RenJi Hospital; Shengjing Hospital; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; Women's Hospital School Of Medicine Zhejiang University; Renmin Hospital of Wuhan University; Tang-Du Hospital; Nanjing Maternity and Child Health Care Hospital; Guangdong Women and Children Hospital; Yantai Yuhuangding Hospital; ShangHai Ji Ai Genetics & IVF Institute; Suzhou Municipal Hospital; Tianjin Central Hospital of Gynecology Obstetrics; Guangxi Maternal and Child Health Hospital

Publications and helpful links

General Publications

• Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev. 2020 Sep 8;9(9):CD005291. doi: 10.1002/14651858.CD005291.pub3.
• Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES, Salem RD. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012 May 2;5(1):24. doi: 10.1186/1755-8166-5-24.
• Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT Jr. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013 Jul;100(1):100-7.e1. doi: 10.1016/j.fertnstert.2013.02.056. Epub 2013 Mar 30.
• Scott RT Jr, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, Tao X, Treff NR. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013 Sep;100(3):697-703. doi: 10.1016/j.fertnstert.2013.04.035. Epub 2013 Jun 1.
• Dahdouh EM, Balayla J, Garcia-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril. 2015 Dec;104(6):1503-12. doi: 10.1016/j.fertnstert.2015.08.038. Epub 2015 Sep 16.
• Murugappan G, Ohno MS, Lathi RB. Cost-effectiveness analysis of preimplantation genetic screening and in vitro fertilization versus expectant management in patients with unexplained recurrent pregnancy loss. Fertil Steril. 2015 May;103(5):1215-20. doi: 10.1016/j.fertnstert.2015.02.012. Epub 2015 Mar 13.
• Mastenbroek S, Repping S. Preimplantation genetic screening: back to the future. Hum Reprod. 2014 Sep;29(9):1846-50. doi: 10.1093/humrep/deu163. Epub 2014 Jul 8.
• Huang J, Yan L, Lu S, Zhao N, Xie XS, Qiao J. Validation of a next-generation sequencing-based protocol for 24-chromosome aneuploidy screening of blastocysts. Fertil Steril. 2016 Jun;105(6):1532-6. doi: 10.1016/j.fertnstert.2016.01.040. Epub 2016 Feb 19.
• Yan J, Qin Y, Zhao H, Sun Y, Gong F, Li R, Sun X, Ling X, Li H, Hao C, Tan J, Yang J, Zhu Y, Liu F, Chen D, Wei D, Lu J, Ni T, Zhou W, Wu K, Gao Y, Shi Y, Lu Y, Zhang T, Wu W, Ma X, Ma H, Fu J, Zhang J, Meng Q, Zhang H, Legro RS, Chen ZJ. Live Birth with or without Preimplantation Genetic Testing for Aneuploidy. N Engl J Med. 2021 Nov 25;385(22):2047-2058. doi: 10.1056/NEJMoa2103613.

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2017
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): June 1, 2020

Study Registration Dates

• First Submitted: March 27, 2017
• First Submitted That Met QC Criteria: April 12, 2017
• First Posted (Actual): April 18, 2017

Study Record Updates

• Last Update Posted (Actual): September 20, 2019
• Last Update Submitted That Met QC Criteria: September 19, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: frozen embryo transfer; preimplantation genetic screening; single embryo transfer; cumulative live birth rate
• Additional Relevant MeSH Terms: Infertility
• Other Study ID Numbers: CESE-PGS

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