First Live Birth Rate With eSET After Preimplantation Methylome Screening (PIMS) Versus Conventional In-vitro Fertilization

Whether Using DNA Methylome to Select Embryos Can Increase the Live Birth Rate During Assisted Reproductive Technology: A Multicenter, Randomized , Open-label Clinical Trial.

To determine whether using DNA methylome to select embryos can increase the live birth rate.

Study Overview

• Status: Recruiting
• Conditions: Reproductive Techniques, Assisted; DNA Methylation
• Intervention / Treatment: Other: Using DNA methylome to select embryos; Other: Using morphologic score to select embryos

Detailed Description

The rationale for the study is to establish the risk/benefit ratio of PIMS in women with in vitro fertilization (IVF) treatment, as DNA methylome is a potential biomarker in blastocyst selection in assited reproductive technology (ART). DNA methylation plays an important role during embryogenesis, global abnormal methylome reprogramming often occurs in human embryos, and DNA methylome pattern is associated with live birth rate. However, there is still no technology using DNA methylome as an indicator in preimplantation embryo screening. Recent paper reported that using Pre-implantation Methylome Screening (PIMS) can select embryos with better methylation state and euploid chromosomes. The efficiency of PIMS needs further validation through randomized clinical trial.

• Study Type: Interventional
• Enrollment (Estimated): 1146
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yuan Gao, Professor; Phone Number: 0531-86569866; Email: gaoyuan@sduivf.com

Study Locations

• China
  • Changchun, China
    • Recruiting
    • Center for Reproductive Medicine, Center for Prenatal Diagnosis First Hospital, Jilin University
    • Contact: Ruizhi Liu, Professor
  • Changsha, China, 410008
    • Recruiting
    • Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA
    • Contact: Lin Ge, Professor
  • Fuzhou, China
    • Recruiting
    • 900 th Hospital of Joint Logistics Support Force
    • Contact: Yun Liu, Professor
  • Fuzhou, China
    • Recruiting
    • Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University
    • Contact: Beihong Zhen, Professor
  • Guanzhou, China
    • Recruiting
    • Guangzhou Womenand Children's Medical Center
    • Contact: Ling Sun, Professor
  • Guanzhou, China
    • Not yet recruiting
    • The Sixth Affiliated Hospital of Sun yat-sen University
    • Contact: Haitao Zeng, Professor
  • Guiyang, China
    • Recruiting
    • Center for Reproductive Medicine, The Affiliated Hospital of Guizhou Medical University
    • Contact: Shunyun Zhao, Professor
  • Haikou, China
    • Recruiting
    • The First Affiliated Hospital of Hainan Medical University
    • Contact: Yanlin Ma, Professor
  • Hangzhou, China
    • Recruiting
    • Assisted Reproduction Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
    • Contact: Songying Zhang, Professor
  • Hefei, China
    • Recruiting
    • The First Affiliated Hospital of Anhui Medical University
    • Contact: Yunxia Cao, Professor
  • Jinan, China, 250012
    • Recruiting
    • Center for Reproductive Medicine, Shandong University
    • Contact: Yuan Gao, Professor
  • Jining, China
    • Recruiting
    • Affiliated Hospital of Jining Medical University
    • Contact: Aijun Yang, Professor
  • Liuzhou, China
    • Recruiting
    • Liuzhou Hospital of Guangzhou Women and Children's Medical Center
    • Contact: Li Fan, Professor
  • Nanjing, China
    • Recruiting
    • The First Affiliated Hospital with Nanjing Medical University
    • Contact: Xiang Ma, Professor
  • Nanjing, China
    • Recruiting
    • Department of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital
    • Contact: Xiufeng Ling, Professor
  • Shanghai, China
    • Not yet recruiting
    • Changhai Hospital
    • Contact: Hongli Yan, Professor
  • Shanghai, China, 200135
    • Recruiting
    • Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine,Shanghai Jiao Tong University
    • Contact: Yun Sun, Professor
  • Shanghai, China
    • Not yet recruiting
    • International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University
    • Contact: Wen Li, Professor
  • Shanghai, China
    • Not yet recruiting
    • Reproductive Medical Center of Ruijin Hospital, School of Medicine,Shanghai Jiao Tong University
    • Contact: Aijun Zhang, Professor
  • Shanghai, China
    • Not yet recruiting
    • Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
    • Contact: Xiaoxi Sun, Professor
  • Shenzhen, China
    • Recruiting
    • Shenzhen Maternity & Child Healthcare Hospital
    • Contact: Xuemei Li, Professor
  • Shijiazhuang, China
    • Recruiting
    • The Second Hospital of Hebei Medical University
    • Contact: Guimin Hao, Professor
  • Suzhou, China
    • Recruiting
    • Center for reproduction and genetics,suzhou municipal hospital
    • Contact: Hong Li, Professor
  • Yinchuan, China
    • Recruiting
    • The General Hospital of Ningxia Medical University
    • Contact: Junli Zhao, Professor
  • Zhengzhou, China
    • Recruiting
    • Department of Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University
    • Contact: Yichun Guan, Professor
  • Zhengzhou, China
    • Recruiting
    • Reproductive Medical Center, Henan Provincial People's Hospital
    • Contact: Cuilian Zhang, Professor
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Shandong University
      • Contact: Zi-Jiang Chen, Professor; Phone Number: +0086 531 85651190; Email: chenzijiang@vip.163.com
      • Contact: Yuan Gao, Professor; Phone Number: +0086 531 86569866; Email: gaoyuan@sduivf.com
      • Principal Investigator: Yuan Gao, Professor
• Thailand
  • Bangkok, Thailand
    • Not yet recruiting
    • Siriraj Hospital, Mahidol University
    • Contact: Isarin Thanaboonyawat, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Women who plan to undergo IVF/ICSI/PGT-A treatment.
2. Women aged 20 years and older.

b) Women who obtain 2 or more good-quality blastocysts that 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.

Exclusion Criteria:

4.2 Exclusion Criteria

1. Women with a uterine cavity abnormality, such as a uterine congenital malformation (uterus unicornate, bicornate, or duplex); untreated uterine septum, submucous myoma, or endometrial polyp(s); or with history of intrauterine adhesions.
2. Women who are indicated and planned to undergo preimplantation genetic testing for structural rearrangements (PGT-SR) or preimplantation genetic testing for monogenic (PGT-M).
3. Women who use donated oocytes or sperm to achieve pregnancy;
4. 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 serum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hypertension, 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
Experimental: PIMS group; Couples in the PIMS group will have up to 6 blastocysts screened with PIMS and a single euploid embryo with the optimal state of whole-genome DNA methylation and the highest morphologic score will be selected for the initial transfer. The optimal state of whole-genome DNA methylation includes methylation level closest to the optimal level (0.26 according to our preliminary results) and proper methylation state for some specific regions.	Other: Using DNA methylome to select embryos; DNA methylation level Embryo with methylation level closest to the optimal level (from one couple patients) is the one for embryonic transfer to uterus
Active Comparator: Conventional-IVF group; For women between 20 and 37 years of age,couples in the conventional-IVF group will have a single best blastocyst by morphologic criteria selected for the initial transfer.For women over 37 years old, couples in the PGT-A group will have up to 6 blastocysts tested with PGT-A and a single euploid embryo with the highest morphologic score will be selected for the initial transfer.	Other: Using morphologic score to select embryos; blastocyst will transferred according to morphologic score or blastocysts will be biopsied on trophectoderm, sequenced with next-generation sequencing (NGS). Euploidy will transferred one by one according to morphologic score.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
live birth rate of initial embryo transfer	Live birth rate is defined as delivery of any viable infant at 28 weeks or more of gestation, after initial embryo transfer in women using the embryos selected through PIMS or PGT-A or morphological criteria alone.	22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Good Birth Outcome rate	Defined as a live birth of an infant born at ≥ 37 weeks, with a birth weigh between 2500 and 4000g and without a major congenital anomaly	36 months
Clinical pregnancy rate	Twenty days after conception, transvaginal ultrasonography will be performed. Clinical pregnancy will be diagnosed with detection of an intrauterine gestational sac.	36 months
Pregnancy loss rate	Number of pregnancy losses / number of clinical pregnancies after transfer.	36 months
Multiple pregnancy rate	Number of multiple pregnancy/number of clinical pregnancies after transfer.	36 months
Duration of pregnancy	Duration of pregnancy is the period between conception and birth.	36 months
Birth weight	Weight of newborns at delivery.	36 months
Maternal complications	Number of pregnancies with complications / number of pregnancies.	48 months
Neonatal complications	Number of live births with neonatal complications / number of live births.	48 months

Collaborators and Investigators

• Sponsor: Shandong University
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; Changhai Hospital; The First Affiliated Hospital of Anhui Medical University; The Second Hospital of Hebei Medical University; RenJi Hospital; Ruijin Hospital; The First Hospital of Jilin University; Henan Provincial People's Hospital; Sixth Affiliated Hospital, Sun Yat-sen University; The Affiliated Hospital Of Guizhou Medical University; Sir Run Run Shaw Hospital; Fujian Maternity and Child Health Hospital; General Hospital of Ningxia Medical University; Reproductive & Genetic Hospital of CITIC-Xiangya; Nanjing Maternity and Child Health Care Hospital; Jining Medical University; ShangHai Ji Ai Genetics & IVF Institute; Suzhou Municipal Hospital; International Peace Maternity and Child Health Hospital; Third Affiliated Hospital of Zhengzhou University; Shenzhen Maternity & Child Healthcare Hospital; The First Affiliated Hospital of Hainan Medical University; 900 th Hospital of Joint Logistics Support Force; Guangzhou Womenand Children's Medical Center; Liuzhou Hospital of Guangzhou Women and Children's Medical Center; Siriraj hospital, Mahidol university, Thailand
• Investigators: Study Director: Yuan Gao, Professor, Center for Reproductive Medicine, Shandong University; Principal Investigator: Ge Lin, Professor, Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA; Principal Investigator: Xiufeng Ling, Professor, Department of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital; Principal Investigator: Xiaoxi Sun, Professor, Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University; Principal Investigator: Hong Li, Professor, Center for reproduction and genetics,suzhou municipal hospital; Principal Investigator: Ruizhi Liu, Professor, Center for Reproductive Medicine, Center for Prenatal Diagnosis First Hospital, Jilin University; Principal Investigator: Songying Zhang, Professor, Assisted Reproduction Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine; Principal Investigator: Shuyun Zhao, Professor, Center for Reproductive Medicine, The Affiliated Hospital of Guizhou Medical University; Principal Investigator: Guimin Hao, Professor, The Second Hospital of Hebei Medical University; Principal Investigator: Yichun Guan, Professor, Department of Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University; Principal Investigator: Aijun Zhang, Professor, Reproductive Medical Center of Ruijin Hospital, School of Medicine,Shanghai Jiao Tong University; Principal Investigator: Wen Li, Professor, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University; Principal Investigator: Cuilian Zhang, Professor, Reproductive Medical Center, Henan Provincial People's Hospital; Principal Investigator: Yanlin Ma, Professor, The First Affiliated Hospital of Hainan Medical University; Principal Investigator: Yunxia Cao, Professor, The First Affiliated Hospital of Anhui Medical University; Principal Investigator: Beihong Zhen, Professor, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University; Principal Investigator: Junli Zhao, Professor, The General Hospital of Ningxia Medical University; Principal Investigator: Xiang Ma, Professor, The First Affiliated Hospital with Nanjing Medical University; Principal Investigator: Yun Liu, Professor, 900 th Hospital of Joint Logistics Support Force; Principal Investigator: Ling Sun, Professor, Guangzhou Womenand Children's Medical Center; Principal Investigator: Hongli Yan, Professor, Changhai Hospital; Principal Investigator: Xuemei Li, Professor, Shenzhen Maternity & Child Healthcare Hospital; Principal Investigator: Haitao Zeng, Professor, Sixth Affiliated Hospital, Sun Yat-sen University; Principal Investigator: Li Fan, Professor, Liuzhou Hospital of Guangzhou Women and Children's Medical Center; Principal Investigator: Aijun Yang, Professor, Jining Medical University; Principal Investigator: Yun Sun, Professor, Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine,Shanghai Jiao Tong University; Principal Investigator: Isarin Thanaboonyawat, Doctor, Siriraj hospital, Mahidol university, Thailand

Publications and helpful links

General Publications

• Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic testing. BMJ. 2015 Feb 19;350:g7611. doi: 10.1136/bmj.g7611.
• Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet. 1980 Oct;44(2):151-78. doi: 10.1111/j.1469-1809.1980.tb00955.x.
• Kalousek DK, Pantzar T, Tsai M, Paradice B. Early spontaneous abortion: morphologic and karyotypic findings in 3,912 cases. Birth Defects Orig Artic Ser. 1993;29(1):53-61. No abstract available.
• Rubio C, Bellver J, Rodrigo L, Castillon G, Guillen A, Vidal C, Giles J, Ferrando M, Cabanillas S, Remohi J, Pellicer A, Simon C. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017 May;107(5):1122-1129. doi: 10.1016/j.fertnstert.2017.03.011. Epub 2017 Apr 19.
• Sacchi L, Albani E, Cesana A, Smeraldi A, Parini V, Fabiani M, Poli M, Capalbo A, Levi-Setti PE. Preimplantation Genetic Testing for Aneuploidy Improves Clinical, Gestational, and Neonatal Outcomes in Advanced Maternal Age Patients Without Compromising Cumulative Live-Birth Rate. J Assist Reprod Genet. 2019 Dec;36(12):2493-2504. doi: 10.1007/s10815-019-01609-4. Epub 2019 Nov 12.
• 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.
• Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet. 2013 Mar;14(3):204-20. doi: 10.1038/nrg3354. Epub 2013 Feb 12.
• Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012 May 29;13(7):484-92. doi: 10.1038/nrg3230.
• Jiang L, Zhang J, Wang JJ, Wang L, Zhang L, Li G, Yang X, Ma X, Sun X, Cai J, Zhang J, Huang X, Yu M, Wang X, Liu F, Wu CI, He C, Zhang B, Ci W, Liu J. Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. Cell. 2013 May 9;153(4):773-84. doi: 10.1016/j.cell.2013.04.041.
• Li G, Yu Y, Fan Y, Li C, Xu X, Duan J, Li R, Kang X, Ma X, Chen X, Ke Y, Yan J, Lian Y, Liu P, Zhao Y, Zhao H, Chen Y, Sun X, Liu J, Qiao J, Liu J. Genome wide abnormal DNA methylome of human blastocyst in assisted reproductive technology. J Genet Genomics. 2017 Oct 20;44(10):475-481. doi: 10.1016/j.jgg.2017.09.001. Epub 2017 Sep 6.
• Hardarson T, Van Landuyt L, Jones G. The blastocyst. Hum Reprod. 2012 Aug;27 Suppl 1:i72-91. doi: 10.1093/humrep/des230. Epub 2012 Jul 3. No abstract available.
• Schieve LA, Meikle SF, Peterson HB, Jeng G, Burnett NM, Wilcox LS. Does assisted hatching pose a risk for monozygotic twinning in pregnancies conceived through in vitro fertilization? Fertil Steril. 2000 Aug;74(2):288-94. doi: 10.1016/s0015-0282(00)00602-6.
• Fiorentino F, Biricik A, Bono S, Spizzichino L, Cotroneo E, Cottone G, Kokocinski F, Michel CE. Development and validation of a next-generation sequencing-based protocol for 24-chromosome aneuploidy screening of embryos. Fertil Steril. 2014 May;101(5):1375-82. doi: 10.1016/j.fertnstert.2014.01.051. Epub 2014 Mar 6.
• Dahdouh EM, Balayla J, Audibert F; Genetics Committee; Wilson RD, Audibert F, Brock JA, Campagnolo C, Carroll J, Chong K, Gagnon A, Johnson JA, MacDonald W, Okun N, Pastuck M, Vallee-Pouliot K. RETIRED: Technical Update: Preimplantation Genetic Diagnosis and Screening. J Obstet Gynaecol Can. 2015 May;37(5):451-63. doi: 10.1016/s1701-2163(15)30261-9.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2022
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: June 28, 2022
• First Submitted That Met QC Criteria: June 28, 2022
• First Posted (Actual): July 1, 2022

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: PIMS-IVF

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