Clinical trial NCT05442125: First Live Birth Rate With eSET After Preimplantation Methylome Screening (PIMS) Versus Conventional In-vitro Fertilization
Official title: Whether Using DNA Methylome to Select Embryos Can Increase the Live Birth Rate During Assisted Reproductive Technology: A Multicenter, Randomized , Open-label Clinical Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Reproductive Techniques, Assisted
DNA Methylation
Lead sponsor: Shandong University
Sponsor class: OTHER
Collaborators: name: RenJi Hospital
name: Reproductive & Genetic Hospital of CITIC-Xiangya
name: Nanjing Maternity and Child Health Care Hospital
name: ShangHai Ji Ai Genetics & IVF Institute
name: Suzhou Municipal Hospital
name: The First Hospital of Jilin University
name: Sir Run Run Shaw Hospital
name: The Affiliated Hospital Of Guizhou Medical University
name: The Second Hospital of Hebei Medical University
name: Third Affiliated Hospital of Zhengzhou University
name: Ruijin Hospital
name: International Peace Maternity and Child Health Hospital
name: Henan Provincial People's Hospital
name: The First Affiliated Hospital of Hainan Medical University
name: The First Affiliated Hospital of Anhui Medical University
name: Fujian Maternity and Child Health Hospital
name: General Hospital of Ningxia Medical University
name: The First Affiliated Hospital with Nanjing Medical University
name: 900 Hospital of Joint Logistics Support Force of PLA
name: Guangzhou Womenand Children's Medical Center
name: Changhai Hospital
name: Shenzhen Maternity & Child Healthcare Hospital
name: Sixth Affiliated Hospital, Sun Yat-sen University
name: Liuzhou Hospital of Guangzhou Women and Children's Medical Center
name: Jining Medical University
name: Siriraj hospital, Mahidol university, Thailand
First posted: 2022-07-01
Enrollment: 1146
Sex: FEMALE
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: live birth rate of initial embryo transfer
timeFrame: 22 months
Secondary outcomes:
measure: Good Birth Outcome rate
timeFrame: 36 months
measure: Clinical pregnancy rate
timeFrame: 36 months
measure: Pregnancy loss rate
timeFrame: 36 months
measure: Multiple pregnancy rate
timeFrame: 36 months
measure: Duration of pregnancy
timeFrame: 36 months
measure: Birth weight
timeFrame: 36 months
measure: Maternal complications
timeFrame: 48 months
measure: Neonatal complications
timeFrame: 48 months
Other outcomes:
Locations:
city: Jinan
country: China
facility: Shandong University
state: Shandong
city: Changchun
country: China
facility: Center for Reproductive Medicine, Center for Prenatal Diagnosis First Hospital, Jilin University
city: Changsha
country: China
facility: Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA
city: Fuzhou
country: China
facility: 900 th Hospital of Joint Logistics Support Force
city: Fuzhou
country: China
facility: Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University
city: Guanzhou
country: China
facility: Guangzhou Womenand Children's Medical Center
city: Guanzhou
country: China
facility: The Sixth Affiliated Hospital of Sun Yat-sen University
city: Guiyang
country: China
facility: Center for Reproductive Medicine, The Affiliated Hospital of Guizhou Medical University
city: Haikou
country: China
facility: The first affiliated hospital of Hainan Medical University
city: Hangzhou
country: China
facility: Assisted Reproduction Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
city: Jinan
country: China
facility: Center for Reproductive Medicine, Shandong University
city: Jining
country: China
facility: Affiliated Hospital of Jining Medical University
city: Liuzhou
country: China
facility: Liuzhou Hospital of Guangzhou Women and Children's Medical Center
city: Nanjing
country: China
facility: Department of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
city: Shanghai
country: China
facility: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine,Shanghai Jiao Tong University
city: Shanghai
country: China
facility: Changhai Hospital
city: Shanghai
country: China
facility: International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University
city: Shanghai
country: China
facility: Reproductive Medical Center of Ruijin Hospital, School of Medicine,Shanghai Jiao Tong University
city: Shanghai
country: China
facility: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
city: Shenzhen
country: China
facility: Shenzhen Maternity & Child Healthcare Hospital
city: Shijiazhuang
country: China
facility: The Second Hospital of Hebei Medical University
city: Suzhou
country: China
facility: Center for reproduction and genetics,suzhou municipal hospital
city: Yinchuan
country: China
facility: The General Hospital of Ningxia Medical University
city: Zhengzhou
country: China
facility: Department of Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University
city: Zhengzhou
country: China
facility: Reproductive Medical Center, Henan Provincial People's Hospital
city: Bangkok
country: Thailand
facility: Siriraj hospital, Mahidol university
Study officials:
affiliation: Center for Reproductive Medicine, Shandong University
name: Yuan Gao, Professor
role: STUDY_DIRECTOR
affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine,Shanghai Jiao Tong University
name: Yun Sun, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-XIANGYA
name: Ge Lin, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital
name: Xiufeng Ling, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
name: Xiaoxi Sun, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for reproduction and genetics,suzhou municipal hospital
name: Hong Li, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for Reproductive Medicine, Center for Prenatal Diagnosis First Hospital, Jilin University
name: Ruizhi Liu, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Assisted Reproduction Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
name: Songying Zhang, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Center for Reproductive Medicine, The Affiliated Hospital of Guizhou Medical University
name: Shuyun Zhao, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: The Second Hospital of Hebei Medical University
name: Guimin Hao, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Reproductive Medicine, the Third Affiliated Hospital of Zhengzhou University
name: Yichun Guan, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Reproductive Medical Center of Ruijin Hospital, School of Medicine,Shanghai Jiao Tong University
name: Aijun Zhang, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University
name: Wen Li, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Reproductive Medical Center, Henan Provincial People's Hospital
name: Cuilian Zhang, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Hainan Medical University
name: Yanlin Ma, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Anhui Medical University
name: Yunxia Cao, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University
name: Beihong Zhen, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: The General Hospital of Ningxia Medical University
name: Junli Zhao, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital with Nanjing Medical University
name: Xiang Ma, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: 900 Hospital of Joint Logistics Support Force of PLA
name: Yun Liu, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Guangzhou Womenand Children's Medical Center
name: Ling Sun, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Changhai Hospital
name: Hongli Yan, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Shenzhen Maternity & Child Healthcare Hospital
name: Xuemei Li, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Sixth Affiliated Hospital, Sun Yat-sen University
name: Haitao Zeng, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Liuzhou Hospital of Guangzhou Women and Children's Medical Center
name: Li Fan, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Jining Medical University
name: Aijun Yang, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Siriraj hospital, Mahidol university, Thailand
name: Isarin Thanaboonyawat, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic testing. BMJ. 2015 Feb 19;350:g7611. doi: 10.1136/bmj.g7611.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.