Cumulative Live Birth Rate With eSET After Preimplantation Methylome Screening (PMS) Versus Preimplantation Genetic Screening
Study Details
Study Description
Brief Summary
The purpose of this clinical trial is to determine the efficacy and safety of DNA methylation level in embryos during blastocyst embryo screening. Subjects with blastocysts on day 5-7 of embryo culture will be biopsied. A Freeze-all strategy and a single frozen blastocyst transfer will be performed till all study-specific embryos have been transferred. Then whole genome bisulfate sequencing will be performed on all cells that obtained from biopsy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
This is a pragmatic randomized clinical trial, the purpose of this clinical trial is to determine the efficacy and safety of DNA methylation level in embryos during blastocyst embryo screening.Subjects with blastocysts on day 5-7 of embryo culture will be biopsied.A Freeze-all strategy and a single frozen blastocyst transfer will be performed till all study-specific embryos have been transferred. Then whole genome bisulfate sequencing will be performed on all cells that obtained from biopsy. The investigators will perform bisulfate sequence for two to seven blastocysts from one couple. The methylation level and genomic copy number variation will be analyzed by using the methylome data. Embryos with aneuploid chromosomes will be rejected for embryo transfer to uterus. The investigators preliminary results indicate that the optimal level of whole-genome DNA methylation is 0.30 ± 0.02. Therefore, embryo with methylation level closest to the optimal level (from one couple patients) is the one for embryonic transfer to uterus. In the control group, euploid embryos selected by preimplantation genetic screening (PGS) will be used to transfer to uterus.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: PMS group Subjects in the PMS group will have blastocyst biopsy and whole genome bisulfate sequencing done with 2 or 7 good-quality embryos on Day 5 to 7. Principle of freeze-all and single thawed blastocyst transfer will be applied. The transfer order of euploid embryos will be determined by DNA methylation level.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: DNA methylation level
Embryo with methylation level closest to the optimal level (from one couple patients) is the one for embryonic transfer to uterus
Procedure: blastocyst biopsy and sequencing
All blastocysts will be biopsied on trophectoderm, sequenced with next-generation sequencing (NGS). Euploidy will transferred one by one according to morphologic score.
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| Active Comparator: PGS group Subjects in the PGS group will have blastocyst biopsy and sequencing done with 2 or 7 good-quality embryos on Day 5 to 7. 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 biopsy and sequencing
All blastocysts will be biopsied on trophectoderm, sequenced with next-generation sequencing (NGS). Euploidy will transferred one by one according to morphologic score.
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Outcome Measures
Primary Outcome Measures
- Cumulative live birth rate [22 months]
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.
Secondary Outcome Measures
- Rate of Good Birth Outcomes [22 months]
Number of good birth outcomes / number of clinical pregnancies over (up to) 3
- Cumulative pregnancy rate [14 months]
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.
- Cumulative pregnancy loss rate [19 months]
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.
- Duration of pregnancy [22 months]
The time from the first day of last menstrual period to the day of delivery.
- Birth weight [22 months]
Weight of newborns at delivery.
- Cumulative incidence of maternal complications during whole [22 months]
Number of pregnancies with complications / number of pregnancies over (up to) 3 transfers within 1 year;
- Cumulative incidence of neonatal complications during whole [22 months]
Number of live births with neonatal complications / number of live births over (up to)3 transfers within 1 year
- Number of embryo transfers to achieve live birth [22 months]
Number of embryo transfers the patients have gone through to achieve live birth.
Other Outcome Measures
- Clinical pregnancy rate after the first transfer [4 months]
Number of women with clinical pregnancies after the first transfer / number of women randomized to the specific group.
- Pregnancy loss rate after the first transfer [9 months]
Number of pregnancy losses / number of clinical pregnancies after the first transfer .
- Live birth rate after the first transfer [12 months]
Number of women with live births after the first transfer / number of women randomized to the specific group.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Women who are participating in preimplantation screening with PGS indications,defined as maternal age above 38 years, repeated implantation failure (RIF) usually defined as three or more transfers of morphologically high-quality embryos without the establishment of pregnancy, recurrent miscarriage (RM) in patients with normal karyotypes (usually at least three previous consecutive miscarriages) and severe male factor infertility (usually defined as abnormal semen parameters).
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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 five of embryo culture will be randomized.
Exclusion Criteria:
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Women with a uterine cavity abnormality, such as a uterine congenital malformation (uterus unicornate, bicornate, or duplex); untreated uterine septum, adenomyosis, submucous myoma, or endometrial polyp(s); or with history of intrauterine adhesions.
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Women with untreated hydrosalpinx.
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Women who use donated oocytes or sperm to achieve pregnancy.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Shandong University | Jinan | Shandong | China |
Sponsors and Collaborators
- Chen Zi-Jiang
- Chinese Academy of Sciences
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic testing. BMJ. 2015 Feb 19;350:g7611. doi: 10.1136/bmj.g7611. Review.
- Chen ZJ, Shi Y, Sun Y, Zhang B, Liang X, Cao Y, Yang J, Liu J, Wei D, Weng N, Tian L, Hao C, Yang D, Zhou F, Shi J, Xu Y, Li J, Yan J, Qin Y, Zhao H, Zhang H, Legro RS. Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. N Engl J Med. 2016 Aug 11;375(6):523-33. doi: 10.1056/NEJMoa1513873. Erratum in: N Engl J Med. 2016 Nov 17;375(20):2010.
- 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, Vallée-Pouliot K. Technical Update: Preimplantation Genetic Diagnosis and Screening. J Obstet Gynaecol Can. 2015 May;37(5):451-63. Review.
- 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.
- 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.
- 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.
- 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. Review.
- 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.
- 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.
- 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.
- Shi Y, Sun Y, Hao C, Zhang H, Wei D, Zhang Y, Zhu Y, Deng X, Qi X, Li H, Ma X, Ren H, Wang Y, Zhang D, Wang B, Liu F, Wu Q, Wang Z, Bai H, Li Y, Zhou Y, Sun M, Liu H, Li J, Zhang L, Chen X, Zhang S, Sun X, Legro RS, Chen ZJ. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med. 2018 Jan 11;378(2):126-136. doi: 10.1056/NEJMoa1705334. Erratum in: N Engl J Med. 2021 Nov 4;385(19):1824.
- 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. Review.
- PMS-PGS