Preimplantation DNA Methylation Test (PIMT) in ART

DNA Methylation Clinical Trial

Official title:

Cumulative Live Birth Rate With eSET After Preimplantation DNA Methylation Test (PIMT) in ART

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03642574
• Other study ID #: PIMT
• Status: Completed
• Phase: N/A
• Start date: September 5, 2018
• Est. completion date: June 30, 2022

Study information

• Verified date: October 2022
• Source: Shandong University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical trial is to determine the safety and effect of methylation level of DNA methylation in embryos on the outcome of assisted reproductive technology (ART) 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.

Description:

The purpose of this clinical trial is to determine the safety and affect of DNA methylation level on ART. 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 whole genome DNA methylation 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 study will examine which kind of methylation level can produce the best clinical outcome for ART. Biopsied cells will perform with preimplnatation DNA methylation test (PIMT). DNA methylation level and chromosome copy number variation will be calculated by using whole genome DNA methylation sequencing data. As we do not kown which kind of methylation state can produce the best outcome in ART practice. This study will try to find a standard of selection embryos according to DNA methylation information. Under current stage, the selection of embryo is according to chromosome copy number. The embryo selection will not consider DNA methylation information for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 182
• Est. completion date: June 30, 2022
• Est. primary completion date: August 28, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

1. 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).

2. 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:

1. 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.

2. Women with untreated hydrosalpinx.

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.

Related Conditions & MeSH terms

• DNA Methylation

Intervention

Procedure:
• CNV
Embryo with euploid chromosome will transfer to uterus. The order of transfer is accroding to morphological grade.

Locations

Country	Name	City	State
China	Shandong University	Jinan	Shandong

Sponsors (2)

Lead Sponsor	Collaborator
Chen Zi-Jiang	Chinese Academy of Sciences

Country where clinical trial is conducted

China, 

References & Publications (12)

Brezina PR, Kutteh WH. Clinical applications of preimplantation genetic testing. BMJ. 2015 Feb 19;350:g7611. doi: 10.1136/bmj.g7611. Review. — View Citation

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. — View 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, Vallée-Pouliot K. RETIRED: Technical Update: Preimplantation Genetic Diagnosis and Screening. J Obstet Gynaecol Can. 2015 May;37(5):451-63. Review. — View 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. — View 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. — View 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. — View 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. Review. — View 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. — View 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. — View 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. — View Citation

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. — View 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. Review. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Clinical pregnancy rate after the first transfer	Number of women with clinical pregnancies after the first transfer / number of women.	4 months
Other	Pregnancy loss rate after the first transfer	Number of pregnancy losses / number of clinical pregnancies after the first transfer .	9 months
Other	Live birth rate after the first transfer	Number of women with live births after the first transfer / number of women.	12 months
Primary	The effect of DNA methylation level on live birth rate	The rate of live birth at different methylation level will be calculated. Live birth is defined as the delivery of any viable infant at 28 weeks or more of gestation, and cumulative live birth rate is calculated by dividing the number of women achieving live birth after transfers (up to 3 transfers of single blastocycst within 1 year).	22 months
Secondary	The effect of DNA methylation level on pregnant rate, pregnant loss rate.	The rate of pregnant and pregnant loss at different methylation level will be calculated. Pregnancy loss refers to a complete spontaneous abortion or a nonviable pregnancy before 28 weeks of gestation.	22 months
Secondary	Duration of pregnancy	The time from the first day of last menstrual period to the day of delivery.	22 months
Secondary	Birth weight	Weight of newborns at delivery.	22 months
Secondary	Cumulative incidence of maternal complications during whole	Number of pregnancies with complications / number of pregnancies over (up to) 3 transfers within 1 year;	22 months
Secondary	Cumulative incidence of neonatal complications during whole	Number of live births with neonatal complications / number of live births over (up to)3 transfers within 1 year	22 months
Secondary	Number of embryo transfers to achieve live birth	Number of embryo transfers the patients have gone through to achieve live birth.	22 months