NCT03642574

Brief 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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
182

participants targeted

Target at P75+ for not_applicable

Timeline
Completed

Started Sep 2018

Longer than P75 for not_applicable

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

August 16, 2018

Completed
6 days until next milestone

First Posted

Study publicly available on registry

August 22, 2018

Completed
14 days until next milestone

Study Start

First participant enrolled

September 5, 2018

Completed
3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 28, 2021

Completed
10 months until next milestone

Study Completion

Last participant's last visit for all outcomes

June 30, 2022

Completed
Last Updated

October 4, 2022

Status Verified

October 1, 2022

Enrollment Period

3 years

First QC Date

August 16, 2018

Last Update Submit

October 1, 2022

Conditions

DNA Methylation

Keywords

Preimplantation Methylome ScreeningPreimplantation Genetic Screeningsingle embryo transfercumulative live birth rate

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (6)

  • The effect of DNA methylation level on pregnant rate, pregnant loss rate.

    22 months

  • Duration of pregnancy

    22 months

  • Birth weight

    22 months

  • Cumulative incidence of maternal complications during whole

    22 months

  • Cumulative incidence of neonatal complications during whole

    22 months

  • +1 more secondary outcomes

Other Outcomes (3)

  • Clinical pregnancy rate after the first transfer

    4 months

  • Pregnancy loss rate after the first transfer

    9 months

  • Live birth rate after the first transfer

    12 months

Study Arms (1)

PIMT methylation

EXPERIMENTAL

Subjects will have blastocyst biopsy and whole genome DNA methylation 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. Only embryos with euploid chromosome will be transfered to the uterus. The outcome of all euploids transfers within 1 year will be followed up. During study, every subject will have at most one live birth.

Procedure: CNV

Interventions

CNVPROCEDURE

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

PIMT methylation

Eligibility Criteria

Age20 Years+
Sexfemale
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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).
  • 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.

You may not qualify if:

  • 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.
  • Women with untreated hydrosalpinx.
  • Women who use donated oocytes or sperm to achieve pregnancy.
  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Shandong University

Jinan, Shandong, China

Location

Related Publications (12)

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

    PMID: 25697663BACKGROUND

  • 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.

    PMID: 7316468BACKGROUND

  • 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.

    PMID: 26168107BACKGROUND

  • 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.

    PMID: 8280893BACKGROUND

  • 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.

    PMID: 23400093BACKGROUND

  • 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.

    PMID: 22641018BACKGROUND

  • 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.

    PMID: 23663777BACKGROUND

  • 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.

    PMID: 29037989BACKGROUND

  • 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.

    PMID: 10927046BACKGROUND

  • 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.

    PMID: 24613537BACKGROUND

  • 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.

    PMID: 29320646BACKGROUND

  • 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.

    PMID: 27509101BACKGROUND

Study Design

Study Type
interventional
Phase
not applicable
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Professor

Study Record Dates

First Submitted

August 16, 2018

First Posted

August 22, 2018

Study Start

September 5, 2018

Primary Completion

August 28, 2021

Study Completion

June 30, 2022

Last Updated

October 4, 2022

Record last verified: 2022-10

Locations

CN(1)