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

Study Overview
=================
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.

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.

Conditions
-----------------
Reproductive Techniques, Assisted, DNA Methylation

Intervention / Treatment
-----------------
* Other: Using DNA methylome to select embryos
* Other: Using morphologic score to select embryos


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women who plan to undergo IVF/ICSI/PGT-A treatment. 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 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. Women who are indicated and planned to undergo preimplantation genetic testing for structural rearrangements (PGT-SR) or preimplantation genetic testing for monogenic (PGT-M). 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.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PIMS group<br>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<br>* DNA methylation level Embryo with methylation level closest to the optimal level (from one couple patients) is the one for embryonic transfer to uterus<br>|
| Active Comparator: Conventional-IVF group<br>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<br>* 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.<br>|

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 |