Cumulative Live Birth Rate With eSET After Preimplantation Genetic Screening Versus Conventional In-vitro Fertilization

Study Overview
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Brief Summary
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The purpose of this randomized clinical trial is to compare the efficacy and safety with transfer of embryos selected by next generation sequencing (NGS) versus conventional morphological criteria. Subjects with 3 or more blastocysts on day 5 of embryo culture will be randomized to the PGS or IVF group. A Freeze-all strategy and a single frozen blastocyst transfer will be performed in both PGS and IVF groups. The primary outcome is the cumulative live birth after transfers of up to 3 single blastocycsts in both groups.

Detailed Description
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This is a multicenter, randomized clinical trial comparing the efficacy and safety with transfer of embryos selected by next generation sequence (NGS) and morphologic criteria versus by morphological criteria alone. Subjects who obtain 3 or more good-quality blastocysts will be randomized to PGS or IVF group. All embryos will be frozen and a single thawed blastocyst will be transferred in both PGS and IVF group. Subjects in the PGS group will have 3 blastocysts sequenced and euploid embryos will be subsequently transferred. Subjects in the IVF group will have blastocysts selected by morphology assessment. The cumulative live birth rate will be counted after transfers of all euploid embryo in the PGS group and 3 blastocysts in the IVF group within 1 year after randomization.

Official Title
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Cumulative Live Birth Rate With eSET After In-vitro Fertilization With Preim-plantation Genetic Screening by Next Generation Sequencing Versus Conventional In-vitro Fertilization: A Pragmatic Randomized Controlled Clinical Trial

Conditions
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Infertility

Intervention / Treatment
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* Procedure: blastocyst morphologic score
* Procedure: blastocyst biopsy and sequencing
* Procedure: freeze-all and single thawed blastocyst transfer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who are participating in their first cycle of IVF or ICSI Women ages 20 to 37 years. Women who obtain 3 or more good-quality blastocysts 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 will be randomized. Exclusion Criteria: Women with a uterine cavity abnormality, such as a uterine congenital malformation (uterus uni-cornate, bicornate, or duplex); untreated uterine septum, adenomyosis, submucous myoma, or endo-metrial polyp(s); or with history of intrauterine adhesions. Women with untreated hydrosalpinx; Women who are indicated and planned to undergo PGD, for example, parental abnormal karyo-type or diagnosed with monogenic disease; 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 se-rum liver enzyme testing); renal disease or abnormal serum renal function; significant anemia; history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident; uncontrolled hyper-tension, known symptomatic heart disease; history of or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma; undiagnosed vaginal bleeding.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PGS group<br>Subjects in the PGS group will have blastocyst biopsy and sequencing done with 3 good-quality embryos on Day 5. 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 morphologic score<br>* Blastocysts will be scored by Gardner morphologic criteria.<br>Procedure: blastocyst biopsy and sequencing<br>* Three blastocysts will be biopsied on trophectoderm, sequenced with next-generation sequencing (NGS). Euploidy will transferred one by one according to morphologic score.<br>Procedure: freeze-all and single thawed blastocyst transfer<br>* All blastocysts will be vitrified in fresh cycle. Single blastocyst will be thawed and transferred.<br>|
| Active Comparator: IVF group<br>Subjects in the IVF group will also comply with the principle of freeze-all and single thawed blastocyst transfer. The order of transfer will be determined by blastocyst morphologic score. The outcome of up to 3 transfers within 1 year after randomization will be followed up. During study, every subject will have at most one live birth. | Procedure: blastocyst morphologic score<br>* Blastocysts will be scored by Gardner morphologic criteria.<br>Procedure: freeze-all and single thawed blastocyst transfer<br>* All blastocysts will be vitrified in fresh cycle. Single blastocyst will be thawed and transferred.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative live birth rate | 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. | 22 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Good Birth Outcomes | Number of good birth outcomes / number of clinical pregnancies over (up to) 3 transfers within 1 year.Good Birth Outcome is defined as live birth of an infant born at ≥ 37 weeks, with a birth weight between 2500 and 4000g and without a major congenital anomaly. | 22 months | 
| Cumulative pregnancy rate | 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. | 14 months | 
| Cumulative pregnancy loss rate | 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. | 19 months | 
| Multiple pregnancy rate | Number of multiple pregnancies / number of clinical pregnancies over (up to) 3 transfers within 1 year. | 22 months | 
| Duration of pregnancy | The time from the first day of last menstrual period to the day of delivery. | 22 months | 
| Birth weight | Weight of newborns at delivery. | 22 months | 
| Cumulative incidence of maternal and neonatal complications during whole gestation and prenatal stage | Number of pregnancies with complications / number of pregnancies over (up to) 3 transfers within 1 year;number of live births with neonatal complications / number of live births over (up to)3 transfers within 1 year. | 22 months | 
| Number of embryo transfers to achieve live birth | Number of embryo transfers the patients have gone through to achieve live birth. | 22 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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preimplantation genetic screening, single embryo transfer, frozen embryo transfer, cumulative live birth rate