2.Comparison of the Live Birth Rate of PGT Versus Expectant Management in Patients With RPL

• Conditions: Pregnancy Outcome; Time-to-Pregnancy
• Interventions: Procedure: undergoing PGT

• Registration Number: NCT05457335
• Lead Sponsor: Shanghai First Maternity and Infant Hospital

Brief Summary

Recurrent pregnancy loss (RPL) is a multifactorial disorder defined by the American Society for Reproductive Medicine (ASRM) as two or more clinical miscarriages (CMs). However, US guidelines differ with European guidelines which defined recurrent miscarriage as three consecutive prior pregnancy losses (The Royal College of Obstetricians and Gynaecologists Green-Top Guideline, 2011). Thus, there is currently no uniformly agreed upon definition of RPL, the ASRM recommends that a clinical evaluation for RPL commence following two early pregnancy losses, and that a threshold of three prior pregnancy losses be utilized for epidemiologic studies (The Practice Committee of the American Society for Reproductive Medicine, 2012).

Although the overall incidence of RPL is low and estimated at 5% of women (The Practice Committee of the American Society for Reproductive Medicine, 2012), it presents a significant diagnostic and treatment challenge for both patients and clinicians. Guidelines for the evaluation of patients with RPL include evaluation of the uterine cavity and blood work to determine parental karyotypes and the presence of anti-phospholipid antibodies (APLA). In at least 50% of patients, however, an etiology for RPL is not identified (Stirrat, 1990; Stephenson, 1996; Stephenson and Kutteh, 2007; The Practice Committee of the American Society for Reproductive Medicine, 2012). The ASRM recommends expectant management as the current standard of care for patients with unexplained RPL (The Practice Committee of the American Society for Reproductive Medicine, 2012). Counseling patients with unexplained RPL to pursue expectant management presents several challenges. Patients often feel an urgency to conceive and expectant management can feel like a passive and time-consuming approach to conception. In addition, patients often carry a significant amount of guilt and grief in association with miscarriage. Attempting spontaneous conception can feel emotionally vulnerable; Despite reassurance of good prognosis, patients doubt that a subsequent pregnancy will be successful (Lachmi-Epstein et al., 2012). For all of these reasons, IVF and preimplantation genetic testing (PGT) have been investigated as a treatment strategy in RPL patients with the goals of shortening time to pregnancy, decreasing CM rates and increasing live birth (LB) rates.

Detailed Description

The role of aneuploidy in CM is well known, with over 50% of pregnancy losses attributed to fetal chromosomal abnormalities (Viaggi et al., 2013). Furthermore, for patients greater than 35 years of age with RPL, fetal aneuploidy is responsible for up to 80% of first trimester losses (Marquard et al., 2010). Due to the prevalence of aneuploidy in first trimester losses and in the RPL population, PGT has been proposed as a method for reducing miscarriage by selecting only euploid embryos for transfer (Shahine and Lathi, 2014). The ultimate effect of PGT on increasing LB rates in the RPL population and the time interval to conception are areas of investigation. Current studies are largely retrospective in design with several limitations. For example: Inconsistent definitions of CM and RPL are employed. In addition, the treatment group (IVF and PGT) has been compared with a variety of control groups including IVF without PGT, a control infertile population, or to predicted LB and CM rates based on age and clinical history, but has not been compared with expectant management (Shahine and Lathi, 2014). Finally, the majority of studies report clinical outcomes only of patients who reach PGT biopsy and/or embryo transfer, so all possible cycle outcomes are not captured (Hodes-Wertz et al., 2012).

For the absence of well-designed prospective studies with high level of evidence comparing IVF and PGT to the current standard of care, expectant management, have been performed to date for the treatment of RPL patients. The objective of this study is to perform an intent to treat analysis comparing live birth rate of IVF and PGT to expectant management in fertile RPL patients in one year followed- up period.

Study Timeline

• Status Verified: 2022-07
• Study First Submitted: 2022-07-11
• Study First Submitted QC: 2022-07-11
• Last Update Submitted: 2022-07-11
• Study First Posted: 2022-07-14
• Last Update Posted: 2022-07-14
• Study Start: 2022-07-15
• Primary Completion: 2023-07-15
• Study Completion: 2024-07-15

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 280

Inclusion Criteria

• Age of women <45 years
• Two or more clinical miscarriages with identified foetal chromosomal abnormalities, or three consecutive prior pregnancy losses between 6 and 20 weeks gestational age, excluding biochemical pregnancies.

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Exclusion Criteria

• Presence of APLA including anti-cardiolipin antibody, lupus anticoagulant and b-2-glycoprotein
• Diagnosis for hypothyroidism and hyperprolactinemia with uncontrolled serum thyroid-stimulating hormone and prolactin
• Having a anomaly uterine cavity
• Abormal parental karyotypes (translocation carriers and monogenetic defect)

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Expectant management group	undergoing PGT	In the this group, one attempt at conception was defined as one calendar months trying to conceive spontaneously. Either in natural cycles for ovulatory women and in clomiphene/letrozol induced cycles for anovulatory women with or without ultrasound monitoring.
PGT-A group	undergoing PGT	For patients undergoing PGT-A, trophectoderm biopsy was performed on good quality blastocysts and about five cells were aspirated gently and separated from the blastocyst by applying multiple pulses of a noncontact 1.48- μm diode laser (Saturn 5 ActiveTM, Cooper Surgical, Inc., CT, USA) through a zona pellucida opening created by the laser. The biopsied cells were washed three times in 1 × phosphate buffered saline (PBS) (Life Technologies, NY, USA), transferred to a PCR tube containing 2.5 μl 1× PBS and cryopreserved at -80◦C until analysis. Genetic laboratories analyzed and interpreted biopsies. The genetic screening was performed using the next-generation sequencing (NGS)-based assay VeriSeq PGS following standard protocols and manufacturer recommendations (Illumina Inc., San Diego, USA）. The PGT-A report can be euploid, aneuploidy, mosaic and non-conclusive. Euploid embryos were transferred while aneuploid and mosaic embryos were not replaced.

Primary Outcome Measures

Name	Time	Method
cumulative live birth rate leading to live birth	12 Months	the ongoing status had to be achieved within 12 months since patient inclusion
time to live birth (TTLB).	24 Months	TTLB was measured as the time from patient inclusion to a live birth.

Secondary Outcome Measures

Name	Time	Method
Euploidy rate of blastocysts	30 days	the number of euploid embryos divided by the total number of blastocysts
Number of oocytes retrieved	14 days	oocytes retrieved per patient
on-going pregnancy per transfer /per PGTcycle/per attempt	3 months	viable pregnancy beyond gestation 8 weeks
Miscarriage rate	3 months	the number of miscarriages before 22 weeks per pregnancy
Cycle Cancellation rate	28 days	number of PGT cycle with no viable embryo to transfer divided by number of PGT cycle initiated
Clinical pregnancy per transfer /per PGTcycle/per attempt for natural conception	28 days	presence of intrauterine gestational sac on ultrasound
Implantation rate	28 days	number of gestational sacs per embryo transferred

Trial Locations

Locations (1)

Shanghai first Maternity and Infant health hospital, Tong Ji University; 🇨🇳 Shanghai, China