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

Shanghai First Maternity and Infant Hospital,

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pregnancy Outcome; Time-to-Pregnancy
• Intervention / Treatment: Procedure: undergoing PGT

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 Type: Observational
• Enrollment (Anticipated): 280

Contacts and Locations

• Study Contact: Name: Zhi Qin Chen, MD; Phone Number: 2078 86-21-540355206; Email: ptchen1@hotmail.com
• Study Contact Backup: Name: Hong Chen, MD; Phone Number: 2345 86-21-540355206; Email: 765230197@qq.com

Study Locations

• China
  • Shanghai, China, 200051
    • Shanghai first Maternity and Infant health hospital, Tong Ji University
    • Contact: Zhi Qin Chen, Master; Phone Number: 2012 86-21-54035206; Email: ptchen1@hotmail.com
    • Contact: Hong chen, Master; Phone Number: 2012 86-21-54035206; Email: charrychin@51mch.com
    • Principal Investigator: Zhi Qin Chen, MD
    • Sub-Investigator: Hong Chen, MD
    • Principal Investigator: Shi Hua Bao, MD
    • Sub-Investigator: Guo hua Li, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infertile women who have medical indication attending the Assisted Reproduction clinic, Shanghai First Maternity and Infant Hospital for IVF will be recruited for study after explanation and counseling if they fulfill the inclusion criteria and do not have the exclusion criteria.

Description

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.

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PGT-A group; 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.	Procedure: undergoing PGT; Preimplantation genetic testing for aneuploidy
Expectant management group; 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.	Procedure: undergoing PGT; Preimplantation genetic testing for aneuploidy

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	: multiple pregnancy, ectopic pregnancy, ,pelvic infection, fetal or congenital defects, obstetric complications, birth weight of babies	2 years

Collaborators and Investigators

• Sponsor: Shanghai First Maternity and Infant Hospital
• Investigators: Principal Investigator: Zhi Qin Chen, MD, Shanghai first maternty and infant hospital

Publications and helpful links

General Publications

• Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999 Nov;14(11):2868-71. doi: 10.1093/humrep/14.11.2868.
• Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT Jr. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013 Jul;100(1):100-7.e1. doi: 10.1016/j.fertnstert.2013.02.056. Epub 2013 Mar 30.
• Lachmi-Epstein A, Mazor M, Bashiri A. [Psychological and mental aspects and "tender loving care" among women with recurrent pregnancy losses]. Harefuah. 2012 Nov;151(11):633-7, 654. Hebrew.
• Marquard K, Westphal LM, Milki AA, Lathi RB. Etiology of recurrent pregnancy loss in women over the age of 35 years. Fertil Steril. 2010 Sep;94(4):1473-1477. doi: 10.1016/j.fertnstert.2009.06.041. Epub 2009 Jul 30.
• Murugappan G, Ohno MS, Lathi RB. Cost-effectiveness analysis of preimplantation genetic screening and in vitro fertilization versus expectant management in patients with unexplained recurrent pregnancy loss. Fertil Steril. 2015 May;103(5):1215-20. doi: 10.1016/j.fertnstert.2015.02.012. Epub 2015 Mar 13.
• Perfetto CO, Murugappan G, Lathi RB. Time to next pregnancy in spontaneous pregnancies versus treatment cycles in fertile patients with recurrent pregnancy loss. Fertil Res Pract. 2015 Apr 21;1:5. doi: 10.1186/2054-7099-1-5. eCollection 2015.
• Shahine L, Lathi R. Recurrent pregnancy loss: evaluation and treatment. Obstet Gynecol Clin North Am. 2015 Mar;42(1):117-34. doi: 10.1016/j.ogc.2014.10.002.
• Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996 Jul;66(1):24-9.
• Stirrat GM. Recurrent miscarriage. Lancet 1990;336:673- 675. The PracticeCommittee of the American Society for ReproductiveMedicine. Evaluation and Treatment of Recurrent Pregnancy Loss: A Committee Opinion. Feril Steril 2012;98:1103 - 1111
• Regan L, Backos M, Rai R. The Royal College of Obstetricians and Gynaecologists. The RCOG Green-Top Guideline No. 17. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage. 2011
• Viaggi CD, Cavani S, Malacarne M, Floriddia F, Zerega G, Baldo C, Mogni M, Castagnetta M, Piombo G, Coviello DA, Camandona F, Lijoi D, Insegno W, Traversa M, Pierluigi M. First-trimester euploid miscarriages analysed by array-CGH. J Appl Genet. 2013 Aug;54(3):353-9. doi: 10.1007/s13353-013-0157-x. Epub 2013 Jun 19.

Study record dates

Study Major Dates

• Study Start (Anticipated): July 15, 2022
• Primary Completion (Anticipated): July 15, 2023
• Study Completion (Anticipated): July 15, 2024

Study Registration Dates

• First Submitted: July 11, 2022
• First Submitted That Met QC Criteria: July 11, 2022
• First Posted (Actual): July 14, 2022

Study Record Updates

• Last Update Posted (Actual): July 14, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: preimplantation genetic testing; live birth rate; expectant management
• Other Study ID Numbers: shanghai first maternity

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No