PGT-A (PGS) fails to reduce miscarriage rate in RPL

PGT-A (PGS) fails to reduce miscarriage rate in RPL

Pregnancy outcomes following in vitro fertilization frozen embryo transfer (IVF-FET) with or without preimplantation genetic testing for aneuploidy (PGT-A) in women with recurrent pregnancy loss (RPL): a SART-CORS study

doi:10.1093/humrep/deab117

Background

In 2018 the American Society for Reproductive Medicine publicly stated that there was insufficient evidence to recommend the routine use of blastocyst biopsy with aneuploidy testing in all infertile patients.

However aneuploidy is responsible for more than half of early pregnancy losses suggesting the use of IVF with PGT-A (preimplantation genetic testing for aneuploidy) may benefit women with recurrent pregnancy loss (RPL).

PGT-A is often recommended by IVF clinics to help select euploid embryos and reduce subsequent miscarriage, although there is a significant lack of high quality studies supporting this recommendation.

Aim

To assess pregnancy outcomes in women with recurrent pregnancy loss or infertility, using IVF with PGT-A compared to IVF without PGT-A.

Methodology

A large multicenter database maintained by the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System (SART-CORS) was utilised for this study.

To minimise confounding factors only autologous frozen embryo transfer (FET) cycles, from 2010 to 2016 was selected for analysis. This meant fresh IVF cycles and IVF cycles using donor oocytes were automatically excluded.

Eligible couples were divided into 3 groups;

  • Experimental group – Couples with recurrent pregnancy loss (≥ 3, ASRM) undergoing FET with PGT-A.
  • Control group 1 – Couples with recurrent pregnancy loss (≥ 3, ASRM) undergoing FET without PGT-A.
  • Control group 2 – Couples with tubal infertility undergoing FET with or without PGT-A.

Clinical pregnancy was defined by the presence of a visible intrauterine gestational sac under ultrasound while a rising beta-HCG level with no visible gestational sac was recorded as a biochemical pregnancy. Spontaneous abortion is the loss of embryo or fetus before 20 weeks gestation and live birth was defined as the delivery of a fetus showing signs of life.

Results

In total 8344 IVF-FET cycles from the PGT-A group and 4287 cycles from the control group met the inclusion / exclusion criteria for this study.

Initial analysis of patient demographic data showed some differences between the experimental group (RPL and PGT-A) and control (RPL minus PGT-A) particularly prior smoking history (35% vs. 22.4%), race, geographic region, obstetric history and indication for IVF, with the later more severe in the control group (male infertility, endometriosis, PCOS) limiting potential bias.

Preliminary analysis of outcomes showed a clear advantage of FET plus PGT-A, in women with recurrent pregnancy loss, with significantly increased live birth rates (48% vs. 34%), clinical pregnancy (59% vs. 47%) and decreased rates of spontaneous abortion (11% vs. 13%) and biochemical pregnancy (9.9% vs. 11.5%).

Interestingly in women with tubal factor infertility, FET plus PGT-A did not show any significant improvement in all outcomes; live birth, clinical pregnancy, spontaneous abortion, ectopic pregnancy or biochemical pregnancy, compared to the same women minus PGT-A and the other group of women with recurrent pregnancy loss minus PGT-A.

Advanced statistical analysis was then performed to better interpret the results according to age groups.

RPL with PGT-A vs RPL minus PGT-A (adjusted Odds ratio)

Live birthClinical pregnancySpontaneous abortion
< 35 years 1.311.260.95
35-37 years 1.451.370.85
38-40 years 1.891.680.81
41-42 years 2.622.190.86
> 42 years 3.802.310.58

Overall the adjusted regression model showed a significant increase in the odds of live birth and clinical pregnancy rates, increasing with age following FET with PGT-A in women with recurrent pregnancy loss, however no significant improvement was seen in the spontaneous abortion rate.

This result reinforces ASRM recommendations that further studies are needed to accurately define patients who will benefit the most from this technology.


SUMMARY: PGS (PGT-A) effect on miscarriage rate in recurrent pregnancy loss

In this large multicenter study, PGS (PGT-A) did not reduce the miscarriage rate in women with recurrent pregnancy loss undergoing IVF-FET, nonetheless a statistically significant increase in clinical pregnancy rates (59% vs. 47%) and live births (48% vs. 34%) per embryo transfer was seen.


Limitations

  1. Retrospective study design.
  2. Database consisted of patients undergoing IVF for other diagnoses, rather than recurrent pregnancy loss alone.
  3. Database lacked clincal details regarding cause of RPL, previous surgical treatments, adjuncts (heparin etc) during IVF or type of PGT-A testing (CGH, NGS).

Funding

No external funding was provided for this study.

Glossary

Adjuncts
Additional treatment (drug or procedure) used to increase the efficacy or safety of the primary treatment.

Adjusted regression model
Statistical modelling to estimate the relationship between a main variable and one or more independent variables.

Aneuploidy
A cell that has a chromosomal anomaly.

Autologous
Cells or tissue from the same person.

Euploid
A cell that has the normal number of chromosomes.

Odds ratio
The odds that an outcome will occur. (Odds ratio = 1.5 means the outcome is 1.5 times more likely to occur)

Similar studies

Sato T, et al. (2019). Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure. https://doi.org/10.1093/humrep/dez229

Practice Committees of the American Society for Reproductive Medicine and Society for Assisted Reproductive Technology, (2018). The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. https://doi.org/10.1016/j.fertnstert.2018.01.002

Chang J, et al. (2016). Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States Assisted Reproductive Technology Surveillance Data, 2011-2012. https://doi.org/10.1016/j.fertnstert.2015.10.018

Kushnir V A, et al. (2016). Effectiveness of in vitro fertilization with preimplantation genetic screening: a reanalysis of United States assisted reproductive technology data 2011-2012. https://doi.org/10.1016/j.fertnstert.2016.02.026

Murugappan G, et al. (2016). Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. https://doi.org/10.1093/humrep/dew135


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