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Meta-Analysis
. 2020 Sep 8;9(9):CD005291.
doi: 10.1002/14651858.CD005291.pub3.

Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation

Affiliations
Meta-Analysis

Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation

Simone Cornelisse et al. Cochrane Database Syst Rev. .

Abstract

Background: In in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI), selection of the most competent embryo(s) for transfer is based on morphological criteria. However, many women do not achieve a pregnancy even after 'good quality' embryo transfer. One of the presumed causes is that such morphologically normal embryos have an abnormal number of chromosomes (aneuploidies). Preimplantation genetic testing for aneuploidies (PGT-A), formerly known as preimplantation genetic screening (PGS), was therefore developed as an alternative method to select embryos for transfer in IVF. In PGT-A, the polar body or one or a few cells of the embryo are obtained by biopsy and tested. Only polar bodies and embryos that show a normal number of chromosomes are transferred. The first generation of PGT-A, using cleavage-stage biopsy and fluorescence in situ hybridisation (FISH) for the genetic analysis, was demonstrated to be ineffective in improving live birth rates. Since then, new PGT-A methodologies have been developed that perform the biopsy procedure at other stages of development and use different methods for genetic analysis. Whether or not PGT-A improves IVF outcomes and is beneficial to patients has remained controversial.

Objectives: To evaluate the effectiveness and safety of PGT-A in women undergoing an IVF treatment.

Search methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2019 and checked the references of appropriate papers.

Selection criteria: All randomised controlled trials (RCTs) reporting data on clinical outcomes in participants undergoing IVF with PGT-A versus IVF without PGT-A were eligible for inclusion.

Data collection and analysis: Two review authors independently selected studies for inclusion, assessed risk of bias, and extracted study data. The primary outcome was the cumulative live birth rate (cLBR). Secondary outcomes were live birth rate (LBR) after the first embryo transfer, miscarriage rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, proportion of women reaching an embryo transfer, and mean number of embryos per transfer.

Main results: We included 13 trials involving 2794 women. The quality of the evidence ranged from low to moderate. The main limitations were imprecision, inconsistency, and risk of publication bias. IVF with PGT-A versus IVF without PGT-A with the use of genome-wide analyses Polar body biopsy One trial used polar body biopsy with array comparative genomic hybridisation (aCGH). It is uncertain whether the addition of PGT-A by polar body biopsy increases the cLBR compared to IVF without PGT-A (odds ratio (OR) 1.05, 95% confidence interval (CI) 0.66 to 1.66, 1 RCT, N = 396, low-quality evidence). The evidence suggests that for the observed cLBR of 24% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 17% and 34%. It is uncertain whether the LBR after the first embryo transfer improves with PGT-A by polar body biopsy (OR 1.10, 95% CI 0.68 to 1.79, 1 RCT, N = 396, low-quality evidence). PGT-A with polar body biopsy may reduce miscarriage rate (OR 0.45, 95% CI 0.23 to 0.88, 1 RCT, N = 396, low-quality evidence). No data on ongoing pregnancy rate were available. The effect of PGT-A by polar body biopsy on improving clinical pregnancy rate is uncertain (OR 0.77, 95% CI 0.50 to 1.16, 1 RCT, N = 396, low-quality evidence). Blastocyst stage biopsy One trial used blastocyst stage biopsy with next-generation sequencing. It is uncertain whether IVF with the addition of PGT-A by blastocyst stage biopsy increases cLBR compared to IVF without PGT-A, since no data were available. It is uncertain if LBR after the first embryo transfer improves with PGT-A with blastocyst stage biopsy (OR 0.93, 95% CI 0.69 to 1.27, 1 RCT, N = 661, low-quality evidence). It is uncertain whether PGT-A with blastocyst stage biopsy reduces miscarriage rate (OR 0.89, 95% CI 0.52 to 1.54, 1 RCT, N = 661, low-quality evidence). No data on ongoing pregnancy rate or clinical pregnancy rate were available. IVF with PGT-A versus IVF without PGT-A with the use of FISH for the genetic analysis Eleven trials were included in this comparison. It is uncertain whether IVF with addition of PGT-A increases cLBR (OR 0.59, 95% CI 0.35 to 1.01, 1 RCT, N = 408, low-quality evidence). The evidence suggests that for the observed average cLBR of 29% in the control group, the chance of live birth following the results of one IVF cycle with PGT-A is between 12% and 29%. PGT-A performed with FISH probably reduces live births after the first transfer compared to the control group (OR 0.62, 95% CI 0.43 to 0.91, 10 RCTs, N = 1680, I² = 54%, moderate-quality evidence). The evidence suggests that for the observed average LBR per first transfer of 31% in the control group, the chance of live birth after the first embryo transfer with PGT-A is between 16% and 29%. There is probably little or no difference in miscarriage rate between PGT-A and the control group (OR 1.03, 95%, CI 0.75 to 1.41; 10 RCTs, N = 1680, I² = 16%; moderate-quality evidence). The addition of PGT-A may reduce ongoing pregnancy rate (OR 0.68, 95% CI 0.51 to 0.90, 5 RCTs, N = 1121, I² = 60%, low-quality evidence) and probably reduces clinical pregnancies (OR 0.60, 95% CI 0.45 to 0.81, 5 RCTs, N = 1131; I² = 0%, moderate-quality evidence).

Authors' conclusions: There is insufficient good-quality evidence of a difference in cumulative live birth rate, live birth rate after the first embryo transfer, or miscarriage rate between IVF with and IVF without PGT-A as currently performed. No data were available on ongoing pregnancy rates. The effect of PGT-A on clinical pregnancy rate is uncertain. Women need to be aware that it is uncertain whether PGT-A with the use of genome-wide analyses is an effective addition to IVF, especially in view of the invasiveness and costs involved in PGT-A. PGT-A using FISH for the genetic analysis is probably harmful. The currently available evidence is insufficient to support PGT-A in routine clinical practice.

Trial registration: ClinicalTrials.gov NCT02268786 NCT02223221 NCT01946945 NCT01977144 NCT02032264 NCT02353364 NCT02941965 NCT03118141 NCT03173885 NCT03214185 NCT03371745.

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Conflict of interest statement

Simone Cornelisse: no conflicts to declare. Miriam Zagers: no conflicts to declare. Elena Kostova: no conflicts to declare. Kathrin Fleischer: no conflicts to declare. Madelon van Wely: no conflicts to declare. Sebastiaan Mastenbroek has performed a randomised controlled trial on the effect of PGT‐A in IVF in women aged 35 and over (Mastenbroek 2007). This was an independent trial funded by the Netherlands Organisation for Health Research and Development.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, outcome: 1.1 Cumulative live birth rate after the first treatment cycle, per woman randomised.
5
5
Forest plot of comparison: 1 IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, outcome: 1.2 live birth rate after the first embryo transfer per woman randomised.
6
6
Forest plot of comparison: 1 IVF without PGT‐A versus IVF with PGT‐A with the use of genome‐wide analyses, outcome: 1.3 Miscarriage rate per woman randomised.
7
7
Forest plot of comparison: 2 IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, outcome: 2.1 Cumulative live birth rate after the first treatment cycle, per woman randomised.
8
8
Forest plot of comparison: 2 IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, outcome: 2.2 live birth rate after the first embryo transfer per woman randomised.
1.1
1.1. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 1: Cumulative live birth rate after the first treatment cycle, per woman randomised
1.2
1.2. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 2: Live birth rate after the first embryo transfer per woman randomised
1.3
1.3. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 3: Miscarriage rate per woman randomised
1.4
1.4. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 4: Miscarriage rate per clinical pregnancy
1.5
1.5. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 5: Clinical pregnancy per woman randomised
1.6
1.6. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 6: Multiple pregnancy per woman randomised
1.7
1.7. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 7: Multiple pregnancy rate per live birth
1.8
1.8. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 8: Proportion of women reaching embryo transfer per woman randomised
1.9
1.9. Analysis
Comparison 1: IVF with PGT‐A versus IVF without PGT‐A with the use of genome‐wide analyses, Outcome 9: Mean number of embryos transferred per transfer
2.1
2.1. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 1: Cumulative live birth rate after the first treatment cycle, per woman randomised
2.2
2.2. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 2: Live birth rate after the first embryo transfer per woman randomised
2.3
2.3. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 3: Miscarriage rate per woman randomised
2.4
2.4. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 4: Miscarriage rate per clinical pregnancy
2.5
2.5. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 5: Ongoing pregnancy rate per woman randomised
2.6
2.6. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 6: Clinical pregnancy per woman randomised
2.7
2.7. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 7: Multiple pregnancy rate per woman randomised
2.8
2.8. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 8: Multiple pregnancy rate per live birth
2.9
2.9. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 9: Proportion of women reaching embryo transfer per woman randomised
2.10
2.10. Analysis
Comparison 2: IVF with PGT‐A versus IVF without PGT‐A with the use of FISH for the genetic analysis, Outcome 10: Mean number of embryos transferred per transfer

Update of

References

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Verpoest 2018 {published data only}
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References to studies awaiting assessment

NCT02223221 {unpublished data only}
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References to ongoing studies

NCT01946945 {unpublished data only}
    1. NCT01946945. Comparison of Standard ART Practice vs. Trophectoderm Biopsy and Whole Chromosome Analysis [Comparison of Standard ART Practice vs. Trophectoderm Biopsy, Whole Chromosome Analysis by Next Generation Sequencing, and Replacement of a Single Euploid Embryo]. clinicaltrials.gov/ct2/show/NCT01946945 (first received 20 September 2013).
NCT01977144 {unpublished data only}
    1. NCT01977144. Solaire [Screening of Low Responders for Aneuploidy to Improve Reproductive Efficiency]. clinicaltrials.gov/ct2/show/NCT01977144 (first received 6 November 2013).
NCT02032264 {unpublished data only}
    1. NCT02032264. Nexgen [Evaluation of the Efficacy of Next Generation Sequencing in Predicting Embryonic Karyotype and Subsequent Pregnancy Outcomes in in Vitro Fertilization Cycles (IVF)]. clinicaltrials.gov/ct2/show/NCT02032264 (first received 10 January 2014).
NCT02353364 {unpublished data only}
    1. NCT02353364. Blastocyst Euploidy Assessment and Conditioned embryO traNsfer (BEACON) [Prospective Randomised Control Trial of Blastocyst Euploidy Assessment and Conditioned Embryo Transfer for Infertility Patients of Advanced Maternal Age]. clinicaltrials.gov/ct2/show/NCT02353364 (first received 2 February 2015).
NCT02868528 {unpublished data only}
    1. NCT02868528. Prospective Randomized Controlled Study of Preimplantation Genetic Screening With Next Generation Sequencing Technology on Advanced Age Women [A Study of Preimplantation Genetic Screening With Next Generation Sequencing Technology on Advanced Age Women]. clinicaltrials.gov/ct2/show/NCT02868528 (first received 16 August 2016).
NCT02941965 {unpublished data only}
    1. NCT02941965. Preimplantation Genetic Screening in Patients With Male Factor Infertility [Preimplantation Genetic Screening in Patients With Male Factor Infertility]. clinicaltrials.gov/ct2/show/NCT02941965 (first received 21 October 2016).
NCT03118141 {unpublished data only}
    1. NCT03118141. Cumulative Live Birth Rate With eSET After Preimplantation Genetic Screening Versus Conventional In-vitro Fertilization (CESE-PGS) [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]. clinicaltrials.gov/ct2/show/NCT03118141 (first received 18 April 2017).
NCT03173885 {unpublished data only}
    1. NCT03173885. Investigating the Cryopreserved Blastocyst's ImplantatiOn Potential After Genetic Screening (BIOPS) [An RCT Evaluating the Implantation Potential of Vitrified Embryos Screened by Next Generation Sequencing Following Trophectoderm Biopsy, Versus Vitrified Unscreened Embryos in Good Prognosis Patients Undergoing IVF]. clinicaltrials.gov/ct2/show/NCT03173885 (first received 2 June 2017).
NCT03214185 {unpublished data only}
    1. NCT03214185. Effects of PGS2.0 in Patients With Unexplained RPL [Effects of Preimplantation Genetic Screening 2.0 on the Clinical Outcomes of Assisted Reproductive Treatment in Patients With Recurrent Pregnancy Loss: a Multi-center-based Prospective Randomized Clinical Trial]. clinicaltrials.gov/ct2/show/NCT03214185 (first received 11 July 2017).
NCT03371745 {unpublished data only}
    1. NCT03371745. The PrISICE Clinical Trial (Pre-Implantation Screening and Investigation on the Cryopreservation of Embryos) (PrISICE) [A Prospective, Randomized, Controlled Clinical Trial Evaluating the Superiority of Preimplantation Genetic Screening (PGS) and Deferred Transfer of Cryopreserved Embryos Over "Freeze-Only" Deferred Transfer Without PGS or Immediate Embryo Transfer During a "Fresh" In Vitro Fertilization Cycle]. clinicaltrials.gov/ct2/show/NCT03371745 (first received 13 December 2017).

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References to other published versions of this review

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