Comprehensive chromosome screening improves embryo selection A meta analysis

Capsule:
In patients with normal ovarian reserve, comprehensive chromosome screening increases clinical and sustained implantation rates, thus improving embryo selection.

Authors:
Elias M. Dahdouh, M.D., M.Sc., Jacques Balayla, M.D., Juan Antonio García-Velasco, M.D., Ph.D.

Volume 104, Issue 6, Pages 1503-1512

Abstract:

Objective:
To study whether preimplantation genetic screening with comprehensive chromosome screening (PGS-CCS) improves clinical implantation rates (IR) and sustained IR (beyond 20 weeks) compared with routine care for embryo selection in IVF cycles.

Design:
Meta-analysis of randomized controlled trials (RCTs) and observational studies (OSs).

Setting:
University-affiliated teaching hospital.

Patient(s):
Infertile couples undergoing IVF.

Intervention(s):
PGS-CCS with the use of different genetic platforms performed on polar body (PB), cleavage embryo, or blastocyst following embryo biopsy.

Main Outcomes Measure(s):
Clinical IR and sustained IR in RCTs as well as OSs comparing PGS-CCS and routine care were determined after a complete review of the literature. Pooled estimates of risk ratios (RRs) with their 95% confidence intervals (CIs) according to a fixed-effects model with the use of the Mantel-Haenszel method were calculated after the meta-analysis. Forest plots are provided for comparative purposes.

Result(s):
Out of 763 citations identified, 29 articles met initial eligibility criteria and were further analyzed. Of these, only three RCTs and eight OSs met full inclusion criteria, allowing direct comparison of PGS-CCS and routine IVF care based on embryo morphology selection. In the RCTs, all embryo biopsies were performed on day 5–6 of embryo development. In the OSs, biopsies were performed on different stages of embryo development, including PB, day 3, or day 5–6. Meta-analysis of the RCTs (3 studies; n = 659) showed that PGS-CCS was associated with a significantly higher clinical IR, with a pooled RR of 1.29 (95% CI 1.15–1.45), as well as a significantly higher sustained IR, with a pooled RR of 1.39 (95% CI 1.21–1.60). Similar findings were shown in the OSs, where the pooled RR for clinical IR was 1.78 (95% CI 1.60–1.99; 7 studies; n = 2,993) and for sustained IR was 1.75 (95% CI 1.48–2.07; 4 studies; n = 1,124). Statistical heterogeneity (I2) was minimal for RCTs and substantial among OSs.

Conclusion(s):
PGS with the use of CCS technology increases clinical and sustained IRs, thus improving embryo selection, particularly in patients with normal ovarian reserve. Results from ongoing RCTs conducted on different patient populations (e.g., decreased ovarian reserve) and different embryo stage biopsy (e.g., PB, day 3) may further clarify the role of this technology.

  • Sesh Sunkara

    This manuscript synthesising the evidence is timely given the reinvigorated interest in the “new PGS” for embryo selection with advances in technology. The manuscript
    addresses whether Preimplantation Genetic Screening by Comprehensive Chromosome Screening (PGS – CCS) improves embryo selection over routine morphological selection and meta-analysis of existing three RCTs shows a significant increase in the implantation rate (IR) with the use of PGS-CCS. We are all too aware that IR is used as a surrogate outcome in IVF studies; the correct unit of randomisation
    for any sound RCT should be per woman and anything other would render it to be
    inferior. In the context of IR as an outcome the unit of randomisation would be
    embryos transferred and as such is futile. Furthermore, focussing solely on
    embryos that are designated as euploid and as such transferred pays little
    attention to the embryos that were perhaps wrongly designated as aneuploid due
    to testing errors or where no diagnosis obtained (although this error is suggested as being low with the new techniques). Besides, in specific poor
    prognosis groups the chances of progressing to the blastocyst stage for biopsy
    is a challenge. These are but few of the technicalities in considering IR as a
    primary endpoint.

    This study highlights the all too well recognised weaknesses with meta-analysis being dependent on the robustness of the primary included studies. The authors have rightly
    acknowledged the limitations in this meta-analysis and as such we are far from
    a conclusion.

    Although initial studies demonstrate encouraging results, it is prudent to approach the role of new PGS-CCS with cautious optimism until validated by rigorous RCTs with
    clinically meaningful endpoints as outcomes. As such the starting point is to
    have a consensus on which group of women is likely to benefit, define outcomes –
    uncontested primary outcome being a singleton live birth along with others such
    as time to live birth, cumulative live births, miscarriage rates and
    cost-effective evaluation. Given the current interest there is an urgent need
    to evaluate the role of new PGS-CCS with robust multi-centred RCTs in order to
    produce a definite answer as to whether or not PGS-CCS improves the outcome of
    IVF treatment.
    Dr Sesh Kamal Sunkara & Dr Yakoub Khalaf

    • Elias Dahdouh

      We thank Dr. Sunkara and Dr. Khalaf for their interest in our recently published
      meta-analysis on CCS use for embryo selection.
      We agree that we are still far from a definitive conclusion about the true benefit of this new PGS technology for IVF outcomes.
      Though randomization was carried out on the basis of presence of blastocysts to biopsy, it is important to highlight that in the pilot study of Yang et al. 2012
      ongoing PRs (beyond 20 weeks) were improved, and in the RCT by Scott et al.
      2013 delivery rates were also increased with PGS-CCS when the same number of embryos was transferred in both CCS and control groups. In contrast, in the
      study by Forman et al. 2013, CCS dramatically decreased the multiple PR (0%)
      while maintaining same ongoing PRs (beyond 24 weeks) when 1 single euploid
      embryo was transferred in the CCS group vs. 2 untested blastocysts in the
      control group. All these data stem from patients with normal ovarian reserve
      and from IVF clinics having enough experience with embryo biopsy and where genetic analyses are carried out on a highly validated genetic platform. It is
      therefore plausible to define this category of good prognosis patients as being
      the one who might benefit from this technology. In addition, by increasing
      implantation rates and improving embryo selection, CCS might be of great
      benefit to some ART programs that are still reluctant to introduce eSET in
      their current practice.
      Results from ongoing trials on PGS-CCS for patients at risk of producing high rate of aneuploid embryos (e.g., AMA, RIF, RPL, and poor ovarian reserve patients) are urgently awaited and are expected to define patients who may or may not benefit from this technique.
      We concur with Dr. Sunkara and Dr. Khalaf in calling for a robust multicenter randomized trial on PGS-CCS before introducing this technology as routine practice. Primary outcomes must include cumulative LBR resulting for both fresh IVF cycles and at least 1 frozen transfer cycle. Standardization for genetic
      analysis, laboratory aspects, and embryo biopsy techniques should be undertaken for all IVF centers enrolled in such study. In our opinion, the aforementioned aspects are crucial for the success of any PGS-CCS program.

      Elias M. Dahdouh, MD, MSc, Jacques Balayla, MD, and Juan Antonio García-Velasco, MD, PhD

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