PRENATAL COUNSELING

Does PGS improve outcomes?

More recently, Mersereau and colleagues reported pilot results from a prospective, randomized, controlled trial that assessed whether PGS could improve pregnancy outcomes. Here, selection of infertile women for the study was not restricted to poor prognosis categories, such as advanced maternal age and recurrent pregnancy loss.

Using the live birth rate as the outcome measure, PGS for seven chromosomes was determined not to be associated with a significantly increased live birth rate among screened pregnancies. Sample sizes had been calculated to establish, with significance, a 50% increase in live births—from 30% in the control (unscreened) population to 45% in the screened population. Secondary endpoints, such as the implantation rate and pregnancy loss, also did not differ significantly between the PGS cases and controls.

Again, technical difficulties of two-blastomere biopsy, with its potential for embryo damage, and the presence of underlying embryo mosaicism represent possible barriers to improving the live birth rate when utilizing PGS.

Technical limitations may be one of the largest obstacles
to applying PGS

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

FISH probes can be chosen to reflect the nature of a given patient’s risk (advanced maternal age, recurrent pregnancy loss) when performing PGS, but the technique itself is limited by the number of probe sites that can be interpreted accurately at one time. Typically, analysis of more than five chromosomes requires two cycles of hybridization, with their associated time requirement and potential for degradation of the single cell.

Alternatively, advances in the analysis of all 23 chromosomes through comparative genomic hybridization may, ultimately, provide an avenue for applying PGS. At the moment, time limitations prohibit comparative genomic hybridization without embryo cryopreservation. Further investigation of other technical limitations, such as the high rate of mosaicism, has revealed that, when two cells are examined and found to be karyotypically discordant, further analysis of the entire embryo will reveal that more than 50% of embryos are, in fact, euploid—that is, chromosomally normal. Random biopsy of the abnormal cell solely would relegate the embryo to nontransfer, despite the predominance of an underlying euploid state.

Understanding of the potential that embryos have to self-correct early mosaicism is growing; we now know that almost one half of embryos identified as aneuploid at cleavage stage correct to euploid if they survive to blastocyst stage. A karyotypic abnormality in a single cell from a day-3 embryo does not always signal an abnormal embryo.

ASRM does not support PGS to improve the live birth rate

This determination by ASRM is based on available evidence about advanced maternal age, recurrent pregnancy loss, recurrent implantation failure, and recurrent aneuploidy loss:

• In women of advanced maternal age, many day-3 embryos display aneuploidy when studied by FISH. In theory, exclusion of these embryos for transfer should improve implantation and live birth rates, but evidence does not support that premise.
  
• Because almost 70% of spontaneous pregnancy loss is caused by a karyotypic abnormality, and women with karyotypically recurrent pregnancy loss are more likely to experience subsequent loss with karyotype abnormalities, the premise of preimplantation screening for aneuploidy also appeared to be well founded. Studies at this time are limited to retrospective series, without randomized controlled trials published.
  
• Among women who experience repeated implantation failure, a finding of more than 50% abnormal embryos isn’t uncommon, yet several studies have not supported an increased implantation rate or live birth rate after PGS.
  

A literature review of PGS calls its introduction “premature”

Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening: “established” and ready for prime time? Fertil Steril. 2008;89:780–788.

After ASRM recognized PGD as an established technique in a 2001 committee opinion, extension of this status to PGS was inadvertently assumed. But PGS is a different testing modality—with different indications, risk/benefit profiles, and efficacy than PGD.

Today, FISH probes are utilized for PGS; the false-negative rate of FISH appears to be driven by the technical constraints of the technology. Potentially increasing the false-negative rate are inadequate hybridization and the use of increasing numbers of probes and hybridization cycles.

Conversely, the false-positive rate—the number of embryos not transferred that are, in fact, chromosomally normal—varies markedly from one study to another, and may be as high as 20% when discarded embryos are more completely assessed.

Similarly, laboratories utilize different methods of obtaining the genetic material. These methods range from biopsy of polar bodies to single-cell blastomere and routine two-cell blastomere biopsy—and, more recently, to blastocyst biopsy. The impact of these various embryo manipulations has yet to be fully considered. Whether biopsy affects the embryo has received little attention.