COMMENTARY

Preimplantation Genetic Screening Associated With Increased Pregnancy Rates

Peter Kovacs, MD, PhD

Disclosures

May 05, 2015

Impact of Blastocyst Biopsy and Comprehensive Chromosome Screening Technology on Preimplantation Genetic Screening: A Systematic Review of Randomized Controlled Trials

Dahdouh EM, Balayla J, Garcia-Velasco JA
Reprod Biomed Online. 2015;30:281-289

Background

At least three things are required for a successful pregnancy during in vitro fertilization (IVF): a healthy embryo, a receptive endometrium, and careful transfer at the proper time in the cycle. IVF has improved significantly in its almost 40-year history. Different types of gonadotropins have been developed that are easier to administer and are associated with an improved safety profile. In addition, numerous stimulation protocols are available that allow us to individually tailor treatments. For example, ultrasound-guided embryo transfer using soft catheters has resulted in atraumatic transfer of embryos into the uterus.[1] Tests can also be used to evaluate the receptivity of the endometrium in order to determine the best time to schedule the transfer.

Despite all these improvements, however, implantation and pregnancy rates with IVF only slowly increase year after year.[2]

The rate-limiting step of IVF is implantation. It requires the proper interaction of a healthy embryo and a receptive endometrium. It often fails due to problems with the embryos. The genetic health of the embryo depends on both its inherited genetic material and on the errors and repairs during the cell divisions. A chromosomally abnormal embryo is unlikely to implant, and when it does it is likely to be lost early on.

Various methods of genetic testing of embryos have been evaluated in past decades. One can test the chromosome content of the polar bodies, but a cleavage-stage embryo (day 3 of development) or a blastocyst-stage embryo can be evaluated as well. In addition, various techniques (fluorescence in situ hybridization [FISH] and comprehensive chromosome screening using different genetic platforms) are available for assessing the chromosomes. However, earlier studies using day 3 biopsy and FISH analysis have not confirmed the expected improvement in IVF outcome.[3,4] This has led to the development of new technologies that have addressed the shortcomings of these earlier tests.

Summary

The authors considered all published randomized trials that used day 5 blastocyst biopsy (trophectoderm biopsy) and comprehensive chromosome screening. After careful review of the literature, three eligible randomized trials were evaluated.[5,6,7]

Yang and colleagues[5] included young (< 35 years) patients with good prognoses in their trial and randomly assigned them to day 5 single blastocyst transfer following either testing by array comparative genomic hybridization or selection based on morphology alone. The mean number of oocytes was 19.5 and the mean number of blastocysts was 8.3. The pregnancy rate was significantly higher in the group in which genetic screening was performed (70.9% vs 45.8%).

Scott and associates[6] randomly assigned women to day 5 transfer after morphology-based selection versus day 6 transfer following genetic screening. Women under the age of 42 (mean age, 32.2 years) with presumed good prognosis were enrolled. The mean number of oocytes was 17.2 and the mean number of blastocysts was 8. Ongoing pregnancy rates were significantly higher in the experimental group when compared with the control group (66.4% vs 47.9%).

Forman and coworkers[7] recruited women under age 43 (mean age, 35.1 years) with normal ovarian function and a presumed good prognosis. In the group with chromosome screening, a single euploid blastocyst was transferred, while in the control group, two blastocysts were selected based on morphology. The mean number of oocytes was 16.9 and the mean number of blastocysts was 5.8. The pregnancy rate was similar in the two groups (60.7% vs 65.1%) but almost half of the pregnancies were twins in the control group while there were no multiples in the experimental group.

The authors of the systematic review concluded that comprehensive genetic screening of embryos using day 5 blastocyst biopsy is associated with increased implantation and pregnancy rates. In addition, this technology appears to be a good tool to limit the number of embryos transferred.

Viewpoint

It seems logical that genetic screening of embryos and the transfer of only euploid embryos should result in improved clinical outcome. Early studies mostly used cleavage-stage biopsy (day 3) and FISH technique to analyze 5-11 chromosomes. Randomized trials, however, have not found a benefit and indeed some found a decline in pregnancy rates.[3,4] This was explained by the harmful effects of cleavage-stage biopsy, the inability to test all chromosomes, and the relatively high rate of mosaicism at that developmental stage.[8]

With the availability of newer technologies, it became a reality to evaluate all chromosomes. The delay of the biopsy to day 5 allows sampling of the trophectoderm and provides more cells for analysis. The rate of mosaicism is much lower at this stage, too. Unless one has a lab in house, however, the embryo needs to be cryopreserved and transferred subsequently in a frozen embryo transfer cycle. The technology is also rather expensive, so a recommendation for routine use requires careful consideration.

The indications for preimplantation genetic testing are discussed in this review as well. Most authorities recommend genetic testing of embryos in women with advanced reproductive age, recurrent implantation failure, recurrent pregnancy loss, or severe male factor infertility. The ability to select a single embryo for transfer is a more recent potential indication.

On the basis of the available evidence, the technology of day 5 biopsy with comprehensive chromosome screening is effective in young, good-prognosis patients. The mean age of the participant was 35 or under in all three studies. They all produced an above-average number of eggs and blastocysts so they represent a rather select group of infertile women. The typical patient is less "ideal," though; the typical patient produces fewer eggs and blastocysts and may not have a cohort of embryos to choose from but has enough for a single transfer.

It also must be pointed out that the results were generated in labs with well-above-average qualities. Therefore, the results cannot be applied directly to an average IVF laboratory. In addition, in the study by Scott and colleagues, the genetic lab was in-house, so the embryo transfer could take place in the fresh cycle. This is not the case for the majority of IVF centers, where the testing is done off-site.

It also would be interesting to compare whether, in good-prognosis patients, the transfer of an untested fresh or untested frozen-thawed blastocyst, or a genetically screened blastocyst, is more cost-effective.

There are still many unanswered questions. Given the currently published evidence, we can conclude that in high-responder, young patients, the use of preimplantation genetic screening at the blastocyst stage improves clinical outcome and can help embryo selection for single embryo transfer.

Abstract

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