Fertility Blog

Comprehensive Chromosome Screening

Comprehensive Chromosome Screening: Selecting Healthy Embryos

Comprehensive chromosome screening (CCS) is an exciting new tool in the field of assisted reproductive technology (ART). We make CCS available to our patients who are undergoing in vitro fertilization (IVF). Previously known as pre-implantation genetic screening (PGS), CCS can screen embryos for genetic problems prior to implantation. This helps ensure the transfer of the highest quality embryos.

By doing so, CCS helps:

  • Improve IVF pregnancy rates
  • Allow for elective single embryo transfer (eSET), which reduces the risk of multiple births
  • Minimize the risks of miscarriage and chromosomal abnormalities such as Down syndrome

The goal of IVF is to identify with the greatest accuracy the embryo(s) that will lead to the birth of healthy babies, one at a time. Fortunately, a wide range of technological advances has contributed to the overall success of CCS, making it superior to previous methods used.

An Earlier Method of Embryo Selection
Traditionally, physicians have selected an embryo by examining it microscopically and assigning a quality grade based on its physical appearance (morphology). Refinements in morphologic grading have improved pregnancy rates and reduced multiple gestations, but this method is far from perfect.

Low pregnancy rates. In 2010, the Society of Assisted Reproductive Technology (SART) reported implantation rates using this method. They ranged from 10 percent in women 41 years and older to 37 percent in those younger than 35.1 Even in donor oocyte cycles, pregnancy rates averaged only about 56 percent. This means that the majority of embryos considered appropriate for transfer based on morphologic criteria do not result in live births.

2 Besides implantation failure, aneuploidy accounts for up to 60 percent of first trimester miscarriages and 5 percent of live births in women older than 40.

Unintended consequences. Physicians needed to correct for this problem and increase the chance that at least one embryo would have the correct number of chromosomes (euploidy) with have a better chance of implantation. So they embraced the practice of transferring more than one embryo at a time. An unintended consequence of this practice, however, was pregnancy with twins and triplets, which can be harmful to the mother and the babies.

A better method of embryo selection was sorely needed.

The History of Chromosomal Screening
The sound concept of screening embryos for chromosomal abnormalities prior to implantation has been around for almost a decade. The goal has always been to increase pregnancy rates and lower the risk of miscarriage or having a baby with Down syndrome by transferring only embryos with the correct number of chromosomes.

Cleavage-stage screening. An early method of chromosomal screening involved evaluating embryos at 2–3 days of development (cleavage stage) using single cell chromosomal analysis. However, early results were disappointing. Randomized control trials showed no clinical benefit.3,4

Disappointing results. Despite its promise, these early attempts did not achieve the desired outcome of improving pregnancy rates for IVF for 3 main reasons:

  • First, cleavage-stage embryos have a 30 percent chance of being mosaic. This means that not all of the cells of the embryo have the same chromosomes. Sampling a single cell can lead to a result that is not representative of the whole embryo.
  • Second, chromosomal analysis using fluorescence in-situ hybridization (FISH) is only possible for a select number of chromosomes. It will miss some abnormalities.
  • Third, taking 1–2 cells from a cleavage-stage embryo with only 6–10 cells total can inadvertently harm the embryo and affect its development.

Improvements in Screening with CCS
Over the past couple of years, advances in the fields of molecular genetics and embryology have helped to overcome each of these challenges.

Most importantly, we can now test all 23 pairs of chromosomes in one setting using advanced molecular genetic techniques that are highly sensitive and can reliably give us the exact number of chromosomes within each embryo.

Blastocyst stage. We are now able to culture embryos to day 5–6 of development (the blastocyst stage). At this stage, the chance of mosiacism is only 3 percent. This greatly improves the predictive value of the genetic testing.

Given that each blastocyst may have more than 100 cells, they are also much more resilient and can better withstand removal of cells (biopsy). This improves the implantation potential of a biopsied embryo.

However, the advent of blastocyst biopsy and new screening methods introduced yet another clinical challenge: The turnaround time for biopsy results is at least 12–24 hours, meaning the uterine lining (endometrium) has already passed its receptive window by the time the results become available.

Fortunately, we can “freeze” embryos at their current developmental stage using the method of vitrification, while we wait for the biopsy results. This doesn't compromise the integrity of the embryos. We can then rewarm the vitrified embryo for transfer at a later, more ideal, time for implantation.

Superior results. Multiple studies published within the past two years have demonstrated clearly superior outcomes in IVF cycles with CCS compared to those not using CCS:

  • The implantation rate of a biopsy-proven euploid blastocyst ranges from 41–72 percent, depending upon the age of the woman.5,6
  • The miscarriage rates range from 10–18 percent and are significantly lower than expected in women of a similar age.

PFC's experience. We started performing CCS at PFC in the fall of 2011 using the genetic lab, Natera (formerly Gene Security Network). Natera uses a single nucleotide polynorphism (SNP) microarray with a proprietary technology called Parental Support.

Since January of this year, we have transferred 38 biopsy-proven euploid embryos in 33 frozen embryo transfer cycles. Most of those patients elected to transfer only one embryo. Our results are comparable to published literature. Our overall implantation rate (including all age groups) is 73.7 percent, ranging from 33–88 percent, depending upon the women’s age (see Figure 1).

By contrast, the implantation rate of untested frozen embryos during the same time period was 54 percent for all age groups, ranging from 25–66 percent (Figure 1).

Although we still need to gather more data on cycle outcomes, our preliminary experience has shown that we have mastered the technical skills necessary to perform CCS and that we have been able to achieve comparable, if not better, results than those published by other major fertility centers in the country.

What is more exciting, however, is the benefit this technology can bring to our patients. We are finally one step closer to helping families to conceive, one healthy baby at a time.

- Liyun Li, MD
PFC Physician

***References***1[https://www.sartcorsonline.com/rptCSR\_PublicMultYear.aspx?ClinicPKID=0](https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0) 2Munné S et al. Maternal age, morphology, development, and chromosome abnormalities in over 6000 cleavage-stage embryos. *Reprod Biomed Online*, 2007;14: 628–634 3 Mastenbroek S et al. In vitro fertilization with preimplantation genetic screening. *N Engl J Med*, 2007;357:9–17. 4Hardarson T et al. Preimplantation genetic screening in women of advanced maternal age caused a decrease in clinical pregnancy rate: a randomized controlled trial. *Hum Reprod*, 2008;23:2806–2812. 5 Schoolcraft W et al. Clinical application of comprehensive chromosomal screening at the blastocyst stage. *Fertil Steril*, 2010;94:1700–1706. 6 Forman E et al. Single embryo transfer with comprehensive chromosome screening results in improved ongoing pregnancy rates and decreased miscarriage rates. *Jr.Hum Reprod*. 2012: 27:1217–1222.
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