PGS (pre-implantation genetic screening) is a process in which doctors test cells from an embryo with the hopes of better identifying the best embryos to transfer, and preventing the transfer of embryos that would have resulted in failed implantations, miscarriages, or offspring with chromosomal abnormalities. PGS (which is also known as comprehensive chromosomal screening or CCS) is a tool to prioritize embryos with the best chances of healthy live births.
Chromosomes are crucial components of our bodies – they contain all the information that informs our cells how to function. Imagine our chromosomes are encyclopedia volumes – we get one set of 23 volumes from our mother’s egg, and one set of 23 volumes from our father’s sperm. The different entries in those volumes are our genes, which tell our cells what to do.
Having extra or missing chromosomes can be catastrophic. Usually, for a pregnancy to proceed at all, an embryo must have the correct number of chromosomes. Otherwise it will fail to implant or lead to a miscarriage. There are exceptions for a few specific chromosomes, where a pregnancy can proceed to term with the incorrect number of chromosomes – the resulting children will have a health issue like Down Syndrome, Turner Syndrome, and a few more.
The primary goal of PGS is to predict which embryos are “euploid,” meaning they have the correct number of chromosomes, and which are “aneuploid,” having the incorrect number, so that by transferring only euploid embryos a patient has the best chances of getting pregnant, staying pregnant, and delivering a healthy child.
For almost any patient at a fertility clinic, it’s an unfortunate reality that the majority of their embryos will be abnormal. As women age, the problem becomes worse, and the chance that any given egg will combine with sperm to create a normal embryo goes down dramatically. The bottom line: there are probably lots of bad embryos we’d rather avoid transferring at any age, and especially the older we get. This is the purpose PGS is trying to serve.
The increasing rate of aneuploidy is hypothesized to be the number one driver of the age related fertility decline. As you can see in the chart below, PGS reveals a drastically decreasing number of normal embryos at every increasing age bracket. This closely mirrors what we see in IVF success rates.
PGS advocates claim PGS has “positive predictive value” meaning that when an embryo is considered by PGS-testing to be “euploid” it’s much more likely to lead to a live birth. The extent to which PGS is actually predictive depends on your clinic’s ability to capture a useful sample of the embryo and your reference laboratory’s ability to make an accurate determination. For instance, at one clinic & laboratory combination in New Jersey, 69% of embryos they considered “euploid” actually led to a live birth. At another clinic in New York, which sends its biopsies to a reference laboratory, 48% of “euploid” embryos led to a live birth. So there is very much a range in PGS’s abilities depending upon who is doing it.
And if neither of those sound very “predictive” bear in mind that when clinics make their best guess of which embryos to transfer without PGS, live birth rates per transfer range from 4% to 40%, depending on the patient’s age.
To test the embryo, an embryologist must biopsy, or cleave, a few cells off the outermost layer of an embryo. This area is called the trophectoderm and it eventually becomes the placenta. One core assumption of PGS is that the cells in this outer layer are representative of the cells in the inner cell mass, which eventually becomes the fetus.
This biopsy is generally performed on Day Five or Day Six of an embryo’s development, when it has reached the blastocyst stage, which means the embryo’s cells have differentiated into an outer layer, trophectoderm, inner cell mass, and a central cavity, rather than just a group of cells. In an earlier era of PGS testing, the biopsy happened on Day Three when embryos had fewer cells, but that’s no longer the standard of care due to a high risk of harming the embryo.
Performing an embryo biopsy takes a lot of skill (link to lab) – embryos are still small and fragile, and cleaving just the right amount of cells (5 – 7) from the right place is something embryologists must master and practice over a period of time. Collecting too few cells lowers the accuracy of the test, collecting too many harms the embryo and the truth is embryologists often don’t know how many cells they’re taking and grab a range from 3 – 20.
Once the cells have been taken, your clinic will most likely freeze your embryo and send the biopsied sample to an outside “reference lab” to be analyzed. Because there is such a small amount of DNA present in these cells, in order to predict the karyotype, or number of chromosomes, labs need to significantly amplify the DNA in the sample. The hope is that in the amplification process, things amplify proportionally, keeping the original proportion of chromosomes from the sample so the lab can accurately predict which chromosomes are present in normal, or abnormal, numbers. The technology used by the reference lab needs to be well calibrated to make sure this is done correctly. Variability of results differs meaningfully between reference labs.
The reference lab will send a report to your clinic, which will show which embryos they believe are euploid, aneuploid, or, possibly, a mix of the two.