Preimplantation Genetic Screening (PGS): PGS is the process whereby the chromosomes in the cells of an embryo (or the polar body of an egg) are examined (karyotyped). Embryo cells that have all 46 chromosomes intact are termed euploid. Those with additional chromosomal material and those with deficient chromosomal material are aneuploid. In younger women, euploid embryos have better than a 50% chance of propagating a viable pregnancy. The chances in women >39y decreases slowly over time but regardless of the woman’s age is still around 40%. For those that conceive using such embryos, the miscarriage rate is well below 10%.
Embryo aneuploidy and “mosaicism”. While most embryo aneuploidy (>70%) originates from aneuploidy that occurs during reproductive division (meiosis) of either the egg or the sperm, the vast majority of cases are egg related. Such meiotic aneuploidy is irreversible and is responsible for >80% of IVF failures and early miscarriages. In contrast, in some cases where both the egg and sperm are euploid and upon fertilization propagate a euploid fertilized egg (zygote), during subsequent mitosis where the embryos cells multiply, some undergo “mutation” and become aneuploid while the majority maintain euploid division. This is referred to as embryo “mosaicism”. Upon reaching the uterine environment, mosaic embryos have the potential to leach out their aneuploid blastomeres, while allowing the euploid cells to multiply in an orderly fashion. This results in autocorrection and in most cases, in the subsequent development of a normal, euploid conceptus/baby.
Since some mitotically aneuploid (“mosaic”) embryos can, and indeed do “autocorrect’ while meiotically aneuploid embryos cannot, it follows that an ability to reliably differentiate between these two varieties of aneuploidy would potentially be of considerable clinical value. The introduction of a variety of preimplantation genetic screening (PGS) known as next generation gene sequencing (NGS) has vastly improved the ability to reliably and accurately karyotype embryos and thus to diagnose embryo “mosaicism”.
The ability of “mosaic embryos” to autocorrect is influenced by the stage at which the condition is diagnosed as well as the percentage of mosaic cells. Many embryos diagnosed as being mosaic while in the earlier cleaved state of development, subsequently undergo autocorrection to the euploid state (normal numerical chromosomal configuration) during the process of undergoing subsequent mitotic cell to the blastocyst stage. Similarly, mosaic blastocysts can also undergo autocorrection after being transferred to the uterus. The lower the percentage of mosaic cells in the blastocyst the greater the propensity to autocorrect and propagate chromosomally normal (euploid) offspring. By comparison, a blastocyst with 10% mosaicism could yield a 30% healthy baby rate with 10-15% miscarriage rate, while with >50% mosaicism the baby rate is roughly halved and the miscarriage rate double.
I advise all patients who subsequently conceive after undergoing ET using such “potentially mosaic” embryos to undergo prenatal genetic testing to rule out the development of an aneuploid fetus so that they can terminate affected pregnancies if they so choose.
Should PGS be done routinely in IVF? When Levent Keskintepe and I first introduced PGS testing into the clinical IVF arena (2005) initial results were most-encouraging. Embryo implantation rates of >50% and birth rates of 50-60% when up to two euploid blastocysts were transferred, were being reported. In addition, the reported incidence of miscarriages and chromosomal birth defects was likewise greatly reduced. In fact, we were so encouraged that most of us predicted that a time would come where full embryo karyotyping through PGS would become a routine part of IVF. But alas…..we were soon to be disappointed when following the widespread introduction of PGS testing success rates started dropping. This was especially the case when PGS was performed on embryos derived from the eggs of older women and women with severely diminished ovarian reserve (DOR). With further investigation it began to dawn upon us that:
- Chromosomal numerical integrity, while being the most important determinant of embryo “competency” was likely not the only factor that impacted embryo “competency”. Indeed advancing age was revealed to increase the incidence of embryo aneuploidy, independent of embryo karyotype and this is probably linked to non-chromosomal, genetic and metabolomic factors that might also be age-related.
- Independent of embryo competency, there are many variables, that can and also do determine IVF outcome and these are often outside the control of the embryology/genetic laboratory. They include selection and implementation of individualized protocols for controlled ovarian stimulation (COS), endometrial factors that determine embryo implantation (e.g. anatomical an immunologic implantation dysfunction), technical skill of the physician performing embryo transfer etc.
- Not all PGS-aneuploid embryos are “incompetent”. Some are mosaic (see elsewhere) and these are often capable of “autocorrecting” upon being transferred to the uterus, and propagating healthy babies. In my experience, embryos that have additional or deficient chromosomal material affecting only one of the 23 chromosome pairs, are the ones most likely to be “mosaic”, while those that have absence or addition of chromosomal material involving several chromosome pairs, are almost always meiotically aneuploid
Against this background, it is my considered opinion that PGS-embryo selection only be considered in the following circumstances:
- Women over the age of 39Y and those who, regardless of age have significant DOR, are running out of eggs and time, and need to “make hay while the sun shines”!
- Unexplained IVF failure.
- Certain cases of recurrent pregnancy loss (RPL).
- Family gender balancing cases
- Women who have alloimmune implantation dysfunction (IID) with activation of uterine natural killer cells (NKa)…see elsewhere.
- Where karyotyping reveals one or other partner to have a balanced chromosomal translocation
- Known or anticipated specific genetic abnormalities
PGS for Gender Selection and Family balancing. Nevertheless, It is an inescapable reality that the very idea of medical sex selection challenges moral and ethical beliefs at their very foundation. Many hold that the growing popularity of gender selection solely for the convenience of altering a family’s gender balance represents an unwanted example of how assisted reproductive technology is subject to abuse…and thus it should be outlawed. They also see it as an example of a disturbing trend towards “designer babies” where genetic engineering could be used to manipulate the intellect, body configuration, build, height, and the talents of future offspring. This assertion is commonly followed by the tantalizing question as to where all this would end and whether we as a society “would really want to live in such a world.” There is, however, one clear exception to the apparent across-the-board opposition to sex selection that is well worthy of mention. This applies in cases where sex selection is used to avoid the occurrence of a serious medical disorder that selectively affects one gender or the other (e.g., Hemophilia, a life threatening bleeding disorder that selectively affects male offspring).PGD using comparative genomic hybridization (CGH) next generation gene sequencing (NGS) which assesse all the embryo’s chromosomes can be used for both detecting all the embryo’s chromosomes and thus can determine embryo “competency” reliably. It also reliably identifies gender.
Sex selection done purely for family balancing is somewhat controversial, raising concern that if widely accessible and freely available, such practice could distort the natural sex ratio, leading to a population gender imbalance. However, for this to happen, there would have to be a significant population preference for sex selection. In reality, the contrary seems to apply, since studies conducted in western societies discount these concerns. In fact, the relatively high cost of IVF with the added cost of gender selection in the United States makes it unlikely that the demand would ever become large enough to impact overall population gender balance. In addition, several studies done in Western countries have shown that the majority of people do not seem to be concerned about the gender of their offspring, and that with a few notable exceptions, gender preference does not appear to be slanted in the direction of either male or female. Thus, from a practical standpoint, such concerns are overstated.
Given that in the United States most couples do not care about the gender of their offspring, and only a minority are interested in selecting the sex of their children there is currently no risk that IVF sex-selection will impact the population gender balance. Thus, in my opinion by and large, freedom of choice should prevail and a service for sex selection should be freely available
So, I absolutely do offer gender selection in the following circumstances.
- Medical Indications for Gender Selection:
- For cases associated with
- Sex-linked genetic disorders or,
- Serious genetic disorders that are more likely to occur in one gender or the other.
- Family balancing
- For couples who have at least one child of the opposite gender to that which they choose for their IVF embryo transfer and,
- For those women who do not have any children at all but prefer to have a child of one or the other gender.
- For cases associated with