Understanding PGS: A Critical Examination of Preimplantation Genetic Screening

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Embarking on the fertility journey is a deeply personal experience, fraught with complex decisions. One such decision is whether to use Preimplantation Genetic Screening (PGS), or as it’s now called, PGT-A (Preimplantation Genetic Testing for Aneuploidies). Touted for its ability to screen for chromosomal abnormalities in embryos, PGS promises improved chances of a successful pregnancy. However, my own journey, coupled with extensive research, has convinced me that this technology is not yet ready for widespread use and is being misappropriately applied.

In IVF treatments, PGS tests a few cells from a specific part of the blastocyst, known as the trophectoderm. The trophectoderm is the outer layer of the embryo that eventually forms the placenta, which is essential for supplying nutrients to a growing baby in the womb. PGS aims to use these few cells to predict the health of the entire embryo.

However, this approach has significant limitations. Embryos are highly complex, and their cells can vary significantly—a condition known as mosaicism. Mosaicism means that within the same embryo, some cells can be normal (euploid) while others may have abnormalities (aneuploid). Since PGS tests only a few cells from the trophectoderm, there’s a real risk that these cells don’t represent the entire embryo accurately.

For example, an embryo might have some abnormal cells in the trophectoderm but could still have a perfectly healthy inner cell mass, which is the part of the embryo that develops into the baby itself. Unfortunately, because PGS focuses on the cells destined to become the placenta, it might lead to discarding embryos that could have developed into healthy babies. 

One of the pioneers of IVF, Dr. Norbert Gleicher, and his colleagues have published case studies documenting healthy ongoing pregnancies and one healthy live birth after transferring aneuploid embryos. In another study, it was shown that mosaic embryos can have a fairly high rate of ongoing pregnancy and live birth, being only marginally worse than euploid embryos.

Using the numbers from the graph above, could you imagine throwing away a mosaic embryo with a 40–44% chance of ongoing pregnancy or live birth when the chance for a euploid embryo is just 52%? Even with more complex mosaics, where the live birth rate drops to 13–25%, that’s not no chance of success, especially if you are someone who doesn’t make a lot of embryos.

The reality is that embryos have some ability to self-correct and allow for euploid cells to take over. Yet, of the 200–300 cells in a blastocyst sent off for PGS testing, only about 5 cells are selected to be tested. It is absolutely insane to think that this could be representative of the embryo, especially when it is only the trophectoderm being tested.

A review of 26 studies looking at the consistent between multiple PGS tests on the same embryo found that 19% of aneuploids were no longer aneuploid with a second biopsy, 7% of euploid were no longer euploid, and 58% of mosaic were no longer mosaic.

This means that many women have what could be perfectly viable embryos discarded as being aneuploid when they really were mosaic with potential for self-correction. The PGS test is a roll of the dice on what cells are selected for testing. You have no actual way of knowing the health status of the embryo at this stage.

The below image illustrates this concept quite nicely. If you have a mosaic embryo with variable numbers of euploid and aneuploid cells, the PGS result depends entirely on which cells are selected to be analyzed. Expectedly, as the prior study showed, the results of analysis can change substantially upon a second biopsy that looks at a different set of cells.

Thus, while PGS aims to increase the chance of a healthy pregnancy by selecting embryos without genetic abnormalities, it also potentially rejects embryos that have a mix of cell types—possibly lowering the overall chance of achieving a live birth due to the self-correcting nature of many of these mosaic embryos. 

This issue of discarding potentially healthy embryos based on limited cell sampling is especially critical for older women. As women age, their embryos are more likely to exhibit aneuploidy and complex mosaicism. Older women also tend to produce fewer embryos per IVF cycle, making each embryo’s potential value higher. By relying on PGS and possibly discarding embryos that show any signs of mosaicism, we risk eliminating embryos that could have developed into healthy babies. This not only reduces their chances of success per cycle but also may necessitate additional, physically and financially demanding retrieval cycles.

There’s also a dearth of scientific investigation looking at how the PGS biopsy affects embryonic development, something noted in a 2016 review article. Since then, two studies published in 2019 and 2021 suggested that the sustained implantation rate between tested and untested embryos was similar, suggesting that the embryos weren’t harmed in a way that would affect the possibility of giving birth to a healthy baby.

However, a 2024 study suggested that a second PGT biopsy reduced the likelihood of clinical pregnancy (30 vs 52%) and live birth (22% vs 33%) compared to just having one biopsy.

Beyond that, a 2024 study in mice found that trophectoderm biopsy, as is done in PGS testing, resulted in unwanted changes in DNA and gene activity in both the placentas and the embryos compared with IVF alone and compared with natural conception. These changes affected the structure and blood supply of the placenta. Even twelve weeks after birth, the young mice from these embryos had higher levels of blood sugar, insulin, and triglycerides compared to those born through standard IVF or naturally.

To summarize, PGS testing has significant limitations due to the complexity of embryos and a condition known as mosaicism, where embryos contain a mix of normal and abnormal cells. This can lead to potentially healthy embryos being discarded if the few tested cells from the trophectoderm are abnormal, despite the possibility that the inner cell mass, which develops into the baby, may be healthy. Studies and case examples have shown that embryos, including those labeled as abnormal or mosaic, can sometimes self-correct, making the limited cell sampling used in PGS not wholly representative of the embryo’s potential. 

This is particularly problematic for older women who have fewer embryos, as discarding one based on partial data could decrease their chances of a successful pregnancy and necessitate further taxing retrieval cycles. Recent research indicates that the biopsy required for PGS can cause significant changes in DNA and gene activity, potentially affecting the embryo’s development and leading to altered physiological conditions in offspring, highlighting the invasive nature and potential risks associated with this procedure.

PGS Doesn’t Eliminate Risks

Even if you transfer PGS-tested euploid embryos, this does not guarantee a complication-free pregnancy or a child free from genetic disorders. Despite the reassurances provided by a euploid diagnosis, several genetic and developmental risks remain that PGS cannot detect or mitigate.

Firstly, chromosomal abnormalities can occur at any point during cell division and development, even after the stage at which the embryo is biopsied for PGS. This means that new abnormalities can arise after the cells have been tested, potentially leading to complications that were not evident during the early screening. Additionally, not all genetic disorders are linked to the number of chromosomes. There are numerous single-gene disorders, such as cystic fibrosis or sickle cell anemia, which are caused by mutations in specific genes rather than an overall chromosomal abnormality. PGS does not screen for these types of genetic issues, as it only assesses chromosomal normality.

The use of PGS does not eliminate the need for further prenatal testing. Techniques such as NIPT, amniocentesis, NT scan, and chorionic villus sampling are still crucial and are recommended for obtaining a comprehensive understanding of the fetus’s health. These tests can detect a range of genetic abnormalities that PGS cannot, providing essential information that can influence pregnancy management and outcomes.

I don’t think these points are communicated clearly and readily by clinics and doctors pushing for PGS testing. It does not provide complete assurance against genetic disorders and developmental issues, nor does it cover all types of genetic testing needed for a thorough assessment of fetal health.

You aren’t free of miscarriage risk, either.

Miscarriages can result from a variety of factors undetectable by PGS, such as genetic mutations affecting individual genes or other developmental issues that arise as the embryo continues to grow and divide. These later-stage mutations and abnormalities can compromise the viability of the pregnancy, despite the initial healthy prognosis given by PGS. For instance, I have experienced two late first-term miscarriages where everything seemed to be developing perfectly until it abruptly wasn’t.

Additionally, factors external to the embryo’s genetic makeup also play a significant role in the continuation of a healthy pregnancy. These include maternal health issues such as hormonal imbalances, immune system responses, and anatomical problems with the uterus, none of which are assessed by PGS.

Basically, while PGS is a valuable tool for reducing the likelihood of chromosomal-related miscarriages, it is not a comprehensive solution. The tool does not address many genetic and non-genetic factors that can critically impact embryo development and pregnancy outcomes. I’m not convinced the risk to the embryos is worth the small potential benefit.

All of these points are illustrated in a randomized controlled trial from 2019 involving over 600 women. There were no differences in clinical outcomes between women who opted for PGS testing and those who didn’t—same rates of ongoing pregnancy (46–50%), miscarriage (9.6–9.9%), and biochemical (8.3–10.6%).

PGS testing can provide a false sense of security. Worse, you can end up throwing away viable embryos thinking that you are shortening the time it takes to have a baby, which may ironically end up making the entire process take longer (and cost more money for both the testing and retrievals).

The Ethics of PGS

The final thing I want to touch on with PGS testing is the ethical considerations. I’m not a fan of PGS testing for the reasons already discussed, but I don’t think that there is anything ethically problematic with it.

Critics often equate PGS with eugenics due to its role in selecting embryos based on genetic characteristics, which can invoke historical abuses where eugenics was misused to infringe upon reproductive rights and promote discriminatory practices. However, the intent and application of PGS today merit a more balanced consideration.

The primary ethical defense of PGS-M (Preimplantation Genetic Screening for monogenic disorders) lies in its aim to reduce the incidence of debilitating and potentially lethal genetic disorders. From this perspective, PGS-M can be viewed as a proactive approach to healthcare, where potential parents seek to spare their offspring from severe genetic conditions that could lead to miscarriage or significant disability. This approach is less about creating ‘perfect’ offspring and more about reducing suffering and enhancing the quality of life.

From a clinical standpoint (as opposed to theoretical), ensuring ethical application of PGS involves clear communication about what it can and cannot do, avoiding over-promises regarding the outcomes, and ensuring that decisions are made based on accurate and comprehensive genetic counseling. This helps ensure that the use of PGS is based on realistic expectations and a deep understanding of the potential impacts, both medically and emotionally.

Conclusion: Caution and Transparency

PGS, designed to screen for chromosomal abnormalities in embryos, promises enhanced pregnancy success rates but comes with significant scientific limitations. The technology tests only a few cells from the trophectoderm, the embryo’s outer layer, which may not accurately represent the overall health of the embryo. Such limited sampling can lead to the discarding of potentially healthy embryos, particularly affecting older women who produce fewer embryos.

Studies indicate that embryos can sometimes self-correct, making the decision to discard based on initial PGS findings questionable. There’s also potential that biopsy procedures used in PGS could lead to detrimental changes in DNA and gene activity, underscoring the procedure’s invasive nature and potential to harm embryo development.

Despite a euploid diagnosis from PGS, numerous risks remain unchecked. Chromosomal abnormalities can develop post-biopsy, and PGS does not screen for single-gene disorders like cystic fibrosis. Therefore, additional prenatal testing remains essential. The technology also does not mitigate the risk of miscarriage, which can result from genetic mutations and maternal health issues not detectable by PGS. 

One of the largest randomized controlled trials investigating PGS testing found that it did not improve rates of live birth, ongoing pregnancy, or miscarriage compared to women who did not test their embryos, challenging the efficacy of PGS in improving clinical outcomes.

Ethically, while PGS echoes historical eugenics in selecting embryos based on genetic traits, its modern application aims to prevent severe genetic diseases rather than pursue genetic perfection. The goal is to reduce suffering and enhance life quality, distancing its intent from eugenics’ abusive history. However, ethical application requires clear communication about PGS’s capabilities and limitations, ensuring decisions are well-informed.

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