New scientific evidence dispute the beneficial effects of PGS / PGT-A in IVF treatment

Angelica Cheng

Active Member
Many fertility clinic websites claim that PGS can improve IVF success for older women and patients with multiple IVF failures or recurrent miscarriages. However, there has recently been increasing contradictory information from different sources, which dispute the beneficial claims of PGS in IVF treatment.

Here is a summary of new scientific evidence that dispute the beneficial effects of PGS / PGT-A in IVF treatment:

1) The biopsy procedure of PGS involve extracting and sampling cells from the outer embryo layer (Trophectoderm or TE) that gives rise to the placenta. This is not representative of the inner embryo layer (Inner Cell Mass, ICM) that goes on to form the actual embryo proper, which gives rise to the baby.



2) Mosaic embryos, which are embryos with a mixture of genetically normal (euploid) and abnormal cells (aneuploid) occur quite frequently and commonly among woman undergoing IVF (17% to 48%, please see link below). PGS often leads to the misdiagnosis and discarding of mosaic embryos, which have been shown to be capable of giving rise to a normal and healthy baby.




3) There is scientific evidence that Mosaic embryos are able to “self-correct”, which increases the chances of a normal birth. This “self-correction” mechanism involve pushing out the genetically abnormal (aneuploid) cells into the outer embryo layer (TE), which gives rise to the placenta.



4) Older women with low ovarian reserves have much fewer embryos during IVF. Therefore excluding or discarding of mosaic embryos that can potentially give rise to a normal baby, would in fact substantially reduce their chances of IVF success. Some older women may have no embryos left to transfer after PGS.


5) The PGS biopsy procedure of extracting cells from the embryo can potentially harm the embryo, and impair it’s development. Experts have pointed out that studies claiming no ill effects to embryos are often based on PGS of excellent-quality, healthy, robust embryos rather than more “delicate” embryos that might suffer more. If you have just one or two embryos, you might decide it is not worth the risk.

 
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Genetic testing of IVF embryos (PGS / PGT-A) – what Singaporean patients should know

Recently, Ms Rahayu Mahzam, Parliamentary Secretary of Ministry for Health — reported that the pilot trial of genetic testing of IVF (In Vitro Fertilization) embryos in Singapore suffers from a high attrition rate of 72% (2nd March 2021). She stressed the need to proceed carefully as there is some risk to the embryo during testing.

This procedure, also known as Preimplantation Genetic Screening (PGS) or Preimplantation Genetic Testing – Aneuploidy (PGT-A), involves screening the embryos of IVF patients whom are not known to be carriers of genetic diseases, unlike the closely-related Preimplantation Genetic Diagnosis (PGD) technique, which specifically tests for known genetic defects carried by prospective parents. Hence, the pertinent question that arises is why is there such a high attrition rate?

Yet at an earlier parliamentary session on 25th February 2021, MP Cheng Li Hui, called for less restrictions to make PGS (PGT-A) more widely available to IVF patients, on the basis that this procedure screens for the correct number of chromosomes to improve the chances of conception.

Hence, Singaporean IVF patients should be made aware of the widespread controversy and accumulating scientific evidence against the medical effectiveness of PGS (PGT-A) in improving the outcome of fertility treatment in patients, whom are non-carriers of genetic diseases.

Currently, PGS (PGT-A) is readily available to Singaporean patients at most foreign fertility clinics, particularly those from neighbouring countries. Indeed, many Singaporean patients who travel abroad for fertility treatment, often end up choosing to do genetic testing of their IVF embryos, not only for sex-selection, but also to eliminate the risks of Down Syndrome in older women and improve success rates.

This is due in large part to aggressive marketing of this technique by foreign fertility clinics, which substantially increases the costs of fertility treatment from 30% to 50%. Hence, it is imperative to highlight the controversial issues surrounding this expensive technique, which Singaporean patients and healthcare policymakers should be aware of.

Currently, there is good evidence that the PGS technique is fraught with false positive misdiagnoses due to the frequent occurrence of ‘mosaic’ embryos in IVF treatment. These are embryos that have a mixture of genetically abnormal and normal cells. Recent studies have shown that such ‘mosaic embryos’ can often give rise to healthy normal babies.

To understand why this is so, imagine the human embryo as containing multiple layers of cells, with the inner layers giving rise to the baby itself, while the outer layers give rise to the placenta and umbilical cord. Indeed, many studies of normal births often detect genetic abnormalities in the placenta and umbilical cord.

This is because nature has an amazing way of correcting genetic defects during the course of normal embryo development, by gradually pushing and segregating genetically abnormal cells to the outer layers that give rise to the placenta and umbilical cord, whilst preserving the genetic integrity of the inner layers that will eventually form the baby itself.

The problem with the PGS technique is that it only extract cells from the outer layers (Trophectoderm) for genetic testing, because sampling cells from the inner layers (Inner Cell Mass that forms the baby)
incurs too much risk of damaging the embryo. Hence the high incidence of false positive misdiagnoses associated with PGS, which often lead to discarding of ‘mosaic’ embryos, many of which can in fact give rise to a normal healthy baby.

Consequently, some studies have reported that PGS in fact reduces rather than improve the cumulative chances of IVF success. Because older women and women with low ovarian reserves usually produce less embryos during each IVF treatment cycle, the discarding of ‘mosaic’ embryos could in fact have a more devastating impact on their chances of success.

For such patients with very few available embryos, every single embryo (including mosaic ones) is more ‘valuable’, and would count more to their chances of reproductive success. Just recently in Australia, a class action lawsuit was launched by patients against Monash IVF for misdiagnosis by the PGS (PGT-A) technique, which led to discarding of their viable embryos that could have otherwise led to healthy births.

Although the PGS technique is often touted to be useful for avoiding birth defects such as Down syndrome in older women, patients must be aware that it is not a foolproof means of screening for genetic defects despite its high cost.

Usually, PGS screens only for a panel of common genetic defects, which excludes many rarer genetic diseases. It is also useless for detecting more complex genetic conditions that involve interaction of multiple genes with various factors within the birth environment, such as Autism Spectrum Disorders (ASD).

Patients should also be aware that the vast majority of genetically-abnormal embryos often fail to implant upon transfer to the womb during the IVF procedure; and even those genetically abnormal embryos that do implant often spontaneously abort at very early stages e.g. biochemical pregnancy.

Hence, patients should consider more economical means of screening for birth defects, such as the new generation of Non-Invasive Prenatal Testing (NIPT), that can screen for genetic defects in fetal DNA extracted from the pregnant mother’s blood sample.

Additionally, patients must also be wary of the aggressive sales pitch and marketing gimmicks routinely used to coax patients to undertake PGS during IVF treatment abroad.

One example is how the concept of relative risks is being misrepresented to patients, to play on their fears of birth defects. For example if the risk of Down syndrome is 0.1 % at age 20, and increases to 1% at age 40 and subsequently to 4% at age 45; then another way of presenting the data would be to say that the risk of Down syndrome increases 10-folds from age 20 to 40, and 40-folds from age 20 to 45.

Hence, through a sly manipulation of words and figures, the risks of genetic defects can be ‘exaggerated’ to patients who are unfamiliar with medical statistics.

Another dubious and ethically-questionable marketing tactic is to manipulate and play on the patient’s biased preference for either a boy or girl child, which may be helped by the fact that PGS is currently the most accurate and reliable embryo sex selection technique that is available in the market.

Last but not least, patients should also be aware of the risks of damaging the embryo during the ‘highly-delicate’ PGS procedure, which involves extracting cells from the embryo after drilling a hole through the embryo shell (Zona pellucida).

The smooth performance of this technique is often highly dependent on the skill and training of the laboratory staff (Embryologist). Even with high levels of training and accreditation, there is still a possibility of human error, particularly in a very busy laboratory that handles several such cases a day.

In conclusion, there is increasing scientific evidence that cast doubts on the medical benefits of PGS (PGT-A). There are certainly good reasons why the PGS technique is so stringently regulated by the MOH here in Singapore at the present moment, which is exercising due diligence to protect the welfare of patients.

Singaporean patients traveling abroad for IVF treatment should be cautious not to be ‘pushed’ into undertaking PGS unnecessarily, by asking themselves why this technique is so severely restricted in their own country, even if it is deemed to be so beneficial by profit-driven private fertility clinics abroad.
 

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Why Assessing Genetic Normality Of IVF Embryos By AI Is A Better Option

With rapid economic growth and urbanisation in Malaysia over the past few decades, there is an increasing trend for women to delay marriage and childbearing, as they now enjoy improved educational and employment opportunities.

However, with older maternal age, there is an increasing likelihood of a woman’s eggs having an extra chromosome copy, which in turn increases the risks of spontaneous birth defects in their offspring.

Besides Down syndrome caused by an extra copy of chromosome 21, older women are also at increased risk of Edwards syndrome (extra copy of chromosome 18), Patau syndrome (extra copy of chromosome 13), and Klinefelter syndrome (extra X chromosome).


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Although such genetic defects in foetuses can be accurately diagnosed in pregnant women by non-invasive prenatal testing (NIPT), they have to face the agonising dilemma of whether or not to abort their unborn child, upon getting a positive diagnosis.

To avoid the moral dilemma and emotional trauma of abortion, it might be preferable for older women undergoing IVF (in vitro fertilisation) to screen their embryos for genetic abnormalities, before transferring them into their wombs.

This may be achieved by a highly expensive and invasive procedure known as Preimplantation Genetic Screening (PGS) or Preimplantation Genetic Testing – Aneuploidy (PGT-A).

Typically, PGS (PGT-A) increases the total IVF medical fees by around 40 to 50 per cent, so it would a lucrative business model for fertility clinics to encourage more patients to add-on this expensive procedure to their IVF treatment.

Nevertheless, patients must be wary of the aggressive sales pitch and marketing gimmicks that could be used on them.

One example is how the concept of relative risk can be misrepresented to patients to play on their fears of birth defects.

For example, if the risk of Down syndrome is 0.1 per cent at age 20, and increases to 1 per cent at age 40, and subsequently to 4 per cent at age 45, then another way of presenting the data would be to say that the risk of Down syndrome increases tenfold from age 20 to 40, and forty-fold from age 20 to 45.

Hence, through a sly manipulation of words and figures, the risks of genetic defects can be ‘exaggerated’ to patients who are unfamiliar with medical statistics.

PGS (PGT-A) is also highly invasive, as it involve drilling a hole through the embryo shell (Zona Pellucida) and extracting cells from the embryo for genetic testing (biopsy), which is potentially harmful, and can impair it’s development.

Many experts have pointed out that studies claiming no ill effects on embryos are often based on PGS (PGT-A) of excellent quality, healthy, robust embryos rather than more ‘delicate’ embryos that might suffer more.

Hence, if an IVF patient has just one or two embryos, it might not be worth taking the risk. No matter how well-trained is the lab staff (embryologist) performing this procedure, there is still a risk of human error.

The more busy the IVF lab is, the greater the risk of human error, as lab staff are under pressure to complete procedures as fast as possible.

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Another deficiency of PGS (PGT-A) is that it involves extracting and sampling cells from the outer embryo layer (Trophectoderm, TE) that gives rise to the placenta and umbilical cord.

This is not representative of the inner embryo layer (Inner Cell Mass, ICM) that goes on to form the actual embryo proper, which gives rise to the baby.

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Mosaic embryos, which are embryos with a mixture of genetically normal and abnormal cells occur quite frequently and commonly among women undergoing IVF.

Genetic testing often leads to the misdiagnosis and discarding of mosaic embryos, which have been shown to be capable of giving rise to a normal and healthy baby.

Fig4.jpg


There is scientific evidence that mosaic embryos are able to “self-correct”, which increases the chances of normal birth. This “self-correction” mechanism involve pushing out the genetically abnormal cells into the outer embryo layer, which gives rise to the placenta and umbilical cord.

Older women with low ovarian reserves have much fewer embryos during IVF. Therefore, excluding or discarding of mosaic embryos that can potentially give rise to a normal baby, would in fact substantially reduce their chances of IVF success. Some older women may have no embryos left to transfer after genetic testing.

Indeed, in neighbouring Singapore, PGS (PGT-A) is still not approved as mainstream clinical treatment
https://www.channelnewsasia.com/new...n-pre-implantation-genetic-screening-14313308, due to ambiguous results and a high attrition rate of 72 per cent in local clinical trials, as reported by the Singapore Ministry of Health in 2021.

Recently, a much cheaper and less invasive alternative to PGS (PGT-A) was announced, with groundbreaking results from an international study published in the reputable Human Reproduction journal.

A novel artificial intelligence (AI) algorithm called “Life Whisperer Genetics” was successfully developed by American health care company Presegen to accurately assess the genetic normality of embryos, based only on microscopy images.

Interestingly, Alpha IVF in Malaysia was a major collaborative partner in the development of this new reproductive technology platform, which is non-invasive, low-cost, and provides results instantly, and therefore very much preferable to the expensive, time-consuming and invasive PGS (PGT-A) technique.

According to Presagen Chief Medical Science Officer Dr Sonya Diakiw, this AI screening technique based on microscopy images alone, may not be as accurate as PGS (PGT-A) itself, which involves actual DNA sequencing.

Nevertheless, a relatively high accuracy rate of 77.4 per cent was reported in Human Reproduction.

This does not compare too badly with results from the PGS (PGT-A) technique, which themselves can be variable, due to their small sampling size.

Typically, PGS (PGT-A) only tests around five cells from a total of around 200 cells in a blastocyst-stage embryo, so it is not always representative of the entire embryo.

Hence, there is a risk of misdiagnosis of false positive and false negatives, particularly with mosaic embryos.

By contrast, the Life Whisperer Genetics AI algorithm is a whole-embryo assessment of genetic integrity that does not require any invasive procedures, which can be used to prioritise embryos for use in IVF procedures.

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Because instantaneous results can be obtained through AI screening, unlike time-consuming PGS (PGT-A) that take at least a few weeks, there is no obligatory requirement to freeze the entire batch of tested IVF embryos, while waiting for the test results.

This could be advantageous for some patients with a few weak embryos that maybe harmed by the freeze-thaw process.
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However, a current deficiency of this new technology platform is its inability to reveal the sex of the embryo, unlike conventional genetic testing with PGS (PGT-A).

It is possible that this might be remedied in the near future, with the development of new AI algorithms that could identify the sex of IVF embryos with some degree of accuracy with microscopy imaging.

Given the much lower costs and reduced risks of harming the embryo, albeit slightly less accuracy and inability to carry out sex selection, it maybe more worthwhile and cost-efficient for patients to do AI-based screening of IVF embryos, rather than actual genetic testing with PGS (PGT-A).

At the end of the day, it is up to patients to decide on the technique that will give them better value for their hard-earned money, based on their individual risk-cost-benefit analysis.
 
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