Is PGS / PGT-A really necessary for an egg donation cycle? Why not do Genetic Testing on the egg donor's blood sample?

A couple of months ago, before all the coronavirus lockdowns, me and my husband visited and inquired about egg donation at three Malaysian IVF clinics. All 3 clinics strongly advocated that we should use PGS / PGT-A with egg donation. They told us that because it is difficult to verify whether the anonymous egg donor has a family history of genetic diseases, we should play safe by using PGS / PGT-A. Apparently, the only information about the donor's family heath history comes from a Questionnaire form that is filled by the donor herself, and the reliability of such information cannot be guaranteed. Additionally, these IVF clinics also attempted to hard-sell PGS / PGT-A by touting the use of the procedure for sex selection, and trying to play on our biased preference for either a boy or girl.

However, I became skeptical when I came across a newspaper article in Today Online entitled: “Overseas egg donors — what Singaporean women should be wary of”. The article suggested that similar genetic tests on the egg donor's blood sample is a much cheaper alternative to PGS / PGT-A for screening the presence of defective genes carried by the prospective egg donor. What I understand is that there is much more DNA genetic material within a blood sample containing thousands of white blood cells, as compared to just a few cells from an embryo biopsy during the PGS/PGT-A procedure, which makes it easier and cheaper to do genetic testing. This made me wonder why none of the 3 clinics that I visited bothered to suggest genetic testing of blood samples. Could this because they wanted to earn extra money from the PGS / PGT-A procedure, rather than doing what is best for the patient? If that is the case, I am extremely angry that the clinics played on our fears of potential genetic defects carried by the anonymous egg donor.

Here is an excerpt from the article:
https://www.todayonline.com/commentary/overseas-egg-donors-what-singaporean-women-should-be-wary

Other claims may have less scientific basis. For example, many foreign fertility clinics strongly encourage their patients undergoing egg donation to utilise preimplantation genetic screening (PGS) to detect genetic defects in the conceived embryos, due to the unknown genetic heritage of the anonymous foreign egg donor. Yet they often neglect to tell patients that similar genetic screening of the donor’s blood sample is much cheaper than PGS.

Patients must also be aware that PGS is not a fool-proof method to detect genetic abnormalities in embryos, despite its high costs.There is a only a limited panel of common genetic diseases that PGS will detect, so it is impossible to screen and verify the entire genome of each individual embryo to be free of genetic defects. One notable example that cannot be detected by PGS is Autism Spectrum Disorders that are caused by multiple genes interacting with multiple factors within the birth environment. Additionally, if the egg donor is very young, it is unnecessary to utilise PGS to screen for Down syndrome that usually arises from genetic abnormalities in the eggs of older women.

Although many fertility clinics claim that PGS can improve the IVF success rates of older women, this only refers to older women using their own eggs, which have a high incidence of genetic abnormalities. PGS will not improve the success rates of older women using a young egg donor.

It must also be noted that PGS is not completely risk-free. There is a small chance of damaging the embryo as this delicate procedure involves drilling a hole through its protective shell (zona), to extract cells for genetic testing.


 

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Here are some interesting video podcasts that cast doubts on the necessity of utilizing PGS / PGT-A in egg donation cycles:


 
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In Malaysia, egg donors are required do blood tests for HIV, HepB and Syphylis at the IVF clinic itself. That is precisely why I am wondering why the IVF clinic cannot just collect extra blood samples for genetic testing at the same time. When I visited those IVF clinics, I was still ignorant so I did not ask about genetic tests on the egg donor's blood sample. It was only after reading the above article that I realized that IVF clinics may be deliberately trying to downplay this alternative option to PGS. It is no wonder that the MOH in Singapore is so strict in banning PGS / PGT-A in private IVF clinics, and allowing only a strictly-regulated clinical trial at government hospitals.
 
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False positives during PGS / PGT-A may arise because of mosaic embryos that contain a mixture of genetically abnormal and normal cells. There have been many reports that these mosaic embryos can give rise to normal healthy births. So the cumulative chance of success may not increase by PGS / PGT-A and may even decrease by excluding "mosaic" embryos, that could have developed into a healthy normal baby. As seen in the attached diagram of a blastocyst stage embryo, the ICM gives rise to the embryo, while the TE gives rise to the placenta and yolk sac. Testing a few cells from the TE only gives you a probability about what's going on in the ICM. An embryo with abnormal (aneuploid) TE but normal ICM most likely will still make a healthy baby.
 

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You can ask your egg donor agency to privately arrange genetic testing of the egg donor's blood sample, instead of doing much more expensive PGS / PGT-A (embryo genetic testing) at the IVF clinic.

Here are the contact information of various DNA-testing companies in the greater KL region:

Genomix Lab
Email:
[email protected]
Website address: www.genomixlab.com
Address: No. 47-3A, Level 3, Jalan PJU 5/12
Dataran Sunway, Kota Damansara
47810 Petaling Jaya, Selangor DE, Malaysia
Tel: +603 6157 2299

Map My Gene Sdn. Bhd.
Email:
[email protected]
Website address: https://mapmygene.com/contact-us/
Address: #05-16 Sunway Velocity,
Designer Office, Jalan Peel,
Kuala Lumpur 55100, Malaysia
Tel: +65-9028-9745 (Singapore telephone number)

Gribbles Pathology Malaysia
Email:
[email protected]
Website address: Address: 2nd Floor, Wisma Tecna
18A, Jalan 51A/223
46100 Petaling Jaya, Malaysia
Tel: +603 78417752

PrimaNora
Email:
[email protected]
Website address: Address: B1-13, TTDI Plaza,
Jalan Wan Kadir 3,
Taman Tun Dr Ismail,
60000, Kuala Lumpur,
Malaysia
Tel: +603 7728 2886

DNA Laboratories Sdn Bhd.
Email:
[email protected]
Website address: http://www.dna-laboratories.com
Address: B1-3 & B1-4, Block Plasma, UKM-MTDC Technology Centre, Universiti Kebangsaan Malaysia, 43650 Bangi, Selangor, Malaysia.
Tel: +603-8925 2700
 

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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Recently, some Australian patients filed a class-action lawsuit against PGS / PGT-A, claiming that misdiagnosis by the procedure led to discarding of their embryos, which could have otherwise given rise to healthy births:


 

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