PGD/PGS in singapore during IVF

honeybaby1

New Member
Hello all,

My DH's semen analysis reported oligoasthenoteratozoospermia with very low sperm count. Chromosome analysis was done and was diagnosed with Y chromosome deletion (complete deletion of AZFc) which is the reason for bad sperm quality. IVF with ICSI is the only option but if we end with a boy, Y chromosome deletion will be inherited which means all sons will have same problem and we dont want to pass on this problem to our next generation. PGS/PGD test can be done to diagnose any genetic diseases in the embryo or check for chromsome imbalance (these tests will also have have gender information of the embryo). I understand PGS/PGD is allowed in Singapore only if there are genetic issues. I have 2 questions..

1. Is Y Chromosome deletion considered as genetic issue and will Singapore Health Board (Medical ethics board) allow PGD/PGS done during IVF?
2. Since this genetic issue is gender specific, will they allow disclosing of gender of the embryo and allow implanting only girl embryo?

Thanks in advance!
 


Hi, I think the best way to find out will be to consult with the IVF doctor and find out if there was a precedent for doing PGD on your condition, however to my knowledge this procedure is only allowed for potentially life-threatening conditions. There is really a lack of information on the public domain on PGD cases in SG so it would be better to check directly with the doctor, or potentially a genetic counselor.
 
Hi honey baby1, I just went through a cycle of IVF PGD myself.
My husband has a pair of chromosomes that has translocation (found during genetic testing) hence we needed the PGD.
To answer your 1st question, yes, your husband’s genetic issue is considered and will be eligible under PGD testing.
For your 2nd question: no, in SG, it is not ethical to disclose gender to couples for IVF no matter the situation. However, what pgd does is that it will give a report on your blastocysts on whether it is chromosomally balanced or not.
And since you say the issue is a Y chromosome deletion, this means that if your blastocyst result is ‘not balanced’, you can assume that it might have been a male, and if the blastocyst result is ‘balanced’, it is almost highly likely that it is a female/ you can regard it as a female. if any of your blastocysts inherits this ‘y deletion chromosome’, it will most probably be diagnosed under PGD as ‘not chromosomally balanced’.
However, you will still need to check with your gynae whether there is a PGD testing kit available for your DH’s condition. Currently there is only one PGD center in SG which is in NUH. but IVF clinics will be able to help check with the PGD center if they have the test kit for this specific condition.
I hope this helps.
 
Hi honey baby1, I just went through a cycle of IVF PGD myself.
My husband has a pair of chromosomes that has translocation (found during genetic testing) hence we needed the PGD.
To answer your 1st question, yes, your husband’s genetic issue is considered and will be eligible under PGD testing.
For your 2nd question: no, in SG, it is not ethical to disclose gender to couples for IVF no matter the situation. However, what pgd does is that it will give a report on your blastocysts on whether it is chromosomally balanced or not.
And since you say the issue is a Y chromosome deletion, this means that if your blastocyst result is ‘not balanced’, you can assume that it might have been a male, and if the blastocyst result is ‘balanced’, it is almost highly likely that it is a female/ you can regard it as a female. if any of your blastocysts inherits this ‘y deletion chromosome’, it will most probably be diagnosed under PGD as ‘not chromosomally balanced’.
However, you will still need to check with your gynae whether there is a PGD testing kit available for your DH’s condition. Currently there is only one PGD center in SG which is in NUH. but IVF clinics will be able to help check with the PGD center if they have the test kit for this specific condition.
I hope this helps.


Honey baby1,

I'm doing PGS IVF next month at NUH. Have had 2 Fresh and1 FET cycles. Last one ended in MC.
Any updates on your IVF PGD cycle? I don't know anyone doing PGD or PGS, I'm interested to hear about your experience and results. Hope you can share!

All the best to you!
 
Hi honey baby1, I just went through a cycle of IVF PGD myself.
My husband has a pair of chromosomes that has translocation (found during genetic testing) hence we needed the PGD.
To answer your 1st question, yes, your husband’s genetic issue is considered and will be eligible under PGD testing.
For your 2nd question: no, in SG, it is not ethical to disclose gender to couples for IVF no matter the situation. However, what pgd does is that it will give a report on your blastocysts on whether it is chromosomally balanced or not.
And since you say the issue is a Y chromosome deletion, this means that if your blastocyst result is ‘not balanced’, you can assume that it might have been a male, and if the blastocyst result is ‘balanced’, it is almost highly likely that it is a female/ you can regard it as a female. if any of your blastocysts inherits this ‘y deletion chromosome’, it will most probably be diagnosed under PGD as ‘not chromosomally balanced’.
However, you will still need to check with your gynae whether there is a PGD testing kit available for your DH’s condition. Currently there is only one PGD center in SG which is in NUH. but IVF clinics will be able to help check with the PGD center if they have the test kit for this specific condition.
I hope this helps.



Hi Azukin,

Thanks for spotting that I tagged the wrong name! Yes, I’d like to know more about your case and your experience with PGD. I’ve also sent you a private message :)

Baby dust to all of us here!

RedNose
 
Hi Astiva

We just had our genetic counselling session and the doctor told us that pgd cannot distinguish between normal genes vs genes with balanced translocation (carrier)? Is that true? Coz another doctor seemed to say that it can be distinguished during PGD...
 
Hi Astiva

We just had our genetic counselling session and the doctor told us that pgd cannot distinguish between normal genes vs genes with balanced translocation (carrier)? Is that true? Coz another doctor seemed to say that it can be distinguished during PGD...

For balanced translocation (my condition), the tech can only differentiate between balanced (normal OR carrier will list as balanced) and abnormal. For other genetic abnormalities, it may be different, I don’t know.
 
I see. Thanks for the clarification. We have balanced translocation too. I seemed to read online that there are new ways to distinguish, maybe it’s not offered in SG?
 
I see. Thanks for the clarification. We have balanced translocation too. I seemed to read online that there are new ways to distinguish, maybe it’s not offered in SG?

There is only one lab in the US that can distinguish between a balanced or a normal embryo: Pacgenomics. I haven’t heard of any other lab who can do this. But why this concern? Carriers are perfectly healthy.
 
Hi Astiva,
I am Nathaniel from CNA. We are still looking to interview a mom/couple/kid who has experienced PGD for a documentary series called "Why It Matters". We were hoping you could help us in our search; is there anyone you know who might be willing to participate in an interview? We really just want to show the efficacy of PGD in Singapore, and the benefits or issues that might come with it. We want to feature the stories of Singaporean moms.

Thank you! You may contact me at [email protected] or [email protected]

I emailed you already
 
Hi, anyone here doing PGS (also known as PGT-A) due to (i) Advanced Maternal Age, (ii) Recurrent Miscarriages, (iii) Low ovarian reserves, and (iv) Repeated IVF failures? Please kindly share your story. I am a bit skeptical of PGS helping to improve IVF success rates because it does nothing to improve egg or embryo quality. I think that it is purely diagnostic and not at all therapeutic.

A parable to illustrate this point is as follows:

A farmer has a hen that has laid 10 eggs. Out of these 10 eggs, only 3 are fertilized and will hatch chicks. The remaining 7 are unfertilized and will eventually go rotten. So the farmer uses a lighted candle in a dark room to look for the presence of a developing chick embryo within each egg, and identifies the 3 fertilized eggs. The lighted candle in this story is equivalent to PGS / PGT-A. Can using the lighted candle increase the number of fertilized eggs and hatched chicks? The obvious answer is no.

So without PGS, patients may have to do more transfers, but eventually, their good embryo will be transferred one day. So the final cumulative chances of success remain the same? Please give your opinion.

Here are some interesting videos that discuss these issues:






 
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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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Hi,
My doc just told us that we need to attend a genetic counselling given our case.
Our doctor suggest that we definitely need IVF+ PGD.
Can I check for PGD, how does it work?
 
What Singaporean patients should know before doing PGS (embryo genetic testing) when going for IVF overseas

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

Is PGS (PGT-A) useful for older women at risk of Down Syndrome, or patients with low ovarian reserves?
 
The Ministry of Health in Singapore has reported that the pilot trial of PGS / PGT-A in Singapore suffers from a high attrition rate of 72%.

The question is Why?


Please see:

MP Rahayu Mahzam on pre-implantation genetic screening

02 Mar 2021 10:48AM (Updated: 02 Mar 2021 05:27PM)


A pilot study on pre-implantation genetic screening (PGS) has had a high attrition rate of about 72 per cent and more data is needed to determine clinical effectiveness, said Parliamentary Secretary for Health Rahayu Mahzam in Parliament on Tuesday (Mar 2). She said the Ministry of Health will try to support as many patients as possible to participate, but must proceed carefully as there is some risk to the embryo. Ms Rahayu was answering an MP’s questions on whether MOH could allow any patient regardless of prognosis to take part in the study and whether full subsidies could be considered.

Could it because there is some problem with the PGS / PGT-A technique itself? Please see the following previous threads:
 
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What Singapore patients should know about genetic testing of IVF embryos ( PGT-A or PGS )?



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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Avoiding the moral dilemma and emotional trauma of Down syndrome abortions by mainstreaming IVF genetic testing (PGS/PGT-A) for older women

Down syndrome is a genetic condition caused by an extra copy of chromosome 21, which is characterized by impairment of mental and physical development, together with increased predisposition to certain medical conditions such as congenital heart defects, diabetes, and Alzheimer’s disease (after the age of 40).

It has a worldwide prevalence rate of approximately 1 to 800 live births, and occurs throughout all ethnicity and social classes. Although the link between older mothers and Down syndrome is well-established, it must be noted that most babies with Down syndrome are born to women below 35 years of age, due to the much higher fertility rates of younger women.

In recent years, there have been a number of local media reports of pregnant women deciding to keep their Down syndrome baby after prenatal testing. Undoubtedly, couples undergo much emotional trauma upon learning the results of prenatal testing, and face an agonizing dilemma of whether to proceed with abortion.

The conscientious objection of some women against abortion should be commended, given the many unique challenges and sacrifices that they face in raising a Down syndrome child.

Highly contentious issue overseas

Currently, this is a highly contentious issue overseas, as evidenced by some recent high-profile court cases.

In the United States, an appellate court ruling upheld Ohio state law prohibiting abortion of Down syndrome fetuses.

In Britain, a review of abortion law relating to Down syndrome is set to be heard at the High Court after vigorous campaigning by pro-life groups.

In India, a legal precedent was set in 2020 by a landmark supreme court ruling that permitted abortion of a 25 week-old fetus diagnosed with Down syndrome; whereas previously, abortion was permitted only for fetuses less than 20 weeks-old.

Difficult moral choices to expectant parents

Undoubtedly, continuous improvements in the accuracy of prenatal screening technology now present difficult moral choices to expectant parents faced with a positive diagnosis, who have to weigh the heavy financial, emotional and physical toll of raising a Down syndrome child, with their conscience, as well as personal and religious beliefs on abortion.

On one hand, there is right-to-life of the unborn child and respect for the dignity of disabled people. On the other hand, there are grave concerns on the happiness and quality-of-life for the child and themselves, together with the nagging fear that they would be unable to cope with the heavy burden of raising a special needs child.

Additionally, there are also risks to the mental, physical, and reproductive health of the patient to consider, when aborting a Down syndrome fetus.

The incidence of Down syndrome rises with increasing maternal age, which is particularly significant for Singapore, given the increasing trend of late marriages and parenthood.

For older women undergoing IVF (in vitro fertilization) treatment, there is a way of avoiding this abortion dilemma and emotional quagmire by genetic screening of IVF embryos prior to transfer into the womb, a procedure known as Preimplantation Genetic Testing – Aneuploidy (PGT-A) or Preimplantation Genetic Screening (PGS).

This is designed for IVF patients without any known heritable genetic disorders.

PGT-A (PGS) service in Singapore

To date, PGT-A (PGS) is still not approved as mainstream clinical service in Singapore, and is restricted to a pilot clinical trial at public IVF centers, in contrast to genetic testing of IVF embryos for patients with known genetic disorders, which was recently approved as mainstream clinical service.

The criteria for participation in this pilot PGT-A trial are that the female patient must be at least 35 years old, or have experienced at least two miscarriages or two failed IVF cycles.

A recent article in Channel NewsAsia (‘So near, yet so far: Aspiring parents and their embryos separated by the pandemic‘, 23 May) reported on local women traveling overseas to do IVF with PGT-A, because this procedure is much more readily available and less strictly regulated abroad, compared to Singapore.

Hence, based on compassionate grounds, to avoid future abortion dilemmas and emotional trauma for older women undergoing IVF, whom are at increased risk of Down syndrome, the Ministry of Health (MOH) should approve PGT-A as mainstream clinical service specifically for such older patients.

Nevertheless in doing so, MOH should ensure rigorous counseling to inform patients of the various downsides and risks of PGT-A.

In particular, patients should be advised to think carefully on the cost-benefit aspect of this expensive procedure that may increase the cost of IVF treatment by up to 50 per cent.

By contrast, prenatal testing for Down syndrome and other genetic defects is much cheaper, albeit the risks of needing to consider aborting an abnormal fetus.

Given the uncertain outcome and high costs of IVF, it may be preferable for some patients with limited funds to cut costs by not doing PGT-A, so as to save money for future IVF attempts.

After all, more than one IVF attempt is usually needed to achieve reproductive success, and it would be financially exhausting to do PGT-A for each and every IVF treatment cycle.

Risk of Down syndrome for women

According to published medical statistics, the risk of Down syndrome for women in their late 30’s, around 37 to 39 years old, hovers around 0.5 per cent.

Even at age 40, the risk of Down syndrome increases to about 1 per cent, and then to around 3.5 per cent at age 45.

Hence, for almost the entire span of a woman’s reproductive life, the risks of Down syndrome are in fact relatively low, at less than 4 per cent.

Ultimately, it is up to patients with limited financial resources to decide whether it is worthwhile taking a calculated risk of avoiding this highly-expensive procedure, to get more shots at IVF.
 

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Utilization of public funding to detect and prevent Down syndrome in older female IVF patients

Unlike subsidizing the genetic testing of IVF patients with known heritable disorders, which is currently being considered by MOH, the utilization of public funding to detect and prevent Down syndrome in older female IVF patients by PGT-A is neither economical, cost-efficient nor politically-justifiable in the long term.

First, there is the issue of personal choice and responsibility for late motherhood, unlike the case of heritable genetic disorders, which is involuntary.

Second, heritable genetic disorders are relatively rare, and represent only a tiny fraction of IVF patients, as compared to the much larger numbers of older female IVF patients, which would mean that subsidies would cost much more.

Third, there is a much cheaper, yet accurate and reliable alternative to detect Down syndrome, in the form of Non-Invasive Prenatal Testing (NIPT), albeit the risks of abortion after positive diagnosis.

Lastly, it would be highly cost-inefficient to subsidize PGT-A for all older women undergoing IVF, given that the risks of Down syndrome do not exceed 4 per cent for almost the entire female reproductive lifespan (20 to 45 years old).

Additionally, patients should beware that PGT-A is prone to false-positive misdiagnosis, leading to discarding of some of their viable embryos that can otherwise give rise to healthy births.

This is because PGT-A sample cells only from the outer embryo layer (Trophectoderm) that generates the placenta and umbilical cord, which is not representative of the inner embryo layer (Inner Cell Mass) that gives rise to the baby itself.

Mosaic embryos containing a mixture of genetically normal and abnormal cells, have demonstrated ability to self-correct and give rise to healthy births. Recently, a class-action lawsuit was filed by Australian patients against misdiagnosis by PGT-A that led to discarding of their viable embryos and consequent loss of chance at parenthood.

Another note of caution is that at a recent parliamentary debate, MOH reported a relatively high attrition rate of 72 per cent for the pilot trial of PGT-A at public IVF centers in Singapore; and consequently voiced the need to proceed carefully, because there are some risks of damaging the embryo by this procedure.

Earlier in 2019, a large international multi-centre clinical trial involving more than 600 patients in the USA, Canada, UK and Australia, reported no significant improvements in pregnancy rates from PGT-A, despite utilizing the latest next-generation sequencing assay for aneuploidy testing.

More choices to circumvent the moral dilemma and emotional trauma of aborting a Down syndrome fetus

In conclusion, by mainstreaming PGT-A for older female IVF patients at higher risks of Down syndrome, this would confer them with more choices to circumvent the moral dilemma and emotional trauma of aborting a Down syndrome fetus.

The primary responsibility of MOH is to ensure that patients make an informed decision, via proper and thorough counseling on the cost-effectiveness and risks of utilizing PGT-A for this particular purpose.

It is also imperative that MOH enact stringent safeguards to prevent aggressive marketing tactics by private fertility clinics that exaggerate risks and exploit patients’ fear of Down syndrome.
 
Is it worthwhile doing IVF genetic testing (PGS / PGT-A) to prevent birth defects in older women?

With an increasing trend of late motherhood, many women across Asia and worldwide are choosing to postpone childbearing while prioritizing lifestyle and career objectives. Nevertheless, the risks of conceiving a baby with genetic (chromosomal) abnormalities increase with older maternal age, the most common and well-known of which is Down syndrome. Worldwide, more than 90% of Down syndrome fetuses are routinely aborted upon positive diagnosis by prenatal testing. However, there are serious risks to the mental, physical and reproductive health of the patient to consider, when aborting a fetus diagnosed with Down syndrome or other genetic abnormalities.

For older women undergoing assisted reproduction treatment, there is a way of avoiding this abortion quagmire by genetic screening of IVF embryos before transferring into the womb, a highly expensive procedure known as Preimplantation Genetic Testing - Aneuploidy (PGT-A) or Preimplantation Genetic Screening (PGS). Hence, the pertinent question that arises for older women undergoing assisted reproduction treatment, is whether it is worthwhile and cost-effective to utilize expensive PGT-A (PGS) for screening and excluding genetically abnormal embryos, as compared to standard prenatal testing techniques that are much cheaper.

What are the different types of genetic abnormalities that occur in older mothers?

Due to a lack of proper separation of chromosomes during egg development in older women, they are at higher risks of genetically abnormal births.

The most common genetic abnormality in older mothers is Down syndrome, caused by an extra copy of chromosome 21. Additionally, increasing maternal age is also associated with elevated risks of Edwards syndrome (extra copy of chromosome 18), Patau syndrome (extra copy of chromosome 13) and Klinefelter syndrome (extra X chromosome - 47,XXY). Among these, only babies with Down and Klinefelter syndromes usually survive to adulthood. The life expectancy of Patau syndrome is around 7-10 days, with 90% dying in the first year of life.

Similarly, the average lifespan for Edwards syndrome is 3 days to 2 weeks, with only 5% to 10% of afflicted infants surviving for over a year. Down syndrome is characterized by a substantial reduction in lifespan to about 60 years, severe impairment of mental and physical development, together with increased predisposition to certain medical conditions such as congenital heart defects, type II diabetes and Alzheimer’s disease (after the age of 40). In contrast, for Klinefelter syndrome (47, XXY), there is only a very slight reduction in lifespan by about 2 years compared to the normal male population (46, XY). Although individuals with Klinefelter syndrome usually have normal intelligence, they suffer from infertility and have small underdeveloped male sex organs, poor motor coordination and weak muscles, reduced facial and body hair, breast growth, and low sex-drive.

According to published medical statistics, the risks of conceiving a genetically abnormal baby for women in their late 30's, around 37 to 39 years old, is approximately within the 0.8% to 1.2% range. By age 40, the risk of genetic abnormalities increases to about 1.5%, and then to around 4.8% at age 45.

Can genetic testing potentially harm IVF embryos?

IVF genetic testing involve drilling a hole through the embryo shell (Zona Pellucida) and extracting cells from the embryo, which is potentially harmful, and can 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. No matter how well-trained is the lab staff (embryologist) doing 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.


What are the challenges associated with IVF genetic testing?

There are several aspects to be considered towards genetic testing in IVF treatment.

  • IVF genetic testing involve extracting and sampling cells from the outer embryo layer that gives rise to the placenta and umbilical cord. This is not representative of the inner embryo layer that goes on to form the actual embryo proper, which gives rise to the baby.
  • Mosaic embryos, which are embryos with a mixture of genetically normal and abnormal cells occur quite frequently and commonly among woman 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. Recently in 2020, a class-action lawsuit was filed by Australian patients against misdiagnosis by IVF genetic testing, which led to discarding of their viable embryos and consequent loss of chance at parenthood.
  • 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.

Are there alternative methods to IVF genetic testing for preventing birth defects in older women?

Yes, there is an alternative method that is much cheaper than PGT-A (PGS). This is known as Non-Invasive Prenatal Testing (NIPT), in which the DNA of fetal cells within the expectant mother’s blood circulation is extracted and tested for genetic abnormalities. Nevertheless, the downside is that NIPT can only be performed after getting pregnant, so the patient has to be mentally and emotionally prepared to abort a genetically abnormal fetus. Additionally, ultrasound can also be used to some extent for detecting Down syndrome, even though the results are not as accurate and determinative as NIPT.


How cost-effective is IVF genetic testing for older women?

Given the uncertain outcome and high costs of IVF treatment, it may be preferable for some patients with limited funds to cut costs by not doing genetic testing, so as to save money for future attempts at IVF treatment, given that cheaper alternative prenatal testing methods are available. After all, more than one IVF attempt is usually needed to achieve reproductive success, and it would be financially exhausting to do genetic testing for each and every IVF treatment cycle. As mentioned earlier, given that the risks of genetic abnormalities do not exceed 5% for almost the entire female reproductive lifespan (20 to 45 years old), it may be highly cost-inefficient to utilize such an expensive procedure for all older women undergoing IVF, In particular, the incidence of genetic abnormalities is typically less than 1.5% for women below 40 years old, so that utilizing PGT-A would be superfluous more than 98.5% of the time. Ultimately, it is up to patients with limited financial resources to decide whether it is worthwhile taking a calculated risk of avoiding highly expensive genetic testing, to get more shots at IVF.


Can you elaborate on the principles and regulations of IVF genetic testing in Singapore?

Singapore healthcare policies allow IVF genetic testing only for mainstream clinical treatment for patients who are sufferers or carriers of known genetic diseases (PGT-M & PGT-SR). Routine genetic screening of IVF embryos of older women (PGS or PGT-A), who are at increased risks of Down syndrome is still not approved as mainstream clinical treatment but is restricted to a tightly regulated clinical trial at government hospitals. To participate in this clinical trial, women have to be 35 years old or older, or have suffered two recurrent miscarriages, or have two failed IVF attempts. Also, there are inadequate and doubtful results from the current clinical trial of IVF genetic testing in Singapore, which was reported to suffer from a high attrition rate of 72%.
 

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.

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.

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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, 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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