Is IVF Genetic Testing (PGT-A) Useful For Older Egg Freezing Patients?

[Angelica Cheng]

Is IVF Genetic Testing (PGT-A) Useful For Older Egg Freezing Patients? – Dr Alexis Heng Boon Chin - CodeBlue

It may be highly cost-inefficient to utilise the PGT-A procedure for older egg freezing patients.

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Is IVF Genetic Testing (PGT-A) Useful For Older Egg Freezing Patients?

Egg freezing has been in the news recently, with Singapore permitting the procedure and extending the age limit from 35 to 37. In Malaysia, elective egg freezing has been available to non-Muslim women for around a decade, and some egg freezers have undoubtedly started using their frozen eggs in IVF treatment.
You are an older woman who had previously frozen your eggs in your mid to late-thirties, and the time has now come to use your frozen eggs in IVF treatment.
A persistent and nagging question at the back of your mind is the risk of your frozen eggs having genetic abnormalities that can potentially give rise to birth defects such as Down syndrome, which is well-known to occur more frequently in older women.
Your doctor then tells you of a highly expensive technique for genetic screening of IVF embryos, known as Preimplantation Genetic Testing – Aneuploidy (PGT-A) or Preimplantation Genetic Screening (PGS), which can increase the costs of IVF treatment by up to 50%.
Nevertheless, high costs would likely be a secondary concern for you. Because your limited number of frozen eggs would represent your last chance of having a child, so you cannot afford for things to go wrong.
Hence, you do not mind spending extra money on genetic testing to avoid birth defects and other complications.
Your doctor will probably tout the additional advantages of PGT-A, such as improving your IVF success rates by weeding out genetically abnormal embryos, as well as enabling you to select the sex of your baby.
You become convinced that highly expensive PGT-A is a good investment; money well-spent to improve your chances of conception, and most importantly to ensure a normal healthy child.
However, be warned that genetic testing with PGT-A is not what it is made out to be.
If this technique is so useful and necessary for older women, why is it still not approved as mainstream clinical treatment in Singapore, which has very high standards of medical regulation?
Currently in Singapore, PGT-A is still considered an experimental technique under evaluation by a pilot clinical trial conducted at government-funded IVF clinics.
As reported to the Singapore Parliament in 2021, the results of this pilot clinical trial are still uncertain and very much in doubt, with a high attrition rate of 72 per cent.
Hence, before adding the PGT-A technique to your IVF treatment, it is important for you to first understand its various flaws and drawbacks, or else this might lead to wastage of your hard-earned money, and even ruin your chances of conceiving a child.
Here are some answers to some frequently asked questions by egg freezing patients considering to add PGT-A to their IVF cycle with frozen eggs.

Why Are Older Mothers More Prone To Birth Defects Caused By Genetic Abnormalities In Their Eggs?
As a woman gets older, there is a higher chance of abnormal cell replication taking place during egg development, resulting in eggs with extra copies of genetic material known as chromosomes, which in turn give rise to birth defects.

What Types Of Birth Defects Commonly Occur In Older Mothers?
Besides Down syndrome, caused by an extra copy of chromosome 21, the frozen eggs of older women are also at higher risk of Edwards syndrome (an extra copy of chromosome 18), Patau syndrome (an extra copy of chromosome 13), and Klinefelter syndrome (an extra X chromosome).
Among these, only babies with Down and Klinefelter syndromes usually survive to adulthood. The life expectancies of babies with either Edwards syndrome or Patau syndrome is extremely short, usually ranging from a few days to a few weeks.
Down syndrome is characterised 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 two 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 and underdeveloped male sex organs, poor motor coordination and weak muscles, reduced facial and body hair, breast growth, and low sex-drive.

What Are The Statistical Risks Of Birth Defects In Older Mothers?
According to published medical statistics, the risks of conceiving a genetically abnormal baby for women around 37 to 39 years old is approximately within the 0.8 to 1.2 per cent range.
By age 40, the risk of genetic abnormalities increases to about 1.5 per cent, and then to around 4.8 per cent at age 45.

Is The PGT-A Technique Effective For Selecting The Sex Of Your Baby?
Yes, it is currently the best technique for sex selection in the IVF market. If you can get pregnant by IVF with PGT-A, then the success rate of sex selection is close to 100%.

 

[Angelica Cheng]

Is The PGT-A Technique Harmful To IVF Embryos?
Genetic testing with PGT-A is highly invasive and involve drilling a hole through the embryo shell (Zona Pellucida) to extract cells from the embryo (biopsy), which is potentially harmful, and can impair its development.
Experts have pointed out that studies claiming no ill effects from PGT-A on IVF embryos are often based on genetic testing of strong good-quality embryos rather than weak poor-quality embryos that might suffer more.
Because older women with frozen eggs tend to have weaker and lower-quality embryos, these may be more prone to damage by PGT-A testing.
The risks of human error should not be overlooked, no matter how well-trained the lab staff (embryologist) is doing this procedure. The busier the IVF lab is, the greater the risks of human error, as lab staff are under pressure to complete procedures as fast as possible.

Are There Additional Drawbacks Or Pitfalls To Genetic Testing With PGT-A?
More recent medical studies have shown PGT-A to have the following drawbacks and pitfalls:

• Genetic testing with PGT-A involves 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.
• There is scientific evidence that Mosaic embryos are able to “self-correct”, which increases the chances of normal birth. This “self-correction” mechanism involves pushing out the genetically abnormal cells into the outer embryo layer, which gives rise to the placenta and umbilical cord.
• Older women with frozen eggs tend to have a limited number of IVF embryos. 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.
• PGT-A requires a second freezing of IVF embryos after initial egg freezing. It takes time to obtain the results of genetic testing after extracting cells from IVF embryos, which must therefore be frozen and cannot be transferred to the patient immediately.
• The detrimental effects of multiple freeze-thawing on the weaker lower-quality embryos of older women are still unknown.

Does PGT-A Actually Improve IVF Success Rates By Weeding Out Genetically Abnormal Embryos?
Egg freezing patients must beware that several large-scale clinical studies published in reputable medical journals have demonstrated conclusively that PGT-A does not improve IVF success rates.
In 2019, a large multi-centre randomised clinical trial (STAR trial) involving 34 IVF clinics in the United States, Canada, the United Kingdom, and Australia, and including 661 patients aged between 24 and 40 years, found no significant overall improvement in IVF success rates with PGT-A.
Subsequently, in 2021, another large multi-centre clinical trial conducted in China, involving 14 IVF clinics and a total of 1212 patients aged between 20 to 37 years, reported similar unfavourable results that were published in the New England Journal of Medicine.
Hence, based on the latest scientific and clinical data, serious doubts about the medical benefits of PGT-A have emerged.

Is There An Alternative To PGT-A To Prevent Birth Defects In Older Women?
Yes, there is an alternative method that is much cheaper than PGT-A (PGS) but with a high level of accuracy. 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 foetus.
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.

Overall, Is PGT-A Worthwhile And Cost-Effective For Older Egg Freezing Patients?
As mentioned earlier, given that the risks of genetic abnormalities do not exceed 5 per cent for almost the entire female reproductive lifespan (20 to 45 years old), it may be highly cost-inefficient to utilise such an expensive procedure for older egg freezing patients.
In particular, the incidence of genetic abnormalities is typically less than 1.5 per cent for women who had frozen their eggs before 40 years old, so that utilising PGT-A would be superfluous more than 98.5 per cent of the time.
For many older egg-freezing patients, especially those already past the age of menopause, their frozen eggs represent their last chance of getting pregnant.
They should therefore think twice before choosing this highly expensive and invasive genetic testing technique, which risks damaging their embryos and possibly lower their chances of conception through misdiagnosis and discarding of mosaic embryos.
Prenatal testing such as NIPT would be a cheaper and less risky choice, which delivers a high level of accuracy.