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Widespread Embryo Genetic Testing (PGT-A) In Malaysia May Not Benefit IVF Success Rates – Dr Alexis Heng Boon Chin

Patients should think twice before choosing to add on the PGT-A technique to their IVF cycle.

A mother with her newborn child. Photo by blankita_ua from Pixabay.

IVF embryo genetic testing, technically known as Preimplantation Genetic Testing-Aneuploidy (PGT-A) or Preimplantation Genetic Screening (PGS), is widely added-on to IVF treatment in Malaysia.

Knowing that prospective parents fear birth defects, Malaysian fertility clinics aggressively market PGT-A as a means of preventing Down syndrome in older women.

This is doubtful given that there is a much cheaper but equally accurate and reliable means of screening genetic defects by Non-Invasive Prenatal Testing (NIPT).

On the sidelines, PGT-A is also discreetly used by IVF patients as a sex selection technique, with the need to prevent Down syndrome in older women being a “convenient excuse” or “cover-up”.

Additionally, PGT-A is also widely touted as a means of improving IVF success rates by weeding out non-viable embryos with chromosomal abnormalities that commonly occur in older mothers.

Nevertheless, in recent years, several large-scale clinical studies published in reputable medical journals contradict such widely claimed beneficial effects of PGT-A in enhancing IVF success. A brief overview of these contradictory data will thus be summarised here. 

The first inkling of the lack of therapeutic benefits of PGT-A in improving IVF success rates came from a large multi-centre clinicial trial (ESTEEM trial) conducted by the European Society for Human Reproduction and Embryology (ESHRE), which involved 9 IVF centres in seven countries and a total of 396 women of “advanced maternal age” (aged between 36 and 40).

The results of this study, published in 2018 in the reputable medical journal Human Reproduction, concluded that PGT-A did not increase cumulative live birth rates in IVF.

Commenting on the trial’s findings, lead author Prof Karen Sermon of the Free University of Brussels in Belgium “saw no benefit” of offering PGT-A to older women, especially in cases where only few eggs have been retrieved. 

Later in 2019, the results of a large multi-centre randomized clinical trial (STAR trial) involving 34 IVF centres in the United States, Canada, United Kingdom, and Australia and including 661 patients aged between 24 and 40 years, were published in “Fertility and Sterility”, the official journal of the American Society for Reproductive Medicine (ASRM).

The latest next-generation sequencing (NGS) technology provided by Illumina Inc. was utilised in this trial, with the trademark name of “VeriSeq PGS”, which claimed to provide comprehensive testing for copy number of all 24 chromosomes of the human embryo.

As reported by the lead author of the study, Dr Santiago Munne of Yale University there was found to be no significant overall improvement in IVF success rates with PGT-A. 

Subsequently in 2021, similar results on the insignificant effects of PGT-A in improving IVF success rates were reported by another large multi-centre clinical trial conducted in China, involving 14 IVF centres and a total of 1212 patients aged between 20 to 37.

This was published in the prestigious medical journal New England Journal of Medicine, with Dr Zi-Jiang Chen from Shandong University in Jinan (China) as the lead author. 

More recently, in 2023, another prominent academic study published in the Journal of Assisted Reproduction and Genetics casts further doubts on the therapeutic benefits of PGT-A in improving IVF success rates.

Based on retrospective analysis of 133,494 IVF cycles recorded within the SART (Society for Assisted Reproductive Technology) Clinical Outcome Reporting System database, it was found that application of PGT-A in all patients with late-stage embryos (blastocysts) available for transfer or screening was in fact associated with a lower cumulative live birth rate than routine IVF.

This negative association of PGT-A with cumulative live birth rate was especially pronounced in patients below 35 years old, even though this was not observed in those aged 40 years and above.

The lead author of this study was Dr Alexander Kucherov from Illume Fertility Inc.

Commenting on these negative results, Dr. Norbert Gleicher, a fertility specialist practicing at the Center for Human Reproduction in New York, claimed that we had reached a dead end for the PGT-A technique.

So why is there hardly any beneficial therapeutic effects of IVF embryo genetic testing? Patients should take note of the following plausible reasons:

  • IVF genetic testing 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.
  • PGT-A is a highly invasive technique that involves 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 PGT-A of excellent quality, healthy, robust embryos rather than more ‘delicate’ lower-quality 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.
Extraction of cells (biopsy) from IVF embryos for PGT-A testing is a relatively harsh and invasive procedure. This may have more harmful effects on lower-quality embryos, which are likely to “suffer” more from the procedure. Note that older women tend to have fewer lower-quality embryos.

  • 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 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.

Hence, based on the latest scientific and clinical evidence that are published in reputable medical journals, and which include large numbers of patients and IVF cycles worldwide, serious doubts on the therapeutic benefits of IVF embryo genetic testing (PGT-A) have emerged.

Patients should therefore think twice before choosing to add on this highly expensive and invasive technique to their IVF cycle.

Dr Alexis Heng Boon Chin, originally from Singapore, is an associate professor of biomedical science at Peking University, China.

  • This is the personal opinion of the writer or publication and does not necessarily represent the views of Ova.

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