Currently, there is an increasing trend of late motherhood in Singapore and many other countries throughout the world, as rising numbers of better-educated women choose to postpone marriage and childbearing in pursuit of career development. Nevertheless, there are heightened risks of conceiving a baby with genetic (chromosomal) abnormalities with increasing maternal age. Such genetic abnormalities usually arise from a lack of proper separation of chromosomes during egg development in older women, the most common of which 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.
Worldwide, more than 90% of Down syndrome fetuses are routinely aborted upon positive diagnosis by prenatal testing. Currently, this is a highly controversial and hotly-debated issue, 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 (Komal Hilwale versus the State of Maharashtra).
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 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 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 PGT-A for screening and excluding genetically abnormal embryos, as compared to standard prenatal testing techniques that are much cheaper? To make an informed choice, patients need to carefully compare PGT-A with standard prenatal testing techniques such as Non-Invasive Prenatal Testing (NIPT) and Ultrasound.
In particular, they should be advised to think carefully on the cost-benefit aspect of PGT-A (PGS) that may increase the cost of IVF treatment by up to 50%. By contrast, standard prenatal testing for Down syndrome and other genetic defects are much cheaper, albeit the risks of needing to consider aborting a genetically abnormal fetus. 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 PGT-A, so as to save money for future attempts at IVF treatment. After all, more than one 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.
According to published medical statistics, the risks of conceiving a genetically-abnormal fetus 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. Hence, for almost the entire span of a woman’s reproductive life, the risks of genetic abnormalities are in fact relatively low, at less than 5%. Ultimately, it is up to patients with limited financial resources to decide whether it is worthwhile taking a calculated risk of avoiding highly-expensive PGT-A, to get more shots at IVF.
Hence, it would be highly cost-inefficient to utilize expensive PGT-A for all older women undergoing IVF, given that the risks of genetic abnormalities do not exceed 5% for almost the entire female reproductive lifespan (20 to 45 years old). 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.
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 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.
In conclusion, although PGT-A can circumvent the emotional trauma and health risks of aborting a genetically abnormal fetus for older women undergoing IVF, patients need to carefully consider the cost-benefit aspect, given the high costs of the procedure and it’s various risks and downsides. It is the responsibility of the relevant health authority to ensure that patients make an informed decision, via proper and rigorous counseling on the cost-effectiveness and risks of utilizing PGT-A for preventing Down syndrome and other genetic abnormalities in older mothers, as well as enact stringent safeguards to prevent aggressive marketing tactics by private fertility clinics that exaggerate risks and exploit patients’ fear of genetic abnormalities.
Dr. Alexis Heng Boon Chin (Associate Professor, Peking University, China)
Biography: Dr. Alexis Heng Boon Chin is a native Singaporean who is working as an Associate Professor at Peking University, China. He had previous worked in the field of IVF research in Singapore.
https://www.focusonreproduction.eu/article/News-in-Reproduction-Aneuploidy-screeningRecommend0 recommendationsPublished in Children