Sociocultural imperatives for Singapore to permit preimplantation genetic testing-aneuploidy (PGT-A) despite uncertain results and ongoing controversy

Dear Editor,

We read with great interest the articles by Zheng et al. [1] and Kucherov et al. [2], which reported conflicting data on the therapeutic value of preimplantation genetic testing-aneuploidy (PGT-A) in improving success rates in clinically assisted reproduction. Indeed, the entire medical and scientific literature is replete with such conflicting data on PGT-A, which in turn casts much doubt on the therapeutic value of the procedure [3, 4], as well as its cost-effectiveness [5, 6].

The Ministry of Health in Singapore (MOH) is well aware of the controversy surrounding PGT-A, which is why to date, PGT-A is still not approved as a mainstream clinical treatment in Singapore [7], unlike the case of PGT-M (monogenic disorders) and PGT-SR (chromosomal structural rearrangements) [8]. Moreover, the government-sponsored pilot clinical trial of PGT-A in public hospitals in Singapore was reported to yield inconclusive results, with a rather high attrition rate of 72% due to withdrawal or cancellation of the procedure arising from various factors, such as failure to obtain blastocyst-stage embryos on day 5 [7]. As reported to the Singapore parliament [7], a total of 367 patients were enrolled in the local clinical trial of PGT-A at public government-funded IVF centers, but only 104 enrolled patients had embryo biopsies performed. Almost half of the patients changed their minds after the ovarian stimulation or fertilization stage and proceeded with embryo transfer directly without performing PGT-A, or decided to freeze their embryos instead. Other patients did not proceed with a biopsy due to medical reasons, such as poor quality of blastocysts or embryo arrest. Out of the 104 patients with biopsied embryos, 69 had euploid embryos, and 60 underwent embryo transfers. This resulted in 31 pregnancies with 15 live births, 8 miscarriages and 8 ongoing pregnancies.

Despite such unfavorable or doubtful results, there are sociocultural imperatives for Singapore to approve PGT-A as a mainstream clinical treatment, which should also be made readily available in the private healthcare sector. The rationale is that from the sociocultural perspective of some Singaporean patients, the benefits of PGT-A in preventing Down syndrome and other aneuploidies associated with older mothers (> 35 years old), together with averting abortion after prenatal testing; would far outweigh the various disadvantages and pitfalls of the procedure, such as misdiagnosis due to chromosomal mosaicism [9], possible reduction in live birth rates [2] due to risks of biopsy damaging the embryo [10], and overall lack of cost-effectiveness [5, 6]. There are various sociocultural imperatives that would favor the uptake of PGT-A in Singapore, which will thus be examined.

First, Singapore had undergone a major demographic shift in the past two decades, with an increasing trend of late motherhood and a drastic reduction in fertility rates [11]. Since 2017, the total fertility rate (TFR), defined as the average number of children that a woman will have in her lifetime, has been consistently below 1.2 [11]. In 2022, Singapore’s resident TFR hit an all-time low of 1.05, dipping below the previous records of 1.1 in 2020 and 1.12 in 2021 [11]. The new generation of better-educated Singaporean women is well-aware that the increasing trend of late motherhood in Singapore is closely associated with higher risks of Down syndrome and other chromosomal abnormalities. Some IVF patients among them would rather spend extra money on expensive PGT-A to avoid the risks of abortion upon positive diagnosis after prenatal testing. Although medical advances have made abortion a relatively safe procedure, vigorous campaigning and publicity stunts by pro-life activists have widely portrayed the procedure as being highly risky, painful and harmful to health, resulting in many women being highly fearful of the procedure. Moreover, a drastic reduction in fertility rates leading to most Singaporean women having only one child [11], would motivate them to invest more in their single offspring, including doing highly expensive PGT-A to eliminate the possibility of Down syndrome and other aneuploidies. In 2022, it was reported that the costs of PGT testing in Singapore ranged from SGD$11,000 to SGD$31,000 (approximately USD$8,000 to USD$23,000) [12]. The costs of the procedure are not covered by insurance, but residents can receive up to 75% fee subsidy from the Singapore government [12].

Second, although Singaporean society has increasingly become more secular in recent years, the majority of the population still hold religious beliefs [13] and are significantly more religious compared to many Western societies. Higher levels of religiosity would equate to greater aversion to abortion, which is unanimously considered to be immoral by all major religious faiths in Singapore [14]. Presumably, some Singaporean patients with strong religious beliefs would be motivated to avoid abortion at all costs, so as not to offend their religious beliefs and hurt their conscience [15]. Adding highly expensive PGT-A to IVF treatment cycles would thus avert the risks of abortion for some older women (> 35 years old) with strong religious beliefs.

Third, Down syndrome and other aneuploidies are heavily stigmatized and scorned in Asian Confucian societies such as Singapore [16]. This contrast sharply with liberal Western values that stress the need to promote the rights of disabled individuals and accommodate their special needs. In the predominantly Chinese culture of Singapore, individuals with Down syndrome and other aneuploidies are often scorned and despised as a burden on society, as well as considered a shame and embarrassment to their families [16]. This would thus motivate some older women (> 35 years old) undergoing IVF to use all means at their disposal to avoid Down syndrome and other aneuploidies, even if that means adding highly expensive PGT-A to their IVF treatment. In the mindset of some prospective parents in Singapore, it would be wiser to spend extra money on expensive PGT-A to ensure the birth of a normal and healthy child, rather than risking abortion or spending more money on the healthcare and upbringing of a disabled child. Hence in this context, PGT-A would play a key role in reassuring IVF patients particularly older women (> 35 years old), that Down syndrome and other aneuploidies would be prevented and the risks of abortion averted, thus giving them much-needed peace of mind during the stressful IVF procedure.

Based on these aforementioned sociocultural imperatives, the Ministry of Health in Singapore should therefore allow local IVF patients the option of adding on PGT-A, despite the current controversy on its therapeutic value [3, 4] and cost-effectiveness [5, 6]. It is anticipated that some older women (> 35 years old) would be willing to spend the extra money and incur the risks associated with the procedure [2, 5, 6, 9, 10], just for the sake of preventing Down syndrome and other aneuploidies, as well as for avoiding the risks of abortion. An appropriate analogy here would be prenatal testing techniques such as amniocentesis [17] and chorionic villus biopsy (CVB) [18]. The risks associated with these techniques are well-known and there are no therapeutic benefits in improving live birth rates.

Yet, it is anticipated that some patients would still be willing to incur the risks and pay for these diagnostic procedures. In this light, PGT-A should be more correctly viewed as a diagnostic cum preventive procedure that incurs some degree of risks, rather than as a therapeutic procedure to enhance IVF success rates. In any case, there should be compulsory counseling for all patients considering PGT-A by a qualified genetic counselor, to ensure that they are well aware of the various disadvantages and pitfalls of the procedure. These include misdiagnosis due to chromosomal mosaicism [9], possible reduction in live birth rates [2] due to risks of biopsy damaging the embryo [10], and overall lack of cost-effectiveness [5, 6]. Additionally, patients must also be informed that mosaic embryos have the potential to self-correct and give rise to a normal healthy baby so that the discarding of mosaic embryos will reduce their cumulative chances of reproductive success [19, 20]. By mandating comprehensive and rigorous genetic counseling, the Singapore Ministry of Health can thus ensure better patient awareness of the various pros and cons of the PGT-A procedure. In particular, it is important to counter aggressive advertising by private IVF clinics that misrepresent PGT-A as a therapeutic procedure that have beneficial effects in improving IVF success rates, because the latest uncertain and ambiguous clinical data [2–4] have cast much doubt on such claims. As mentioned earlier, patients should be strongly advised to view PGT-A more accurately as a diagnostic cum preventive procedure that carries some degree of risks, similar to amniocentesis and CVB.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.