Donation of surplus IVG-derived eggs for mitochondrial or ooplasm transfer to improve egg quality in older women - a solution for overcoming age-related female infertility in Singapore?
Published in Social Sciences, Cell & Molecular Biology, and General & Internal Medicine
In 2018, Singapore's Bioethics Advisory Committee (BAC) conducted a public consultation on mitochondrial genome replacement therapy (MGRT), ostensibly to prevent mitochondrial diseases such as Leigh syndrome. Subsequently, it issued an interim report in 2021, which stated that the BAC will continue to monitor developments in the field and revisit the issue when further scientific evidence and clinical experience become available. This was due to the available medical and scientific data being inadequate for them to make an informed judgment at that point in time.
If MGRT is permitted in Singapore in the future, it is anticipated that preventing mitochondrial diseases such as Leigh syndrome would be of little relevance and insignificant economic value, given the minuscule number of local IVF patients who would need such therapy. Instead, the lucrative market and major focus of MGRT will be on overcoming age-related female infertility in Singapore, via mitochondrial or ooplasm transfer to improve the egg quality of older women undergoing IVF treatment. This is because current sociodemographic trends point to increasing numbers of Singaporean women delaying marriage and childbearing, which has spurred the legalization of elective egg freezing as a solution to mitigate the rising incidence of age-related female infertility in the country.
This is not solely due to local women becoming increasingly fixated on pursuing educational and career aspirations. Instead, national statistics would point to a more subtle trend of highly educated Singaporean women facing many difficulties and challenges in the local dating and marriage market, with an increasing shortfall of "good-enough" eligible bachelors that can match them in terms of income and educational qualifications. This is because, like most other countries, women tend to graduate at higher rates from universities than men in Singapore. For instance, the Singapore Department of Statistics reported that in 2021, 64 percent of women aged 25-34 years had a university degree compared to just 56 percent of men. Due to hypercompetitive social norms in a shame-based Confucian society such as Singapore, women are disincentivized from "marrying down" to men with lesser income and lower educational qualifications, as this would mean a significant "loss of face" (丢脸) for them and their families.
The major challenge in the clinical application of MGRT in ooplasmic transfer to improve the egg quality of older women undergoing IVF is the shortage of available donors and the relative scarcity of donor eggs. This problem is further exacerbated by strict laws in Singapore that ban payment to egg donors, as specified by the Human Cloning and Other Prohibited Practices Act of 2004.
However, rapid progress in the field of in vitro gametogenesis (IVG) might provide a solution to this problem of donor egg shortage, by enabling the scaling-up and mass production of laboratory-grown human eggs from reprogrammed stem cells (i.e., induced pluripotent stem cells - iPSCs). Already, there have been promising results with mice and rats. Research teams in Japan and China have successfully produced healthy live offspring using IVG-derived sperm and eggs from the skin cells of mice and rats, which could in turn reproduce normally to generate subsequent generations of healthy offspring. More intriguingly, researchers were even able to create mice with two "dads" by utilizing IVG technology to derive eggs from one of the male parents. Similarly, mice with two "mums" have also been created by deriving sperm from female mice. Such scientific advancements will likely be translated from rodent models to human clinical applications in the near future.
Nevertheless, given the technological complexity and labor intensity of the IVG procedure, the costs are expected to be very high, so it is anticipated that this procedure can only be afforded by the rich. However, bespoke IVG for individual patients who can afford the procedure is expected to produce a surplus of laboratory-grown eggs that can be readily donated to other patients in need. Moreover, once the skin cells of individual patients have been reprogrammed into iPSCs, these are theoretically immortal and can perpetually be utilized for mass-production of donor eggs, thus facilitating scaling-up of a continuous production cycle that would ultimately cut costs through "economy-of-scale". Hence, for many poorer older women who cannot afford bespoke IVG for themselves, ooplasm donation from surplus IVG-derived oocytes offers a much cheaper alternative for improving their egg quality to conceive a genetically related child of their own. However, some pertinent legal and ethical challenges have to be addressed before such a technique is permitted in Singapore.
First, there is the issue of informed consent in the procurement and donation process. In particular, there is a risk that once the IVG process is initiated for some fee-paying individual patients who can afford the procedure, the process will be kept continuously running to produce surplus eggs for donation, without the patient's knowledge and consent. This is because it may be more economical to obtain surplus IVG-derived donor eggs from a continuously running and scaled-up production cycle, rather than starting the entire IVG process from scratch. Hence, there is a dire need for a rigorous vetting process to ensure informed consent from patient donors, together with regular impromptu spot-checks and stringent audits of laboratories handling the IVG procedure. It must be noted that human mitochondrial genome diversity is sufficient to enable molecular tracking of the donation process (i.e., mitochondrial DNA sequencing), which should be enforced ad hoc if there is any suspicion of duplicity or foul play during the procurement and donation consent process.
Second, there is the question of whether the donors of IVG-derived eggs should be fairly reimbursed or compensated for their donation, since they would have spent so much of their own money on the IVG procedure. This might, however, conflict with current Singapore healthcare regulations that ban payment to egg donors, in particular the "Human Cloning and Other Prohibited Practices Act" of 2004. While there are certainly valid ethical concerns about undue financial inducements of egg donors and commercialized egg trading, such ethical problems are arguably less severe in the case of financial reimbursement for the donation of surplus lab-grown eggs produced via IVG. This is because it can be justified that the patient donors are only getting a partial refund of the large sum of money that they have already spent on the IVG procedure, so the issue of undue financial inducement is much less problematic than in the case of monetary payments to non-patient egg donors.
Third, there is the question of whether the donation of IVG-derived eggs predominantly to overcome age-related infertility rather than prevent mitochondrial diseases is medically justifiable, given that the problem of chromosomal aberrations in the eggs of older women will not be overcome by mitochondrial/ooplasm transfer. Hence, older women must be made aware that whole egg donation (whether derived from IVG or conventional donors) may be expected to yield higher pregnancy success rates than ooplasmic transfer from donated surplus IVG-derived eggs. This is because the problem of chromosomal abnormalities in their own "aged" oocytes cannot be overcome through such a technique. Hence, there must be transparent advertising standards and comprehensive counseling to ensure that older women are properly informed of the limitations and risks of such a procedure.
Finally, there are lingering concerns about the possible reduction of human mitochondrial genome diversity within the population via widespread ooplasmic donation from relatively few patient donors undergoing the IVG procedure. Nevertheless, it must be noted that compared to the nuclear genome, human mitochondrial DNA (mtDNA) exhibits a relatively low level of diversity, with most individuals sharing a near-identical sequence. Currently, it is unknown how a possible reduction in mitochondrial genome diversity due to widespread ooplasm donation might exert detrimental effects on public health. Caution and restraint must therefore be exercised in this regard, and efforts must be made to widen the available pool of ooplasm donors from patients undergoing IVG. Perhaps, it may be prudent to put a cap on the total number of donations that can be made from a single ooplasm donor, as in the case of conventional egg donation. For example, in Singapore, there is currently a limit of five live births per egg donor.
In conclusion, these aforementioned ethical issues must be properly addressed with relevant regulatory safeguards being put in place before Singapore permits the donation of surplus IVG-derived eggs for ooplasmic transfer to improve egg quality in older women, as a solution for overcoming the increasingly prevalent problem of age-related female infertility in the country.
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