IVF genetic testing (PGT-A) very much in doubt and under scrutiny

[Angelica Cheng]

PGT-A under the Spotlight | Stanford Law School

The birth of the first in vitro fertilization (“IVF”) baby, Louise Brown, in 1978 gave hope to thousands of people suffering from infertility. Sin

law.stanford.edu

PGT-A under the Spotlight

The birth of the first in vitro fertilization (“IVF”) baby, Louise Brown, in 1978 gave hope to thousands of people suffering from infertility. Since then, new technologies have been developed as add-ons to IVF. These add-ons are not integral to the IVF procedure, however, they are being sold to consumers on the basis that they will increase the chances of having a live birth. One add-on to IVF is preimplantation genetic testing for aneuploidies (“PGT-A”).

PGT-A is a test used to determine if there are any abnormalities in the number of chromosomes of embryos (aneuploidy). Aneuploidy mostly leads to spontaneous abortions and causes recurrent pregnancy loss, however, in some cases, aneuploidy embryos are viable and give rise to living birth. Children born with aneuploidy have genetic conditions such as Down Syndrome, Turner Syndrome and Klinefelter Syndrome. PGT-A tests are marketed as an add-on to IVF which will increase implantation rates and decrease miscarriages, and overall increase the chances of a successful live birth without genetic abnormalities.[1] Despite the high costs of PGT-A as an add-on to IVF, it has become appealing to consumers since it is marketed by the fertility industry as a “mature technology and an established diagnostic test”.[2]

To perform PGT-A tests, DNA has to be obtained from embryos for analysis. The approach most widely adopted in practice today to obtain DNA for PGT-A testing is by performing a biopsy from a blastocyst 5-6 days after conception. The blastocyst is made up of embryonic cells and extraembryonic cells. The embryonic cells form the inner cell mass of the blastocyst, which will lead to the development of the fetus, and the extraembryonic cells form the trophectoderm of the blastocyst which will form the placenta. The biopsy is performed from the trophectoderm which is made up of extraembryonic cell lineage cells. This extraembryonic cell DNA is analyzed to determine if the embryo contains a normal or abnormal amount of chromosomes. The number of chromosomes detected from the biopsied cells is interpreted to be representative of the entire embryo, to establish which embryo will be transferred for implantation.

The standard guidelines that have been followed for years by most fertility clinics are that if an embryo contains a normal amount of chromosomes (euploidy) the chances of successful implantation and live birth are higher than when an embryo with an abnormal amount of chromosomes (aneuploid) is transferred. There is however a gray area of interpretation in PGT-A results when the results indicate that an embryo is a mosaic, which is when some of the DNA indicates that the embryo is a euploid and other cells indicate that the embryo is an aneuploid.

The Preimplantation Genetic Diagnosis International Society (“PGDIS”) issued a position statement in 2016 on chromosome mosaicism. According to this statement, they suggested the range for defining an embryo as having chromosome mosaicism is if the amount of aneuploid DNA is between 20% – 80%. If an embryo has less than 20% aneuploid DNA then it is considered to be a euploid (normal) and ready for transfer, however, if it has more than 80% aneuploid DNA, it is considered to be an aneuploid (abnormal) and should not be transferred.[3] If an embryo falls within the 20-80% range of aneuploidy, the transfer should only be considered after obtaining expert advice and genetic counseling. This standard has been followed by fertility clinics conducting PGT-A tests since 2016 without confirming the hypothesis that an embryo with 20%-80% aneuploidy will be more likely to lead to chromosomal abnormalities and a lower possibility of a viable pregnancy.

PGT-A accuracy and effectiveness

The success rate of PGT-A tests has recently been questioned following the publication of studies which shed light on PGT-A test data. In 2019 the STAR study was published which compared the live birth rate of patients who underwent PGT-A tests on their embryos before transfer for implantation, and patients whose embryos only underwent morphological assessment before transfer for implantation. The data revealed that there was no significant increase in live birth rates, or decrease in miscarriage rates among patients who performed PGT-A tests, compared to those who only performed morphological assessments.[4]

The standard set by the PGDIS has also been questioned based on the cell lineage from which the DNA for PGT-A testing is obtained.[5] As mentioned above, the biopsy for DNA is from the trophectoderm which consists of extraembryonic cells. These cells will go on to form the placenta and not the fetus itself, and therefore differ from embryonic cells. One key distinction between extraembryonic cells and embryonic cells is that embryonic cells can self-correct their number of chromosomes as opposed to extraembryonic cells, who if contain an abnormal amount of chromosomes cannot self-correct. The notion of self-correction in embryonic cells was recently illustrated in a study which revealed that in a mosaic embryo, the euploid embryonic cells rescue some of the aneuploid embryonic cells.[6] Another study on embryos, which were considered to be abnormal following a PGT-A trophectoderm biopsy test, reported 8 live births with a normal amount of chromosomes from these “abnormal embryos”.[7] These findings challenge our current understanding of the accuracy and effectiveness of PGT-A tests performed on trophectoderm cells and the subsequent if embryos should be transferred or not.

These question marks that have been placed over the accuracy and effectiveness of PGT-A tests raise a few questions: if PGT-A tests are not as accurate and effective as claimed by the fertility industry’s marketing campaigns, should they still routinely be used as an add-on to IVF cycles? How many false positive mosaic or aneuploid embryos have been disposed of due to the standards that the industry has set? How many people were indeed able to have their own genetic child, but due to false positive mosaic or aneuploid embryo results used other alternatives such as gamete donation or adoption?

 

[Angelica Cheng]

PGT-A regulation

The United States currently has one of the most permissive regulatory frameworks for PGT-A with no federal or state statutes, legislation or regulations. The Food and Drug Administration (“the FDA”) does also not provide any oversight over the PGT industry and has never approved or validated the PGT-A test. Private parties such as professional societies have taken regulation into their own hands and have issued policies, guidelines and standards, however, this self-regulation is without enforcement and it is left up to the provider and the consumer to decide to what extent the policies, guidelines and standards are followed.[8]

Given the recent scrutiny of PGT-A’s accuracy and effectiveness, the regulatory lacuna surrounding PGT-A has also been under the spotlight. Arguments against the federal regulation of PGT-A list the lack of federal funding for IVF and subsequent PGT-A as one of the reasons why the federal government should not get involved in its regulation. Further, since the FDA is not regulating clinical practices, the absence of a federal agency responsible for the regulation in this field would complicate federal regulation. The current debate around abortion, which is in close proximity to the IVF and PGT debate, also suggests that Congress is unlikely to pass a federal law governing PGT. Individual states could attempt to regulate PGT-A, however for the same reasons as mentioned above, regulation by individual states will also not be without difficulty.[9]

On the other hand, it has been argued that given the lack of knowledge on the accuracy and effectiveness of PGT-A, stricter regulations should be in place and such regulations should come from the industry itself.[10] Multidisciplinary committees that will not only have the best knowledge of the state of the technology and industry itself but who will also act in the best interest of the consumers should be considered. This will allow for the ethical application of PGT-A in cases where it is deemed necessary for the benefits to outweigh the costs until more robust evidence is available on the accuracy and effectiveness of PGT-A.

PGT-A comes with promising applications, and rightfully so, as it gives people suffering from infertility and genetic heritable diseases increased chances to have the family they desire. However, the group of people seeking to use PGT-A as an add-on to their IVF cycle is in a vulnerable position. The majority of people going through IVF are desperate for it to be successful given not only the high costs of IVF but also the physical and emotional toll that it takes. IVF is a high-risk high-reward industry, and the add-ons to IVF are being sold as something that will add to the high-reward equation of IVF.

The market for PGT-A is driven by desperate customers, who most of the time do not have extensive knowledge of the accuracy and effectiveness of PGT-A other than the information that is being told to them. When faced with a decision on whether they should utilize PGT-A, which on the face of it seems to add to the high-reward side of IVF, it is almost a “no-brainer”. The PGT-A market has therefore grown to such an extent that today almost all fertility clinics provide this add-on to their IVF menu.

Reasons to be concerned about the PGT-A market and its regulation are twofold. Firstly, consumers are being sold products that “overstate the benefits and underestimate the losses.”[11] Consumers are not fully informed about the accuracy and effectiveness of PGT-A while fertility clinics, knowingly or unknowingly, benefit from this information gap. It has been argued that the PGT-A market is unique in the sense that it is harder for consumers to objectively conclude if the service (PGT-A testing) is worth purchasing or not since each consumer’s decision will depend on their own personal circumstances.[12] The market will therefore not be able to correct itself if the service is not as effective, and it might be necessary for regulatory intervention to protect consumers.

Secondly, the demand for PGT tests will increase in the future. It has been argued that with whole-genome sequencing becoming more accessible and cheaper, together with the promise of induced pluripotent stem cells, we will enter an era of “easy-PGT” making PGT tests easily accessible and cheap, which will in turn drive up its demand.[13] Another factor that might increase the demand for PGT-A in the near future is the recent ban on abortion in some individual states. With less access to abortion, people who are worried about passing genetically heritable diseases to their offspring, are more likely to utilize PGT-A to be more certain about their offspring’s genetic makeup, since the option of an abortion at a later stage is less likely.[14] With this increase in the demand for PGT-A, if the standards upon which PGT-A results are being interpreted are not scientifically tested and accurate, we might see PGT-A causing a decrease in the live birth rate of IVF.[15]

Both of these concerns regarding PGT-A point towards areas where regulation, from either the government or the industry itself, might be a helpful solution. Regulation surrounding the marketing of PGT-A and the type of informed consent obtained from patients before undergoing PGT-A might assist in customers making an informed decision based on reliable data. Further, regulation based on scientifically tested standards for transferring viable embryos for implantation might be a solution, to instead of decreasing the live birth rate of IVF, allowing PGT-A to live up to the promise for which it was created, increasing the live birth rate of IVF.

If the current regulatory framework for PGT-A remains as is, I cannot help but wonder if the PGT-A industry will follow the same regulatory trend which is currently being observed in Big Tech companies like Facebook and Google. Starting off with the utopia of all the wonderful promises that they bring, and a few years down the line, after a few scandals with real-life consequences, being viewed as a state of dystopia, with governments and lawmakers trying to play catch-up to fix and regulate the unintended consequences of a billion dollar self-regulated industry.

This is not to say that no good can come from PGT-A. It is a powerful technology which should be applied within unambiguous scientifically tested guidelines and standards.

[1] Joyce Harper et al., Adjuncts in the IVF laboratory: where is the evidence for “add-on” interventions?, 32 Hum Reprod 485 (2017).

[2] Richard J Paulson, Hidden in plain sight: the overstated benefits and underestimated losses of potential implantations associated with advertised PGT-A success rates, 35 Human Reproduction 490 (2020).

[3] PGDIS Newsletter, July 19, 2016. PGDIS POSITION STATEMENT ON CHROMOSOME MOSAICISM AND PREIMPLANTATION ANEUPLOIDY TESTING AT THE BLASTOCYST STAGE, https://www.pgdis.org/docs/newsletter_071816.html

[4] Santiago Munné et al., Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial, 112 Fertility and Sterility 1071 (2019).

[5] Norbert Gleicher et al., The uncertain science of preimplantation and prenatal genetic testing, 28 Nat Med 442 (2022).

[6] Min Yang et al., Depletion of aneuploid cells in human embryos and gastruloids, 23 Nat Cell Biol 314 (2021).

[7] D H Barad et al., IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study, 37 Human Reproduction 1194 (2022).

[8] Jack Wilkinson et al., Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons, 112 Fertil Steril 973 (2019)

[9] Michelle Bayefsky, Who Should Regulate Preimplantation Genetic Diagnosis in the United States?, 20 AMA Journal of Ethics 1160 (2018).

[10] N. Gleicher et al., The 2019 PGDIS position statement on transfer of mosaic embryos within a context of new information on PGT-A, 18 Reproductive Biology and Endocrinology 57 (2020).

[11] Paulson, supra note 2.

[12] Wilkinson et al., supra note 8.

[13] Henry T. Greely, The End of Sex and the Future of Human Reproduction (2016).

[14] Henry T Greely, The death of Roe and the future of ex vivo embryos, 9 Journal of Law and the Biosciences lsac019 (2022).

[15] N Gleicher, V A Kushnir & D H Barad, Worldwide decline of IVF birth rates and its probable causes, 2019 Human Reproduction Open hoz017 (2019).