New research casts fresh doubts on genetic testing ( PGS / PGT-A ) for improving IVF success rates

[Angelica Cheng]

New research casts fresh doubt on a common procedure that promises to increase the odds of IVF

New research casts further doubt on a common — and controversial —procedure that promises to increase the odds of IVF.

www.statnews.com

New research casts fresh doubt on a common procedure that promises to increase the odds of IVF

A common in vitro fertilization procedure offered to patients with the promise of increasing their likelihood of successful pregnancy actually does not improve healthy patients’ chances of going home with a baby, according to new research published in the New England Journal of Medicine this week.

The study focuses on preimplantation genetic testing for aneuploidy, or PGT-A, which screens embryos for chromosomal abnormalities that could keep them from implanting. The diagnostic tool has been controversial for decades, since no rigorous studies have conclusively proven the test improves the odds of having a baby. Studies as far back as 2007 showed an earlier, more invasive version of the test, called PGS, harmed patients’ chances of having a child. Nonetheless, PGT-A has been sold to prospective parents across the world, bolstering the multibillion-dollar industry of reproductive medicine.

Clinicians and researchers told STAT say they believe most providers have good intentions, but they are still offering patients an unproven, expensive, and possibly risky procedure.

“I do not suspect that clinics have been performing PGT-A for financial reasons in face of the realization of the questionable evidence supporting it,” said Hank Greely, chair of the steering committee for the Stanford Center for Biomedical Ethics. “Instead, the procedure has seemed that it should work, or perhaps even must work, and so help prospective parents realize their dreams. But expectations, and hopes, need to be weighed by evidence and, right now, the evidence for widespread PGT-A screening is, at best, weak.”

The new research, a randomized controlled trial of 1,212 patients, found that PGT-A did not benefit women ages 20 to 37 with a good prognosis for live birth, when compared to conventional IVF.

“This raises the possibility that some patients may have paid for this expensive treatment, and in doing so, may have reduced their chances of having a baby through IVF,” said Jack Wilkinson, a research fellow at the University of Manchester in the U.K. who analyzes reproductive medicine data. “The result is in line with other good-quality studies which have failed to find any benefit of PGT-A.”

From July 2017 to June 2018, researchers at 14 academic fertility centers in China randomly split 1,212 patients into two groups: regular IVF and PGT-A. All of the patients were women who already had a good prognosis for live birth and whose eggs, when fertilized in IVF, resulted in three or more healthy blastocysts, or five-day-old embryos. Embryos that survive to the blastocyst stage stand a good chance of implantation once placed in the uterus. The researchers then followed patients for a year from when the women were assigned a group — tracking the success of up to three transferred embryos.

Those using donor eggs or sperm, with known uterine abnormalities, or with conditions that could make for dangerous pregnancies, were excluded from the study. Patients who planned to use other, noncontroversial versions of PGT to screen for genetic diseases like cystic fibrosis, or parental chromosomal issues, were also left out. All patients were entering their first IVF cycle, which is typically a month-long process that involves stimulating the ovaries, retrieving viable eggs, fertilizing them, growing an embryo in a lab and implanting the embryo.

Unlike other researchers who have studied PGT-A, the researchers in China who authored this multi-center study focused on what they call “the most important patient-centered outcome” — cumulative live birth rate — instead of success rate per embryo transfer, senior author Zi-Jiang Chen told STAT. In other words, the study asked: for a patient with a good prognosis, “What’s the chance I’m gonna take home a baby?” as Marcelle Cedars, president of the American Society for Reproductive Medicine, put it.

In the study, 77% of women in the PGT-A group had a live birth, compared to 81.8% of women in the conventional IVF group.

The data suggests, “in a good prognosis patient, you aren’t helping these people,” said Cedars, a professor of reproductive endocrinology and infertility at the University of California at San Francisco School of Medicine.

Yet Chen, the senior author, said, “We cannot completely deny PGT-A.” More research is needed to know if the test could help certain patient populations, experts said. For example, the study results suggest that those who received PGT-A had slightly lower rates of miscarriage, and that PGT-A patients became pregnant with fewer embryo transfers. Expanding the patient pool, including all available patient embryos in the study (instead of just three), and tracking outcomes from the very beginning of treatment, at the start of ovarian stimulation, would also paint a clearer picture, Cedars said.

Both proponents and critics of PGT-A will say there is evidence that the transfer success rate is higher with PGT-A than in conventional IVF. Since the test is used to identify and discard flawed embryos, leaving a pool of only the “strongest” contenders, the success rate per embryo transferred into a patient will automatically go up.

However, the chances of successful pregnancy overall don’t increase, because “you don’t add any embryos, you don’t pick embryos out of thin air,” said Sebastiaan Mastenbroek, a clinical embryologist at the Center for Reproductive Medicine at the Amsterdam University Medical Centers, who set off a firestorm when he published one of the first studies showing PGS could harm a patient’s chances of getting pregnant.

In simple terms: if a patient has six embryos, and two are discarded because a PGT-A screening found a problem, it’s the mathematical difference between dividing the number of successful pregnancies by the four remaining embryos, rather than the six at the start.

Many papers that focus on the success rate per embryo transfer don’t account for the embryos that were thrown out but could have been viable, Cedars and Mastenbroek told STAT. Studies have shown that even young embryos with chromosomal abnormalities can lead to healthy live births, since the test may show false positives or negatives, and genetic quirks may be weeded out during fetal development, or abnormalities may only be present in certain cell lines, and not all of them.

Those studies also don’t account for IVF treatments that were started but did not result in an embryo transfer or pregnancy because all embryos were labeled as aneuploid by PGT-A, therefore overestimating the success of PGT-A, Mastenbroek said.

In the past 20 years, “viable, healthy embryos have been thrown away in the bin and, with that, you’ve lowered the pregnancy rates of hundreds of thousands of women,” he told STAT. “That’s shocking.”

The NEJM study, which was led by Junhao Yan of Shandong Provincial Clinical Research Center for Reproductive Health, is one of several that have shown no improvement in cumulative live birth rates when patients undergo PGT-A. But still, there remains a paucity of high-quality, large-scale, randomized controlled trials, according to Mastenbroek, who conducted a systematic review and meta-analysis of scientific literature on PGT-A for the Cochrane Collaboration.

“If after 25 years, a field is not able to prove that something works, something is wrong, either with the technique, the information, or with the field,” he said.

Supplementary procedures, such as PGT-A — which is listed alongside dozens of other add-ons at IVF clinics in the U.S. and abroad — can be sold to patients even when there is little to no scientific evidence that they increase patients’ chances of having a child. Assisted reproduction is largely unregulated in the U.S. Because these procedures are not tested like drugs, IVF add-ons don’t need to be shown to benefit the patient before entering the market. Many of the add-ons rest on flimsy science and big marketing budgets, targeting patients desperate for anything that will improve the odds of having a child.

 

[Angelica Cheng]

PGT-A is one of the most widely used add-ons, though it’s difficult to say exactly how often it is used because of incomplete data reporting. Some clinics use the test on a majority of patients, while others rarely do — a divide that illustrates the ongoing debate about the test. “That, in itself, is very strange,” said Mastenbroek, who wrote an opinion piece to accompany the study in NEJM. He added that in conventional IVF, daily inspections of embryos under a microscope are effective at ranking embryos based on their implantation potential. So if PGT-A is shown to be bad at its primary task — accurately identifying non-viable embryos — its use would be extremely limited, possibly to the point of obsolescence, he said.

It’s somewhat difficult to study PGT-A in the U.S., given restrictions on federal funding for certain types of research involving embryos, Cedars said. Research from other countries is helpful, but reproductive medicine also works differently — frequently, in private practices owned by large companies — within the confines of the American health care system.

Much of reproductive medicine in the U.S. takes place in private clinics, so providers compete for patients. If a patient is insistent upon receiving PGT-A or another supplemental procedure, doctors might succumb to the pressure in lieu of losing a patient to someone else, said Mastenbroek, who does not offer PGT-A at his clinic.

For patients, it can be disorienting trying to figure out what is best, especially when jargon-laden scientific literature exists both in support of PGT-A and against it. And the difference, sometimes, to the untrained eye, is the splitting of a hair in the data.

A recent example: Earlier this month, a study came out suggesting PGT-A offered some benefits over regular IVF. Wilkinson, the Manchester biostatistician, calls the paper “critically flawed,” and said it compared “lots of apples with lots of oranges.” The senior author of that study, Darren Griffin of the University of Kent in the U.K., said, “PGT-A is targeted to patients of advanced maternal age, recurrent implantation failure, recurrent miscarriage,” and therefore he didn’t expect it to work in the younger, healthier patients Yan studied.

It’s a contradictory finding that only adds to the confusion among patients trying to muddle through the data. And the data on the treatment still doesn’t cut it, experts said.

“When a treatment hasn’t been adequately tested, the worst case scenario isn’t that it has no effect. It could actually make things worse,” said Wilkinson. “This point is usually ignored.”

 

[Angelica Cheng]

https://www.nejm.org/doi/full/10.1056/NEJMoa2103613#author_affiliations&uccLastUpdatedDate=2021-09-12%2004%3A39%3A23.44%20%2B0000&uccLastUpdatedDate=2021-09-12%2004%3A39%3A23.44%20%2B0000

Live Birth with or without Preimplantation Genetic Testing for Aneuploidy

Abstract
BACKGROUND
Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF).

METHODS

In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A.

RESULTS
A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, −4.6 percentage points; 95% confidence interval [CI], −9.2 to −0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, −3.9 percentage points; 95% CI, −7.5 to −0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups.

CONCLUSIONS
Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141. opens in new tab.)

https://www.nejm.org/do/10.1056/NEJMdo006264/full/

 

[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

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.