It’s a test that promises to give a once-over to an embryo before it even gets a shot at becoming a baby, by counting its chromosomes.
But, does it work?
That’s still a matter of debate.
By Alison Motluk
This chromosome-counting technology is called “preimplantation genetic testing for aneuploidy” or more commonly, PGT-A. The idea is that an embryo with the correct number of chromosomes is more likely to be healthy and therefore, less likely to be miscarried. And that should speed up the time it takes to become a parent.
The U.K.’s fertility regulator, the Human Fertilisation & Embryology Authority, gives PGT-A a red light, saying there is “no evidence” from randomized controlled trials that it improves a patient’s chance of having a baby. A study last year in the New England Journal of Medicine concluded that in women with a good prognosis, regular old in vitro fertilization (IVF) worked just as well without PGT-A. A few U.S. fertility doctors have gone even further, declaring the technology a “dead end” and calling for it to be restricted to research.
Yet PGT-A is offered far and wide, and many fertility doctors consider it useful. Some even call it “revolutionary” and believe that all patients should have the option of using it. PGT-A involves making a small hole in the outer shell of a five- to seven-day-old embryo, which has reached the blastocyst stage, then using a tiny pipette to suction out a half dozen or so cells.
These cells, plucked from the trophectoderm — the part of the embryo that will go on to form the placenta, not the baby itself — are sent to a specialized lab for testing. In the meantime, the embryo is quick-frozen and stored until the results come back a few weeks later.
A healthy person has 46 chromosomes. If all of the biopsied cells have the correct complement, the embryo is deemed euploid, or good. But if all of them have, say, three copies of chromosome 18, which means the baby could die before or shortly after birth, it will be deemed aneuploid, or not good. Sometimes there’s a mix of good and bad, which is called “mosaic,” and other times, though rarely, the results are simply “inconclusive.”
The process isn’t cheap. It can cost anywhere from $3,000 to $8,000 per cycle, say experts. Despite the controversy and cost, PGT-A is becoming increasingly popular in Canada. According to the Canadian Assisted Reproductive Technology Register, 3,974 IVF cycles used PGT-A in 2020, up from just 160 in 2013. That means 26.1 per cent of all IVF cycles used PGT-A in 2020 compared with just 1 per cent seven years earlier. But doctors remain divided.
“PGT-A is one of the real revolutions in reproductive medicine,” says Crystal Chan (MD ’07, MSc ’12, PGME ’13, ’15), an assistant professor in the Temerty Faculty of Medicine’s Department of Obstetrics and Gynaecology.
The first big revolution, says Professor Chan, was being able to make embryos outside of the body, be it through IVF, in which sperm and egg are placed together in a petri dish, or by intracytoplasmic sperm injection (ICSI), in which sperm is injected into an egg.
The first outside-the-body conception that led to a live birth occurred in the U.K. in 1978 with the birth of Louise Brown — 44 years ago. The second revolution, says Chan, was being able to vitrify and therefore store excess embryos for future use.
PGT-A, which gives us a way to select which embryos to use, and in which order to use them, is the third big revolution, says Chan, who is also a reproductive endocrinologist and infertility (REI) specialist, and a co-owner and the scientific director of Markham Fertility Centre.
PGT-A is commonly recommended for people who are older, have recurrent implantation failure or unexplained infertility, or who have already given birth to children with chromosomal abnormalities. People wanting to reduce the length of time it takes to get pregnant are also advised to consider it.
Chan, who describes Markham Fertility Centre as a “genetics-forward kind of clinic,” offers PGT-A to all of her patients as an option.
“I always talk about PGT-A when I’m talking about IVF,” says Chan. She points out that everybody makes aneuploid embryos. “It doesn’t matter if you’re 22 years old or 42 years old,” she says. Chan is not alone. Other fertility experts are also in favour of the procedure.
Heather Shapiro (PGME ’92), an associate professor in Temerty Medicine’s Department of Obstetrics and Gynaecology, says her patients use PGT-A for a variety of reasons, including avoiding a miscarriage. Miscarriage may not be a big deal for some people, she says, but for others, it can be traumatic.
“There’s a lot of data showing that people abandon treatment more often after miscarriage than after just a failed IVF cycle,” says Professor Shapiro, who is also an REI at Mount Sinai Fertility and Director of the MHSc embryology program at Temerty Medicine.
Enthusiasts notwithstanding, the scientific literature on PGT-A remains equivocal about the benefits. Does the procedure help patients who suffer recurrent pregnancy loss? There is “insufficient evidence.”
Does it help women over age 35 achieve a viable pregnancy more quickly? No randomized controlled trials have tried to answer that question. Most important of all — because this is the only real point of assisted reproduction — does PGT-A improve the chance of going home with a baby? The answer is no.
Despite the controversy and cost, PGT-A is becoming increasingly popular in Canada
Both Chan and Shapiro acknowledge that PGT-A does not increase the likelihood of giving birth to a baby in any given IVF cycle. “It’s not going to make a bad embryo good,” says Chan. But could PGT-A actually make a good embryo bad? That has been a lingering question.
One concern is actual damage to the embryo by taking out a few cells from the trophectoderm. Placental tissue is extremely important for implantation, says Robert Casper, a professor emeritus at Temerty Medicine’s Department of Obstetrics and Gynaecology. A trophectoderm biopsy could actually reduce the chance of implantation, says Professor Casper, who is also the Scientific Director at and a founding partner of TRIO Fertility in Toronto.
Another, perhaps larger, worry is that PGT-A might be relegating perfectly good embryos to the trash bin. At issue is whether cells that go on to become the placenta really give an accurate picture of the inner cell mass, which becomes the fetus. (It’s widely agreed that it would not be safe to take cells from the inner cell mass.)
Shapiro is confident that “the biopsy is a pretty good representation of what’s happening in the whole embryo.”
Chan also thinks so, but cautions that PGT-A is not a diagnostic tool but a screening test. “No screening test in all of medicine is completely accurate,” she says.
All patients considering PGT-A at both Markham Fertility Centre and Mount Sinai Fertility see a genetic counsellor to understand the benefits and limitations. Casper is less convinced. He thinks the findings from PGT-A could be misleading. The trophectoderm, he says, can have a variety of cell lines and “doesn’t always reflect what’s actually going on with the baby.”
But if you happen to pick up all abnormal cells, the embryo will be discarded. “My recommendation to my patients, at least right now, is if you have a small number of embryos, three or fewer, you shouldn’t do PGT-A,” says Casper. Because it’s way too risky that you could throw away a normal embryo, and you’ve only got a few to work with.”
Even a mix of good and bad cells can present a problem. Until recently, such mosaic embryos were considered unusable and tossed out. Recently, however, physicians have been cautiously transferring mosaic embryos — and finding that they often develop into what appear to be perfectly healthy babies.
The Canadian Fertility and Andrology Society, an advisory body for fertility care professionals, has published a guideline on PGT-A. (Chan is one of the guideline authors, and Shapiro sits on the clinical practice guideline committee that helped develop it.)
The guideline suggests that in select patients, PGT-A can “improve the likelihood that a transferred embryo will lead to a viable pregnancy,” but concludes that “the current data do not support the universal use of PGT-A for all patients undergoing IVF.”
Karin Hammarberg, a registered nurse and senior research fellow at Monash University in Melbourne, Australia, wonders how well people understand the limits of PGT-A and its risks, at least when it comes to how the test is used in Australia. “People pay an awful lot of money for this,” she says.
Hammarberg and colleagues studied how Australian clinics portrayed PGT-A on their websites and found that the benefits tended to be highlighted and the risks minimized.
“I think the gap is in the transparency and the accuracy of information,” she says.
She thinks patients need to carefully consider whether they will really benefit from PGT-A. What are the risks? What are the costs? What are the other options? And what happens if they just forego this sort of testing altogether?
“I think most people are able to make very good decisions for themselves,” says Hammarberg, “as long as they have accurate and really transparent information.” ●