What Singaporean patients should know before doing PGS (embryo genetic testing) when going for IVF overseas

[Angelica Cheng]

There are plenty of arguments against doing preimplantation genetic screening - PGS / PGT-A, and it’s up to you to decide if they outweigh the pros…

PGS testing: is PGS worth it? (And how much does PGS cost?)

What is preimplantation genetic screening (PGS testing)? Who should use it? What are the pros and cons of PGS? Read this before going ahead with PGS testing

theduff.co.uk

Argument 1 against PGS: it’s expensive

Paying an extra $5,000 (ish) per cycle – on top of the $10,000 or so you’re already paying for IVF– is a LOT. Plenty of couples decide it’s better to put the money towards future cycles instead.

Argument 2 against PGS: you’ll have to freeze all your embryos

You have no choice about this: you’ll have to freeze all your embryos because there’s a delay in getting the results through. While many/most clinics now report frozen success rates on par with fresh ones, there’s still a risk that you may have a delicate euploid embryo that can’t survive the freeze-thaw process but would cope with a fresh transfer. Plus it means more waiting around before you can do an embryo transfer.

Moreover, there is evidence that the IVF embryos of older women don't survive the freezing process as well as the embryos of younger women. For older women, fresh embryo transfer is recommended:

Argument 3 against PGS: it gives patients a false sense of hope

Many patients aren’t really told what PGS attempts to achieve, and as a result they see it as something that will improve their chances of success.

PGS testing can improve a woman’s chances of faster success per egg retrieval procedure. (FYI When we say “per egg retrieval procedure”, it means “per batch of embryos created from one IVF cycle”. It could therefore mean “one embryo transferred” for one couple and “four embryos transferred – one after the other” for another couple.)

Why can PGS improve a woman’s chances of faster success per egg retrieval procedure? Because a chromosomally normal embryo will be selected for transfer first, whereas without PGS, no one knows if the embryo about to be transferred is euploid or not.

But if someone has zero euploid embryos after a cycle of IVF, PGS can only remove the time-wasting – not the heartache (or costs associated with each transfer).

Not only that, but we need to remember that plenty of euploid embryo transfers don’t implant/lead to miscarriage too – either because of bad luck, or because something else was wrong with the embryo.

As the American Society for Reproductive Medicine (ASRM) says, “Genetic screening may help identify couples who have an increased risk of age-related or familial genetic disorders and birth defects. No single test, however, can accurately predict the risk of all defects in a child, and many birth defects, such as those related to environmental and toxic exposures and those that are random and unexplained, are not genetically based and may not be detected with genetic screening.”

Argument 4 against PGS: there’s a risk the embryo will be harmed during the biopsy

There’s currently no evidence (for blastocyst-stage embryos) that this is the case. But at least one expert has pointed out that studies claiming no ill effects to embryos are often based on biopsies of excellent-quality, robust embryos rather than more “delicate” embryos that might suffer more.

If you have just one or two embryos, you might decide it’s not worth the risk.

(Note: some believe that there’s a higher prevalence of aneuploidy in couples undergoing IVF or another assisted reproductive technology when compared to embryos conceived naturally. Rather than blaming PGS for causing the aneuploidy, they suggest that people undergoing IVF are more likely to have a higher chance of creating aneuploid embryos in the first place.)

 

[Angelica Cheng]

Argument 5 against PGS: the sample of cells is unrepresentative (and therefore inaccurate)

There are a couple of issues here:

• Issue 1
  
  With PGS, usually five cells are biopsied from an embryo that contains anywhere from 80 to 200 cells.
  
  Let’s say all five cells come back euploid. These five cells are supposed to represent the entire embryo, and – while there’s definitely a chance that the other 150-odd cells in the embryo are aneuploid – it’s more likely that the embryo as a whole is (as the biopsy would suggest) euploid.
  
  When it comes to mosaicism detection, things get trickier. If, for example, one of those cells is aneuploid and the other four are euploid, the official diagnosis would be “low-level mosaicism”. Yet our biopsied sample might be unrepresentative, and we don’t really have any idea just how mosaic that embryo is. In fact, it could be the case that the other 150-ish cells are all perfectly euploid, and the one aneuploid cell is an outlier. Using the “20%” rule discussed earlier, that embryo should in fact be considered “euploid” and prioritised for transfer.
  
  This isn’t just a theory. Many times, scientists have taken discarded mosaics and re-tested the entire embryo; they’ve found (again and again) that the original diagnosis was inaccurate.

• Issue 2
  
  The cells biopsied are taken from the trophectoderm (the cells that eventually form the placenta). But many (like these authors) wonder how accurately a trophectoderm biopsy represents euploidy/aneuploidy in the rest of the embryo.
  
  Likewise, this article reports that “a trophectoderm biopsy specimen… might not necessarily be representative of the rest of the embryo in all instances… An important question is whether the proportion of abnormal cells in a mosaic biopsy specimen has any value for predicting the status of the remainder of the embryo.”

Argument 6 against PGS: the classifications are made up and arbitrary, and will therefore lead to throwing away perfectly good embryos

Some scientists don’t like the classifications given to different kinds of embryos with PGS 3.0. For example, these authors point out that, “The irrationality is… demonstrated by an embryo with 19 percent mosaicism now being allowed to be transferred as ‘normal'; yet an embryo with 21 percent aneuploidy load is considered ‘abnormal-mosaic'.”

These authors agree: “The demarcation at the lower end (20% aneuploid DNA) was a purely technical one based on the minimum sensitivity level of next generation sequencing (NGS) platforms… the sensitivity limitations of a piece of laboratory equipment now officially determine embryo fate.” Read their full report for a particularly scathing review of PGS classifications and methods.

As PGS 3.0 classifications are – by most admissions – completely arbitrary, is that right and fair? It could be argued that if PGS had never been conducted in the first place, we’d be none the wiser – and maybe that’s a better place to be.

Adding to the point above… some have found that once you have mosaic embryos on your hands, there’s barely any difference in pregnancy/birth rates – regardless of the extent of the mosaicism.

Argument 7 against PGS: there’s lots to suggest that mosaic embryos self-correct

Many specialists believe that mosaics are often able to self-correct their chromosomal abnormalities – although no one really knows why. (Various possible explanations have been suggested, but there’s nothing definitive.)

While the results of many studies imply that embryos diagnosed as mosaic have far worse prospects for survival (which in turn implies that only a certain amount of self-correction takes place), that doesn’t take away from the fact that many of them do seem able to self-correct.

Perhaps the low survival prospects among mosaics is because PGS is currently performed mainly on “high risk” embryos – that is, embryos from women who are older or who have a history of miscarriage.

Perhaps plenty of women not doing PGS have embryos that would be considered mosaic (even high-level mosaics), but they’re not being tested – and perhaps the “high risk” embryos have other reasons for miscarriage/implantation problems other than the abnormalities picked up by PGS.

Which leads to the question… if more women of all ages and risk profiles start opting for PGS in future, could we actually see pregnancy and birth rates decrease as a result – because women are being told their embryos are no good for transfer?

PGS seems to be becoming more and more popular, so we may well get our answer one day…

Self-correction and the potential of mosaic embryos to implant

www.focusonreproduction.eu

Are mosaic embryos the 'dark horse' of IVF?

Not every embryo contains 46 perfect chromosomes. Some have more, others have fewer. The result is a common abnormality known as aneuploidy, which occurs in as many as 80 percent of human embryos.

medicalxpress.com

Genetic testing IVF embryos doesn’t improve the chance of a baby

Women aged over 35 are sometimes offered genetic testing of their IVF embryos to rule out abnormalities. But it’s expensive and doesn’t increase their chance of a baby. In fact, it could reduce it.

theconversation.com

Abnormal cells in early-stage embryos might not preclude IVF success

The presence of an abnormal number of chromosomes in the genetic profile of early-stage embryos may be far more common - and potentially less threatening - during normal human development than is currently appreciated, according to new research from biologists.

www.sciencedaily.com

Abnormal cells in embryos might not prevent IVF success

Study shows that chromosomal abnormalities in embryos may be more common than previously thought, may lead to development of healthy babies during IVF

hub.jhu.edu

The transfer of chromosomally 'abnormal' embryos can still result in pregnancy in IVF: New study helps resolve controversy over self-correcting 'mosaic' embryos

IVF embryos whose cells have mixed chromosomal profiles -- one normal, another abnormal -- still have the potential to implant in the uterus and become a healthy pregnancy, according to a new study.

www.sciencedaily.com

Abnormal Cells In Early-Stage Embryos Might Not Preclude IVF Success « News from The Johns Hopkins University

Johns Hopkins University

releases.jhu.edu

Argument 8 against PGS: if your clinic is using PGS 1.0 or PGS 2.0, steer well clear!

PGS 3.0 has its problems (see above!), but earlier technologies had far worse issues. Find out which type of PGS your clinic offers before making a decision about whether to go through with it.

 

[Angelica Cheng]

So… is PGS testing worth it?

It depends. Many of those “cons” are only cons if you’re unaware of what PGS aims to achieve. If you decide to do PGS knowing full well what it’s for, and what it can and can’t do, you may well find it useful to have the information available to you.

But what about the fact that PGS testing might not be accurate?

Most studies suggest that PGS is very good at determining whether an embryo is euploid or aneuploid; it’s less good at figuring out levels of mosaicism. As embryos at all levels of mosaicism have been transferred successfully in the past, it seems to me that it makes the most sense to keep them all, rank them according to perceived mosaicism, and attempt to transfer them all (if necessary) over time.

As Michael Summers, Consultant at The Bridge Centre, says, the problems with accuracy in diagnosing mosaics mean we shouldn’t discard them after PGS testing. Instead, we should first order the embryos after conducting embryo grading, then shift “the rank order of embryos for transfer” after PGS, but keep hold of them all.

More and more clinics are following this model – but you’ll need to ask your own clinic what they do.

Anything else I should consider?

YES! A few random, unrelated points:

• Whether you do PGS or not, it’s a good idea to do a prenatal screening test once pregnant. Prenatal screening is a simple blood test combined with a scan, which tells you the odds that your baby has any of the three chromosomal disorders mentioned earlier that can survive pregnancy: Patau syndrome (“trisomy 13”), Down syndrome (“trisomy 21”) or Edward syndrome (“trisomy 18”).
  
  (While the vast majority of embryos that test normal with PGS and implant will have a normal number of chromosomes, there’s still a very small chance that PGS gave you a “false negative”. That’s why it’s still recommended to get prenatal screening.)
  
  If your screening test shows that there’s a high chance of a chromosomal abnormality, you can then – if you want to – have a more invasive test to get a definitive yes/no answer.

• If you’ve read my article on embryo grading, you’ll know that it’s another method embryologists use to determine the health of an embryo.
  
  As briefly discussed above, embryo grading is a largely subjective assessment of the “morphology” (the visual appearance) of embryos under a microscope. Certain visual characteristics imply that it has a better chance of implantation, pregnancy and birth.
  
  Annoyingly, an embryo’s “grade” seems to have almost no correlation with whether it has chromosomal abnormalities or not. The very most we can say is that if your embryo grades aren’t top notch, it mayyyybe increases the risk that those embryos have chromosomal abnormalities too. But there are plenty of examples to the contrary.
  
  Most embryologists agree that aneuploidy/euploidy is a far more important determining factor than an embryo’s grade. But we shouldn’t ignore embryo grading entirely – and I assume that embryologists would look at embryo grades AND PGS reports when deciding which embryo(s) to transfer.
  
  Here’s a story about a doctor who believes that “If you have a good-looking embryo, forget the aneuploidy,” and has successfully transferred aneuploid (!) embryos with a good morphology. It’s just one anecdote, but it shows how non-cut-and-dried these things are.

• Give some thought to your age (or your age when your eggs were collected). As we know from earlier, if you’re under the age of 40, your batch of embryos will contain about 40–50% euploids (ish) – so you might prefer to forego the PGS and try your luck. If you’re over the age of 40, your batch of embryos will contain about 10–20% euploids (ish) – so it might make more sense for you to do PGS.

• Warning: controversial opinion (which isn’t MY opinion!) coming up! Dr Geoffrey Sher, a renowned endocrinologist in the US, points out:
  
  “Given that about 50% of the eggs (and thus resulting embryos) of young women are euploid and competent, the transfer up to 2 non-PGS tested blastocysts would likely yield the same results as would the transfer of a single PGS-tested euploid blastocyst. It follows that a patient/couple who are capable and willing to engage a twin pregnancy (which would occur in roughly 25% of such cases), might get as good a result by simply transferring two (2) untested blastocysts and in the process avoid the additional cost of PGS.”