PGS testing explained

We have been receiving a lot of questions from readers on Preimplantation Genetic Screening (PGS) and we wanted to know more and so turned to a fantastic embryologist, Danielle Breen, for answers . . .

Reader’s question

Q: “I have had 2 failed rounds of IVF. Both rounds ended in miscarriage. I am scared to have another round of IVF in case I miscarry again. Do you think I should go for PGS? Do you think my embryos are ‘faulty’ and causing my miscarriages? Would PGS testing help? Should I ask for this test?”

A: Firstly, I am sorry to hear about your losses and completely understand your fear of that heartache a third time. PGS, is when a biopsy of cells from the embryo is taken to check the number of chromosomes that it has. Studies on the products of conception, which have sadly miscarried, showed that in approx 70% of miscarriages this was due to chromosomal imbalances.

So although not all miscarriages are due to chromosomal abnormalities, PGS  testing would ensure that this potential reason for pregnancy failure or loss is eliminated.

My recommendation would be to talk to the medical team at your clinic, for them to use your cycle and medical history to advise if they think PGS is a suitable treatment option for you. For example, by reviewing your blastocyst development rates in your previous cycle as PGS is routinely performed on Day 5 or 6 so your embryos must reach blastocyst stage to be tested.

The terminology explained

What is PGS testing?

PGS, or more recently renamed PGT-A, is when a biopsy of cells from the embryo is removed to check the number of chromosomes that it has.

(PGS stands for Preimplantation Genetic Screening and PGT-A stands for Preimplantation Genetic Testing for Aneuploidies).

PGS can only be performed on fertility treatment cycles involving an egg collection, to screen embryos created in the lab, before an embryo transfer is planned. This enables the selection of the embryo with the best chance of implanting and achieving a successful and healthy pregnancy, based on the genetic status of the embryo. PGS also avoids using embryos that would fail to implant or create abnormal pregnancies that would either miscarry or lead to fetal abnormalities.

Can you explain what chromosomal abnormalities are? If your embryo has any chromosomal abnormalities at all, will you miscarry or fail to implant?

The egg and sperm each contain half the genetic material needed to make a normal healthy baby. PGS checks that the number contributed by each the egg and the sperm at the point of fertilisation, add up to the correct and balanced total number.

The egg and sperm should contain 23 chromosomes each. At fertilisation these chromosomes pair up, to make a total of 46 chromosomes in the embryo, set as 23 pairs.

A well known example of an error in the chromosome number, which can still result in pregnancy and live birth is Down Syndrome, when there are 3 copies of chromosome 21 instead of 2 copies. However, when there are errors in the total number of chromosomes, the embryo is most likely to fail to implant or miscarry.

How is the procedure carried out?

The biopsy is usually performed on Day 5 or 6, at the blastocyst stage of development. At this stage the embryo has many more cells, so the biopsy process of removing approx. 5 or so cells has minimal impact on the total cell mass of the remaining embryo.

Another reason we perform the procedure on blastocyst stage embryos is that at this stage the embryo will have specific cell populations; the inner cell mass which would go on to develop into the baby and the outer layer of cells which would go on to for the placenta. During the biopsy procedure we would only ever remove cells from the trophectoderm layer for testing.

In preparation for the biopsy a small hole is normally made in the shell of the embryo, usually on D3. This ensure that as the embryo grows, becoming a blastocyst, the outer layer of cells naturally begin to escape (hatch) out of this hole, making it easier to remove these cells for testing.

The procedure involves using special microscopes which have micromanipulation tools attached to them and a special laser beam that can be used to safely separate the joining cells in order to remove the sample for testing. Once the biopsied cells have been removed, the blastocyst itself is frozen to allow the time necessary for the genetic testing to be completed. The biopsied cells are also frozen and transported to the genetics lab for testing. The genetics tests cannot be performed in the fertility clinic because they require destroying the cells to release and sequence the DNA (chromosomes) stored inside them.

What is the difference between PGS and PGD?

Both of these procedures involve removing cells for Preimplantation Genetic Testing.

PGS is where the ’S’ stands for Screening and is done to check the total number of chromosomes in the embryo. This is part of a screening tool to help select the embryos with the best potential. PGS is often referred to as a cycle add-on as patients’ can chose to have this as an additional procedure to try increase their chances of a successful pregnancy/reduce their chances of miscarriage or failure.

PGD is where the ‘D’ stands for Diagnosis and is done to confirm the genetic status of an embryo. This is part of a diagnostic tool to help select embryos without risk of inheritable genetic conditions. PGD is applicable when either one, or both of the potential parents know that they have a genetic condition in their family bloodline, which they are at risk of passing on to children of their own. PGD requires more special work-up prior to the embryo biopsy, to ensure the testing is tailored to the individuals and the condition that the diagnosis is screening for.

How do you find out if the creation of the abnormal embryo was the ‘fault’ for want of a better word, of the man or the woman?

In the same way that we can’t always link embryo quality back to either male or female origin. It is not always evident whether the source of a genetic error was the sperm or the egg.

However, we do know that errors with the eggs chromosomes is significantly linked with female age. Something that not everyone is aware of is that a female is born with every egg she will ever have. Meaning that every year a lady ages, her eggs are also aging. Unfortunately this means that by the time a lady is in her early 30s, on average a third of embryos created from her eggs will have chromosomal abnormalities. This is something reinforced by the evidence that the risk of miscarriage and Downs Syndrome increase significantly with female age.

So for women aged 40 or over, unfortunately the most likely source of the genetic ‘fault’ is the woman’s eggs.

If you can find out if it is down to the man or the woman, what do you do?

If the cycle and medical history has revealed a strong indication of a issue with either the sperm or eggs, resulting in abnormal embryos there are 2 options:

• Batching cycles of PGS to biopsy as many embryos as possible to try and improve the chances of finding ‘normal’ embryos for transfer.
• Gamete donation options, such as the use of donor eggs. All egg donors in the UK must be under the age of 36 years and therefore have much lower chances of chromosomal abnormalities.

What happens if all of the embryos are abnormal?

Sadly this is one of the biggest risks with PGS, that you either fail to make blastocysts, and nothing is suitable to biopsy, or that all the biopsied embryos are confirmed as abnormal.

Legally clinics cannot transfer an abnormal embryo in the instance that a normal embryo is available. In the absence of any normal embryos, most clinics would still advise against the transfer of genetically abnormal embryos due to the correlation with miscarriage and risks of fatal abnormalities.

Both genetic counselling and local clinic support/counselling is available to all patients undergoing PGS.

Is there a way of making healthier embryos next time, on another round?

The most significant impact on embryo aneuploidy (incorrect chromosome number) is the age of the egg. Therefore the best chance of increasing embryo health is to avoid delaying starting a family. Very little else can be done to impact egg health, as they are made before a lady is even born.

Sperm DNA integrity is thought to be impacted by social and environmental factors e.g. smoking, diet, testicular temperatures etc. and therefore reducing these to improve sperm DNA fragmentation may help.

Are there any risks to the embryo when the test is carried out?

The embryo Biopsy procedure has been modified to the blastocyst stage embryo to ensure minimal risk and damage to the embryo. On average <5% of embryos are damaged by the procedure, these are usually reduced quality embryos that were borderline criteria for biopsy suitability.

Are they any alternative tests that can assess the embryo in a less intrusive way?

No – Embryo biopsy is the only accurate way to assess the embryos genetic status and pregnancy potential.

Embryo grading has been proven to be unrelated to embryo genetic results and can therefore not substitute preimplantation testing.

There is ongoing research on the use of time-lapse monitoring to try identify embryo markers that could indicate genetic status, but none of these have been conclusive as of yet.

Is this a test you can request?

PGS is a significant additional procedure which requires adequate discussion and understanding before undertaking. Patient’s can request PGS, but this should be done with a member of the medical team to be able to fully discuss the benefits and limitations of the test in relation to each individual.

The patient groups that are most likely to benefit from PGS are

• Females aged over 40 using their own eggs
• Females with a history of 2 or more miscarriages
• Females with a history of previous abnormal pregnancies/live births
• Females with a history of multiple failed IVF attempts

Is it expensive?

Yes – due to the highly specialised procedure and genetic processing PGS can be a substantial additional fee on top of your IVF/ICSI treatment costs. Clinics may package the pricing depending on the total number of embryos biopsied.

If the embryos come back as normal, but you have a history of miscarriage of failure implantation, what should you do next?

Once you have confirmed ‘normal’ embryos with PGS in storage then every effort must be made to ensure the frozen replacement cycle is optimised to give each embryo the best chance of working.

As the embryos will have already been frozen as pat of the biopsy procedure, there is no rush to have the transfer performed in a set time period. This allows for any extra scans or tests which may be recommended to first ensure the endometrium is receptive and ready to try and establish pregnancy.

It is strongly recommended to have single embryo transfers (SET) using PGS confirmed normal embryos, as there is no benefit of using a second embryo which would only put you at risk of twins.

We can’t thank the fantastic Danielle Breen of Thames Valley Fertility, (part of The Fertility Partnership) enough for her wonderful explanations and advice.

Have you used PGS? Has it helped you? Are you considering preimplantation genetic screening? We would love to hear from you at mystory@ivfbabble.com or on social @ivfbabble