IVF, miscarriages and PGT-A / PGS genetic embryo diagnosis
Miscarriages are a constant worry in all pregnancies, not just those achieved through IVF. Patients who use assisted reproductive technologies are especially afraid of the possibility; often their journey has already involved much loss. What can be done to minimise the risk? If you suffer from recurrent pregnancy loss, what are your options?
To answer these questions – and more – we invited Dr Maria Arqué, the International Medical Director at Fertty International. She agreed to use her experience and knowledge to explain the topic of miscarriage to us in great detail.
IVF and miscarriages – real patients stories
– a couple who tried to conceive a child for two years – three spontaneous pregnancies with miscarriages
She began her presentation by introducing a couple of patient cases. The first case concerned Michelle and Mark who were a couple who tried to conceive a child for two years.
They had three spontaneous pregnancies together – all of them miscarriages (one with Down syndrome, one with Turner syndrome and one not analysed). Michelle was 43 years old, while Mark was 40. Fertty ordered a full panel of tests they usually perform in cases of recurrent pregnancy loss. Michelle’s tests all came back normal; she was clean for antiphospholipid syndrome, her karyotype was normal, and so was her thyroid function. Mark’s test were also normal.
The doctors concluded the miscarriages happened because of the advanced maternal age – Michelle was over 40 years old. Oocytes naturally decline in quantity and quality as a woman gets older, which was likely causing the miscarriages. Egg donation was proposed as a possible solution, as was PGT testing – both options, after all, significantly decrease the risk of miscarriage, and preventing the patients from going through more grief and disappointment was a high priority.
The patients decided to undergo an egg donation cycle with PGT-A testing; they ended up with five blastocysts, four of which were genetically normal. The best one was transferred and the other three frozen. Michelle and Mark had a positive pregnancy test and then a healthy live birth.
– 32 year old womand and 36 year old partner, trying to conceive for three years, two miscarriages between weeks 8 and 10
The second case concerned 32 year old Jeanna and 36 year old Peter, who were trying to conceive for three years. Jeanna had two miscarriages between weeks 8 and 10. Her tests came back normal but Peter had a sperm issue – oligoasthenoteratozoospermia. This mouthful of a term describes a condition in which the concentration, motility, and the morphology of sperm were considerably lower normal. The genetic fragmentation rates of the sperm were abnormal as well; the FISH test also revealed abnormalities. Doctors at Fertty recommended an IVF cycle with Jeanna’s own eggs and PGT to only select chromosomally normal embryos. Jeanna responded well to the stimulation, which resulted in three blastocysts, one of which was euploid. Transferring that embryo resulted in a healthy pregnancy.
Dr Arqué went on to explain that there is a natural decline in fertility that progresses with age. Women have a certain amount of eggs that they are able to produce; their number and quality goes down with age, becoming more pronounced after the age of 35. The drop in egg quality, in turn, causes increased miscarriage rates. The older the woman, the higher the chance her eggs will contain genetic defects.
Up to 75% of all conceptions will not result in full-term pregnancies; this applies to the population as a whole, not just to people struggling with infertility – genetic errors in embryos also occur in natural cycles.
What is the likelihood of having embryos that are chromosomally normal?
When the eggs are retrieved from the donor, we can reasonably expect that around 61% of the embryos are going to come back normal. When we’re 35 or younger, around half of the embryos are going to be euploid. Once we cross that limit, however, there’s a significant decrease in the amount of healthy embryos, which becomes even more severe after the age of 40. When we are over 42, less than 11% of embryos may be chromosomally healthy..
There is also an age-related decline in the number of live births for babies born out of cycles in patients who are using their own eggs. This is also caused by the decreasing quality of oocytes. However, using donor eggs live birth rate remains at a stable level, independent of any age-related factors.
PGT is a family of diagnostic technique used to determine if an embryo is chromosomally normal. Depending on the problem we are facing, we can use different techniques. One of them is PGT-A, which is used to detect aneuploidies. PGT-SR checks for any structural chromosomal abnormalities, such as reciprocal translocations, Robertsonian translocations, inversions, or deletions. When it comes to genetic abnormalities or specific mutations of some genes, PGT-M is used. It comes in handy especially if someone in either patient’s family is affected – thanks to PGT-M, embryologists can avoid creating embryos that are carriers or are affected.
PGT is performed on blastocyst stage embryos. A biopsy of the trophectoderm is performed and around five cells are taken out for analysis. The embryos are then vitrified while the results are being generated, which usually takes up to twenty days. If the embryo is healthy, the patient can carry on with an endometrial preparation and embryo transfer. If there are no viable embryos to transfer, the clinic arranges a consultation to discuss the next steps with the patient.
Thanks to PGT-A, we can avoid transferring aneuploid embryos, which increases the pregnancy rate per transfer, decreases the miscarriage rate, and increases the live birth rate.
PGT-A is a recommended diagnostic procedure for patients who are infertile or sterile, those who have hereditary diseases, those with chromosomal abnormalities, as well as those whose maternal age is over 38, those whose sperm quality is low, who have had several IVF failures, and others.
Other candidates for PGT-A are those who have had recurrent miscarriages. For those patients, a full panel of specific tests is performed. Around 60-80% of miscarriages are caused by chromosomal abnormalities – which is why PGT is recommended. The simple act of making sure the transferred embryo is chromosomally healthy provides a significant decrease in pregnancy loss rate.
Patients who are carriers of hereditary diseases caused by a mutation in a single gene should also consider PGT testing. Nearly 40% of cases of paediatric emergencies have a genetic basis. In Canada, 2-5% of the children born have genetic diseases or congenital alterations. Globally, 0.3% of all births are affected by monogenic diseases. Patients who have chromosomal reorganisations like Robertsonian translocations or reciprocal translocations are also good candidates for PGT, as only as much as 30% of embryos from affected patients are normal.
What are the pros and cons of PGT?
PGT, however, is not yet perfect. Embryo mosaicism is still a major issue in PGT-A testing. The term “embryo mosaicism” means that there are two cell lines in the embryo. One line does not carry genetic alterations, while the other does. The likelihood of having mosaicism does not increase with maternal age. Embryos have a natural capacity to self-correct small genetic anomalies or defects; embryos with low rates of mosaicism can repair themselves and result in a successful pregnancy.
What to do when embryo mosaicism occurs? First of all, a consultation with a geneticist is required to make sure that the embryo is safe to transfer. The patient then needs to be fully informed that if the embryo is transferred, they have a lesser likelihood of implantation, and that there is a higher risk of having a child with chromosomal abnormalities.
Doctors are often asked about egg donation and PGT. Although donation cycles have lower rates of pregnancy loss or implantation failure, there is still a possibility of adverse outcomes. Donors are not perfect – the rate of aneuploidy in the embryos they generate could be as high as 60%, depending on the lab or the centre where the treatment is conducted. For this reason, PGT-A is still worth performing in donation cycles.
Questions and Answers from the event
We have had two miscarriages; we’re affected by male factor infertility. Our DNA fragmentation is very high – it was 41%, now it’s at 20%. Does a “normal” embryo as indicated by the PGS test mean the embryo was made with good sperm? Does it mean no DNA damage is present? I’m about to undergo my fourth embryo transfer – what are its chances?
Without the information about your age or the quality of the blastocyst it’s hard to give an accurate answer – if the blastocyst was of good quality, the chances for a pregnancy are between 50 and 60 percent.
Do you recommend PGD for egg donation?
As I explained in the presentation, that really depends on each patient. I would recommend PGD for any patients who want to minimize the risk of a miscarriage, as it minimizes the number of embryo transfers that need to be performed – we know which embryos are chromosomally normal and they are the only ones we transfer.
I am interested in an egg donation cycle at your clinic, but I don’t see any mention of blastocyst guarantees? How many blastocysts does recipient get? What do you do if there are no blastocysts?
We actually have a blastocyst guarantee – the patient is guaranteed at least one good quality blastocyst from the donor’s eggs, as long as there are no issues with the male factor. On average, we have two or three blastocysts per cycle.
Is it the recipient who decides whether or not she wants to have the PGD test, or is it decided by theclinic?
It depends on the case – there are cases in which there is a medical reason for a PGD test, for instance if the patient is afflicted with hereditary diseases or if there is a high risk of chromosomal abnormalities. In other cases, such as when the patient wants to minimize the time to pregnancy or if they have suffered repeated miscarriages, the PGD test can be requested by the patient.
What kind of PGD alternatives did you mean?
There are a couple of options depending on the situation: the first one, obviously, would be simply not to perform PGD and accept all the risks. In case of a high indication of chromosomal abnormalities in embryos, the alternative to PGD testing would be to use donor eggs; if the abnormalities are caused by the male factor, the alternative would be to use donor sperm.
You mentioned indications for PGT-A – is abnormal sperm DNA fragmentation an indication for the test, as it wasn’t on the list?
Yes, abnormal sperm fragmentation is an indication for PGT-A testing. We also use time-lapse technology to select embryos with the least amount of fragmented DNA. There are of course other factors that have to be taken into consideration based on the individual case history.
Is it possible to transfer the embryo during the natural cycle in an egg donation treatment?
Yes, although it depends on whether or not the cycles of the patient and the donor need to be synchronized and whether fresh or frozen eggs will be used. The synchronization is very important, as the egg retrieval date must be carefully matched with peak endometrial receptivity.
How long does PGD testing of embryos usually take?
It takes about two to three weeks to receive the results. There is also a test called PGD Express, although it is not recommended; while it provides results in 24 to 48 hours, it does not provide nearly enough information when compared to the standard PGD test.
Can immune issues affect implantation?
Most likely, yes. When it comes to immunology, reproductive science agrees that it plays a major role, but we’re still trying to understand its full extent. We know for sure that patients with immunological issues have lower implantation rates; certain issues play a bigger role than others and they can affect the chances of conception.
My husband has low sperm count and high DNA fragmentation. I’m 36 and he’s 34 years old. My AMH is very good. We had two failed IVF cycles; I have a frozen embryo left over, but I’m afraid to transfer as I’m afraid of another miscarriage. Do you think PGT-A would be a good option, or should we go with egg donation?
Considering your age and your AMH, we can safely assume that your egg quality is not the problem; focus on your husband instead. He should avoid smoking, drinking alcohol, switch to a healthy diet, exercise and avoid saunas and other hot environments to increase his sperm quality. Then you should undergo another IVF cycle, using the (tile?) technology to use the least fragmented sperm and then employ PGT-A in order to minimize the risk of chromosomal abnormalities.
Can I have a fresh transfer with PGD testing?
Yes, as I mentioned earlier, there is the PGT-A Express test which allows for a fresh transfer; however, that route raises certain issues for biologists. Every embryo is different and some may be a little slower in their development; as such, they may not be in the best time to perform a biopsy. The results of such biopsies are less reliable than a full PGT-A test.
Is it true that some embryos which appear morphologically normal can turn out to have chromosomal abnormalities and that embryos which are weak morphologically can turn out to be healthy?
Yes, it’s true, on both counts. Usually, when embryos that look bad morphologically they likely also carry chromosomal abnormalities; however, sometimes embryos which look average get transferred and result in successful pregnancies.
My NK cells test was done via blood test. Is this okay, or is a biopsy better?
When it comes to NK cells, it’s important to remember that the blood is not going to be the environment in which the embryo’s going to live – that would be the uterus. As such, in order to get a full assessment I would recommend also performing an endometrial biopsy in order to confirm that the alterations found in the blood can also be found in the uterus.
As the miscarriage rates grow with age, is there a “cut-off point” at which there’s a strong recommendation to use donor eggs instead of own eggs? Is it dependent on age and/or individual medical factors?
There is no clear cut-off point, as it’s dependent on the individual patient. For example, for patients who are 40 and have a very low ovarian reserve, egg donation would be my first recommendation, as that’s the route that gives them the best chance for a positive outcome. There are, however, older patients who still have a good ovarian reserve. Even if the egg quality has diminished to the point that we get one good egg out of every 20 we retrieve, as long as we get that one good quality egg, that patient still has a decent chance of getting pregnant using her own eggs. Although it all is patient-dependent, age and the ovarian reserve are the most important factors that determine the prognosis and the recommended course of action.
Additionally, I’d also say that I would not recommend a patient over 45 to go ahead using her own eggs, as past that age the chance of getting pregnant using your own eggs is extremely low.
Do you recommend the ERA test before egg donation?
The ERA test, or the endometrial receptivity test is very helpful, but I would not recommend it to every patient – those who had repeated implantation failure and those who have had good quality embryos transferred without any success would be well advised to go through with an ERA test. If you want to do the test anyway just to be on the safe side, it’s perfectly fine, but medically speaking, unless you have any of the indications I mentioned, it’s not strictly necessary – out of every 100 patients that undergo ERA testing, around 70 have completely normal results. That means it’s only necessary in about 30% of cases.
If 60-80% of miscarriages are caused by aneuploid embryos, what about the rest of the cases? Is there a different route they should follow? Is it really possible to distinguish these two groups before making the decision about PGT-A?
The other causes of miscarriages are uterine malformations and other uterine factors like polyps and fibroids which can interfere with the process, or abnormalities such as thrombophilia. Tests for these issues are always done before we indicate the need for PGT-A. If we determine that the miscarriages aren’t a result of chromosomal abnormalities in the embryo, then the underlying issue is diagnosed and treated before the next attempt.
Do you find donors who look like the patient?
Yes. Under Spanish legislation egg donation is anonymous; that means you can’t know the identity of the donor. However, that same law also states that the clinic must look for a donor who looks as much as the patient as possible. We are assisted in this process by an artificial intelligence device called the PhenoMatch which analyzes over 100 different points of the face to try and find a donor that matches the patient’s appearance as much as possible.
Could you describe what kind of information patients get from the PGT-A test result? Who makes the final decision about which embryos to transfer?
The PGT-A test determines which embryos are euploid, or which embryos are chromosomally normal. That means the results show you which embryos are completely normal, which are abnormal and which are mosaic. For the latter, some information is available as to what kind of mosaicism is present. Once we know which embryos are normal and which aren’t, the decision about which embryos to transfer is very clear; we transfer the normal embryos. In case of mosaic embryos, the decision whether or not to transfer them is based on the percentage of mosaicism and its type. There are guidelines and indications as to what to do in those cases.
Do you check the level of estrogen and progesterone the day before the transfer? Mine was checked before the transfer and my progesterone level was 8,3. The transfer failed. I was told at another clinic that my level of progesterone was too low – apparently, it should be over 10. Is that true?
Yes, we check the levels before the transfer; it’s one of the new protocols we put in place, as there is more and more data showing that progesterone levels are very important in patients who are undergoing frozen embryo transfers or who do egg donation IVF cycles. Before we start the patient on progesterone we check its levels – they should be negative, which avoids the displacement of the implantation window. We check the levels again before the transfer. If the results come back with a progesterone level below 10, the patient continues to use vaginal progesterone and starts using injections as well.
As for your case, we can’t say for sure that the transfer failed because of the progesterone level – if the embryo was chromosomally abnormal, that could be one of the reasons for failure.
Can a PGT-A biopsy be done on day 3? Is it better than a biopsy on day 5?
The biopsy can be performed on both days. The difference is in cell numbers – day three embryos have between six to eight cells. The biopsy on day 3 takes a single cell. Because that’s between 12.5 to 16.6% of the entire embryo, the risk of damage is a little bit higher than with biopsies conducted on day 5; we also get less information. On day 5, embryos have between 100 and 150 cells, which allows us to take more cells for analysis with smaller risk of damage. We also get more reliable information.
Does the PGT-A test reveal the embryo’s sex?
Even though we could know the sex of the embryo during the PGT test, in Spain gender selection is illegal. As such, that information is not available in the test result and we cannot choose which embryos to transfer depending on their sex.
Can you describe the outline of the IVF process with PGT-A from start to finish? I’m going to be travelling to your clinic from Ireland and I’m trying to calculate how many trips it would take.
If you’re starting the IVF process with us, it would begin with an initial online consultation which is free of charge – we can do it through WhatsApp, Skype etc. Once we know more about your specific case, we will recommend you the tests we need to perform. When you decide to start the process, the stimulation can be done in Ireland and you can perform the scans we need at your local gynecologist. You need to come over the day before the egg collection, preferably with your partner so that he can produce a fresh sperm sample.
Afterwards we generate the embryos and let them grow in the lab until they reach the blastocyst stage.
You can return to Ireland following the sample collection. We will call you on day one to inform you of the results of the fertilization, then again on day three to explain the quality of the embryos and finally on day five or six to inform you how many embryos are candidates for biopsy. After about two or three weeks, we will present you with the results of the PGT-A test. If there are good quality embryos ready to be transferred, that’s when we schedule the date of your next visit to prepare you for the transfer. What that means is that you will start endometrial preparation with your next cycle, which will take around 10 to 12 days, followed by a scan. Once we think your endometrium is ready, we will start you on progesterone and plan the transfer, after which we will sort the embryo for you accordingly.
Do you offer embryo adoption treatments?
Unfortunately not, as we don’t have embryos available for adoption in the bank at the moment, however, for patients considering that kind of treatment we can offer what is called a “mini egg donation” which is cheaper and which guarantees four mature eggs from the donor available for your use.
I had a consultation with you a few months ago. I have some questions I would like to ask you. Is it possible to have a short Skype meeting?
Please contact the team at Fertty International at firstname.lastname@example.org and ask my colleagues about scheduling another consultation with me.
I am very interested in a mini egg donation. Can I schedule a Skype consultation with you?
Absolutely. Please contact us at email@example.com and ask to schedule a consultation with me.
Some error has occured.