Have you experienced miscarriage after IVF? Have you considered having PGT-A done? Dr Alejandra Aguilar Crespo, a Gynaecologist and Consultant Specialist at Equipo Juana Crespo, Valencia, Spain, answers patients’ questions about miscarriage, IVF and genetic testing PGT-A.
Dr Crespo explained that the risk of miscarriage in the general population is around 15% whereas, after an IVF treatment, it is 20%. Why is it higher after an IVF treatment? It’s usually because people who go through IVF are older and have several other pathologies. There are several causes of miscarriage, the most common one is the genetic abnormalities of the embryo. Around 60% of first-trimester miscarriages are due to embryo chromosomal abnormalities. Normally, every human has 46 chromosomes, and if there is 1 additional or 1 that is missing, the embryos cannot sometimes develop, or it can result in, for example, Trisomy 21, called Down syndrome, but most of the time it will result in a miscarriage or implantation failure.
It’s important to mention that the older the woman is, the higher risk of genetic abnormalities, therefore, the highest risk of miscarriage. A woman who is over 40 years old, statistically, has a 40% risk of having abnormal embryos. We can check the embryos with the use of PGT-A (Preimplantation Genetic Testing for Aneuploidy), which is a test that allows us to check if the embryo has a correct number of chromosomes. That way, we can find out if the reason for the miscarriage was the aneuploid embryo or if it was a different cause.
The second most common cause of miscarriage is Thrombophilia and antiphospholipid syndrome, this condition can cause clotting problems. These clots can go through the placenta, which can make the embryo die.
The third cause issues with the uterus, either anatomic or uterine ones. And it is the cause in around 25% of cases. Most of the time it is adenomyosis, uterine fibroids, adhesions, polyps or malformations, such as the septate uterus, T-shaped uterus, etc. Therefore, it’s important to evaluate the cause of the first miscarriage and check if it was the embryo, the uterus or other cause.
Some other causes can sometimes be controversial and have not been fully investigated yet, such as cervical insufficiency, but that can happen in the second trimester of pregnancy, not the first one. Other causes can be either environmental factors or high sperm DNA fragmentation.
PGT is the pre-implantation genetic testing and A is for aneuploidies. We do a biopsy of the embryo, and we take a sample of the embryo. It should be a day-5 embryo (blastocyst), the lab needs to guarantee a proper culture to the blastocyst stage, which is a five or six-day embryo. We take five to ten cells of trophectoderm, which is the external part of the embryo, and it will be the placenta. We cannot biopsy the inner cell mass, because the embryo would die. So we take a sample of that, and then we analyze the embryo, we analyze these cells. The technique is called next-generation sequencing, which is a complicated genetic test, but this is the technique that we use to check the karyotype of the embryo, we can rule out aneuploid embryos. It will tell us if the embryo is normal, abnormal or mosaic. A mosaic embryo has normal and abnormal cells together.
The risk of miscarriage in the general population after a spontaneous conception is 15%. Regarding the age is 15% and after an assisted reproductive technique is around 20%. Here, we have to differentiate the recurrent pregnancy loss, which has different entities and because treatment is different. People who have more than three miscarriages in a cycle or even in spontaneous conception, they are more likely to have another miscarriage. After an IVF treatment, the risk is around 20% because, as I told you before, people going for an IVF are usually older than people who conceive spontaneously. Other reproductive pathologies such as adenomyosis, fibroids, hydrosalpinx can lead to a miscarriage. It depends, but the risk is slightly increased.
It depends on the age of the women, f. e. when we use donor eggs, these oocytes come from donors. The donor has to be young, between 18 and 30-35 years old, so the risk of chromosomal abnormality is very low, and I’ve told you before the most frequent cause of miscarriage is a genetic abnormality of the embryos, so the risk of miscarriage will also be decreased. In a woman who is 32 or less than 35, the risk would probably be the same as using a donor. In general terms, we need to personalize each treatment and each patient but, it depends on the age, and after the age of 40, the risk of miscarriage increases because the risk of chromosomal abnormalities is high. We had several pregnancies where a woman was pregnant with her own eggs at the age of the 42 -44, but it depends on the situation of each patient.
Depending on the number of miscarriage, that’s for sure, and if you had more than two miscarriages, the risk of having another one is high. Older mothers have a higher risk of miscarriage. I must reassure you that women who had their first miscarriage after the first cycle, they have around 40-45 % of increased odds of live birth, after subsequent cycles compared to women who had no pregnancy. After a first miscarriage, there is increased anxiety, and many people want to cancel it, as it is very emotional. We always reassure them, that it’s better than a negative test. We will try, to improve it, and try to find the reason for miscarriage if it was because of the embryos, or uterus etc. So the short answer is no, you will not have increased chances of having another miscarriage.
Well, no. I want to be very clear, in our clinic we personalize each case, it’s crucial to be aware, that the PGT-A is a very effective tool, but for those who will benefit from it.
We have two types of patients, low-risk patients and high-risk patients. The patients who are called high-risk, are the ones who have chromosomal abnormalities in the karyotype, or they have some monogenic disease. It is mandatory to perform the PGT-A for people who have a chromosomic problem. We have to do the PGT-A to try to increase the pregnancy rates and decrease the miscarriage rate without any doubt.
On the other hand, we have high-risk patients who f.e. have recurrent implantation loss, implantation failure, older women or male with severe factor. In that case, it’s controversial to use PGT-A.
There are pros and cons to this. In our clinic, we think that it’s a well-known fact that PGT-A decreases the risk of miscarriage and improves implantation rates. Imagine that we have an older woman with polycystic ovaries, she will have a lot of embryos. And yet because of her age, she will have a lot of abnormal embryos, we can perform the PGT-A to decrease the time or the treatments until a pregnancy.
If we have ten embryos and then we know that probably because of her age, we’ll have three or four normal embryos. We can do the PGT-A to try to decrease the time until her pregnancy, and also it will decrease the twin pregnancy rate or multiple pregnancies. Because in that case, we’ll transfer more than one embryo to get one pregnancy. So that is why it is better to do the PGT, in that case. It’s important to say that PGT-A is still a developing technique. We need to have a very good laboratory because the lab needs to guarantee a good culture to blastocyst, it needs to guarantee an efficient vitrification technique, and also that the embryo will not be damaged after the biopsy. So indefinitely, the patients will need to rely on the embryologist skills, and sometimes some clinics don’t have these conditions.
Another thing is that sometimes we don’t have any embryos to be biopsied. F.e. women who have a low ovarian reserve, we don’t have any embryos to be biopsied, this can increase their anxiety and also increase the cancellation rates.
Women with very poor egg quality, f.e. women who have endometriosis which affects the oocytes, that will mean the embryos also will be of poor quality. So sometimes they might not even reach the blastocyst stage. So in that case, in our clinic, we need to think of what want, an opportunity or security. At times, these patients with low ovarian reserve or with endometriosis will benefit more with an embryo day-3 transfer. If we did a biopsy on an embryo coming from an older woman with endometriosis, we would probably kill the embryo, even if it is euploid. In this case, we cannot assure the patients that after the biopsy, the embryo will survive. We need to guarantee it, we need to allow them to have a transfer, and sometimes the transfer is done on a day-3 or even a day-5 without any biopsy.
The last thing is that to do the biopsy, we need to take a sample of 5 to 10 cells, and these cells they come from the trophectoderm, and we can find a false positive. It means that the cells that come from trophectoderm do not correlate very well with the inner cell mass. If the lab informs us, that this is an abnormal embryo and it is not true, it is a false positive. It is connected with mosaics. A mosaic embryo has normal cells and abnormal cells. It has been proved, that at least 20% of the embryos from a cycle are mosaics. These mosaics have slightly less implantation rate and clinical pregnancy rate than a euploid embryo. It means that this embryo can lead to a healthy baby. If we do the PGT, this embryo in some clinics, they will be ruled out, depending on the level of the mosaicism, whether it is a low-risk mosaic or high-risk mosaic. It depends on the location of the abnormality, the percentage of chromosomes affected. There is this type of disadvantage, which are the mosaic embryos, so PGT-A is a useful diagnostic tool, but we need to focus on personalizing the treatment, and we need to choose it but not for all patients.
From my point of view, I would not. Usually, they are low-risk patients, I mean every donor is checked for the monogenic disease, karyotype etc.
For people who are going through an egg donation, the risk of miscarriage is similar to the general population. There is no higher risk of miscarriage. Also, when it comes to genetic testing, we need to focus on the other causes of miscarriage in that population, but I will not recommend it. If the patient asks for it, because she had a lot of previous egg donation treatments that ended up in miscarriage, we can offer it, but not in the first consultation. It will not be beneficial for such a patient.
This technique depends on the embryologist skills, so the embryologist must be very well-trained. The biopsy is taking cells, and this produces rupture of the embryo. Usually, we don’t harm the embryo, and it’s a very safe technique, but it’s an invasive technique. In the future, we probably will be using a non-invasive pre-implantation genetic testing. If we have a well-trained embryologist, I think that 90% of those embryos will survive after the biopsy.
Most of the time, it’s done on a fresh cycle. It can be done in both. But from our point of view, it’s better to do on it on a fresh cycle. When we freeze an embryo, and then warm it and refreeze, the embryo will lose its potential. It’s better not to touch it too much.
After the fertilization, we culture the embryo until blastocyst, and we do the biopsy, and we freeze the embryo. If it was in a frozen cycle, the embryo reaches blastocyst, we freeze it, and we defrost it, and then we do the biopsy. It’s not very healthy for the embryo. Sometimes we have patients who have embryos in another clinic, and they want to transfer them. It might be mandatory to do the biopsy, because of a chromosomal abnormality, or if there were previous miscarriages. Then we have to do the biopsy, and we do it.
We prefer to do another cycle and do the PGT-A in a fresh cycle, then use the frozen ones because the embryo loses its potential and its implantation potential.
A lot of patients after a first miscarriage want us to give them heparin or aspirin. We need to explain to them that in the absence of thrombophilia, clotting problems, it hasn’t been demonstrated that this treatment improves the outcome. No reproductive society recommends this treatment empirically. It’s true that in our clinic, almost 90% of our patient has adenomyosis, and the implantation rate has decreased risk compared to the general population.
In those cases, we use heparin, but only after the transfer and when we see the pregnancy test. If we use heparin, which is an anticoagulant, it can provoke a miscarriage. Unfortunately, we have had cases where the patient used heparin without our prescription, they have taken heparin or aspirin, and they started bleeding and miscarried. If you do not suffer from thrombophilia, there is no need for you to take it. If the patient does not have uterine fibroids, we use it to improve the pasteurization of the uterus, but we only give it to them for max. 10 -12 days, not more.
Unfortunately, we cannot change the age of the women, but we have several tools to try to decrease the risk or prevent any possible miscarriage. F.e. a healthy lifestyle, so no smoking, no drinking alcohol, staying away from toxins. If you have any endocrinopathy or problems such as diabetes, this should be well controlled. To check the uterus, usually, we do it during the first consultation, we perform a 3D ultrasound scan, and we can perform hysterosalpingography (HSG)to check the endometrial cavity. Then if we suspect adenomyosis or Mullerian malformation, we can perform an MRI. If we suspect endometritis – a chronic inflammation of the endometrium, we can perform hysteroscopy. And if this patient has the endometritis, we can treat it. If the patient has any genetic issues, we can perform a Karyotype test, to double-check our chromosomes. Another thing, if we see a thrombophilia problem, or after a second miscarriage, we’ll do a blood test to rule it out. After the first miscarriage, we do not perform it, most of the time. We will then, do embryo stereoscopy to check what is the cause of miscarriage and if it is a genetic or uterine problem. And then, of course, the PGT-A if it’s needed.
I mean, I think it is a very effective tool, but our future is the non-invasive biopsy, and as I told you before, it depends on each situation and the patient’s opinion.
If a patient has any chromosomal disorders, it’s mandatory to perform it, to decrease the miscarriage rate and to have a healthy baby. Our objective is not to give a pregnancy, we want healthy babies at home, so I think it is a useful tool. However, with the increase of the PGT-A, people are performing it in all cycles, no matter the case, so I think we need to reevaluate when to use it, whether this patient will benefit from it, or If the biopsy will not harm the embryos. It is crucial to personalize each treatment.
A difficult question indeed but in my opinion, not so much. At this point, I can’t imagine a robot doing a biopsy – we are treating embryos, not working on a car, or doing something like that. We need to be very, very careful, and I think we have very talented embryologists who can perform the biopsy with the best outcomes. In 10 years, it might be different. From my point of view, I don’t think it will be helpful.
First of all, I’m sorry about that. As I told you, we need to have a diagnosis when you had a miscarriage, we don’t know if this embryo normal or was abnormal, so this is the first thing we need to check, the main cause. If it was an abnormal embryo, we know the cause because the embryo was not good and stopped growing. If the embryo was normal, we also have another cause, as I told you before depending on the age, we have uterine causes. In our study, we found that among those embryos which were normal, a hundred per cent of them had a uterine cause of miscarriage. In our clinic, at least 90% of women have adenomyosis which is a very chronic pathology and can lead to miscarriage. It’s not very well-known, but it affects the uterus and compromises the pregnancy. I don’t know with this much information, what was the cause. It does depend on the age, if the embryo was normal or abnormal, on the uterus, or if you had previous pregnancy etc. If you’re older than 37 years old, probably it would be an abnormal embryo, but we need to find the diagnosis.
In such a case, I would recommend doing PGT-A. Even if, you’re under 35 years old. To better evaluate the situation, if it is a problem with the embryos or the uterus, so try to find a correct diagnosis. If you had more than one miscarriage, you could try to do PGT-A, to find the cause.
If you never had an IVF treatment, I would not recommend doing the PGT because, from your AMH, which is low, I would expect not to have a lot of embryos from the stimulation. Given your age, we know that you will have probably 30 to 40% or half of the abnormal embryos and in such case, I cannot guarantee that those embryos will reach the blastocyst stage. So in that situation, we would want to give you an option for a transfer, and we wouldn’t recommend PGT-A.
If you’re talking about 1.5 pmol/l – it is a low ovarian reserve. If you are speaking about 1.5 ng/ml – it is a good ovarian reserve. With 1.5 and having two embryos, we don’t know if they are Day-3 or 5, but two embryos we would expect. Keep in mind, that quality does not mean quantity. The quality is connected with age. We always prefer low quantity in a patient who is less than 35 years old than a lot of embryos from a patient older than 40. AB and BB, these are good quality embryos, and probably with those embryos, your chances of being pregnant are good, depending on your age.
No, when you have a D&C, it is worse. When you have a miscarriage treated by D&C or by oral pills, or vaginal pills, this harms the uterus. It is a piece of old information. In our clinic and a lot of clinical trials, we found that after a miscarriage, the risk of damaging the uterus is high, so it is not the truth.
I do not know why some clinics would not perform a PGT-A on one embryo. From my point of view, if the patients only have one embryo, we need to do the biopsy for them. Sometimes, clinics prefer to accumulate embryos, and then do all the biopsies in all of them because it would be cheaper for the patient, but if the patient only has one embryo, this could be biopsied. What risk on the embryo to the embryo a biopsy? It depends on the quality of the embryo, techniques used, embryologist’s experience, and embryo quality, or the age of the woman.
Depending on the situation, if there is no clinical risk, if the couple hasn’t got any chromosomal disorders, we need to personalize the case. If we want to rule out any chromosomal disorders on the embryo, we need to do a PGT. If we are sure that this is not the cause of implantation failure or previous miscarriages, probably we won’t do it. If we think that we are facing a uterine problem, we will treat this uterine problem before doing a PGT-A.
And I think you are wondering why the embryo is abnormal if both of you are genetically healthy. When the oocytes start to divide, and the oocytes are old, there are a lot of mutations on these oocytes. The division of the cells has a lot of mistakes which results in abnormal oocytes. The spermatozoid fertilized the oocytes, and they will give abnormal embryos. Even if you are genetically perfect, your oocytes are not genetically fine.
That’s not true, because normally when we guarantee embryos, we have a policy that when we select the donor, this donor should be in the best health, and she will provide very good embryos because if she doesn’t, we won’t select this donor. So we guarantee that with this embryo, it will end in the pregnancy. It is not wasting time because the risk of miscarriage due to chromosomal abnormalities in egg donation is low, less than 10%, and it is the same rate of miscarriage as in spontaneous conception.
The clinic usually guarantees a very good laboratory, those that work with the best technology, Best incubators. You can ask them for some certificates, what sort of training the embryologist had. They are improving their techniques every day, with each cycle. I think that big clinics have the best labs.
So in that situation, I still think there is no recommendation of doing the PGT-A, we can select a donor compatible with you and your partner, it can also be a proven donor. In that case, the risk of miscarriage will be very low. Usually, if you have a miscarriage at your age with a donor, it will be because of a uterine problem or other problem. If this will be a reason which will increase your anxiety, we can perform it, it is not recommended, but we can do it. This will increase the cost as well though.
In Spain, gender selection is forbidden. When the embryologist does the biopsy, no one knows the gender of the baby. But it is true – the PGT-A is the only way to predict the gender. When there is some hereditary disease, we need to perform a gender selection, of course, we will analyze it, and transfer the selected embryo.
Definitely, not. It depends on the situation and the age of the women. An embryo coming from an older woman, in a reproductive term, these embryos have low quality, and even if we biopsy a frozen embryo, and we don’t have a genetic diagnosis, we need to rebiopsy it, and that kills the embryo. It is better not to touch it. Sometimes, we need to do it, even though we know in advance that probably implantation rate will be decreased a lot so, in my opinion, it’s better to get other embryos or get one more cycle and rebiopsy those embryos.
This is very controversial because a lot of people have a lot of randomized control trials about the immunity status, the natural killers, the cytokines etc. but it has not been demonstrated that the immunotherapy improves the outcome. The treatment with prednisone, the testing for natural killers and this kind of thing is not recommended. No reproductive society recommends these tests. Even if they had a lot of published articles saying that the treatment with prednisone has been good after a miscarriage, or this will improve the implantation – it’s not true, it’s not recommended. We do use prednisone at times when a patient has some immune disease or endometriosis. We can use it to balance the patient’s immune status.
You are the, a prototype patient of our clinic, and I will explain why. First of all, biochemical pregnancy means you had a positive urine test or positive blood hormone test, and then once we do the scan we cannot see, and anything or the embryo has not implanted. Biochemical pregnancy usually is due to a tubal factor, uterine factor, transfer factor – the transfer technique is very important. A transfer with pain or bleeding is a negative or a biochemical pregnancy, and also it can be an embryo factor, but this is controversial. After biochemical pregnancy, we need to see what happened, possibly it is because of uterine factor. If you have endometriosis, we need to focus on the uterus. You are 35 years old, you are young, so I expect to have very good embryos, even if you have endometriosis. You had hysteroscopies, laparoscopy and, even were treated for immunology. Hysteroscopy and laparoscopy always should be done by a reproductive surgeon. The reproductive surgeon needs to restore the functionality, and I don’t know if those were done by a reproductive surgeon, and what exactly was found.
The immunology, I do not recommend to treat the immunology as it hasn’t been proved it increases the outcome. About ERA, ALICE and EMMA, again those are controversial, in our clinic when it comes to ERA, we don’t believe it will change our approach. The endometrium is different each month, so one month you can be receptive and then, the next month not. In general, this will not give much information. It is crucial to rule out the endometritis because, after three biochemical losses, something happens, I’m sure. Possibly, it is a uterine cause, and we need to perform some test, f. e., MRI to check it, and your fallopian tubes as well. We need to focus on the sub endometrium and the walls of the uterus. Chemical pregnancy means that the endometrium is well prepared. In your case, I believe you have a uterine factor.
The synechiae uterine is usually the cause of implantation failure and also miscarriage. This is one of the most difficult things to treat. After your six hysteroscopies, there is a problem of the endometrium, and sub-endometrium. We would treat it with mini hysteroscopy, and we’d put a balloon inside the uterus, to try to avoid the synechiae. After we perform it, we would give you some drugs, to try to increase the endometrial thickness.
Sometimes, there is also a condition, called Asherman syndrome which can be caused by D&C, and by previous miscarriage. If in your endometrium, you only have half the problem of adhesions, we do the surgery, put a balloon for at least six weeks, to try to prevent the synechiae. If the endometrium is not growing well, we have other tools, but this is indeed very difficult. About PGT-A, that depends on your age, your ovarian reserve, and if it is low, I would not recommend it. And if you had miscarriages, and if you have a good ovarian reserve, you would probably have good enough embryos, my advice would be to do it, depending on the previous cycles. Adenomyosis is also a problem, and it is probably a cause of miscarriage, so PGT-A would not help. Even if you had normal embryos, and we’d put it to a patient with adenomyosis and synechiae uterus – it would not implant, or end up in miscarriage.
It’s possible, although this embryo will lose quality because it is a rebiopsied embryo. For sure, we can do it, as a procedure we can perform it, but it is not very recommended. If it is someone’s last chance, we could perform it.
Our recommendation probably will be going through egg donation because of the age. When I’m having patients who are 50, they cannot go through with own eggs because those will be of poor quality or even if we tried, we would need at least 100 oocytes to get a normal embryo, and that would be very expensive. To prepare for the treatment, you should have a healthy lifestyle, no alcohol, no smoking, decrease the caffeine intake. If you have any pathologies, if you are overweight, you would need to lose weight, if you have diabetes – it would need to be well-controlled and so on. And then, once you come to the clinic, we will evaluate your case and provide a proper treatment plan.
If it is candida or bacteriosis, we need to check the vagina culture. It depends on the type of causes. Probably, two weeks will be enough. You should take probiotics because it will restore the vaginal flora. You need to be sure that you are clear from this infection, it is best to be in a healthy stage before the IVF treatment.
Not at all. The quality is related to age, while the quantity is related to what we have inside our body at that time. A woman who is less than 35, and has low quantity, she has the same chance of pregnancy as a woman in this age. Low quality comes with age. As I’ve mentioned, we prefer a woman who’s less than 35 with low quality, than an older woman over 40 with a lot of oocytes, as half of them will be of very poor quality, so it’s not related.
I would advise a general check of your uterus, fallopian tubes and if we don’t find anything that suspects a miscarriage, we would probably perform a PGT-A. If we don’t know if your embryo was normal or abnormal, we would do a PGT-A. Again, it is depending on your ovarian reserve, your uterus – whether it is ok. We cannot advise you to go for PGT-A without seeing you before and checking all those things I’ve mentioned.