In this session, Dr Héctor Izquierdo, Fertility Expert & Gynaecologist at IVF-Spain, Alicante, has been talking about coping with repeated pregnancy loss. How it should be assessed, what tests should be done, and what are the chances of getting a successful outcome after a thorough examination.
Miscarriage is every loss of the pregnancy before week 20, and it happens in 20 to 25% of pregnancies, those are biochemical pregnancies, which means that 1 in 4 women can miscarry at the early stage of pregnancy without noticing it. Repeated pregnancy loss (RPL), also known as recurrent miscarriage, is defined as more than 3 consecutive pregnancy losses. The most common causes of pregnancy losses are genetic causes, such as karyotype alterations of the genitors or the embryo. Pregnancy loss till week 11 is mostly a sign of genetic cause. Other factors include immunological alterations, infections during the pregnancy, bloating issues, viral infections during 1st trimester, bacterial infections, parasites, and endometrial receptivity. Other risk factors include obesity, pathologies such as hypertension, diabetes, multiple pregnancies, but also lifestyle and stress.
There are different types of pregnancy losses, there is biochemical pregnancy, where you have a positive pregnancy test, but you don’t get to see an embryo on the ultrasound. Therefore, this pregnancy was just biochemical. Early miscarriage means a miscarriage before week 14 of pregnancy, late miscarriage is before week 24 of pregnancy, and premature delivery happens after week 24 of pregnancy. Depending on the kind of pregnancy loss, the medical approach will be different.
Some complementary tests can help diagnose the cause of recurrent miscarriage. Those include karyotype testing, and PGT-A, which allows for checking if the embryos are genetically normal before the transfer. Other tests include antibody serology tests to check for the presence or level of specific antibodies in the blood, such as HIV, Hepatitis. Thrombophilia testing, a thorough study of the uterus (HSG-HSC), ER-Map / IMAP.
PGT-A test to provide information on whether the embryo is genetically normal or not before the transfer. How is it done?
During PGT-A, 16 to 20 cells are removed from a blastocyst and biopsied to see if they are genetically normal or abnormal. When a patient had previous repeated miscarriages,
we try to obtain the highest number of eggs to create as many embryos as possible to test them. Genetically normal and only viable embryos will be then transferred. t
Another solution could be egg donation. It is the best solution in cases of very low ovarian reserve and quality issues. Oocytes from a younger donor mean that the quality of the oocytes will be much better, so there is a higher probability of genetically healthy embryos. In Spain, the egg donation equation is based on 2 principles, first anonymity and phenotype matching. Every woman who donated her oocytes is thoroughly screened, she cannot be a carrier of any genetic disease.
Implantation is a dialogue between the embryo and the endometrium, and it is very important to check the window of implantation (WOI) to make sure the embryo will be transferred at the proper time.
Another useful test is the endometrial receptivity test called ER Map, it checks the genetic expression of 48 genes, and it’s a great diagnostic tool for endometrial receptivity based on the transcriptomic signature.
Immunological diseases like antiphospholipid syndrome, lupus, and immune reactions, all these factors are very important to be described in the immunological analysis. We can do the test for NK cells (Natural Killers) as well as check the compatibility of HLA-C and TH1, TH2 balance, which allows us to see if we need to make any changes in the therapy plan that would allow this patient to get pregnant and support a pregnancy.
IVF with PGT-A was suggested, and for 2 days 5 embryos were obtained, but both were aneuploid, therefore, there were no embryos to transfer. Egg donation has been recommended, fresh single embryo transfer was performed, and the patient got pregnant and delivered a healthy child.
Day 5 embryo transfer was suggested, 25 eggs were obtained, 8 blastocysts were produced, and after genetic screening 6 were euploid, but the 1st transfer was negative. For the second attempt, we decided to check endometrial receptivity, normally patients are receptive on day 5 and half of the progesterone, however, this patient was pre-receptive, and after 7 days of progesterone the result was receptive, and the patient got pregnant.- Questions and Answers
Yes, an infection that can cause recurrent miscarriage is one of the reasons why we do a biopsy to test the endometrial lining, and that can be a chlamydia infection. Previous chlamydia infection can produce inflammation from the endometrial lining that would stop the woman from getting pregnant. Although this infection won’t be there anymore, we can do a biopsy from the endometrial lining, check if some mark called CD 138 or plasma cells are higher than normal. If that’s all, then therapy with Doxycycline 100 milligrams 2 times a day for 14 days, have shown to increase the chances of a pregnancy. All the infections that can cause persistent miscarriages are toxoplasma and some viral infections that are also treatable.
First, we’re going to talk about 2 sides. The first is the medical side, the major problem causing women not to get pregnant or miscarriage repeatedly are genetic causes. The second, implantation window is also very common, the previous infection and coagulation or immunological problems are also very common.
The major problem these women need to face are, first, frustration, there’s a lot of frustration knowing that I get pregnant, I get to produce an egg, I get to have implantation, I get to see an embryo, perhaps a heartbeat and then lose them. That gives this woman a sense of frustration for not being in the position of taking care of this pregnancy. There is also a lot of regrets and guilt. These are all 3 major psychological issues that are involved in a patient who’s having repeated loss.
You are one of those patients that I’ve been talking about in my presentation regarding ER map. We look at the endometrial lining and immunology because NK cells are not the only ones there. Therefore, we do a mapping from these cells, we check what’s the perfect therapy for you.
Intravenous immunoglobulins are for patients who have high antibodies, and for example, a lot of lymphocytes B in blood, but NK cells alone haven’t shown any benefit with IVIG. In this case, I would like to look at your endometrial lining to do some photos to give you some comments regarding this question.
I would like to tell you that that doesn’t happen, but I’m pretty sad to tell you that we don’t know everything about reproductive medicine, we’re working on that, we’re researching a lot, there are a lot of people working for us in laboratories trying to find some other cases, but we still have patients that we don’t get to get pregnant. That’s why I showed in my statistics that we don’t have 100% success rates.
There are immunological factors, there are also factors in the embryos themselves that we don’t know and therefore cannot change. I would need to have more information from you to tell you if there is something I could change for your next treatment. Don’t be discouraged, try to get information, but I’m sorry to confirm that there are also patients who regardless of all the help and the best medicine, we cannot make pregnant.
There is still a lack of studies, scientific data on this. As I said before, there is the possibility from the body of a patient rejecting the embryo because it’s acknowledging or seeing it as not part of the body. One option that’s possible is to take lymphocytes and prepare the endometrial lining to accept this embryo and allow it to attach. It looks promising, but at this moment because I haven’t seen studies proving that’s going to be successful.
There are many innovative therapies like this that we also offer, for example, patients with atrophy, a refractory endometrial lining that is not responding very good to any stimulation, we offer them platelets rich plasma (PRP), hoping that I will help them to have some better endometrial lining, that’s also experimental. For me, as an expert, as a man of science, it’s very hard to have a point of view of something that has no scientific data supporting it.
What we’ve been trying to do is adding medication on top of the therapy to try to make it better, and that’s what’s not positive. I would like to have a look directly at your endometrial lining to make sure that we are not disbalancing your therapy because most of the things you’re talking about there, although they are not contra-productive, they have different effects.
Therefore, I would like to know which type of alteration from the natural killer cells you have to give you the perfect therapy. IVIG might be a solution for you if some alterations support that. Otherwise, it’s a very expensive medication that doesn’t help anyone. Adding medication on top of the rest just to try something else is not my thing
No, not at all. If I have 10, 12, 15 eggs on a cycle, I can assume not testing things before the transfer. In a woman who is 40 and above, the chances of finding more than 1 embryo are not high. Therefore, this embryo is gold and diamonds, and I’m not allowed to do a transfer before I’m perfectly sure I’ve done everything to make sure I’m transferring this beautiful, perfect embryo in an environment that’s going to accept it. Therefore, for patients above 40, it’s my recommendation to test everything before we do a transfer. How come? Because we don’t know if we’re going to have the second embryo in the future, that’s really important.
PGT-A is very reliable. There are always false negatives and false positives, but in PGT-A, it’s very low. It’s also possible that when we transfer euploid embryos having a normal endometrium, we can also miscarry. A normal endometrium with no alteration, good progesterone is not all. As I said before, many factors need to be taken into account.
It is possible in my clinic. That’s something that we don’t do that rarely. PGT-A, as you know, is not allowed in every part of the world, then some patients who have the embryos produced somewhere else sometimes decide to take them to us, so we can test them genetically before we transfer them. It’s also possible, and it’s a recommendation in patients who have repeated failure, and I still have embryos somewhere else in Europe.
Not really. First, let’s go to what’s DNA fragmentation is. As you know, the DNA, when we see it in a karyotype, we see it as chromosome’s, but that’s not the way it’s transported to the sperm or the egg. In the sperm, it’s just a mass of a wall together. Then the fragmentation of this means there is some part of this chain that’s broken. If that’s so, it might be some feathers in the DNA that cannot be properly transported into the embryo.
Therefore, this embryo won’t produce a non-genetically healthy embryo, but it won’t produce an embryo at all. On the third day, where the DNA from the sperm activates, that’s going to start problems, there are going to be a lot of fragmentation of the cells, and the blastocyst is not going to evolve properly.
You’ve poked out a very sensitive topic for me. Before going ahead with reproductive medicine, I was working in Fetal medicine for a very long time. I was taking care of women with high-risk pregnancies or issues in the pregnancy, and when you transfer a PGT-A tested embryo, more than one in a cycle, you’re having 3 issues.
The first of them is you’re probably producing a twin pregnancy what’s also a risk and a problem. Twin pregnancies are more likely to miscarry, those pregnancies are more likely to produce other diseases like preeclampsia, gestational diabetes, early delivery and other problems. Therefore, we shouldn’t transfer more than one genetically tested embryo.
The second factor is that if it’s complicated for your endometrium lining to accept and tolerate one genetic embryo that’s not proper, try to do it twice. Therefore, applying two can produce the rejection of those two embryos.
The third factor is wasting embryos. Why? The increase of the success rate with transferring two PGT-A tested embryos instead of one it’s just 5%. In my clinic, if you’re transferring one PGT-A embryo after the other, then increase the chance of getting pregnant above 20%. Therefore, you’re missing a 15% chance of getting pregnant when you’re transferring two embryos at once. So I always say, don’t ever transfer a PGT-A tested embryo with more than one embryo.
There are so many hormonal imbalances that can affect pregnancy. I’m going to talk about the 3 major ones. The first of them is the thyroid. How do you treat it? We need a TSH level at 2 if possible, and we need to have good antibodies against thyroids. TPO, TG need to be good. Second, if the prolactin level in nanograms or decilitre is higher than 9, it is less likely to get pregnant.
Therefore, these patients need therapy with Cabergoline once a week before you do the transfer. Other endocrinological or hormonal factors that may affect fertility are hormonal issues with the blood sugar process – insulin and those factors may affect you from getting pregnant. Then we can treat them with Metformin or other treatments that can help you with that.
Other than genetical issues of the sperm itself proven by a FISH test or by Karyotype from the donor sperm or your husband, the morphology, the progression, the motility, the DNA fragmentation are factors that can stop you from having blastocyst, but it’s not being proved that can affect the chances of you having repeated pregnancy loss.
It all depends on what types of embryos are they. Is it a day-3 embryo, a day-5 embryo because it’s a very different thing. Is that a 5-day embryo with genetic alterations, is it a day-5 genetically tested embryo and what type of patient is getting this. A 20-year-old woman, a 40-year-old woman, or a 49-year-old woman. In my personal opinion, my key to this situation is if we’re making a day-3 transfer, which I don’t really like, but I always also do it if patients desire to do so, we can transfer 2 embryos at the most. If we’re transferring a day-5 embryo, but a patient is close to 40, and that’s not a genetically healthy embryo. Since we know that these embryos are not going to be genetically healthy, you might as well transfer 2.
In the same case, let’s talk about a 43-year-old woman if she happens to produce 3 embryos, the chances that these 3 embryos are genetically healthy are not that high. If this patient wants to avoid a second or a third transfer to get the genetically healthy embryos, she might as well discuss with her doctor and getting a chance at transferring 3 embryos at once. I won’t do that, but to say that it’s wrong, it’s the end of the story, we need more information to know if that’s good or right.
The last situation is that the most important thing is if you discussed this with your doctor thoroughly. If you were properly informed, the doctors told you the risks and the advantages, then the patient is responsible for the decision. I think those are the three major key points.