Repeated Miscarriages

Explained by: Anna Galindo Trias, Dr., Gravida International Center of Assisted Human Reproduction
Category:
From this video you will find out:
  • When are repeated miscarriage and recurrent pregnancy loss (RPL)?
  • What are the statistics?
  • The etiology of miscarriage
  • Aneuploidy (numeric and structural aneuploidy) and miscarriage
  • Thrombophilia, uterine abnormalities as possible causes of miscarriage
  • Endocrine and metabolic factors in pregnancy loss
  • Infections, chronic endometritis and other asymptomatic infections as a reason for miscarriage
   

Everything you need to know about repeated miscarriages

Watch the webinar with Dr. Anna Galindo Trias, Medical Director at Gravida International Center for Assisted Human Reproduction located in Barcelona, Spain. Dr. Galindo explained the most common causes of recurrent pregnancy loss.

Everything you need to know about repeated miscarriages - Questions and Answers

I have had two miscarriages since March this year. We have had ICSI via donor eggs. My husband had sperm sorting after DNA fragmentation test. I have had ERA test and UMA test and the results have been good. I am now being put on dexamethasone ready to transfer again in a week with a FET. Are there any  more tests that I can have done? I also had hysteroscopy and that was normal.

You’ve gone through many tests. First of all, I would focus on trying to take out factors, for example, thrombophilia. Have you gone through thrombophilia testing? Maybe the microbiota because sometimes the hysteroscopy is good but the microbiota is not good. In patients who had donor egg embryos usually, the aneuploidy is a problem that is lower risk because it’s a younger egg and the rate of aneuploidy is low so we tend to think that it’s the mother, not the pregnancy, some factor that could be here interfering. Let’s check now if we have a good structure of the uterus if we have no thrombophilia if we have good timing so you have the ERA test. The ERA test helps us more with implantation failure but also with miscarriage risk. UMA test – I’m not sure what it is. Could you clarify?

Out of all of these, you have gone through and the thrombophilia test, etc. what else would I study? Of course, I assume that you have thyroid function normal and all this metabolic discharge undisturbed. What’s is left is immunology. The problem is that immunology is very center dependent. How would I approach this field? OK, the thyroid is normal. What I would recommend is to go for the embryo transfer with the recommendation of your center. If you have another miscarriage, analyze the miscarriage to know if the karyotype is normal.

Confirm that it’s a normal pregnancy if you went through another miscarriage. If it happens next time, I don’t wish it happens, but if it did, confirm that the pregnancy is normal and then approach the KIR study which gives us an idea if there’s something that could cause the lack of inflammation that the protoderm needs to go through and also the NK cells and all this study. Dexamethasone is an anti-inflammatory so it’s covering partially if there is an excess of inflammation, it covers it and it decreases it so to me it’s a good approach. On the other hand, if you had thrombophilia, we would know if you could benefit from heparin plus or less aspirin.

Some IVF centers give heparin empirically. We tend to do it based on thrombophilia treatment. Definitely, if you go for this embryo transfer and it’s another miscarriage, analyze the miscarriage to know exactly where we are at. If you had to go for another one, maybe check the immunology.

Does this impact an older mother using donated embryos with much younger donors?

When an older mother uses an egg donor, this aneuploidy factor decreases radically. We can have aneuploidy in all groups of embryos, from the youngest donor to the oldest patient. But the rate of aneuploidy for less than 35 years old could be 30%, and 70% of euploidy so normal embryos to over 40-70% aneuploidy and 30% euploidy meaning normal. So these ratios are very favorable when we go for an egg donor. We have an observation that we had gone through and some colleagues have the same but it’s a feeling, in the case of very young donors, at 18 or 19 years old the reproductive system is still a little immature and sometimes there’s a little higher aneuploidy rate compared with donors aged 20-something. This is just a feeling now that some patients are really mature in the system and some patients are not yet ready. Their system is still developing. But there’s a low rate of aneuploidy so it doesn’t impact theoretically the aneuploidy if you are using young donors. If you ask me what’s the age ideal age? From 22 to 30 would be my choice.

In the case of trisomy, is the third chromosome always from the mother?

This is a complicated question. Usually, the trisomy is typical from the egg and in general that the monosomy which is the loss of one chromosome, we have to consider more the male factor. Mostly, but not always. When we find monosomy, we should think about both parents but include male in the pot. When it’s trisomy of one chromosome or maybe two, it’s more the egg. There are some chromosomes that are more typical from the egg meaning the 16th, 13th, all the -teens are more typical from the egg. The sex chromosomes are not typical of the egg. The sex, the XX, Y or XY chromosomes usually are from more either male or both parents but not typically from the egg. The typical chromosomes from the egg are the -teens. The first and second chromosomes are sometimes from a male. Some publications say also chromosome five but usually, it’s from a female.

What about chromosome seven trisomy?

The chromosome seven is not typically from a male as far as I remember but it’s a big chromosome so it’s not really typically from the egg but if I had to bet I would bet for the egg, more than sperm. But it’s not typically from the egg.

Is Parkinson’s disease a genetic disease? If one of the parents suffers from Parkinson’s disease, is it necessary to go for PGT-A and PGT-SR?

PGT-A and PGT-SR are specifically for the number of chromosomes or parts of chromosomes. Parkinson’s disease is a genetic tendency. There’s a lot of genes involved and described in this degeneration of the glands inside that leads to  Parkinson’s disease. The problem with PGT is that we need to know what we are looking for. There are three types of PGT: PGT looks for numerical abnormalities this means the viability of the embryo, this means when there’s a trisomy when there’s a  partial defect when there’s a triploidy when we know that the potential of this embryo is null, it would lead to a miscarriage, it won’t implant but will never lead to a healthy baby. So it’s more tests for the viability of the embryo, except for Down’s syndrome – it’s the only one that could be born with a pathology, with the number of chromosomes we are talking about, big chunks of information. The SR (in PGT-SR) is for structure.

As I told you, a piece of one chromosome in another chromosome, an exchange of information between two chromosomes so the information is there but the location is unusual so when the cell has to organize the material it gets lost and loses or gains material. This can be detected with PGT-SR.

There is another type of PGT which is PGT-M. This is used for monogenic disease. These are genes that we know, we can define them and we know that an alteration of a particular gene is the cause of a disease. So we need to know what we are looking for. There are some diseases that are pretty easy to look for.  For example, Huntington’s disease is caused by a particular gene that we have defined and when it’s mutated, this will cause sickness. So we look for this gene in the embryo because we know what we are looking for. Unfortunately, we don’t have the capacity of reading all the genomes in one embryo and we don’t know what we are reading which is worse. We know the letters but we don’t know what they mean in some areas of the genome.

So we define this genome but we do not know. With Parkinson’s and other diseases, there’s an enormous variety of genes and sometimes there’s no specific gene defined so we can’t really detect the sickness if we don’t know what we are looking for. If there’s some disease running in the family, we can find this gene that is causing the sickness. But with Parkinson’s, as far as we know, we don’t have this specific gene to test in the embryos, unfortunately.

I lost two pregnancies at age 40 and 41 so moved to donor eggs and donor sperm. My first transfer failed and the second has ended in a blighted ovum. Both donors had proven fertility. Am I the problem or rather the embryo? What tests should I be trying to get to determine this?

I would start suspecting that there’s something that we should test in you. What I would go for is study phase one which means thrombophilia, the structure of the uterus and functionality of this uterus meaning either hysteroscopy to see the endometrium, microbioma. If during this phase one, they find something that could be treated, let’s treat it and go for another transfer. Even though, when everything is normal, we could go for another transfer because we have to make a difference. With your own eggs it was probably aneuploidy, with a donor it is probably another factor that we have to suppose is coming up. It could also be a chance.  What I would go for, is the first phase of the study. If everything is normal, should I go for another transfer or I want to look for more? If I find something, treat it and go for another transfer.

I’ve had five miscarriages and three failed IVF attempts. I’m now 41, my ovarian reserve is normal for my age. I have not been diagnosed with any disease and is considered healthy.  No doctor has an explanation. We are now considering an egg donor but I’m worried that given my history of miscarriages it will not work. Do you think it is worth trying? Are there any exams I need to do prior to the egg donor transfer to ensure my body will carry the pregnancy to term?

If these five miscarriages have been in your 30s or 40s we can assume that the aneuploidy was the reason. It’s a pity that we don’t have a study of the chromosome profile of this pregnancy. The question is should we worry about you or it’s just the quality of the egg/pregnancy that led to those miscarriages. That’s why I’m very strongly advising the general gynecologist to test karyotypes of the pregnancies because this would shed some light on the etiology of these miscarriages. So if these miscarriages were in your 40s, the aneuploidy could be the only problem and a donor egg would solve this problem. What I would do is the basic study before going for egg donation. I think it’s worth trying but, if you were my patient, I would do a screening of thrombophilia, thyroid function and a basic structure of the uterus, the basic studies to make sure that we are not going to get into another higher risk than what’s expected of another miscarriage. Everyone wants to make sure that we want to give the best chances but, theoretically, if these miscarriages were around 40, maybe the aneuploidy is what we should think of.

I had 7 ICSI cycles and 12 transfers with 20 good embryos. I was three times pregnant and I had three miscarriages at 5-8 weeks. In every pregnancy, I was bleeding. Should I take Heparin and  Aspirin if I have thrombophilia and if I’m bleeding?

First of all, please tell me were these embryos tested? Because if you had 12 transfers with 20 good embryos what I would have done is to test these embryos to see if there’s a high rate of aneuploidy or not. This is the first thing. When we treat with Heparin, it is because we tested positive for thrombophilia. If you had been tested for thrombophilia and found out that there’s a thrombophilia, what we do is treat with Aspirin if it’s acquired from five weeks or six weeks before we start treatment.

Even though it may seem contradictory, Aspirin prevents bleeding because it allows the trophoblast to implant in a better way so there’s not that much fragility of the vessels and there’s less bleeding. If we have a patient with thrombophilia and we treat with Heparin and Aspirin and they bleed while they are pregnant, we sometimes stop the treatment for a few days until they stop bleeding but we restart the treatment if there’s a thrombophilia because we know that these vessels need to be taken care of despite this bleeding. We are pretty reluctant to stop Heparin or Aspirin.

Sometimes we stop it for a few days and then we restart. I’m assuming that there’s a thrombophilia detected. If it’s just empirical treatment, we relax more about these bleedings, we stop it, we restart it but we are more relaxed about it. When there’s a thrombophilia diagnosed, we get more strict about it. We know when to stop Heparin even though the bleeding goes down, we are stopping this to create new vessels with good function.

What do you think about KIR Genotype AA and HLA-C2C2 by the mother and HLA-C1C2 by the father? Is it possible to have a baby in this combination?

It’s a good question. With KIR and the HLA haplotypes, there’s continuously new information popping out but, theoretically, what we assume right now, at least  in our program, is that in case of KIR AA, the material that you put inside the uterus should have less C2s than the mother herself. This means that in this case we could have embryos that are C2C2 or C2C1 but these cases are the ones where we only put one embryo back because if we are putting two embryos back, we are risking to put four C2s inside the uterus which overwhelms the system that is reluctant to get this C2. So KIR is friendly with C1 when endometrium AA gets an embryo that is C1C1, it’s easy for this endometrium to implant it.

When it’s C2, depending on the body’s tolerance to C2 and depending on the body recognizing it, in these cases, I would transfer only one embryo at a time. If it doesn’t work, the problem can be an excess inflammation or a defect of inflammation. In KIR AA, they have a problem or difficulty to start this inflammation that means the implantation. Sometimes we give some inductors of colonies, some treatments that induce the start of inflammation to help. But, usually, putting one embryo in these cases, we would have two C2s, which should be enough.

What does Tevagrastim do? How does it help? I am due to take it after my next transfer via injection.

We haven’t used Tevagrastim. We are not really familiar with it so I can’t really answer your question because I don’t have experience with this.

I lost my pregnancy at 14 weeks. I was tested and was normal, male tests, too. We struggle to make embryos in IVF. If I get an embryo in my next IVF, would it be good to add Aspirin, Heparin and Prednisolone? I have done herederatyn thrombophilia and all is normal. I’m 41. EMMA and ALICE tests were normal.

If you lost your pregnancy at 14 weeks and tested normal for karyotype, it seems that something might be going on with either vascularization or excessive lack of inflammation, with the quality of placentation of this pregnancy. I would go first for an IVF and test the embryos to look for the euploids and then test for the acquired thrombophilia. Because the antiphospholipid syndrome is one of the causes of late miscarriages (over 12 weeks) and also I’d take a look inside the uterus to see if the endometrium is okay. If everything is normal, maybe I would treat you with Aspirin and Heparin. I’m not sure about Prednisolone because if you have a lack of inflammation or difficulty in starting inflammation that is needed for good placentation wouldn’t be the best approach. But it’s just an opinion. Probably if I added something empirical, I would just add Aspirin and Heparin. I would test a little more if we have normal embryos to transfer.

Authors
Anna Galindo Trias, Dr.

Anna Galindo Trias, Dr.

Dr. Anna Galindo Trias has been a Medical Director at Gravida International Center of Assisted Human Reproduction of Barcelona, Spain since 2010. She studied in Spain, Australia and the USA. Between 2003-2004 she studied at the Research Fellowship and Medical Observer at Center for Reproductive Medicine and Infertility, New Presbyterian Hospital-Cornell Medical Center, New York, USA. She has been a speaker at numerous national and international meetings and conferences. Dr. Anna speaks Catalan, Spanish and proficient English.
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Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her travelling, biking, learning new things or spending time outdoors.

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