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What are the prospects for IVF patients experiencing recurrent miscarriages?

Dr Manuel Izquierdo
Director of Medical Quality & Consultant Gynaecologist, IVF Life Group

Category:
Miscarriages and RPL, Success Stories

recurrent-miscarriages-prospects-IVFWEBINARS-IVF-Life-Madrid
From this video you will find out:
  • What types of pregnancy loss are there?
  • What’s the definition of recurrent miscarriages also known as Repeated Pregnancy Loss (RPL)?
  • What are the most common causes of recurrent miscarriages?
  • What kind of exams/tests can help prevent pregnancy loss?
  • Does PGT-A (Preimplantation genetic testing for aneuploidy) increase live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure?
  • What solutions are there for chromosomal, receptivity and immunological issues?

What are the prospects for IVF patients experiencing recurrent miscarriages?

What are the most common risk factors for miscarriages?

Watch the webinar on recurrent miscarriages and prospects for patients. Our presenter Dr Manuel Izquierdo, Director of Medical Quality & Consultant Gynaecologist at IVF-Life Madrid, has discussed the main causes and possible treatment options as well as provided 2 different patients’ cases.

Types of pregnancy losses

There is a biochemical pregnancy, which is a miscarriage that happens very early on, we can detect pregnancy hormonal levels, but we can’t confirm biochemical pregnancy. Another one is an early miscarriage, which is defined as a pregnancy loss before 12 weeks, and late miscarriages occur after 12 weeks onwards. Premature delivery is related to delivery before week 37 of pregnancy. Depending on the kind of pregnancy loss we are facing, the medical approach will be very different. Recurrent miscarriages also called Repeated Pregnancy Losses (RPL) are miscarriages that occur before the week of 20, and it’s about 20-25% of all pregnancies, but it’s important to remember that recurrent miscarriage is not so frequent. It affects about 1% of women, the classical definition is being more than 2 miscarriages in a row for women over 35 years old or women under 35 years old having fertility problems. It is usually considered 3 consecutive miscarriages in women under 35 years old, not knowing they have a fertility issue.

Causes of pregnancy loss

There is a biochemical pregnancy, which is a miscarriage that happens very early on, we can detect pregnancy hormonal levels, but we can’t confirm biochemical pregnancy. Another one is an early miscarriage, which is defined as a pregnancy loss before 12 weeks, and late miscarriages occur after 12 weeks onwards. Premature delivery is related to delivery before week 37 of pregnancy. Depending on the kind of pregnancy loss we are facing, the medical approach will be very different. Recurrent miscarriages also called Repeated Pregnancy Losses (RPL) are miscarriages that occur before the week of 20, and it’s about 20-25% of all pregnancies, but it’s important to remember that recurrent miscarriage is not so frequent. It affects about 1% of women, the classical definition is being more than 2 miscarriages in a row for women over 35 years old or women under 35 years old having fertility problems. It is usually considered 3 consecutive miscarriages in women under 35 years old, not knowing they have a fertility issue. Causes of pregnancy loss Most of them are caused by genetics, the most frequent cause is the chromosome number alteration in the embryo. Most of the embryos that have a bad chromosome number or aneuploidy will not implant, but many of them will implant and end in a miscarriage. This alteration in the number of chromosomes can occur by an error in the egg formation or sperm. Sometimes it is related to issues in the chromosome composition of the parents. Immunological alterations are less frequent, there can also be coagulation issues. There can also be some thrombophilia factors, there is an ongoing debate about infections during the first 3 months of pregnancy and their relation to the miscarriages. Another cause can be endometrial receptivity, most of them are related to non-implanting embryos or biochemical miscarriage. Other health risk factors like obesity or associated pathologies like polycystic ovaries (PCOS) there are some doubts about this condition as most of the time miscarriage, in these women are more related to the glucose metabolism than the polycystic ovaries by itself. Other conditions such as non-treated or not well-treated diabetes, multiple pregnancies because there could be limited space in the uterus for containing more than 1 pregnancy and sometimes it is a factor for having a miscarriage as well as some cervical incompetence, which means that the cervix is a bit more open than expected, and it contributes to miscarriage, and we mustn’t forget about lifestyle factors.

Recurrent miscarriages – complementary diagnosis & tests

As the chromosome factor is probably the most important, it’s mandatory to do karyotype testing on the patients. Karyotype means the study of the chromosomes in the cells of the blood. Another test that can be performed is PGT-A, which is a chromosomal analysis of the embryos. Thrombophilia testing is a blood test that is looking for coagulation conditions, another essential exam is a very detailed study of the uterus, some uterine abnormalities are related to miscarriage, such as the septate uterus. Although some randomized clinical trials are saying that the factors affecting uterine abnormalities are not always involved in this, once we know about the septate uterus or a fibroid in the cavity, we need to advise the patients that this factor is contributing to the miscarriages or the implantation of the embryo. It’s always recommended to consider correcting these abnormalities. The most significant tool for assessing the uterine conditions is a 3D ultrasound scan, but many times it is completed with Hysterosalpingography (HSG) or hysteroscopy, where we can see the uterine cavity with a small camera. Other complementary tests, such as endometrial receptivity mapping (ER-Map) or immunological map (IMMAP), are sometimes indicated.

IVF with PGT-A

How can we tell if an embryo has a good chromosomal composition? We can select the embryos that reach day-5 blastocyst with a biopsy coming from the outer cells and taking some of these cells with a very small biopsy, and we can have a chromosomal analysis of these cells. The idea is that the karyotype coming from these external cells will be possibly the same as the whole embryo. There are a lot of publications that show this will contribute to decreasing the time to achieve pregnancy and increase the chances of having an ongoing pregnancy. To perform this procedure, we need to do an ovarian stimulation because if we have more than one embryo, we increase the probability of having 1 good embryo to transfer, and it’s always better to have more than one embryo. After that, we will retrieve eggs and then go ahead with in vitro fertilization, the embryos develop in the lab for 5 five days, and then the biopsy is performed. After the biopsy, we need to freeze the embryos and then wait for the results. Once we have the results, we plan the transfer. How is the chromosomal analysis performed? We have a very useful tool called Next Generation Sequencing (NGS) thanks to that, we can have a picture for every number of chromosomes. Nowadays, we can tell that most likely that this particular embryo will be euploid, and this one will be aneuploid. What is our expectancy of having euploid embryos in terms of the age of the women? The main factor is women’s age, and our statistics show that under 35 years old, 62% of the blastocyst stage embryos implant, and over 40 years old, we see a decrease in implantation rate, it’s around 18% of implantation. What happens if we perform PGT-A, there is at least the same implantation rate, and sometimes it’s even a bit higher because we are discarding all the aneuploid embryos and will not implant. Therefore, PGT-A in these older women is balancing the most important effect of the women’s age. However, it is critical to mention that not only older age is the reason for having chromosomal abnormalities. Having a low ovarian reserve means we may not get a good number of embryos, which we could study. At 36-37 years old, there is an increase of aneuploid embryos, while at 44 years old women are having 90% of aneuploid embryos. That means we need a lot of embryos to have a chance of detecting aneuploidies at the same the miscarriage rates increase. Aneuploid embryos are the most frequent cause of miscarriage.

Chromosomal abnormalities, receptivity & immunological issues – solutions

If a patient is not having a good number of embryos or has a lot of aneuploid embryos, a good alternative is to consider egg donation. PGT-A testing is not needed in egg donation cycles most of the time because, in Spain, it is mandatory for women who donate their eggs to be under 35 years old. There is 30% of aneuploidies in these cases, therefore PGT-A is not considered to be beneficial in egg donation cycles.

Egg donation

In Spain, it is mandatory to have a very detailed study before being accepted into the egg donation program. A lot of candidates are not passing through this intensive testing in terms of genetic studies, psychological evaluation, etc., and we always match the patient’s phenotype with the donor. How does the egg donation cycle work? We usually perform a trial cycle, we offer the patients the possibility of preparing the uterus in advance to check the recipient’s response, and we perform an ultrasound scan and hormonal tests to ensure the endometrium is in a good condition for implantations. Once we confirm the endometrium is in a good condition for implanting, in terms of very good lining, good measurement and good hormonal levels, we do the embryo transfer. The cumulative pregnancy rate in egg donation is the highest in all fertility treatments. After the 1st embryo transfer, the implantation rate is 70%, and in the 2nd embryo transfer cumulative pregnancy rate is 91%, and after 3 embryo transfers, there are more than 95% chances of pregnancy.

The window of implantation (WOI) – ER-Map

What about endometrial receptivity? Implantation is considered a conversation between the embryo and endometrium. We know that the receptivity and endometrial receptivity are related to the progesterone exposition. Once we have a good endometrium, we start with progesterone supplementation, we have the same days of progesterone most of the time as a day-5 embryo, so 5 days of progesterone and so on. This is the general rule, but some patients diagnosed with repeated implantation failures may have a narrower window of implantation or displaced window of implantation. Therefore, we have a test called ER-Map to check the receptivity of the endometrium and sometimes it is pre-receptive or post-receptive. What does it mean? This tells us that the best moment for placing the embryo in the endometrium if it is post-receptive should be performed a few hours before we normally do, and the other way around if it is the pre-receptive, it means the endometrium is not good enough at this point, and we need to wait some more time. These tests are useful because they will tell if the window of implantation is at a good point or if we need to move this window of implantation.

Immunological tests

Sometimes miscarriages also occur due to some immunological issues. As mentioned before, there are some thrombophilia factors. It is related to the blood clots in the very small vessels that can interfere with the circulation between the placenta and the endometrium. There are some issues like antiphospholipid syndrome where our antibodies affect this coagulation condition. In such cases, sometimes we advise proceeding with the treatment with low-dose aspirin or heparin. There is a lot of research about immunology cells like natural killer cells (NK cells), HLA antigens and lymphocytes about compatibility and the relation with KIR receptors (killer cell immunoglobulin-like receptors) in the woman, etc. Nowadays, it’s still a field that is being studied. When is this immunological testing suggested? It is recommended when we have discarded the most common causes related to genetics, thrombophilia factors etc.

Real-life case studies

The first case study presented was about a 42 years old woman with 2 miscarriages and 2 previous IUIs and IVF cycles. She had a very low ovarian reserve, AMH was 0.3 ng/mL, and antral follicle count (AFC) was 2. We performed PGT-A genetic testing on 2 day-5 embryos, but both were aneuploid, which meant there were no embryos to transfer.
  • 42-year old, 2 previous miscarriages, low ovarian reserve, 2 previous failed IUIs, 2 previous failed IVF cycles
We suggested going for egg donation as she had a very low ovarian reserve, a low number of embryos and the two embryos were aneuploid. Her first single embryo transfer was successful and she had a positive pregnancy test and a healthy child. The second case study was about a younger woman with a good ovarian reserve and good antral follicle count. She was 27 and had previous IVF cycles with day-3 embryos. She didn’t have miscarriages, but this is to show the advantage of considering genetic testing in similar cases.
  • 27-year-old with a good ovarian reserve, good antral follicle count, 2 previous failed cycles
She had 25 eggs and a lot of embryos, and we suggested doing PGT-A and decreasing the probability of transferring aneuploid embryos. From 8 blastocysts, we had 6 euploid embryos, and the first single embryo transfer was negative when we performed the endometrial receptivity mapping (ER-Map), we detected that her endometrium was pre-receptive, and we needed to wait extra days. This endometrial receptivity test told us that the best day was to do the transfer 2 days later.

Conclusions

It’s important to remember that 65% of patients having recurrent pregnancy losses are expected to have a healthy child on the next try. Two-thirds with no intervention are having a healthy child. Most of the time miscarriages are related to the embryo that is failing. We can study it, and sometimes only by performing this, we succeed on the next try.

What are the most common risk factors for miscarriages? - Questions and Answers

Is a pregnancy with a young woman’s donor egg the same as a donor’s pregnancy? Does the age of the donor count for the success of the pregnancy?

Here in Spain, and I think most of the countries are allowing egg donors to be under 35. The reason is very clear, the pregnancy chances are mostly the same in the range between 18-20 years old and 35 years old, and it does depend on the donor’s age when we transfer the embryos to a woman who is 40 or 44 years old. We have the pregnancy chances of the woman who donated the eggs, we cannot see a great difference between the donor’s age. We have similar pregnancy rates, and all the groups have similar pregnancy rates. The research is showing no significant difference between the age of the donor.

I have had 5 transfers, 3 failed implantation followed by 2 miscarriages. My clinic wants me to try again with another transfer and not do PGT-A testing. Should I just try again or do further testing?

It’s a very difficult question to answer. If you transfer a new embryo, you could succeed, not all the miscarriages are related to genetics. Possibly you could do endometrial receptivity testing or immunological tests, it’s very difficult because we don’t know if you performed any extra tests. My recommendation will be to perform uterine assessment, ultrasound scan, and hysteroscopy as well. Remember that sometimes transferring a new genetically tested embryo is not a guarantee, sometimes it succeeds, and sometimes we have no clear answer and the reason.

Any thoughts on endometriosis as a potential reason for recurrent losses of PGT-A-tested euploid embryos?

Our knowledge is that endometriosis is affecting the ovarian response most of the time during ovarian stimulation, and sometimes it affects the quality of the eggs. It is very important to note that we have the same pregnancy rates in egg donation when we transfer an embryo to a woman having endometriosis. Endometriosis is not related to embryo implantation, it is sometimes confusing for the patients because endometriosis comes from the name endometrium, and they think they have an inflammation of the endometrium. Endometriosis means having endometrial tissue out of the place of the uterus. It doesn’t mean you have a problem in your endometrium and your uterus and with implantation. Another thing is adenomyosis, which means endometriosis inside the muscular tissue in the wall of the uterus. This could impact endometrial receptivity because it is very near the endometrium. It could cause an imbalance in the receptivity. Adenomyosis is related to embryo implantation, but I cannot tell that having an endometrioma or a cyst in your ovaries is related to decreased endometrial receptivity and endometrial embryo implantation. In the egg donation cycles, when we transfer embryos to women suffering from endometriosis, the implantation rates are comparable to women who don’t have endometriosis.

For a person with a first miscarriage without knowing the cause, is it advisable to go into IVF? What tests are expected to be done by the person?

After one miscarriage, even without knowing the cause, the recommendation is to try again. Most of the time, you will not need to perform a fertility treatment. Embryo selection with genetic testing is only statistics but on the other hand, if you performed fertility treatments on everyone who had one miscarriage we could be over treating them. Most of them will never need an interventional treatment. Having a miscarriage is very common in the human race, we have a lot of miscarriages and it is predicted that after having 1 miscarriage, 80% of the time in the second pregnancy you will not suffer a miscarriage. This is only statistics, but because medicine is not an exact science, we always provide the statistics to expect what might happen in similar cases. Most women get pregnant with no intervention and have a healthy child.

Is it better to have medical management of miscarriage as opposed to D&C surgery? Are there risks of scarring in the lining?

It depends. Nowadays, we offer to consider medical management because it has no intervention, it’s a very clean way to remove the remains of the miscarriage from the uterus, but sometimes it is not easy, and the medical management is not working, and it is necessary to offer surgical intervention. We prefer medical management in the first line, but it depends on the patient. Some patients are saying that they prefer to finish this as soon as possible and want to go for surgery and then leave the clinic in a couple of hours. I will not be waiting if I can remove it by myself. However, the best option is to do a medical intervention as the first line of treatment. There are a few risks that D&C can cause. However, there are very few cases, so don’t be afraid of surgical removal, although the best option is to consider the medical management first.
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Authors
Dr Manuel Izquierdo

Dr Manuel Izquierdo

Dr Manuel Izquierdo is part of the IVF-Life group as Director of Medical Quality and Consultant Gynaecologist. Graduated in Medicine and Surgery from the University of Salamanca, specialising in Gynaecology and Obstetrics, from the Hospital Universitario Fundación Jiménez Díaz. Dr Izquierdo also holds an MSc in Human Reproduction from the Complutense University of Madrid. Dedicated to the field of fertility for more than 25 years, he has developed his profession in different centres, always projecting his vocation of help and service to patients until today.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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