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.
