During this session, Dr Natalia Szlarb, Gynaecologist & Fertility Specialist at UR Vistahermosa discussed the main causes of miscarriages and how to prevent them.
Dr Szlarb started by defining repeated miscarriages and explained that this is more than 3 unsuccessful transfers in reproductive medicine. That means if you had 3 transfers that ended with negative pregnancy tests or with miscarriage, you are defined as a repeated miscarriage patient. We have to be aware that in such a situation, the female’s age plays the most important role, the older the patient, the lower the genetic quality of the eggs and embryos we’ll have. In women older than 35 years old, the pregnancy rate without genetic testing of embryos is just 18%. When the embryos are genetically tested and selected, the pregnancy rates are more than 60%. If all embryos are genetically abnormal, then the only way we can help is through egg donation. In such a situation, the cumulative pregnancy rate after 3 transfers is more than 90%.
Age-depended success rates in ART
The pregnancy rates published in 2012 showed that if 4-6 embryos are coming from egg donors or young patients (under 35 years old), the pregnancy rates are higher because the number of genetically normal embryos is about 55-40%. In patients at the age of 35-37 years old, about 40% of embryos are good, at the age of 38-40 years old, 37% of embryos are good, at the age of 41-42 years old, 20% of embryos are good, and at the age of 42 or more, just 10% of embryos are good.
Therefore, it is recommended to perform a genetic selection of embryos in patients older than 35. The most common reason for miscarriages is the advanced maternal age and the genetic quality of embryos. That is due to advanced maternal age, and the older the patients are, the lower number of good, healthy embryos they generate. If the embryos are not genetically tested in patients of advanced maternal age, even if the embryos are A or B quality, even if they attach to the uterus lining, they can still be miscarried.
Repeated miscarriages – immunological issues
One other reason for repeated miscarriages is also immunological issues. The most common reasons for immunological miscarriages are autoimmune diseases such as antiphospholipid syndrome, where the white blood cells are producing antibodies against platelets. These platelets are getting sticky and develop blood clots. This is why the implantation does not occur.
Patients with high NK cells have a higher chance of miscarriage than patients without those issues. All patients with NK cell issues are treated with intralipid protocol and Prednisone. KIR polymorphism is quite important when we talk about the KIR-HLA selection, especially when your first egg donation cycle failed. The compatibility of HLA-C is another important thing, the donor is matched to you according to your KIR receptor, and the HLA of your partner. There is a special protocol to follow to get as high pregnancy rates as possible.
When we’re talking about TH1 +Th2 ratio balance, both tacrolimus and sirolimus are used to decrease the response of Th1 cells, which are embryotoxic and favour Th2 balance to make your immunological system embryo friendly.
Miscarriages – age-related issues
The majority of women are thinking about getting pregnant in their mid-30s, and this is the moment when fertility drops dramatically because of egg quality. Therefore, it is crucial to evaluate ovarian reserve as the older a woman gets, the lower quality and quantity of eggs she’s going to have.
Ovarian reserve is calculated on the female’s age, her Anti-Müllerian hormone
(AMH) and Antral Follicle Count (AFC). AFC is checked through a transvaginal scan, where a doctor specialized in reproductive medicine sees the ovaries differently than a general gynaecologist.
AMH tells us how many eggs you are going to get and when there’s a low AMH level, which means below 1 ng/ml, it is recommended to do embryo banking. 2-3 cycles are done to create a few embryos. The goal is to get at least 6 embryos and check which ones are genetically normal.
At the age of 42, the majority of embryos are genetically abnormal, and it is recommended to proceed with egg donation treatment. With abnormal embryos, there is a higher risk of not only Down’s syndrome, but also other complex genetic abnormalities.
Miscarriages – male factor
When we’re talking about miscarriages, we cannot forget about the male part, fertility issues are not only a woman’s thing. Infertility causes due to male factor occurs in around 40% of all cases. All patients need to have a sperm analysis in the first appointment, but the DNA fragmentation has to be checked as well. The male factor has been underestimated, we know that it’s not only the quality of sperm, such as volume, concentration, motility and morphology, that we have to look at but also the DNA fragmentation. There are various ways to select good quality sperm, such as MACS, Ferticert, IMSI, etc., and decrease the chance of miscarriage.
Receptivity issues
Receptivity issues cause embryo implantation failure when the embryo is not transferred to the uterus lining on time. The implantation window is combined with immunological testing of your endometrium and also screening for infections like Chlamydia, Mycoplasma. The receptivity window can be checked with the ERPeak test. During this endometrial biopsy, 48 genes are checked. There is a moment in the window of implantation where there’s the best receptivity, and this is the moment when the embryo has to be transferred into the uterus. The majority of patients have 5 days window, and there are a few that have 6-7 seven days.
Case studies
A female patient was 42 years old and came to UR Vistahermosa clinic for an egg donation cycle. She had a low ovarian reserve, and previous IUI failed cycles. She came into the clinic for an egg donation cycle and her first and second egg donation cycle was negative, her 3rd attempt ended up in a miscarriage. All the immunological and endometrial study was performed between the 1st and the 2nd transfer. And it was found that the embryos that she miscarried in her double embryo transfer were that one of them was genetically normal, and the other one was with Trisomy 13, and that was the reason for a miscarriage. This sometimes happens in egg donation cycles, even though embryos are from a young donor, some embryos could be genetically abnormal. Therefore, a second egg donation cycle was performed, this time with genetic testing, and the patient got pregnant.
The most common genetic abnormalities that we face due to advanced maternal age are Down’s syndrome, Edward’s syndrome, and Patau syndrome, and we have to understand that even though the donors are young, nobody’s perfect, and some of them may also have genetic abnormalities.
The second case presented a young 27-year-old woman where 25 eggs were retrieved, she was triggered with agonists, and she got 8 embryos that developed to the blastocyst stage. Out of 8 blastocysts, 6 were genetically normal, the transfer was performed, and the pregnancy test was negative. Before the second transfer, a receptivity test was performed, and it turned out that the implantation window was displaced, instead of 5.5 days of progesterone intake, which is normal, the implantation window was receptive at day 7 of progesterone. A double embryo transfer was performed on day 7 and the patient got pregnant with healthy twins.
Sometimes, if the first transfer doesn’t work, I recommend a single embryo transfer, but many times, the patients want to go for a double transfer for their second attempt, and when we check and perform a receptivity test, quite often it ends up in the twin pregnancy.
Take home messages
The most common cause of miscarriages is advanced maternal age and lack of genetic selection of embryos. The second reason is immunology, but also uterus lining receptivity issues, the male factor, all those factors need to be considered and thoroughly studied to find the best solution.
