In this session, Dr Natalia Szlarb has been discussing the causes of repeated implantation failure and provides options that can help you improve your chances.
Dr Szlarb started by explaining the definition of recurrent implantation failure, which is a lack of pregnancy after at least 3 transfers with good-quality embryos. The definition does not specify if embryos of good quality should be on day-3 or day 5 of development.
The first thing we have to have is a healthy embryo, in egg donation cycles, the eggs come from a young, fertile donor, so in the majority of cases, there is no need to perform genetic selection, but in patients of advanced maternal age, so people who are older than 35 years old, it’s always best to transfer only euploid blastocysts. Therefore, the first thing we have to focus on is embryo quality. The second thing to solve the problem of recurrent implantation failure is the uterus lining, the endometrium. There was a study published in 2015 where 60 000 blastocysts from all around the world were genetically examined, and it showed that 60-70% of all donor embryos are euploid, and in other age groups the number of genetically normal embryos is age dependent. At the age of 35, statistically, every other embryo is healthy, at the age of 40, 20-30% of embryos are healthy, and at the age of 43, less than 10% of your embryos are healthy. Therefore, in patients of advanced maternal age, the genetic selection of an embryo is the only way to diagnose a healthy embryo.
In 1950 or 1955, 30% of all the mothers were 20-24 years old, now there is only 14% of mothers at the same age. In 2017, the majority of women having children in England and Wales are between 25 and 35 years old. Also, 20% of women have children between 35 and 39 years old, and as we know, the quality of the eggs between 35 and 39 drops dramatically.
Mother’s age & ovarian reserve
To assess your ovarian reserve, we need to check your AMH and Antral Follicle Count (AFC). AMH levels show your overall ovarian reserve, it can tell us the number of eggs or embryos we can expect if we were to perform a cycle. When your AMH is higher than 2 ng/ml, we expect around 20 eggs in a mild IVF cycle. Antral Follicle Count (AFC) is a transvaginal ultrasound where doctors specialising in reproductive medicine or their sonographers see how many antral follicles you have in both ovaries.
The mother’s age is the main factor in implantation issues. As the woman gets older, there is a higher risk of genetic abnormality. The most common risk of Down syndrome is Trisomy 21, there is 1 chromosome in position 21 too much, and this can cause mental retardation. The second common abnormality is Trisomy 18, called Edward’s syndrome, and Trisomy 13 is Patau syndrome. These are the most commonly described age-related abnormalities that women’s eggs are generating.
Most infertility issues that men have started in their 50s, and 60s, and it’s due to erection issues, but that can be solved easily through medication like Viagra. At a certain age, testosterone production drops. However, it’s important to mention that around 40% of infertility cases are due to male factors. It is very often recommended for men to not only take vitamins and start to ejaculate more frequently, but also some men and their hormonal adults allow using injections the same as female FSH/LH-based medication to support sperm production.
Every man, on the day of the first appointment, gets a sperm analysis. According to World Health Organization criteria from 2010, here are the norms:
Total sperm count in ejaculate: 39–928 million
Ejaculate volume: 1.5–7.6 mL
Sperm concentration: 15–259 million per mL
Total motility: 40–81%
Progressive motility: 32–75%
Sperm morphology: 4–48%
Another test that is also routinely done is DNA fragmentation, if there is a high DNA fragmentation, a high dose of vitamins C, and E treatment and high ejaculation frequency and fertilization with fresh sperm are recommended. Magnetic-activated cell sorting (MACS) is also advised if the DNA fragmentation is more than 30%.
IVF & PGT-A
In IVF and PGT-A, when the biopsy is performed, 5-6 cells are taken out of each embryo, and it is sent to the genetical testing lab, and the results will show how many genetically normal embryos we have. Sometimes, we can retrieve16-20 eggs if a woman has a good ovarian reserve and is 30-35. When we generate 16-20, some other complications like infection and post-egg retrieval bleeding can happen, therefore, every patient gets medication to prevent inflammation to support their blood clotting after the egg retrieval. After 1-2 hours after the procedure, the patient can go home. Then, the embryos are genetically tested and frozen.
To avoid recurrent implantation failure, the first step in your treatment is to define how many eggs and genetically normal embryos we will be able to generate, depending on your age and AMH. Then your eggs are going to be processed, and after the genetic testing, the embryos will be frozen. Step number 2 is to go back for 1 day for frozen embryo transfer, in step 2, it is necessary to focus on your uterus lining and prepare your endometrium.
Having 5-6 blastocysts up to the age of 35 gives you a 90% of probability that you’re going to have 2 children. Therefore, it’s worth thinking about your fertility when you are young because, in 1 cycle, we can plan your entire family. The problem starts when women are getting older and do not generate as many eggs at once, then embryo banking is an option.
In advanced maternal age, if you do not genetically test your embryos, the pregnancy rates are about 18%. If you go for IVF with PGT-A, after 1 transfer, 60% of all patients get pregnant, after 2 transfers, it’s 80%, and after 3, it’s 91.3%. The more embryos you have, the higher the cumulative pregnancy rate.
Embryo banking cycles are for patients whose AMH is under 2 ng/mL according to European units, in the UK, the threshold is more than 14 pmol/L The issue that we have is that if we generate 10 eggs in a cycle, out of those 10 eggs, we will get 5 blastocysts and out of 5 blastocysts, at the age of 35-37, 44% of embryos are going to be healthy, but at the age of 41-42, only 17% of embryos will be healthy. We have to be aware that out of 5 embryos, we can only have 1 healthy embryo.
PGT-A with embryo banking is recommended for patients with a diminished or low ovarian reserve who still potentially due to their age can generate genetically normal embryos. Normally, the cut-off age for using own eggs in reproductive medicine is 42-43. We know that patients older than 43 have less than a 10% probability of finding genetically normal embryos. Sometimes, the patients are doing an IVF cycle or embryo banking cycle at the age of 46, and we know that they will generate eggs and we will get embryos, but statistically, less than 10% of them will be healthy. If after 1 IVF cycle with PGT-A at the age of 46, we are not getting a genetically normal embryo, you will receive a document, which will tell you about genetic abnormalities your embryos have due to your age. In such cases, the best chance of achieving a pregnancy is going for egg donation.
In Spain, egg donation is allowed for more than 30 years, it’s the country with the longest experience in egg donation in Europe. It’s important to remember that egg donation is a last and very unique step in infertility treatment. According to Spanish law, egg donation is anonymous, so you will know details like age and type of donor you will have, nothing else. The donor and recipient must be matched, sometimes it’s like looking for a twin sister, somebody who looks like you, and have the same colour of hair, skin, etc.
According to Spanish law, it is possible to treat women until they are 50 years old and 11 months. The donor has to be under 35 years old, and all donors are screened for infectious diseases, genetic diseases and mental health, such as schizophrenia, depression, personality issues or no drugs. The second step of a donor selection process is to find out about your characteristics, for example, how tall you are, your haircut, skin colour, blood type and whether you want to match a blood type to a donor or not, etc. It’s also important to discuss if you should tell your child or not about his origin, and of course, you will be supported throughout the whole process.
Before the transfer, a mock cycle is performed, then with artificial hormones, your natural cycle is mimicked to see which dose of hormones you need to grow a good thickness of a lining, and it is always between 7 and 12 millimetres. This dose of hormones is adjusted, you will be on estrogen for 15 days and 5 days on progesterone, then you will be synchronized with the donor, and you stop a birth control pill together with your donor. You are prepared for the transfer while the donor has her egg retrieval. For egg donation treatment, you have to stay in Spain for a week so the team can work with the fresh eggs and fresh sperm. If frozen sperm will be used, you can stay for a long weekend and just for the transfer. It all depends on the partner’s sperm.
If your first egg donation cycle fails, we need to evaluate it because it is different from your own eggs. Why? Because with egg donation after the first transfer, 70% of patients should have a positive pregnancy test. Usually, patients after the first unsuccessful transfer get something called uterus lining biopsy, where their immunology is checked as well as their Natural Killer cells (NK cells), cytokines, chronic endometritis, but also chlamydia infection. It is also important to check your uterus lining receptivity window, 70% of all a patient needs 5.5 days of progesterone to open the implantation window, some others need 6 or 7 days of progesterone to open the implantation window.
- 42-year-old woman with low ovarian reserve (AMH: 0.3 ng/mL and AFC:2) with 2 previous failed IUI cycles and 3 previous IVF cycles
As we know, at 43, less than 15-17% of embryos are healthy, so we know we will have few eggs and few chances of having genetically normal embryos. We suggested IVF with PGT-A, where we received 2 blastocysts, 1 of them was with Trisomy 21 and the other one with Trisomy 13, so we had no embryos to transfer. Therefore, we suggested going ahead with egg donation treatment. We performed a single fresh embryo transfer, and the patient got pregnant and delivered a healthy child.
- 27-year-old patient with AMH of 3.5 ng/mL, and AFC:20, she had 2 previous failed IVF cycles with day-3 embryos
We got 25 eggs, and we performed IVF with PGT-A, we got 8 blastocysts, 6 embryos were euploid, and one was transferred, but the result was negative. After 1 unsuccessful transfer with 1 genetically normal embryo, we decided to do further investigation. Statistically, with the genetic testing performed, 70% of all the patients get pregnant after the first transfer. Therefore, we did an endometrial receptivity test (ERMap), and we saw that this patient needed 7 days of progesterone to open the implantation window. We did a second transfer with 2 embryos and the result was healthy twins. We do not recommend double embryo transfer most of the time, and we always make it clear, that patients need to sign a consent to have a double embryo transfer.