During this webinar session, Dr Yasmina-Ben-Aicha, Obstetrics & Gynaecology & Reproductive Medicine Specialist at Equipo Juana Crespo, Valencia, Spain explained the main causes of RPL, provided treatment options, and shared her own patient’s story.
Dr Yasmina-Ben-Aicha presented a case of her 37-year-old patient whose 3 previous pregnancies ended in a miscarriage. The patient was looking for pregnancy after 4 years with her husband, she has had regular periods, her BMI was 20, and she was suffering from dysmenorrhea. She had subclinical hypothyroidism, and she was taking Eutirox of 50 mg per day. Her husband was a healthy 38-year-old man with a BMI of 21 with a normal semen analysis.
The patient got pregnant 3 times, but each time, it ended in a miscarriage. They proceeded with another IVF treatment, however, no pregnancy was achieved. On their 3rd IVF attempt, they decided to proceed with IVF and PGT-A testing to check the embryos, they also used Embryoscope to see the embryos during the development, and they used the MACS method to check and select the sperm. They obtained 6 eggs, 5 of them were mature, 4, they got 3 day-5 and 1 day-6, and the result after PGT-A revealed 3 euploid embryos. At that point, we knew she was able to have normal embryos. It’s important to mention that she has had a normal thrombotic risk profile after checking the implantation failures, the couple had a normal karyotype, and she had performed ERA/ALICE/EMMA tests that were normal. In total 4 embryos were transferred before she came to our clinic (Juana Crespo).
When the couple came to the clinic, we needed to perform a gynaecological checkup, we have done an ultrasound, and we found a retroverted uterus, a small myoma, which was a subserosal myoma, and we saw that the patient had a good ovarian reserve with a total of 12 antral follicles. We also did an MRI study, and we saw that the sub endometrium was thickened. We did a mock cycle, and after the endometrial preparation to check the situation before the endometrial preparation, we found an endometrium thickness of 12.3 millimetres, the myoma on the fundus and adenomyosis in the anterior wall. We decided to perform a diagnostical hysteroscopy, and we were able to see that there was a normal aspect in the posterior wall and some inflammatory points like small polyps in the anterior wall. In the end, we diagnosed an endometrial and sub endometrial problem in the anterior all plus adenomyosis.
The plan was to do a short protocol using 225 units of FSH and 75 units of Menopur and whether to do PGT-A or not, which would depend on the number and the quality of the embryos, as we knew that this couple was able to have normal embryos. The second step was preparing the uterus and going for an embryo transfer.
We started the egg stimulation process with 225 units of FSH and 75 units of Menopur, we decided to go with a dual trigger, we gave the patient Ovitrel plus Decepeptyl, and we obtained 10 eggs, 9 of them were mature, 8 of them fertilized and we decided to vitrify the embryos, 4 on day-5 and 2 on day-6. It was necessary to prepare the uterus, and we couldn’t go for a fresh transfer and perform PGT-A because we were not sure if the embryos will reach the blastocyst stage as they were of medium quality on day-3. In the end, we decided to freeze all embryos that reached the blastocyst stage without PGT-A.
After that, we started the uterine preparation. We did a surgical hysteroscopy to perform a metroplasty to remove some points of fibrosis and to prepare the uterus to revascularize the uterus. We found some moderate fibrosis, and the anterior wall was a bit affected, and after the hysteroscopy, we gave her a treatment to prepare the uterus with Estradiol valerate and also Decepeptyl as well as Femara to decrease the adenomyosis.
After this, we decided to go for an endometrial preparation, we started with a substitute cycle with 3 milligrams of estradiol. We performed a scan on day eight after starting the treatment, and the endometrium thickness was 7.2 mm, the patient was suffering from flushes which was an effect of Decapeptyl. We performed a diagnostic hysteroscopy, and we found some isolated micropolyps on the anterior and posterior wall, so we decided to cancel this endometrial preparation to give some antibiotics and probiotics to treat this.
At the end of the same month, we started another endometrial preparation with a substitute cycle, we decided to increase a bit the dose to 4 mg of estradiol valerate with a previous GnRH. We performed a scan on the 9th day after the start of the treatment, and we found an endometrium of the triple line at 6.7 millimetres, it was quite good, so we decided to go ahead with the embryo transfer. We transferred 1 day-5 embryo, there were no complications, and we gave the patient Heparin after the transfer till the pregnancy test, but unfortunately, the result was negative.
We decided to discuss the case to analyse all the points, and we thought that if the substitute cycle was not working, we should go for a natural cycle and use more embryos because this patient had normal embryos. Therefore, we decided to change the strategy and go for a natural cycle, we found an endometrial thickness of 11 millimetres and a dominant follicle of 15 millimetres, so we decided to go ahead. We prescribed some vitamins for antibiotics and Euthyrox because of her hypothyroidism background. We performed an ultrasound the morning before the transfer, and we saw an endometrium thickness of 8 millimetres, and we decided to transfer 2 day-5 embryos. There were no complications, and the patient was also taking the heparin after the embryo transfer till the day of the pregnancy test, and the result after this endometrial preparation was positive.
This information is from the guidelines from the European Society of Human Reproduction and Embryology (ESHRE) regarding recurrent pregnancy failures, which are defined as having 2 or more pregnancy losses. It’s important to know that pregnancy loss increases after 40 years old. The couple should also be aware that maternal obesity could play a negative role in recurrent implantation failure as well. However, some complementary tests are not required by the ESHRE guidelines, and they include the screening for antiphospholipid antibodies, the anticardiolipin antibodies and the beta 2 glycoprotein, also the anti-nuclear antibodies (ANA), and it’s also significant to check the thyroid to see if it’s necessary to stabilize it. It is not recommended to check for the HLA determination or the NK cell testing.
- Questions and Answers
Hormonal imbalance can be related to the thyroid or the ovaries. When it comes to thyroid dysfunction, there are some treatments that we can do. There are also some hormonal imbalances when we have some disorders in the FSH, LH. When we have a polycystic ovary, also we can have some hormonal imbalance, so we have to arrange it during the ovarian stimulation. We work together with the endocrinologist when there are some problems with the thyroid, we can work with them and just give medication.
Normally, we try to work multidisciplinary to arrange it and make a good treatment for the patient. In a general medical background, the TSH is normal till 4. However, when we are looking for pregnancy, the recommendation is to have a TSH lower than 2.5. That’s why even if it’s 3, your GP will tell you, it’s a good level, but when we look for pregnancy to have a healthy first trimester of the pregnancy, the good level is lower than 2.5. We recommend checking it with your endocrinologist or starting with a low medication and performing a blood test 4 weeks later.
We have to take into account what’s adenomyosis. Adenomyosis is like an inflammation, some points of endometriosis inside the uterus, inside the wall that are just giving inflammation, and it causes bad preparation of the uterus. Most of them, we can check with an ultrasound, but sometimes, we have to do some mock cycles, some trials, give some medication to see how the uterus is responding when destructions are high.
Normally, the most effective way is to do an ultrasound. Sometimes, we perform an MRI at some specific points of the cycle. We also perform a laparoscopy to check the ovaries, the fallopian tubes. However, that will not give us information related to adenomyosis.
In that situation, it’s important to normalize it and double-check with your endocrinologist that there’s nothing else to add or check before controlling it as much as possible. If you’re not going to use your own eggs when you go for an embryo transfer, and there’s no male problem, we can just avoid the PGT-A.
It all depends on the reason for the previous miscarriages, that’s why it’s really significant to know the case and the reason. For example, if these two miscarriages happened because of an abnormal embryo, I would be more confident to go with the embryo donor cycle with no other treatment or no other points to check. If the embryos were normal, then we have to look further, and check the uterus or look for some endocrinological disorders, etc. There are some unknown reasons sometimes. We always try to find the reason for the miscarriages to occur.
Recently, there are some discussions because the sperm is playing a part. Nowadays, there are some extra tests, but we don’t know exactly how to use them, they are related to DNA fragmentation. Some studies show that they play a part. Some of them are not giving a lot of importance to that factor, so there’s a discussion.
Here, in our clinic (Juana Crespo), we pay more attention to the egg and the uterine factor. Sometimes, when there are is bad sperm, we check further, but we don’t pay a lot of importance to the DNA fragmentation because we have to take into account that in the sperm, most of the time, there are millions of spermatozoa, and we have experienced embryologists who can check and select the perfect spermatozoa to fertilize the eggs one by one.
The spermatozoid is giving the chromosomal information, and a good egg could improve a medium or low sperm sample. Some groups say that they take it into account, others say that it’s not worth it, and they are not paying a lot of attention to it. It’s still being discussed.
That’s a difficult question, so it is true, there’s some percentage of unexplained infertility cases. Personally, and here in our clinic, we always want to know the cause because it’s not bad luck, we want to know why as all the doctors, I guess, we like to know the reason, to analyse the case. Most of the time, we can find the reason.
Although, sometimes we think that it’s the cause. Each couple and each case is completely different, you cannot compare situations, but I always try to find the reason and improve that situation to get a good result.
As I said previously, the sperm plays a part. The most important thing with the sperm is the appearance and the specific selection. Even if there is no motile sperm, the ICSI method solves that problem.
The motility gives us the information that the sperm is not able to reach the fallopian tube and the egg in that situation. When we go for a testicle biopsy, for example, we obtain spermatozoa with no motility, so it’s only to give the chromosomal information, it does not affect it at that point.