In this webinar, Dr Nadia Caroppo
, Gynaecologist and The Head of the International Medical Team at Equipo Juana Crespo, Valencia, presented discussed 1 tough real-life case about a couple after recurrent implantation failure. Dr Caroppo explained the main causes, and what steps should be taken to get to the final positive outcome.
Recurrent implantation failure – real-life case
Dr Caroppo presented a case study about a couple with 6 years of primary infertility. The female patient was 46 years old, and she had a long history of dysmenorrhea. She was pregnant 3 times, but 2 of them were biochemical pregnancies.
She was checked for implantation failure panels, which were negative, her uterine NK cells were normal and immunological tests to check the KIR HLA did not seem to be a problem. She was diagnosed with adenomyosis and leiomyomatosis. Her partner was a healthy male with a normal karyotype, and the sperm count was normal, but he had a high simple chain DNA fragmentation of 67%. They were directed to go for an egg donation program because of the patient’s advanced maternal age, and they underwent 2 egg donation programs with 2 different donors in another clinic.
- a 46-year-old with a partner, 2 previous failed egg donation cycles, 8 embryos transferred in total, 2 biochemical pregnancies, previously diagnosed with adenomyosis and leiomyomatosis
During the first egg donation treatment, the patient underwent laparoscopy with left salpingectomy, but at the clinic, they entered into the uterine cavity and sutured it, after that, the patient underwent a surgical hysteroscopy and Asherman’s syndrome was discovered. It means that there is scar tissue, and sometimes it sticks to the cavity and the uterine walls between them.
In the second egg donation program, she underwent the same preparation with loads of vaginal oestrogens and transdermal patches because the endometrial lining did not grow much. This time, they also used the immunological schemes with Neupogen, IV intralipids infusions, and heparin, and they added Atosiban, which is a uterine contraction inhibitor. She had a single embryo transfer on day-3, and 2 other embryos were vitrified, but the result was negative. The last transfer was painful, and the patient bled right after the transfer.
When the patient came to the clinic (Juana Crespo) for the first time, we examined her thoroughly, and we found that she had a globular uterus, she had a retroverted uterus, diffuse cystic adenomyosis that was affecting the lining and the sub endometrium in the anterior and posterior wall, she had 2 subserosal leiomyomas that were not a problem in terms of implantation and a very thin endometrial lining which was not trilaminar and a very small cavity. The 3D ultrasound scan showed a tubular uterus, and in her right ovary, she had endometrial endometriosis implants. The diagnosis was: adenomyosis, endometriosis, Asherman’s syndrome, and an endometrial factor because the endometrial lining did not grow sufficiently.
We designed a plan, we decided to perform a pelvic MRI in a luteal phase, that means under the effect of the progesterone, treat the uterus and then synchronize her preparation with a fresh donor and a low dose of oestrogens to prepare the uterus. Because of the previous diagnosis of Asherman’s syndrome, we also wanted to perform a diagnostic hysteroscopy before the embryo transfers to make sure that the uterine cavity and endometrial lining were okay.
The MRI showed a cyst, and cystic adenomyosis, there was also the subserosal leiomyoma, which wasn’t of great importance. The plan was to do a surgical treatment, we did a hysteroscopy with a metroplasty, and during her diagnostic procedure, we saw that she had an endometrial polyp, sub endometrial cystic adenomyosis in the right corneal area, and it was Y-shaped uterus. She also had left coronual synechiae and moderate fibrosis. Then we decided to give her trimestral analogues to dry out all the cystic adenomyosis. Two months after that, we did a vaginal scan, and she had a complete regression of those lesions, therefore, we decided to go ahead and do the endometrial preparation, synchronize her with the donor and go ahead with a fresh transfer.
We started with 1 mg of estrogen vaginally, and we gave her oral pentoxifylline to make sure that correct a flood of blood arrives at the endometrial lining, and this is something that is given to very hard uteruses. We also added a high dosage of vitamin E, which is another thing that we use to increase the endometrial lining. We did a vaginal scan, the endometrial lining was thin but knowing that she had a very thin endometrial lining in the past, we decided to perform the diagnostic hysteroscopy, and we saw that she had synechiae again in the internal cervical orifice and in the left ostium where she had the previous pregnancy and that they were liberated. Nonetheless, the endometriosis had a polypoid aspect, so we had to rule out another factor which was endometritis that could have been implied in implantation failures.
Finally, the results of the biopsy weren’t negative for chronic endometritis, but positive for bacterial endometritis. There were bacteria that are called streptococcus that is very common, and it’s seen in the natural flora of the vagina and the uterus, but it grows in a much higher percentage, and so we have to treat it because that is not balanced, and it’s an agent that can irritate the endometrial lining and cause implantation failures.
We decided to provoke a period and restart the uterine preparation. This time we gave her fewer oestrogens, the same scheme with pentoxifylline and vitamin E and vaginal probiotics, we did the ultrasound scan, and the lining was very nice, a perfect lining should indeed measure between 7 and 8 millimetres or 9, some patients even with 6 millimetres are capable of getting pregnant.
We did another diagnostic hysteroscopy, and the endometrial lining was perfect, so we started luteal phase support with vaginal pessaries, and intramuscular progesterone, and we gave her heparin, but just after the embryo transfer and until the pregnancy test. We did a uterine scan before embryo thawing just to check the endometrial lining, we saw good endometrial compaction, a very good aspect of 6 millimetres, and we decided to thaw all the embryos because we were not capable of doing the synchronized cycle. We thawed 2 blastocysts of great quality, we did an embryo transfer with a mock embryo transfer first to have to know exactly how we have to get inside the uterus before we go to actual embryo transfer.
This couple had a positive pregnancy test, with very high hCG corresponding to a twin pregnancy. The fact is that she had some small haematoma impeding during the implantation process, therefore, bed rest was indicated because she had a very irritable uterus. These haematomas are typical in women who have severe adenomyosis. At the 25th week of pregnancy, she was admitted to the hospital because of a shortening of the cervix, twin pregnancy, and severe adenomyosis. Therefore, IV contraction inhibitors were administered, corticosteroids to mature lungs in the babies and magnesium sulfate to protect the babies neurologically, and afterwards, she was discharged with daily subcutaneous progesterone injections until the C-section was programmed. During the C-section, mild placental accretism was discovered, no blood transfusion was needed, and the babies were healthy newborns. They were admitted to the ICU due to prematurity, but they were discharged, and they are now very healthy.
Uterine & endometrial factors involved in recurrent implantation failure
What should we do when we have recurrent implantation failures? We should have a good diagnosis, that’s the first part, and in this case, the adenomyosis is a chronic benign disease that is only cured with menopause, and this implies ectopic endometrial and stromal glands that generate a thicker muscle, and so the uterus tends to be more rigid or thicker. There are different types of adenomyosis, and this pathology is linked to many things, it’s related to ageing and painful periods, and this implies biomechanical factors, how the uterus contracts to get rid of the period, especially in retroverted uteruses or women who experience severe dysmenorrhea during their life, inflammation issues and appendicitis achievable pathology can start all these things, it’s very linked to autoimmune disease intolerances to lactose and gluten too.
Several coexisting factors can contribute to adenomyosis. To investigate it, we use vaginal scans, 3D scans, Pelvic MRI and hysteroscopy, but we should never rely only on one diagnostic tool unless we don’t have the opportunity to go ahead and perform other ones. We have surgical medical treatments that are personalized according to the type of uteruses we have. There’s no one woman equal to another one, especially with these pathologies.
Adenomyosis may be asymptomatic, or you can have any type of other symptoms such as abnormal bleeding, pain or reproductive failure or discover this because you do not get pregnant or you fail with pregnancies. Adenomyosis and endometriosis can coexist in a high percentage of patients, so it’s very common to see women who have endometriosis and then have the uterus affected and vice versa.
Endometritis is a chronic inflammation of the endometrial lining, it’s diagnosed with the presence of plasmatic cells in the endometrial stroma or bacteria. This is only diagnosed with diagnostic hysteroscopy and biopsy, and it’s not visible on the ultrasound. This decreases the receptivity and implantation of our embryos, and the prevalence in the general population is very variable, it’s between 0.8% and 19% of women who have this. Some women have endometritis, but they still get pregnant and have ongoing pregnancies. It’s very common to see endometritis in women with endometriosis and adenomyosis. We tend to do biopsies or directly treat patients because we know what a perfect endometrium looks like and gets pregnant. The uterine vagina is very important because the uterine cavity and the vaginal cavity are not aseptic cavities. There is a population of bacteria that have to be there, but lactobacilli have to be tough to prevail over all the other ones because they are the regulators. When there is a dysregulation in the endometrial flora, you tend to have more endometritis and implantation failures. We always give oral probiotics, and sometimes vaginal probiotics.
Not only good quality or euploid embryo is important, but also how you do every transfer technically. You don’t have to have any bleeding or feel pain during the procedure or 48 to 72 hours after the transfer. If you do transfer, when you feel pain, the uterus automatically contracts and will spit out everything it has inside. That is why we do more mock embryo transfers just to make sure that we know exactly how to get inside the uterus. Some women do not get pregnant because they have very difficult embryo transfers, this is something that we always do to know how to get inside or if we have to do something in preparation for that embryo transfer.
A correct diagnosis and a correct treatment is the key to success to get pregnant. Getting pregnant is very difficult, it’s not just having sexual intercourse, and that’s it. That happens to a very small portion of the population. The basis of everything is having a good diagnosis, and if we have a good diagnosis, we know which enemy we have to fight against. What usually happens is that the uterus is the best incubator, and it’s the forgotten piece of the puzzle.