In this session, Dr Ksenia Khazhylenko
, Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED – Fertility Center discussed 1 complex case about a couple with previous IVF failure and diagnosed with recurrent implantation failure. Dr Khazhylenko explained the tests performed and the treatment plan in detail that allowed the couple to achieve a pregnancy and a healthy baby finally.
Dr Khazhylenko started her presentation by emphasizing that the definition of recurrent implantation failure (RIF) is one of the most complicated and most controversial in reproductive medicine because there is no consensus between experts, society, and countries when it comes to defying it. Some consider recurrent implantation failure as some unsuccessful attempt, some that are at least 2 or 3, 4 failed attempts. Many questions arise in regard to embryo quality. Does it mean that the embryo has to be of high-grade morphologically, or does it need to be genetically tested? Should we keep in mind the age of the patient over 40 if it’s genetically tested? Therefore, there are a lot of questions and not as many answers to this.
There are a lot of different situations which cause implantation failure and starting with gamete quality and uterine factors as well as thrombophilia, etc. We need to keep in mind that not all these factors are evidence-based. Some of them are just logical, others are more controversial.
Recurrent Implantation Failure (RIF) – real-life case
The case presented by Dr Khazhylenko described a case of a young patient who came to the clinic (IVMED) when she was 32 years old. She never got pregnant, and she was diagnosed with unexplained fertility, which means that she didn’t have any problems with ovarian function, fallopian tubes or uterine anatomy, her partner had a normal semen analysis, and they had normal coital frequency.
First IVF attempt
When she started the treatment, she was 32 years old, so she had a good prognosis. The couple decided to start IVF, and on the first attempt, she got 12 eggs and 5 good quality blastocysts, 1 of them was transferred in a fresh cycle, but she didn’t become pregnant. They tried with the second transfer, and she became pregnant, but she miscarried very early on. After that, the couple decided to genetically test the embryos. Two of the three embryos were euploid, which was a good result. Before the next. transfer, the doctor decided to do a diagnostic hysteroscopy, and it is uterine was normal, and the endometrial biopsy was negative. They also did an endometrial scratch before the transfer, and then 1 one euploid blastocyst was transferred, but she didn’t become pregnant again.
Before transferring another embryo, they did additional tests on thrombophilia, and even though this patient didn’t have any individual or family risk factors, they found prothrombin 2 (an inherited condition that increases your predisposition to develop abnormal blood clots in the veins and lungs), that was the reason for previous failures. They repeated the frozen transfer where they transferred a genetically tested blastocyst, and they prescribed Low-molecular-weight heparin (LMWH) plus aspirin, but the patient didn’t become pregnant. This was their 4th transfer and the last frozen embryo.
Second IVF attempt
Therefore, the couple started their second IVF attempt, but before stimulation, her husband had done a DNA fragmentation test, which was normal. During the egg retrieval, 15 eggs were obtained, 5 blastocysts were biopsied and frozen, and out of 5 embryos, 4 were euploid. Their doctor decided to do additional tests, and they wanted to check the patient’s window of implantation, it turned out that it was displaced, it was 1 day later, which means it was the day after a conventional implantation window. When we take the endometrial biopsy to check the window of implantation, they also studied NK case levels in the endometrium, and it was discovered that they were also elevated in this patient. Therefore, again transfer number 5 was performed with 1 euploid blastocyst was transferred, before the transfer, the patient was prescribed immunoglobulin infusion (IVIG), but the result was also negative.
The 6th frozen transfer was done, again they prescribed immunoglobulin infusion (IVIG), Prednisone was added, taking into the account thrombophilia prothrombin 2 mutation, they also added low-molecular-weight heparin (LMWH) plus aspirin, however, the result was negative.
After this attempt, the couple came to our clinic (IVMED) with their 2 remaining embryos. We summarized all the previous attempts to understand the reasons for the failures.
- 1st fresh transfer – no add-ons
- 2nd frozen transfer – no add-ons
- 3rd frozen transfer – HSC, CD-138, endometrial scratch
- 4th frozen transfer – LMWH + aspirin
- 5th frozen transfer – displaced WOI, IVIG
- 6th frozen transfer – displaced WOI, IVIG + LMWH + aspirin
After reviewing the case, Dr Khazhylenko emphasized that the patient got pregnant after the second transfer, which could mean that she had a prolonged window of implantation. According to Dr Khazhylenko, a patient who previously had a pregnancy after standard transfer could have a normal window of implantation. Regarding the NK cells, it could be a temporary situation. Sometimes, in some patients, high NK cell levels can be just temporary, it doesn’t mean that in the next cycle, the NK cell level will be the same. Another thing is that after the ultrasound, it was found that the patient had adenomyosis, and in this type of situation, estradiol in ART cycles is not recommended because estradiol can increase the development of adenomyosis. Generally, patients with adenomyosis and endometriosis need some pre-treatment before going ahead with embryo transfer. We know that adenomyosis is a very strong inflammatory environment for the embryos during the implantation process, and we know that adenomyosis increases sub-intermediate contractility in the patient, especially after the transfer, and it can cause cavity deformation and the progesterone resistance.
After the reevaluation, the next approach was to use a long preparation with agonist gonadotropin (GnRH) releasing hormone, and Atociban to decrease the sub endometrial contractions, and taking into account possible high NK cells to use intralipid infusions before the embryo transfer, plus additional progesterone for luteal phase support because it’s well known that progesterone can decrease the NK cells levels in a patient with high levels. We also proposed to avoid taking estradiol due to her Prothrombin 2 level mutation. We also wanted to do it in a natural cycle.
- agonist GnRH from the middle luteal phase twice
- monitoring of LH surge (natural ovulation)
- vaginal progesterone after ovulation
- intralipid infusion 5 days before the embryo transfer
- embryo transfer on a conventional day (LH+6)
The result was finally positive, fortunately, she had an uncomplicated pregnancy, and she gave birth to a baby boy.