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Ksenia Khazhylenko, MD
Obstetrician-gynecologist, Fertility specialist & Geneticist, IVMED
Category:
Miscarriages and RPL, Success Stories
During this webinar, Dr Ksenia Khazhylenko, Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED – Fertility Center talked about 2 of her past patients who experienced recurrent miscarriages and were able to finally achieve their final goal – a healthy baby.
Dr Khazhylenko started by presenting the first case about a young patient who was 28 years old and her husband of much older age at 54. They had 5 previous biochemical pregnancies (she had a positive pregnancy test, but her hCG of max, 300 UI/mL). When she came to the clinic, she was exhausted and disappointed and wanted to find a reason for her miscarriages and wanted to check all options.
Firstly, we checked her test results, and she had a normal karyotype, normal BMI, normal uterine anatomy, and she had a normal ovarian reserve, her husband, despite his age, had normal semen parameters. She also had a normal thyroid function and endometrium with no signs of endometritis, however, she also had a higher risk of traumatic events because she had a high level of antiphospholipid antibodies and was also a smoker, she smoked 10 cigarettes a day for a very long time. Additionally, she was homozygous on PAI-I, plus her mother died quite early from thrombosis at 46 years old, and it’s always important to check a family history. She had a very high risk of thrombotic events during pregnancy, and she had recurring pregnancy losses, the antiphospholipid syndrome is a big problem during the pregnancy. It’s significant to mention that thrombotic events can happen a bit later in the second and third trimesters. There is some publication about antiphospholipid antibodies in patients who underwent IVF programs where they suggest that patient sometimes such patients can have even increased possibility to become pregnant in IVF program, but unfortunately, this can result in a miscarriage during the second and third trimester.
Therefore, we’ve explained that the reason for her early miscarriage was an antiphospholipid syndrome, although the most common cause of early pregnancy losses is chromosomal pathology. We advised to either continue with a natural conception and antithrombotic therapy or go ahead with IVF and PGT-A with antithrombotic therapy using low molecular weight heparin and aspirin. The patient decided to proceed with IVF, so we started with ovarian stimulation.
We obtained 20 eggs which was a good result for her age, and almost all eggs were fertilized, we got 8 blastocysts, and it was again a good result, but PGT-A testing revealed that only 1 embryo was euploid, the rest were abnormal. Therefore, the first conclusion was that all previous pregnancy losses could be because of chromosomal issues. We did an embryo transfer with 1 euploid embryo in a natural cycle, and we started low molecular weight heparin (LMWH) and aspirin from the embryo transfer, and 12 days later, she got a positive pregnancy test.
After 2 weeks, she had her first ultrasound, and it turned out to be a twin pregnancy despite transferring a single embryo. Approximately 2% of single embryo transfers can end in a twin pregnancy because of embryo splitting in the very early stage after implantation. However, the majority of these twins are monozygotic, so they come from 1 embryo, and usually, in this type of twins, when we do the first ultrasound, we can see just one amniotic sac, however, in this case, we saw 2 amniotic sacs with 2 different embryos.
What can be the reason for such a situation? It’s possible that it was not the splitting of the embryo, but that it was a natural conception before the embryo transfer. We always recommend using contraception before transfer in a natural cycle, but unfortunately, not all patients go forward with our recommendations. Therefore, dichorionic twins, in this case, meant that it was due to a natural conception plus a pregnancy from the transfer, but it was good news because this was a program with genetic testing, and we knew that 1 embryo was healthy, however, we didn’t know anything about the second embryo.
The antithrombotic therapy was very complicated during the pregnancy because the patient bled from early pregnancy, it wasn’t just spotting, it was severe bleeding sometimes, we decided to stop aspirin, and it was cancelled in a typical week of pregnancy, and later we have cancelled LMWH at 12 weeks. The pregnancy progressed normally till 30 weeks of pregnancy, but then intrauterine growth restriction started from one fetus, and after 1 month, the condition of one of the fetuses became worse. Therefore, we decided to induce delivery, the delivery was done by caesarean section, and 2 baby girls were delivered, the discordance between these twins was almost 50%, but fortunately, despite this both girls were healthy, and now they are 6 years old, and they are identical. This was a very uncommon situation with monochronic twins with 2 different amniotic sacs, it was really rare.
The conclusion from this case is that Repeated Pregnancy Loss (RPL) can be caused by different conditions, and despite some very obvious conclusions, we need to continue our examination even if we think we know all the possible reasons.
Early losses mostly happen due to chromosomal pathology, so we need to provide full examination at all costs. The next conclusion is that antiphospholipid syndrome means a higher risk of pregnancy, and without treatment, a patient often has not just pregnancy losses but also complications with neonatal risks, so the treatment is very important.
If we suspect chromosomal pathology is the reason for recurrent miscarriages, we should at least discuss the IVF program with PGT-A, which can be very helpful in this situation. We should also strongly recommend contraception before transfer in the natural cycle and we should keep in mind that sometimes single embryo transfer can result in twins.
It all depends on the term of pregnancy. In early pregnancy, the most common problem is chromosomal pathology, but if we are talking about late-term miscarriage, it is 22 weeks of pregnancy here in Ukraine, it’s more about blood clotting problems. In the middle of these terms, we are talking about uterine issues, endometrial abnormality, chronic endometritis, and also shortening of the cervix, which usually starts from 14-16 weeks of pregnancy. These are the most common reasons.
When we are talking about 20 to 24 weeks of pregnancy, it’s not a miscarriage, it’s pregnancy loss, there are many different causes for this.
When we are talking about karyotyping, it doesn’t give us extensive information because chromosomal pathology in embryos mostly happens during conception, when sperm fertilizes the eggs. In the majority of cases with chromosomal pathology in the embryo, the parents have a normal karyotype, but a normal karyotype doesn’t mean that you didn’t have a problem with the chromosome. Therefore, chromosomal pathology seems realistic in this situation.
It would be better to discuss this with the patient, there are 2 ways, IVF program with PGT-A or natural conception. There are a lot of so-called immunological tests, but these tests are not yet evidence-based. IVF with PGT-A, in this case, can be very helpful even if the reason for the miscarriages was not because of chromosomal pathology. When we provide genetic testing of the embryo, we can explain the prognosis for you, and we can find out the reason for the previous situations because we know how many normal and abnormal embryos we normally have for each specific age group.
If the result, let’s say is in the middle of normal and abnormal embryos typical for this age, it means that the previous miscarriages were not caused by chromosomal pathology and we need to continue and look for something else, maybe there are some immunological problems, blood clotting problems and so on.
Chronic endometritis in a patient with RPL is different from the infertility patient group. When we learn that the patient has chronic endometritis after miscarriage, we never know if the reason was the condition or because of miscarriage. Chronic endometritis is not just inflammation, it means there are changes in endometrium sometimes with micro polyps, sometimes with polyps, sometimes with uterine adhesions. If after treating endometritis, we see some changes in the endometrium on an ultrasound, it is better to do a hysteroscopy.
If there are no signs of endometrial pathology on ultrasound, we just need to treat it. Then I recommend checking it to make sure that we have treated endometritis, so perform a biopsy of endometrium a month or two months after the treatment.
After treating chronic endometriosis, at least 10% of the patients will have positive results again. The main question is: What to do with this patient? There is no international recommendation for this situation. When the second tests are positive, it’s hard to offer any recommendations.
For patients who are undergoing an IVF program, the answer is much easier. In such patients, we can use some medications to kind of turn off the menstrual bleeding for 1 to 3 months.
One of the main reasons for chronic endometritis recurrence is uterine bleeding every month, and this is possibly a reason for the recurrence of inflammation of the endometrium. In such a case, when we plan embryo transfer, we can use different medications, stop the bleeding for 1-3 months and then do embryo transfer. This is usually a strategy that is effective enough.
It’s important to know if your embryos have been genetically tested. Usually, we talk about NK cells in fertility programs where the patients already had checked their embryos genetically. If they are not tested, we don’t know the chromosomal status of the embryos, it’s not a good idea to focus only on NK cells. If they are genetically tested, there are a lot of ways that we can check it, but as I have mentioned, it’s not evidence-based at this moment.
I don’t have enough information, and there are different types of treatment, NK cells are 70% of all immune cells in the endometrium, you need to do some additional tests to study different parts of the immune system in the endometrium, in the blood.
For a high level of NK cells, we can use intralipid infusions, which is the most popular method nowadays. It’s very effective, and this was a very low possibility of side effects, so this is the most popular treatment of high-NK cell levels. Keep in mind that it can be about different immunological disorders, the first, and most important would be the genetic status of all the embryos.
It’s strongly recommended to check antiphospholipid antibodies for RPL patients at any term of pregnancy losses. There is a strong association between antiphospholipid syndrome and recurrent miscarriages.
Regarding thrombophilia, it’s a bit different. There is not enough proof for the association between thrombophilia and the risk of pregnancy.
When we test the patient for thrombophilia, it’s not about the real risk for the pregnancy, it’s about general risk. Thrombophilia testing was performed for patients whose relatives had thrombotic events. For those patients, thrombophilia risk means just having an additional higher risk of thrombotic events in the future.
For RPL patients, it’s a bit different. Looking at my first case, Victoria was tested for thrombophilia, the result was that she had a middle risk of mutation, but she had other risks, antiphospholipid antibodies, she was a smoker, this is an additional risk for the thrombosis, she had a family risk of thrombotic imbalance from relatives of the first degree. It means that even if she doesn’t have any thrombophilia mutation, she has enough thrombotic risk, therefore it’s better to double-check it.
Thrombophilia risk means that this patient has a bit higher risk of thrombotic events during her life, but it doesn’t mean that it was the reason for recurrent miscarriage or any miscarriages. Fortunately, approximately, 95% of all patients with mutations don’t have any thrombotic events during their life. Fortunately, 95% of all patients don’t need this test.
I see patients in my practice during my consultation where they had 3 or 5 miscarriages, and after a second miscarriage, they were performing different tests, and they were positive for some thrombophilia mutation. Then during the 3rd or 5th miscarriage, she was still unsuccessfully treated with heparin, and she had a miscarriage anyway. The reason was different, so testing for thrombophilia is not obligatory, it’s not helpful.
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