In this session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, shared his experience on how to deal with recurrent miscarriages and provided some real case studies explaining the steps that can be taken to prevent them.
Dr Tsakos started his presentation by explaining the definition of recurrent miscarriage, which is two or more miscarriages, and of course, they have to be addressed with a special team, they have to be addressed holistically, and they have to be addressed systematically so that we don’t miss anything out. If we add two more factors to recurrent miscarriages, one important factor is age. The value or the importance of a miscarriage is different if someone miscarried at 25 and if someone miscarried at 40. That reflects on the level of investigations we will probably initiate. There’s also another concept which is a recurrent IVF failure, it’s not just the miscarriages that should be investigated, but also if someone has 1,2, 3 failed IVFs that interact with some similar factors, many times with miscarriages.
If we look at female anatomy, we know there is the uterus, fallopian tubes and ovaries. There is a misconception that the ultrasound scan is the golden standard in diagnosing female anatomy, we have to be aware that this is not true. The ultrasound scan is a very significant tool, technology is getting better by the year, however, it is not the golden standard. It’s crucial to remember that female anatomy cannot be thoroughly assessed by a scan alone. The second misconception is that the tubes are not necessary, not important. If we’re doing IVF, that’s wrong, they may be significant. If the tubes are seriously affected by infection, and if the tubes suffer from a condition called hydrosalpinx, which is a big infection that’s causing fluid and toxins to accumulate within those tubes, they may affect the success of IVF, but also the outcome of pregnancy, they may cause miscarriage. The third misconception is that we don’t care about conditions like endometriosis or we don’t care so much about conditions within the uterus when we’re having IVF or when somebody is conceiving naturally, this is not true. Therefore, female anatomy is very essential and the assessment by ultrasound scan, no matter how high-tech, is not 100%.
It turned out that the cause of the recurrent miscarriages and failed IVFs was uterine malformation. The uterine malformation is a condition that some women are born with. In the picture shown, there is a uterine malformation type 1. There are a lot of different types of malformations, but this is a fairly common one amongst infertility and patients with repeated miscarriages. It is called the uterine diaphragm, most people would call it uterine diaphragm, there are different terminologies. It means that instead of having 1 cavity, there are 2 smaller cavities, so there’s a division of the cavity into 2.
In that first case, this woman in her mid-40s was fully investigated, she had lots of scans by lots of different doctors, she had miscarriages and failed IVFs, and the problem was this diaphragm. This lady came up to the age of mid-40s without knowing that not only did she have a double uterus, but she also had a double vagina. This malformation had to be corrected surgically through hysteroscopy, and then she underwent successful IVF, and she delivered beautiful twins.
Therefore, it’s important to remember that if you do have a problem with miscarriages or IVF failures, do not rely on the scan alone and request to have further investigations to ensure that you do not suffer from a uterine malformation.
Hydro is water, salpinx is a tube in Greek. It means that fluid accumulates in the tubes. In the picture shown, there is an X-ray, Hysterosalpingography, or HSG, and there is a lot of literature proving that it is important to exclude hydrosalpinx before doing IVF or before completing miscarriage investigations.
This particular patient underwent treatments, she had miscarriages, and she came up to her mid to late 40s before she found out that with the X-ray HSG she had hydrosalpinx. In most European clinics and most U.S. clinics, HSG is not one of the standard tests before IVF and may not even be a standard test after a miscarriage or miscarriage. It may be substituted by either a high-tech ultrasound scan or an ultrasound aided tubal assessment called HyCoSy or HyFoSy. Unfortunately, HyCoSy or HyFoSy and high definition scans are not 100% accurate in diagnosing hydrosalpinx.
Therefore, in cases of miscarriages and failed IVFs, it is significant to perform a standard X-ray HSG. If you are diagnosed with hydrosalpinx, remove it laparoscopically. The patient had a laparoscopy to remove her tubes, and then she had two beautiful children consecutively, not at the same time, through IVF.
Bear in mind the possibility of hydrosalpinx in case of miscarriages, and again some people do not quite grasp that there is a possibility of conceiving naturally even with the hydrosalpinx in place, however, there’s an increased risk of both miscarriage and ectopic pregnancy.
The miscarriage itself and perhaps the surgical evacuation, Dilation, and curettage (D&C), or even the medical evacuation may cause an additional problem, which may be the endometrial adhesion. Therefore, one of the reasons why we don’t like many miscarriages is that despite the origin and the aetiology, despite the reason a couple miscarried in the first place, the miscarriage itself may cause damage to the endometrial cavity as it did in this case. It caused this band of tissue, scar tissue, which decreases the risk of miscarriage. That was a case of endometrial adhesion, which was successfully divided and led to a spontaneous natural pregnancy.
I would like to highlight the importance of anatomy assessment. The main reasons for recurrent miscarriages or repeated IVF failures may be hormonal. We may have some thyroid defects, Polycystic ovaries may be linked with miscarriages and anatomy defects. On top of those, I would add polyps that could be in the cavity, I would add fibroids, either big fibroids or smaller ones that affect the cavity. The genetic issues may cause miscarriages, so we always suggest the karyotype testing of both couples. I feel that the patients that eventually come to an IVF clinic are not the standard patients in which karyotype disorders are uncommon. We do identify quite a few patients every month with karyotype abnormalities. Even cystic fibrosis, genetics may affect miscarriages. Serological blood testing and vaginal and cervical swabs may identify infections. Screening for medical conditions is important, diagnosing diabetes or starting phases of diabetes conditions like Lupus, etc. Other factors such as lifestyle issues may affect the fertility potential and also increase the miscarriage rate. Heavy smoking, alcohol, drug consumption and medications may also cause miscarriages. If we’ve excluded those important issues, we can always think of unexplained factors, but if we thoroughly rule out the majority of factors in the majority of situations, we may identify a reason, and we should be able to treat it accordingly.
Fibroids are very common, the vast majority of soft tissue tumours are benign tumours, although some of them may become malignant even in younger patients under the age of 50.
Dr Tsakos also mentioned one of his past patient’s cases. A lady had a very small fibroid, it was less than 3 cm, it wasn’t even touching the cavity, but it ended up being diagnosed as a sarcoma, which is a malignant fibroid tumour, she had to undergo a hysterectomy. She felt very lucky that it was diagnosed before IVF because she’s had lots of miscarriages before, and if that lady got pregnant through IVF, the tumour would have been undiagnosed for at least 10 months, and that would have been detrimental to her health.
Pedunculated submucosal fibroids and submucosal fibroids may affect and be associated with the miscarriage. Subserosal, intramural fibroids are not associated with miscarriages and are of no importance unless they grow fast or become bigger than perhaps 4-6 centimetres. The diagnosis is usually done by ultrasound, however, if we want to ensure that the cavity is normal we still need to do a hysteroscopy and decide if those need to be treated or not.
The golden standard in diagnosing the endometrial lining is hysteroscopy. It is now becoming more and more routine test on almost every who is attending a fertility clinic with a history of either miscarriage or before embarking on IVF. It’s an outpatient procedure, it’s inexpensive, and it’s highly accurate. The value of hysteroscopy has been proven and scientifically discussed.
I would be very optimistic. Use your own eggs. 38 is young, your AMH is fine, you have embryos, and you’ve been pregnant before. Go ahead and use your own eggs. I’m sure you will make it. A miscarriage at eight and a half weeks maybe a slightly positive sign that you can get pregnant. So, use your own eggs and keep trying. As to thrombophilia, you should get treatment. I’m not going to go into details, but thrombophilia is one of the important reasons for miscarriages, pregnancy complications and health issues in the future.
There are different degrees and different variables in diagnosing thrombophilia, however, if it has been diagnosed, there’s no harm at all in preventing any possible contribution of thrombophilia in your pregnancy by taking a small dose of low molecular weight heparin, based on your weight, and also perhaps a small dose of aspirin. So, get some prevention treatment, which I would probably continue up until 12 weeks and then reconsider whether I would use it for a longer period. So, low molecular weight heparin and aspirin. And keep going with your own eggs. Two grade 1 frozen embryos would probably give you one or two beautiful children, so please let us know what has happened, and I would highly encourage you to keep going.
I will tell you from my experience, and I will tell you about the challenges, and I will tell you why in our practice, we only use fresh eggs from the donor, frozen sperm from the husband or partner if there’s a couple or frozen donor sperm. We always do frozen embryo transfer of the blastocyst. This is one of the three options that the egg donation programs provide for the patients. Options one is the fresh collection, i.e. a collection from the donor and fresh embryo transfer. The second option is a frozen egg from the donor and fresh embryo transfer. That is what we are doing now.
What is the challenge of using fresh eggs from the donor and fresh embryo transfer? Two challenges are becoming even more complex now with the COVID situation. When we match a donor, they also state when they’re available to do IVF. So imagine a situation when a perfect match for Alison would-be donor, number one who would be available for an egg collection in December or the end of October because of other commitments, and Alison may not be available to travel for her treatment those days. There is often a discrepancy between the availability of one or the other party. This is challenge number one. The second challenge is when the donor is flexible, they can do the stimulation any time, and the recipient is flexible, i.e. they could come to the clinic anytime, we try to synchronize them. When synchronizing a donor with a recipient, there is a chance of 80% of perfect synchronization, not 100%. It happens because to synchronize you and the donor, you would have to have medicated cycles. We would have to medicate both of you so that you go parallel. However, medication is not always a hundred per cent effective, and a difference of plus or minus one or two days in the egg collection and the embryo transfer may have a huge impact on the success rate.
Factor number three is the patient experience, the donor experience, as well as the clinic experience. When we stimulate the donor and the patient and prepare a patient for embryo transfer, we’re stressed. We’re almost as stressed as you are for different reasons. We want everything to be perfect, so you can imagine the stress. We measured all of that, my team and I, we’ve audited the stress levels, and we found that when we were trying to synchronize the cycles, our patients and donors, and the clinic staff were stressed too. This affected the experience of the team. Why are we stressed? Because we wanted not only the donor to be stimulated perfectly and create perfect eggs, but we had an extra added stress of the time. Everything had to be done on time to be in parallel with the recipient, and then we found that some recipients take a longer time for the endometrium to be perfect. Some of them took 11 days, some 15 or 17 days. Why cannot we wait once the synchronization process starts the trigger? It cannot wait more than 24 hours, so then we had to cut corners. We had to decide what to sacrifice: would we sacrifice the endometrium and the potential implantation success, or would we sacrifice the quality and the quantity of the donor’s eggs. That was too much. On top of that, we found that the success rate was about 10% less with synchronized cycles, unfortunately. The stress levels were much higher, and the matching was not brilliant. After all, we found that the recipients travelling from Europe, UK, America, Australia would rather compromise the donor than compromise themselves because they only had very limited time, so we stopped that. We dropped it.
Frozen eggs are a huge challenge because an egg is only a potential embryo. It means that you may thaw an egg or six eggs or ten eggs, and you may have 1 embryo, 2 embryos or no embryos of top quality. By disconnecting the treatment cycle with the embryo transfer cycle, we disconnected the timing, the availability of our patients, we disconnected the stress, so we only had to focus on one thing at a time. First on the donor, then the recipient. We can handle that better, and our patients could handle that better. This is why we ruled out the 10% chance that for some reason the donor wouldn’t do well. Some donors don’t stimulate well. We sometimes have to cancel them. Or they stimulate relatively okay, but they don’t create good eggs or mature eggs. Or they create very good eggs, but for some reason, the eggs do not connect very well with the sperm we have available, and therefore, we have no embryos, or we only have 1 embryo, in which case we probably cancel the cycle, and we run another donor. For all those reasons, in my practice, I discourage anything except using fresh eggs from the donor, creating the blastocyst so that we know we have the blastocysts. We say goodbye to the donor and focus on the recipient so that we prepare the recipient perfectly. Having the blastocysts in hand, we can provide the recipient with one or two top quality blastocysts at a time.
I don’t, and it’s not legal either in Greece. At the moment, the evidence is that PGT-A may be viable for women with repeated miscarriages, women of advanced reproductive age, in particular over 40 years old. PGT-A is a tool, but if we want to be strictly scientific and not very commercial. We will have to use it with specific indications, and those indications do not apply in the egg donation cycles. In egg donation cycles, donors are under 30, at least in my clinic. They are healthy females under 30, with a health history and so forth, so they do not qualify for the medical indications of PGT-A, and the Greek authorities decided that to avoid monetization of commercial use of PGT-A, they forbid that. It cannot be applied, it’s not legal to apply PGT-A in the egg donation cycles.
We’re very aware that thrombophilia has become a widespread problem. The diagnostics are readily available and fairly inexpensive. We have learned a lot about thrombophilia and its impact on fertility and pregnancy over the last 10-15 years. We are very aware that thrombophilia testing and thrombophilia factors may affect pregnancy outcomes. We know that, and therefore we incorporate this into our practice even before a miscarriage.
When we do a standard fertility questionnaire and standard fertility history, we try to identify any risk factors for thrombophilia. The panel can include quite a few tests, from one or two tests to up to 20, we look at individual factors. In case of even a single miscarriage, I usually run a small panel of thrombophilia testing, and in case of more than one or two miscarriages, I would highly recommend the full panel of thrombophilia testing. The patient would be treated accordingly to the results. As I mentioned before, heparin with a combination of aspirin.
The answer is yes, I do.
Presumably, you’re speaking about miscarriages after IVF. It depends. I would exhaust all the diagnostics and re-evaluate the diagnostics. Sometimes, for example, somebody has had an x-ray or HCG 4 years ago, and in the meantime, they may have developed hydrosalpinx without knowing, or they may have had a hysteroscopy 2 or 3 years ago, and since then, they may have had a couple of D&Cs or an infection, that may have affected the endometrium. I would repeat the diagnostics. I would refresh and perform as many diagnostic tests as possible. Then it comes to the question of age and what kind of IVF we do.
If somebody’s over 40 and they’ve had 2 or 3 miscarriages, 4 miscarriages with their own eggs, I would start thinking about two options. One is performing IVF with PGT-A so that at least you ensure that the embryos you’re transferring are chromosomally normal, we call them euploid, and full hormonal support and heparin support and aspirin and steroid support. The second option would be to move on to egg donation. If you’ve never had PGT-A and you wish to exhaust the chance of creating euploid embryos, I would probably suggest having PGT-A at 41. I would fight for it. It depends on how you feel, but I would fight for your own eggs.
I would check the male, your partner thoroughly: karyotypes, cystic fibrosis, semen analysis, infection screen, general tests. Make sure your male is healthy, your sperm is healthy and then ensure that everything is normal with you. I would recommend hysteroscopy, HSG to rule out hydrosalpinx. Check your hormones, especially the thyroid, vitamin D levels, infections. Make sure you are fit as a fiddle before you move on. Let’s put it this way, what is acceptable with egg donation and what’s not. If we have reasonable sperm and we create top blastocysts, we would expect around a 55% pregnancy rate per single embryo transfer. With 2 embryo transfers, roughly about 75 or 80% of our patients should be pregnant. The remaining 20% I think we should heavily investigate.
Provided you have top-quality embryos, I would make sure that the environment is 100% healthy. Hysteroscopy, HSG, hormonal testing screen and then very good preparation of the cycle. Let’s not forget that there are various protocols to prepare the cycle, i.e. it can be a natural cycle or a medicated cycle. In the medicated cycle, you take estrogen orally or vaginally, or you may take patches. The endometrium forming is checked if it is normal. You measure the hormones as well because sometimes there is some sort of hormone imbalance that we don’t pick up by just doing a scan. Some people just use the ultrasound scan and measure the endometrium before a frozen embryo transfer. In my practice, we rely on blood testing as well as hormonal testing to ensure that we meet some standards. We try to correlate that with the findings of the endometrium. We want the progesterone to be very low before we start the preparation of the cycle and so forth. Meticulous monitoring of the cycle is important, and the laboratory is important, who is performing the embryo transfer is important. Make sure it’s not a difficult embryo transfer. Maybe a small dilatation in a cycle or two before the embryo transfer may facilitate it. Getting the most experienced member of the medical team for the embryo transfer may be good because we all have little different results. I would encourage you to try that. There’s still a chance you will get pregnant with those frozen embryos, as long as every detail is checked.
I tend to compare IVF with cooking. I mean, there are dozens of tiny pieces that add to the puzzle, and anything can happen. You can have the perfect embryos, and for some reason, you may have a difficult embryo transfer, which will compromise everything. You can have embryos that are not so wonderful and, for some reason, didn’t thaw very well or thawed partially, or didn’t expand. There are a lot of factors that may affect success, unfortunately. And that’s why IVF is very meticulous work, and we all suffer from a bit of OCD. Attention to detail is important, everything has to be perfect: from the perfume that is not allowed in the lab to the people that we have to have. We have only the necessary number of people because even breathing through the mask may damage the environment and create volatile objects in the air. There are a lot of fine details. We need to ensure that our patients understand the drugs and that they take them correctly. We cannot over treat.
If you’re in doubt about the absorption of the tablets, in my opinion, I wouldn’t hesitate to use vaginal or transdermal estrogen, and of course, progesterone is also significant: how many days you take it, when we start, how we administer it, how we monitor it and so forth. There isn’t very sound evidence in giving steroids to everyone or even some of our patients, or there’s no sound evidence of using aspirin. We have some meta-analysis saying that perhaps it makes no difference, but maybe a subgroup of patients would benefit from that. Recently, there was a study in human reproduction about the benefit of low molecular weight heparin in the case of thrombophilia. I think we must focus even more on the difficult cases, it’s just that sometimes in the busy clinic, you cannot focus on the difficult case. You just treat everyone the same, and perhaps sometimes we miss a little significant piece of detail, that’s why I think it’s very important what you’re doing with the webinars because our patients need to be educated so that they know themselves what to ask for what to challenge and what to request sometimes.
In terms of age, I have to say that fertility over the age of 40 is decreasing rapidly. Even male fertility is reduced after the age of 40 or 50. Generally, miscarriage by itself is not necessarily an adverse factor, depending on what it is caused by. I cannot answer this question. All I can say is that over the age of 45, there’s a very small fertility window. However, we do have numerous patients in that age group where we have to be very meticulous, and usually, egg donation is the way forward.
Don’t forget that ensuring that we have a normal embryo is only one of the 50 factors of IVF success. It’s not a solution to all our problems by itself. It is important, but we have to ensure that the rest of the female organism is healthy. We should take things individually. 45 is the new 35 in terms of many aspects, but I think we should be careful when we treat women over the age of 40 or 45. Firstly, we have to make sure that we do not compromise their health, and secondly, we need to ensure that we haven’t missed any factors significant for IVF success.
The first egg donor may have had polycystic ovaries, and they may have had poor quality eggs, or in the first egg donation cycle, perhaps the sperm may have been affected by some infection or by some issue that, perhaps, affected the fertilization. It could have been some sort of other issue that is very difficult to pinpoint, but it’s not unlikely, and this is one of the reasons why we disconnect the cycles. For example, in my clinic, we would cancel the first cycle, we wouldn’t count it at all. If we create one blastocyst, we give the couple the option to cancel at no cost to themselves, and we run another donor because we don’t like that outcome. In general, a 30-year-old donor is still a very young donor, so you know 20 eggs from a 30-year-old donor is a lot. Another issue with egg donation is the way you stimulate your donors and what you are after. In general, we don’t like to overstimulate our donors. We like to aim at a smaller number of eggs, between 10 and 12 eggs. We are talking about mature eggs, of course. We may have 20 eggs, but not all of them would be mature.
I think this proves my point that we don’t like parallel cycles, synchronized cycles because we don’t like to be faced with the situation when synchronized women from different areas after all this effort produce just one embryo. That’s why we would rather stimulate the donor first and ensure that we have at least 3 blastocysts, otherwise, we cancel the cycle and move on to another donor.
DNA fragmentation is not affecting the outcome of IVF. Whether they performed ICSI, that’s another issue. I mean, there is a difference between ICSI and standard IVF. In my practice, we always perform ICSI on egg donation cycles just to ensure that we won’t have any fertilization issues unexpectedly. If they use ICSI, DNA fragmentation is relevant.