Recurrent pregnancy loss

Explained by: Raul Olivares, Dr., Barcelona IVF
Category:
From this video you will find out:
  • Should patients be treated once we find out what the problem is or is it worth to carry out all the studies and only start once we’ve discarded all the causes of recurrent pregnancy loss (RPL)?
  • Is it worth treating all patients starting ART as if they were potential cases of RPL? (Using steroids, heparin, aspirin as standard therapies in the first treatment)
  • Do intravenous immunoglobulins or intralipids help in cases of RPL?
  • How can we be sure that there are no genetic issues in the oocytes or the sperm?
  • Is there anything patients can do to reduce the risk of miscarriage (rest, take progesterone, improve their diet, etc.)?
  • How useful is checking thrombophilies or antiphospholipid antibodies in cases of RPL?
 

All you need to know about recurrent pregnancy loss

During this Online Patient Meeting, Dr. Raul Olivares, Medical Director & owner of Barcelona IVF, answered patients’ questions about recurrent pregnancy loss.

All you need to know about recurrent pregnancy loss - Questions and Answers

Should patients be treated once we find out what the problem is or is it worth to carry out all the studies and only start once we’ve discarded all the causes of recurrent pregnancy loss (RPL)?

Well, this is a tricky question. The fact is that usually, patients who go through a recurrent pregnancy loss have such a big emotional burden that when they decide to come to you to see if there is anything that we can do, they want to avoid any further miscarriage. As I’ve said, there are a lot of cases in which there are mixed factors. Probably not factors that are 100% the reason for the problem but as I say sometimes 0.1 plus 0.1, plus 0.1 zero makes a 0.5, 0.6 so higher risk of having a miscarriage. One of the things that we are going to see in this kind of patients is that we can only talk about risks. There’s no way we can reassure them that everything is okay, there is no way we can guarantee that this is the main problem that has caused the miscarriage because most of the time we are not going to know why they have miscarriages. So our opinion is that once you identify a patient that can be classified into this group of recurrent pregnancy loss, it’s usually better to carry out all the tests. There are some more sophisticated or controversial that could be just postponed, but at least all the standard ones that we have that we know for sure that is useful in this kind of patients should be done. We don’t want to transfer healthy, genetically tested embryos into a patient that may have a clotting issue and end up in a new miscarriage. This kind of embryos become very valuable and cannot forget that in some cases we may be successful without any kind of treatment, without any IVF, so in some cases applying a correct treatment may be enough, but if we have to go through IVF, we must be as sure as possible that once we transfer the embryo, this is going to be, not just a pregnancy most of the time these patients have Got pregnant several Times, we need to be as sure as possible that this is going to be an ongoing pregnancy. These patients don’t want to get pregnant, those patients want to have a baby because they can get pregnant on their own, most of the time.

Is it worth treating all patients starting ART as if they were potential cases of RPL? (Using steroids, heparin, aspirin as standard therapies in the first treatment)

No, I mean if these embryos are so valuable and so why don’t we just cover all the different possibilities I personally do not recommend doing that. In the end, we have to work as doctors, so the first thing that we need to do in the first round of IVF is to try to identify. Because, the dialogue between the patient and the doctor keeps being the main tool to identify risks, problems and then we can recommend tests or treatments to solve those problems later. So in this kind of cases, we need to do a really long questionnaire, ask many different things and only if we identify there could be any factor, any risk then we can add them on top of that, and we may discuss this afterwards because I’m pretty sure there are going to be some questions about the use of steroids, immunoglobulins, immunology in general. We do not recommend steroids, probably in very exceptional circumstances because they have known drawbacks and potential side effects in patients and pregnancies. Heparin and aspirin at least they don’t have side effects, but I think that they should be recommended only in cases in which we think that they are going to be useful. The first thing that we need to do unless the patient comes to our clinic because she has a recurrent pregnancy miscarriage if we are going to do an IVF. We don’t need to apply all these treatments, wait for for the patients to become candidates to these treatments because this is not the medicine. I don’t think that this is how medicine should be done in this scenario.

Do intravenous immunoglobulins or intralipids help in cases of RPL?

That’s a question that could take a whole seminar. My short answer will be, no. Basically, the things that these kinds of treatments are supposed to fix problems that are based on theories that we now know that is not true. The thing is that for many years there was a concept which was called the immunological tolerance in which it was supposed to mean that the woman has to accept the baby, assuming that half of the genetic staff of that baby was not the mother’s genetic staff, so there would be a kind of rejection. They thought that this rejection was mediated by cells that were in the endometrium. The most famous cells would be the natural killers NK, but also lymphocytes Th1, Th2, there are a lot of tests that were developed assuming that there was something inside of the uterus that could attack and kill the embryo. We now know that this is not true at all, I mean there are natural killers in the endometrium, there must be natural killers in the endometrium, there must be Th1 in the endometrium. So the thing is that this kind of cells especially the natural killers are not cytotoxins, they don’t kill cells except in very exceptional circumstances. They don’t behave like the natural killers in the blood which are the ones that are usually tested, so there is no correlation between what happens in the bloodstream and the endometrium. The natural killers in the endometrium are supposed to help the embryo implant, so if somehow we want to reduce the levels we may be impairing the implantation. This is why we don’t recommend steroids. On top of that immunoglobulins are very expensive. There are a lot of reviews what we call Cochrane reviews, people who are specifically investing time on studying all the different articles published across the world and compare the results to try to gather as many patients as possible to see if there is any real evidence of that. There is no evidence so far that the immunoglobulins may help to reduce the risk of a recurrent pregnancy loss, and the same happens with intralipids. Both treatments may have severe side effects. Intralipids are made of sodium, and some people who are allergic to the sodium may have severe reactions against them. Immunoglobulins are a biological product, they are obtained from other people, so they have prions and other things that could be transmitted. They could be tolerated very badly, so I don’t think that there is any reason nowadays to use any of these two treatments in cases of recurrent pregnancy loss.

How can we be sure that there are no genetic issues in the oocytes or the sperm?

If we take into account the different factors that may increase the risk of miscarriage, genetics is by far the most important thing. It is very difficult to study because we would have to take the embryo that has been miscarried and then test it as if we do an amniocentesis or something like that, so it’s really difficult to know the exact incidence of genetic issues in the embryos. I would say that probably 70% of the miscarriages are due to genetic problems if not more, so the thing is that these genetic problems can either come from the egg or the sperm, but sometimes they can come even from the same embryo. The most common reason to have genetic problems in the embryo is the abnormalities in the eggs which is age-related, so it means that when a woman’s get older there is a high risk of having genetic problems just because the eggs are as old as a woman. The woman is born with a fixed number of eggs, men produce new sperm every day, so it seems to be different in the sense that the age is not such a relevant issue in men, in terms of higher risk of miscarriage. As I’ve said, most of the time the genetic issues are because there is something wrong in the egg or the sperm though. As I’ve said especially in the initial stages where the embryo is doing a lot of cell divisions that could be an error in this cell division process. That could be inherited in all the cells that come from this line and in the end, maybe an important issue that may make the embryo stop development, just because of a genetic problem. In oocytes, it is very difficult to check the genetics. The thing is that the only way we can obtain the oocytes is doing an IVF, and doing an IVF just to pick up the eggs and see if they are normal or not is worthless because if we have the eggs what we have to do is create embryos. In the sperm it is not so difficult, there are at least two different studies that can be done, one is called the FISH which stand for Fluorescence In Situ Hybridization, and then we can also do a meiotic study on the sperm. These two tests are designer in a way that they are going to check if the percentage of sperm that carries genetic abnormalities is normal or is higher compared to the normal population, and it’s important to know that these genetic issues are much more common in males who have a male factor, especially a low count in the spermiogram but can also be a problem in patients who have a completely normal spermiogram. In our opinion, the male factor is normally not considered, as long as the man has a normal karyotype. As long as the karyotype is abnormal then the male factor is considered to play a role in the miscarriages but if the karyotype comes out normal, and the sperm is okay, usually no one checks the other aspects of the male factor, that can also be relevant in terms of increasing the miscarriage rate and these two tests that are done on the semen the FISH and the mitotic studies would allow us to know if there is any kind of higher genetic risk if we use that sperm. If we wanted to study the sperm, we can use FISH or a meiotic study. If we want to use the oocytes and check the oocytes, the only way is to do an IVF, obtain the embryos and carry out the pre-implantation and genetic diagnosis on those embryos. If you previously tested the sperm and you know that the sperm is okay, any or most of the issues that you find in the embryos are going to come from that, so this is kind of an indirect way of knowing the genetic quality of the eggs, but you need to first check the sperm to see if there is any problem in that.

Is there anything patients can do to reduce the risk of miscarriage (rest, take progesterone, improve their diet, etc.)?

It’s a pity, but I honestly think that patients can do very little. I don’t mean that if you just do a lot of exercises or if you have a very stressful life you cannot have a miscarriage, but recurrent miscarriages mean that there is something really important inside. This is probably not related to your quality of life unless you’ve been really exposed to toxins or things like that. The progesterone is one of the most common things that we have been doing for years and years. When someone has a miscarriage, once you get pregnant, start taking the progesterone to support, but the fact is the luteal deficiency which means that the progesterone levels are low is not so common, especially in cases of natural recurrent miscarriages and other things patients who go through IVF which in some cases could be good to increase the progesterone levels. With regards to resting, my feeling is that it’s only useful in cases in which the patient is having a kind of a threat of miscarriage. If they have some light bleeding or you see something wrong in the scan which looks like there is a hematoma or something like that but having a rest is not going to prevent. For many years there was something called tender loving care which was supposed to improve the results of the patient. So there was the theory that if you do more scans if you see the patient more often if the patient feels that you are taking better care of her than any other patient because of the heart condition the results are going to be better. Unfortunately, this is not like this, we know now that this kind of love tender care does not improve the ongoing pregnancy rate.

With regards to the diet, there is only one thing that for sure is related to a high risk of miscarriage which is obesity because of the all the endocrine abnormalities that the obesity causes, impairs the implantation and increases the miscarriage rate, so in some cases, it would be really worth to lose weight before getting pregnant because this is going to reduce the risk. The only problem with this kind of approach is that sometimes patients may have other more important factors which may increase the miscarriage rate like age. Sometimes the time that you need to reduce the weight is something that patients can not afford because they are 40 and they cannot spend one and a half year losing weight. In this kind of cases, what we recommend is to do an IVF. Get the oocytes, create the embryos if it’s necessary because as I’ve said before we prefer to discard all kind of problems that can increase the miscarriage rate, carry out a pre-implantation and genetic diagnosis to confirm that those embryos are genetically normal and then leave them frozen until the patient is ready for the transfer. Once we have the embryos, they are not going to become older, they are going to be exactly the same quality, so the patient can invest 6 months, 9 months, 1 year and lose the weight and return to a normal body mass index or at least to lower the BMI to a level which is not associated with such a high risk of miscarriage.

How useful is checking thrombophilias or antiphospholipid antibodies in cases of RPL?

In my opinion, this is really useful because it’s probably one of the few conditions that we are sure that is related to a higher risk of miscarriage there are different problems, but they cause the same problem inside of the woman’s body. The thrombophilias are conditions in which the coagulation does not work as expected either because there are abnormal levels usually deficiencies or low levels of some proteins or because there are mutations in some coagulation factors. The most common is a factor – II or factor- V, which may increase the risk of having clotting issues in the surface between the placenta and the uterus. This is the main reason why they are related to recurrent miscarriage or sometimes obstetric complications like eclampsia and preeclampsia in later on pregnancy. The surface that is between the placenta and the uterus has this kind of local thrombosis that at some point creates problems to supply all the things that the embryo needs or the fetus need to grow. The antiphospholipid antibodies are antibodies that attack specific substances that are in the surface of the placenta, but they cause exactly the same problem, local thrombosis and also leads to the same problems with the thrombophilias, they have a short time effect like miscarriages and a long time effects like preeclampsia or fatal deaths in the second or third trimester of pregnancies.

The only issue is that, with regards to thrombophilias, is that with the standard tests that are those tests that we have been doing since the mid-90s, we check for a Leiden, which is a mutation of factor V, for the mutation of factor II, as I’ve said protein C and deficiencies and things like that. We are only covering up to 25% of the thrombophilias. So in some cases, it is worth to do another test that we have which is called Thrombo inCode that checks for different mutations that are not tested in the standard treatments like factor XII or factor XIII. Other mutations of factor V because in these cases, there might be also another problem, another thrombophilia that cannot be so easily detected. If you think that there could be this problem, sometimes despite getting normal results, we may still consider giving aspirin or heparin. As I’ve said, we don’t know more about this kind of things. We cannot discard that in a couple of years we may be able to identify another mutation that is also related. Like it has happened recently with factor XIII which has shown to be very relevant in terms of a really good implementation. The only difference between being able to identify if any of these tests are abnormal or when we give heparin or aspirin, in let’s say an empirical way, without having real evidence, is that in this kind of problems like thrombophilias and antiphospholipid syndrome they can also produce problems later in pregnancy. In these cases, the treatments heparin and aspirin should be taken throughout all the pregnancy, not just the first 3 months, the whole pregnancy and even a couple of months after delivery. It could be useful not just because it would let us know if these are the reasons for the miscarriages but also because it could help us prevent some complications during pregnancy.

How do you feel about prednisolone and clexane protocols? I have had 3 transfers with yourself 1 failed and 2 losses and not sure what else we can try?

As I’ve said, sometimes it’s very difficult. I mean prednisolone is something that I really don’t believe unless there is some kind of autoimmune disorder and already known autoimmune disorder in patients. The main reason is that it is a drug that is not free of risks for the babies, I mean the steroids are classified as a potential danger for the pregnancy and also because in some cases we may create a problem that is not there. All kinds of steroids are supposed to reduce those cells that are working in the endometrium and that the embryo needs to have correct implantation, so we have to be very careful about how we use them. In a very small percentage of cases that we use them, we just give them a very low dose and only around the day of the embryo transfer because what we want from the prednisolone is to make sure that the implantation takes place. So once the embryo has implanted we prefer to stop them.

Clexane which is heparin is completely different, I mean that the first thing is that it has no drawback, it has no relevant side effects so we have a standard protocol which that in cases in which there is a recurrent pregnancy loss, we recommend taking clexane and 40 milligrams a day. If there is no evidence of any clotting problem in the first three months of pregnancy, if there is any evidence of thrombophilia or antiphospholipid syndrome then we usually work coordinated with the haematologist that is going to check if the levels, the doses are enough and how is going to be taking it during the whole pregnancy. I’ve got cases in which clexane at the usual protocol 40 milligrams is not enough, I’ve got patients in which they have been on doses as high as a 100 milligrams a day which is really huge doses, but in these cases, there is usually a haematologist who recommends these doses. We are not used to working with this drug. Apart from this kind of thing, I would love to have more information from you, about different aspects, if the sperm has been tested, if there is any other thing in the uterus like fibroids or an abnormal shape, anatomical issues which may also increase the miscarriage. Just focusing on prednisolone, I usually don’t recommend it and clexane, yes, at the standard dose so 40 milligrams a day.

I had one miscarriage at about 6 weeks without reproductive assistance at 40, then later tried 3 IVF from an egg donor, which resulted in one pregnancy which ended in chemical miscarriage just before 6 weeks. Would this be a case to do further tests or to handle differently?

There is a lot of confusion with that because people usually talk about 3 IVF attempts, and probably this patient meant 3 transfers. For us an IVF means full treatment, in which you have to include all the fresh and frozen embryos, and sometimes you have patients who have been through 3 IVF, and they have only had 1 egg donation and 2 transfers of frozen embryos but obtained from the same donor, so it is a full cycle. I’m going to try to answer in both scenarios, I mean if you’ve really been through 3 complete full cycles of egg donor with 3 different donors, and the only thing that you’ve got is a chemical miscarriage, you have to test the sperm, the oocytes are not going to be the problem, you can have bad luck with 1 donor in 1 treatment, but having bad luck with 3 different donors is very unlikely. So we have to focus on those things that were common between the different cycles, the sperm and the uterus. It’s usually much easier and cheaper checking the sperm doing a FISH or doing a meiotic study to see if the sperm carries genetic issues, and if it is normal then you can focus on checking if there is anything wrong with the uterus or in the woman’s body. If we are just talking about 1 cycle, the first thing that I have to say is that even the best donor can have a poor cycle, and having a poor cycle does not necessarily mean that the eggs are of bad quality. It means that there is a high risk of having genetic issues, but 1 cycle is not enough to be sure that using an egg donor does not guarantee that the eggs are going to be of good quality. Assuming that you’ve had transfers of blastocysts at day-5, in this case, you’ve had two miscarriages, the main difference is that probably the first one was due to your age at 40. Now if the donor was a young girl, we cannot completely discard egg problems, it looks very unlikely though. I would suggest going through different tests that I have explained, from thrombophilia and antiphospholipid syndrome. Perhaps FISH to confirm that the sperm is okay before moving forward and then if everything is okay, go for another treatment. Sometimes in patients that have their own cycles, so they are not menopausal, and they still ovulate, and they have been through different treatments using hormone replacement therapies or using estrogens and using progesterone either pills or patches. One thing that we have observed that in some cases what could increase the ongoing rate is working with a natural cycle, so when we have to transfer the frozen embryos, we don’t use Progynova or any other estrogen, and we recommend a natural cycle in which we check how the follicle grows and when the follicle is around 16-17 millimetres. We trigger ovulation, we add some progesterone, and then we transfer the embryo 5 days after the ovulation. There are some studies, it’s still controversial, but some studies have suggested that the natural cycle whenever is possible, could have similar implantation rates but the ongoing pregnancy rate seems to be slightly better. The hormones the HRT is a standard procedure and what we assume is that, in most cases, it works very well, but when it does not work, considering a natural cycle can improve. If you have been using hormonal replacement therapies and you still have your period, and your cycles consider a natural cycle if you still have some frozen embryos.

I’m 41, and I’ve had three-four rounds of ICSI and three miscarriages (at 5,7 and 13 weeks). At 13 weeks we had products tested, and it was karyotype normal and male. I had the hereditary thrombophilia screen and all normal. My and my partner’s karyotype are normal. Any other tests you can recommend? I only ever get one embryo.

We tend to think that all miscarriages are due to the same problem, and it makes sense. In terms of the statistics as an event happens, again and again, it is usually because there is a common problem, most of them are caused by the same issue. We cannot discard that sometimes the patients who have a problem, might have other issues that can also lead to a miscarriage. F.e., in cases in which we have identified that there is a genetic problem, either because the karyotype was abnormal or the FISH was abnormal. We have done an IVF, we have genetically tested the embryos with PGS pre-implantation and genetic screening, we have transferred genetically normal embryo, and the patient has had a miscarriage. We are never going to completely avoid the miscarriage. Sometimes, the miscarriages are due to problems that appear in the embryo, and some of them are absolutely unavoidable. There are problems with abnormal development, there are always going to be problems of implantation that we are not going to be able to fix, because the dialogue between the placenta and endometrium is barely known. We know very few things, we have a lot of information but we have not yet connected all these information to know why genetically normal embryo coming from a fertility proven girl does not implant. I’ve got cases of patients who have decided to carry out a PGS in an egg donation cycle without having any problem in the sperm, and we have transferred genetically normal embryos, and they have ended up in miscarriages. So the fact that the embryo was a male is very significant because sometimes when the embryo is checked, and the karyotype is of a woman it’s difficult to know the carrier that belongs to the mother or belongs to the fetus, but if it’s a male it should be the karyotype of the fetus. One very important thing about aspirin, it’s very common to see patients and start aspirin when they start the treatment or when they are about to have the transfer or even when they are pregnant, that’s completely useless, aspirin in order to have a full anticoagulant effect, you need to start it 4 weeks before the embryo transfer, so if you have not started at the beginning of the previous cycle of your stimulation, you are not going to get a full anticoagulant effect. The same with heparin, it works much faster, we usually start heparin when the patient starts the treatment to prepare either for the IVF or the hormonal replacement therapy in a donation because, with this 2 weeks, we have enough time and should be starting at the very beginning because the use of hormones is either because you are being stimulated or you are adding estrogens to the therapy may launch some very subtle coagulation issues at the endometrium that if we start the heparin too late, may not have time enough to fix them. Aspirin – 4 weeks before the embryo transfer, heparin at the beginning of the treatment regardless of being IVF or not. In your case, it’s the factor 41, so the fact that the pregnancy reaches week 13 and any genetical issue happener, does not mean that the other 2 could have a similar problem. If you consider a new round of IVF, my recommendation would be to check the sperm first and then consider IVF with PGS. This is the only way we’re going to know the real genetic quality of the embryos, and also it will help us to see if the genetic has played a relevant role in your miscarriages. My recommendations in your case are that if you check the sperm and the sperm is normal, I would suggest egg donation because age is going to make everything getting worse. Completing the antiphospholipid syndrome and screening of the thrombophilia if you have not it done it yet.

One thing that I would like to point out is that recurrent pregnancy loss cases are very complicated. I just want to make sure that patients understand that with a limited amount of information that I have it is very difficult to give a correct answer. We need to evaluate many different things in these cases and discard many problems to make sure that we are given the right answer.

Have you used intrauterine G-CSF to this kind of cases? Any experience?

Granulocyte colony-stimulating factor, this has been quite popular in America, but it was mostly used to increase the implantation rates, in cases of recurrent implantation failures, I know that the person who had the first study which suggested it was useful, carried out a second study much bigger with more people and concluded that was useless. Nowadays, it is not recommended in the standard practice because there is no evidence that it helps, and as I’ve said if it could be useful, it would be in cases of the recurrent fail implantation failures, not cases of recurrent pregnancy losses. I’m not aware of any study that has used this to fix this problem.

Any experience of the use of antioxidants?

Antioxidants also are still very popular, but the relevance that they play, especially on the women side is very low. Antioxidants have proved to improve the spermiogram, but in those patients who had a better spermiogram, they have not led to more babies, which are what we want. So it has improved the overall quality of the spermiogram, but this has not translated into more babies. It’s true that these studies are still ongoing, and I don’t know if any particular one like coenzyme q10, DHEA but as far as I know, and I did very exhausting research 3-4 months ago because I prepared a lecture about diet and IVF, there is no evidence that the antioxidants improve the quality of the eggs and no evidence that antioxidants improve the implantation rates, so with regards I know that DHEA has been suggested to improve the genetics of the eggs, that’s very controversial and there are only very small studies with a very low quality of evidence have suggested this.

I have had  4 miscarriages in the last 4 years, my TSH is 3.3. Do you think this could be the issue? Should I get a more thorough check of my thyroid before I think about starting IVF/ egg donor treatment? I’m 45.

I assume you had 4 natural miscarriages, therefore, most probably the case here is the age. The TSH is also slightly controversial because we usually consider that normal levels should be below 4, but in patients who are trying to get pregnant, some studies suggested that if the TSH was higher than 2.5 there could be some problems at the initial stages of the pregnancy because at these stages, because of the number of cell divisions the embryo is going to do, there is a very high demand of thyroxine and those patients with TSH between 2.5 and 4, maybe in this kind of border situation, that once they need to produce this extra thyroxine to help the embryo evolve, they may have problems. This is why when TSH is higher than 2.5, we usually recommend patients visiting the endocrinologist to decide if it’s worth taking low doses of thyroxine just to keep the thyroid relaxed and in the initial stages, but in your case, probably you don’t need to do any further testing of the thyroid, and because of your age, I think that your age is enough to explain your miscarriages and if you’ve got pregnant 4 times at this age. If you will go for an egg donation, the pregnancy rate is going to be absolutely gorgeous because you implant very well, so once we change the eggs, your pregnancy rate should be over 60-65% with 1 embryo.

What exactly is a missed miscarriage? I had a 16 weeks miscarriage.

I’m not sure what this does mean. We have 3 different types of miscarriages. We have the biochemical miscarriages which are when someone gets pregnant but has the miscarriage before we can do any kind of tests to confirm clinically that she’s pregnant. That means that she has a positive and a few days later, she starts bleeding and having a miscarriage. This is what we call a biochemical miscarriage. In IVF there are a lot of biochemical miscarriages, especially natural cycles. We have many patients that are not aware of it. Biochemical miscarriages are very difficult to identify in natural cycles. In IVF, it’s much easier because we know when the patient has got pregnant so sometimes we have very low betas 20-25 that go up for a few days and then go down and these are the kind of a pure chemical miscarriage. Then we have the blighted ovum or anembryonic pregnancy, those are the pregnancies in which we can see the sack inside of the uterus but no evidence of embryo. These are mostly due to chromosomal abnormalities. Then we have the clinical miscarriages in which we identify the embryo, we can sometimes even see that there is a heart beating and a couple of weeks later the patient comes, the embryo is not there, or we can still see the embryo, but with no heartbeat, in these cases, the reasons are could be in 50 % due to the embryo either anatomical abnormalities like cardiac problems or things like that or chromosomal abnormalities and the other half are due to issues with the implantation, thrombophilia and antiphospholipid syndrome.

At 16 weeks, miscarriage is considered up to 20 weeks. At 16 weeks we are talking about the fetus, and if the fetus was tested and was anatomically normal this could be due to antiphospholipid syndrome, it could be due to placental issues that are not related to any kind of the immunological condition. Sometimes is what we call a sudden death which can happen after the baby’s born, but it can also happen inside the womb. At 16 weeks, they usually do genetic testing of the fetus, which is what I would initially recommend. They also do a necropsy, so they are going to be able to check if anatomically the fetus was normal. If both tests are normal, you would have to consider antiphospholipid syndrome or an unexplained fetal death which is something that can happen.

I am diagnosed with implantation failure. I am 35 years old and have endometriosis. I had ICSI with PGD. I have achieved a biochemical pregnancy, many negative transfers, and a natural biochemical pregnancy. What happens to me? They took hydrosalpinx from me. I had 5 normal embryos, lack of implantation.

Well, it is quite a difficult condition because you had PGS. I would like to know how did you respond to the IVF, if your ovarian reserve was normal or not, how many embryos were tested, how many of these embryos were and then based on that because in most implantation failures are due to abnormalities in the embryos. The hydrosalpinx sometimes plays a role, it is a small amount of fluid that is inside of the tubes.

One of the things that sometimes we recommend in this case is adding aspirin and heparin as I have explained before, starting with the aspirin 4 weeks before the embryo transfer. Probably you also had some frozen embryo transfers. One thing that could be interesting in your case is that because of the hydrosalpinx, sometimes, there is a problem that has to do with endometrium, it could be either chronic asymptomatic endometritis which is an infection that is not going to cause you any pain, any issues, any discharge, any fever, but is causing excessive inflammation in the uterus or sometimes there could be an abnormal microbiome which means that inside of the endometrium there should be a different percentage of bacteria as it happens in the vagina there should be more than 90% of lactobacilli.
The diagnosis of the endometritis is very subjective when it is done in hysteroscopy. You can see that it is a bit deeper vascularized, there is a big redness because of the vascularization but the only way of discarding that there is a bacteria there, that can cause any problem, is doing an endometrial biopsy. We have to test one is called Emma the other one is called ALICE and the ALICE checks if there is any small amount of the DNA of bacterias which is very accurate diagnosing endometritis, and the EMMA checks that the percentage of normal bacterias is correct one. If they were normal there is no need to repeat them, we only need to repeat EMMA and ALICE when they are abnormal. ALICE is usually treated by giving you an antibiotic but if you had a positive ALICE, we recommend doing another biopsy to confirm that the bacteria is no longer there. Sometimes bacteria may be resistant to the antibiotics, so it’s worth doing another biopsy to confirm that the bacteria is gone.

If the EMMA is abnormal we will recommend vaginal probiotics to restore the normal population of bacteria, and it is not usually needed to redo a biopsy because in this case, the second biopsies have confirmed that in more than 95% of cases the flora is normal. The only thing that I would suggest in your case then, it may surprise you, it would be checking the sperm. The reason is that, in the DNA of the sperm, there is some study that has suggested that it is very active at the surface of the placenta, so the sperm may play a relevant role in the implantation. I’ve got cases in which we have been able to demonstrate that there was a genetic problem in the sperm that we have done PGS to choose the genetically normal embryos and the patients have not gotten pregnant. I had a very spectacular case. We demonstrated that there was a genetic problem in the sperm, the couple decided to try with the man sperm and went through PGS, they did 8 egg donation cycles, that means 8 donors, we transferred 25 euploid blastocysts, and we only had 2 biochemical miscarriages. At that stage, we were so desperate that surrogacy was suggested. Because of the abnormal genetic problem of the sperm, we recommended double donations, so changing the egg and the sperm because it was already an egg donation and see what happens. It was much easier to do a double donation than to consider surrogacy, so they eventually decided to do a double donation, we had 5 or 6 blastocysts, we transferred 2 and she got pregnant with twins, and she had 2 babies. In the end, this is a cycle that in my opinion, confirms that sometimes when you check the sperm and you have an abnormal genetic or abnormal problem it’s like an iceberg, you see what is outside the water but you cannot see everything below. In this case, we did exactly what was supposed to do, there was a genetic problem, we did a lot of PGS, no results, we changed the sperm, and she got pregnant on the first transfer with twins, and now they are 3 years old.

So that’s why sometimes it’s worth to do, some kind of genetic testing on the sperm despite transferring genetically normal embryos because if there is anything abnormal, probably you would have to consider a change in the sperm.

With regards to the FISH, it is a test that only checks 3 chromosomes, it has a good sensitivity that means that when we have an abnormal FISH, we know that in 93% the sperm is normal or not, but there is a 7% of cases where FISH is normal, but it still could be a genetic problem in the semen. In such cases, the meiotic study is recommended as it checks the different phases of the semen, how the sperm divides so it basically let us see how the chromosomes behave and also if there is some kind of problem in the middle and not like that is not evident in the final product in the sperm, it can also be detected.

So do you not believe in Lymphocyte Immunization Therapy (LIT)?

No, this test is now forbidden here in Spain. It’s a recommendation of the Spanish Fertility Society. We have had some cases of a severe reaction against that and because you are exposed to the kind of a transplant, you are exposed to lymphocytes of your partner. Lymphocyte Immunization Therapy means that you are given lymphocytes from your partner in order to acquire a kind of tolerance of that. So, if this is what you mean the treatment is now contraindicated and it’s not recommended or allowed in Spain because of the risk involved when it’s used.

What is the experience of polymorphism in the Karyotype?

Well one of the main limitations of the PGS is that we have a very limited amount of cells to study when we do PGS in the blastocyst, we get between 3 and 5 cells, so there is kind of mosaicism or polymorphisms. If you mean by polymorphism that there are some kind of abnormalities that are considered to be normal like chromosomal inversions or something like that where the karyotype is I not normal, but there is no known clinical problem that comes from that abnormality. Another thing is the mosaicism it means that the number of cells affected by the genetical abnormality, the percentage is very low and I’ve seen patients with a complete Down syndrome in which only 5% of the cells were affected by the trisomy. The trisomy not necessarily affects the whole cells, and if the mosaicism is very low, it could be difficult to detect by the PGS because of the number of cells that we can study. So if you have mosaicism or polymorphisms that only affect 5-10% of the cells, of the embryo you may get 3-4 or 5, and all can be normal, but the embryo may still have a problem, so this is one of the limitations that we have with the PGS, this is why when we have this kind of abnormalities in the karyotype we need to be very careful and inform a lot the patients just to make sure that we detect that in the embryos.

I am 48 had 6 egg donor transfers 3 different donors, all implantation failure except last one biochemical pregnancy 10 weeks. I had a natural pregnancy at age 44 with the same partner. I had thrombophilia, HSG, FISH for sperm, Karyotype, ERA, hysteroscopy all normal. Also, tried intralipid, prednisolone in some cycles. I have currently prescribed levothyroxine to prepare for the next transfer. It was suggested to do a natural cycle but my periods are now irregular since I had a hysteroscopy in November. Are there any other options? What is the ideal TSH level to help with implantation problems in egg donor transfer? I have been prescribed levothyroxine due to 6 failed egg donor transfers (3 different donors).

As I’ve said TSH ideally should be below 2.5, as long the TSH is below 2.5.5 it is okay. There are now kind of groups in America that according to new studies are suggesting that we can go back to the standard level of 4, but it is still controversial, but it is very easy to correct that, we are happy to keep levels between 2.5 until we have more evidence that we can go back to the standard levels of 4. Well in your case probably and according to the results, the tests that you mentioned, you have 2 different things that you can try. I’ve seen that you’ve had an ERA done, I don’t know if you have had EMMA and ALICE done because these tests are quite new and I’ve I found them very useful.

Probably this was a miscarriage due to the genetic problems because between 8 and 10 weeks is when they are usually due to genetic problems. So the first thing is that I would recommend checking EMMA and ALICE to discover any kind of chronic inflammation. I had cases of young patients who have had IVF being younger than 35, so these girls could be considered as if they were egg donors, that after several transfers, unsuccessful transfers we have done the EMMA and ALICE, there were really important abnormalities, that we have corrected, and after that, at the first transfer they have got pregnant, so these two test sound very promising to me. These tests are going to explain a lot of unexplained implantation failures and the other thing as you’ve had the FISH done on the sperm, I don’t think that is necessary to do the DNA fragmentation. In your case, I would recommend doing a meiotic study to see if your husband is within that 7% of cases in which the FISH is normal, but there are genetic problems that cannot be detected by the FISH.

What vitamins or supplements would you recommend in early pregnancy to prevent miscarriage?

In some studies the only vitamins, the only substance that has to improve this is the folic acid. In those studies, they suggested that instead of the standard dose of 400 milligrams, to 800 milligrams, so two pills a day, could reduce the miscarriage rate. Any other antioxidants, vitamins, so far there is no evidence that any of them could help the embryo become genetically normal or implant in a better way or get rid of any correlation or proper immunological problems. If we just accept that so far there is no evidence that any substance can improve the quality of the eggs or can improve the genetics of the sperm except in very specific cases of DNA fragmentation as a standard routine. I wouldn’t recommend it in a specific treatment, in a patient with a recurring pregnancy loss.

I am 35 and have had 3 miscarriages within first 8 weeks of pregnancy (4 years of trying to receive).n1 natural, 1 with IUI, 1 with IVF. My genetics say that I have an inversion on Chromosome 9 p12q13. In Germany, PGS is not allowed, so I am treated in the normal IVF cycle, but I fear that this will happen very often due to that genetics. Do you recommend me to get PGD?

Yes, I would recommend PGS, inversion on chromosome 9 is one of this kind of things that sometimes is considered to be normal with no genetic problem. Probably, in your case what I would suggest is first to check the genetics of the sperm because if there is something wrong in your karyotype and something wrong in the FISH, then probably adding the two different factors is going to make it very difficult to obtain genetically normal embryos. Then, if you have an inversion of chromosome 9, I would suggest PGS, which I would suggest in most cases of the recurrent miscarriages because this is the only way of being sure that the embryos are genetically normal as genetics are usually the main reason of miscarriage. If we test, let’s say six embryos and five are abnormal, this is going to be very important to consider that probably the genetics are playing a very relevant role in the miscarriages. If we do PGS in seven embryos and six are normal, well then you better focus on other things. I’ve seen cases in which PGS can be very different from cycle to cycle, but to me, in cases of recurrent pregnancy loss, it’s very important to be sure that we are transferring genetically normal embryos. Once we have those genetically normal embryos then since they are going to be frozen, we may have time to check all the factors and to be sure that whenever we transfer them, the environment is the best that we can get.

I had preeclampsia in 7th month after egg donation. I am a 45+. What medication/tests would you recommend for the next attempt?

One of the things that have been suggested in these cases is that the HRT the hormone replacement therapy that is usually used during egg donation could increase the risk of preeclampsia. It is not well known why, but the big studies that we get from the countries when they have the national registries in which there are thousands of thousands of people. They have suggested that in cases in which there is a history of preeclampsia, one of the best things that you can do if it is possible, is to work with the natural cycle. To transfer the frozen embryos and in cases in which you are working with fresh eggs, we need to use hormones to synchronize the cycle between the donor and the recipient. In these cases, where there has been preeclampsia what we recommend is a segmented cycle. We obtain the eggs, we create the embryos, we freeze them, and then we transfer them in natural cycles, whenever is possible because obviously if the woman is menopausal, there is no other way. Then, we try to do it with the lower doses of estrogen, with 4 milligrams and see if you have had good thickness. In these cases, what we recommend is a kind of a dummy cycle in which work with different amounts of drugs, just to see which is the lowest dose that allows us to get the right thickness.

I had a biopsy during hysteroscopy, it showed some kind of inflammation. This inflammation was not recognizable during the hysteroscopy, but the sample test showed something. I was given antibiotics doxycycline. Two months later, I got pregnant with my own embryo transfer, but the pregnancy stopped developing in a 6-7th week. Was this EMMA? It was 5 years ago, later the doctors told me they do not do this analysis any more as it is not relevant for the implantation. I was told, the endometrium is not tested like this anymore, and the doxycycline is not given. Before it was even given just in case, in a cycle before but without the biopsy.

No, it was not EMMA because it is available for 3 years now. Probably, during hysteroscopy, they were seeing that there was a very vascular size in the endometrium, very red, with a lot of vessels suggesting that there was some kind of inflammation or in some cases they were taking samples were put on an endometrium culture as when you f. e. you have a urine infection, and you have your urine culture, it was a similar thing but done in the endometrium. In some cases, it was positive, and then we used to give antibiotics, doxycycline is still used, it is not contraindicated, and it is a drug that is very useful against chlamydia, mycoplasma, ureaplasma and things like that. Now, we have also EMMA. I don’t think that this is related to your miscarriage because EMMA as far as we know is related to implantation not with miscarriages. If you had treatments and you’ve not got pregnant or if you’re planning to have more treatments, EMMA and ALICE could be a good option, just to make sure that what you had a few years ago is now gone.

What do you think about KIR AA and HLA C2C2 by women and HLA c1C2 by men? Is it possible to have a baby in this combination? Which medicines will be useful?

This is very controversial. I’m going to try to explain it because it’s probably one of the most difficult things to understand or to translate to understandable words. The KIRs are killer inherited receptor, so these are receptors that are on the surface of the natural killers. The HLA are histocompatibility antigens, so these are antigens that are shown in the placenta, are not responsible, in some cases, some of them, in the fact that you can reject a transplant. So the HLA belong to the embryo, the KIR, the receptors belong to the mother. There are two interactions at the implantation between the HLA and the KIRs. There are two different profiles of KIRs, we have haplotype A and the haplotype B. The haplotype A is when the patient is AA, that means that has inherited one A from the mother and one A from the father, so the woman is AA, that means that she has haplotype A. If the kids are AB or BB we call it a haplotype B. The HLA could be C1 or C2, and again, in this case, we have C2 C2, but the man or the woman can be C1 C1 or C1 C2 depending on what has been inherited by the parents. It is well known that in places where the woman is AA, there are very few embryos C2 C2 because this relationship is not good, and in cases in which there are a lot of patients that are KIR B, the most common are C2 C2 because there is a correlation between a bad relationship with the C1 C1. The theory nowadays is that in cases, in which the embryo has more C2 than the woman, there is a kind of bad reaction.

This is becoming relevant in egg donation because if the embryo has more C2 than the woman, but this C2 comes from the men and one from the donor, so the woman is not dealing with her own C2, she’s dealing with two C2, that one comes from the man and the other from the donor, the reaction could be even worse. When the woman is haplotype A, and the embryo has more C2 than her, there could be a problem. The thing is that there is one study carried out in the United States in which they check the HLA that the embryos had, they show that it was haplotype A C2C2, or haplotype B C1C1 so that this kind of problems were correlated.

Some drugs have been suggested that are not approved for these treatments, drugs that are supposed to regulate it. So far, there is one study that suggested to choose those embryos that have equal or lower C2 than the mother and transfer them before. The thing is that what we are now recommending is that, this abnormality, this problem of a higher miscarriage rate seems to take place only when we are transferring more than one embryo because then the amount of C2s that the woman has to deal with is really high. When you transfer just one embryo this kind of high risk of miscarriage is not so evident, so when there is this incompatibility when the woman is haplotype A, and a man or the donor are C2 C2, or we think that there could be high chances that the embryo can have more C 2 than the woman what we are recommending is the elective single embryo transfer, and there is a study carried out by a Spanish group that confirmed that if an elective single embryo transfer was done the miscarriage rate was absolutely normal. This is very new, we are still gathering data. I’ve read 3 different theories and so far no one has proved to be the definitive one. We’re still learning, it could be relevant, and we may have ways of selecting the embryos and choosing the right combination, but so far it is very controversial.

Authors
Raul Olivares, Dr.

Raul Olivares, Dr.

Dr. Raul Olivares began working in assisted reproduction in 1996. In 2003 he created one of the first Spanish international Departments in the Institut Marques, and was its Director until 2010. He became the medical director of Barcelona IVF in 2010. Dr. Olivares says: "I would describe myself as a vocational doctor. As far as I can remember from my childhood, my dream was not to be a doctor; rather it was to bring children into the world. Firstly I made it come true in the delivery room, where I thoroughly enjoyed myself, and now before conception. I am one of those who believes that while the end result is essential, it is not the only thing that matters. That is why I have always defined Barcelona IVF as a philosophical programme because, when we started it, we gave up many amenities in trying to fulfil our dream of successfully performing the medicine we like. I truly believe that assisted reproduction should be like this, a strange combination of idealism whilst keeping our feet on the ground. The speed in which we acquire knowledge is dizzying and this leads to our results improving; however, we must of course always try to ensure that the entire process is worth it, without losing sight of the fact that our end goal is to fulfil the dreams of those that trust us."
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her travelling, biking, learning new things or spending time outdoors.

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