We invited Dr Juan Carlos Castillo from the Instituto Bernabéu in Spain to give a presentation on “Recurrent and spontaneous miscarriages. Are donor eggs a cure?”
Recurrent pregnancy loss and spontaneous miscarriage are the incredibly sad sides of the joy of pregnancy. There is an expectation that other than morning sickness and swollen ankles, becoming pregnant and carrying a baby to term are easy feats. However, for many couples, that is simply not the case; assisted conception is required, and miscarriage can be a devastatingly painful reality.
In this webinar, recognised fertility author, speaker and expert Dr Castillo, discusses research into whether donor eggs could be the cure for those who live with the desolation of baby loss, however early into a pregnancy.
“Pregnancy requires little more than implantation of a developmentally competent embryo into the receptive endometrium” – simple hey? Yet, it’s not.
Sadly, 15-25% of pregnancies are clinically recognised as ending in a miscarriage, the majority of which will happen before a gestation period of ten weeks. Regrettably, around 4% of couples will experience recurrent pregnancy loss (RPL), which is defined as miscarrying in two, or more, pregnancies, from the time of conception until twenty-four weeks, in both natural and assisted conception. Whilst, technically, becoming and remaining, pregnant should be simple, we all know, that for many of us, it isn’t.
Dr Castillo’s research shows that both medical and family history should be used to tailor diagnostic investigations into RPL and, that in terms of prognosis, the maternal age and number of miscarriages are of utmost importance. The risk of pregnancy loss rapidly increases after a woman turns forty, with the lowest rate of miscarriage in those below thirty-five. Smoking, being significantly under or overweight, will also have an impact, as does caffeine and alcohol intake and high-intensity exercise. However, research has shown that there is no direct evidence which links stress and recurrent pregnancy loss; repeated miscarriage will, inevitably, cause both physical and mental pressure, but it is not to blame.
When looking into the medical reasons behind recurrent and spontaneous pregnancy loss, Dr Castillo advises that miscarriage is attributed to either embryonic or uterine factors, put simply; a problem with the embryo or the uterus. If embryonic factors are the cause, this could be due to chromosomal or other, developmental, abnormalities, and is likely to fall into one of two categories; cytogenetic, where there is an abnormal number of chromosomes in a cell, medically referred to as aneuploidy, or, the abnormalities could be structural. Studies estimate that circa 60% of sporadic miscarriages are due to cytogenic chromosomal abnormalities, and mainly as a result of a specific kind of aneuploidy; a trisomy. Trisomies are understood to be, in part, age-related.
However, these are not the only problems to affect an embryo and in 2-5% of RPL couples, structural abnormalities, due to unbalanced translocations, were found to be a factor. Unbalanced translocations occur when a portion of one chromosome is transferred to another, creating a loss, or gain, of genetic material, thus causing a chromosomal imbalance that could generate abnormalities and explain the miscarriages. Chromosomal imbalances can happen as a result of either parent. It isn’t female-specific.
Treatment options for embryonic abnormalities include an embryo biopsy, at the blastocyst (5-day) stage, in order for the cells to be genetically analysed. Depending on the outcome of the biopsy results, a change in the gametes could be suggested, e.g., use of a donor.
Not all pregnancy loss is due to embryonic anomalies though, and uterine factors can be the source of spontaneous or reoccurring miscarriage.
The advice, of Dr Castillo, is that all women, suffering from recurrent pregnancy loss, should have a uterine anatomy assessment. There are now surgical correction procedures and medication available, which can help if an anatomic uterine factor is discovered to be the determinant of miscarriages.
Hormonal and metabolic factors should also be considered when studying pregnancy loss, specifically thyroid abnormalities. Thyroid hormones are critical for foetal development, and thyroid hormone disorders are known to be associated with loss of pregnancy. For couples experiencing RPL, testing of thyroid function is recommended and, should an issue be discovered, can usually be treated. Uncontrolled, or undiagnosed, diabetes, increased prolactin levels and vitamin D deficiencies could also be a cause, however, the evidence, linking these conditions to RPL, is inconsistent, and therefore routine testing is not currently recognised as a guideline recommendation.
In order for a pregnancy to be sustained, a normally functioning immune system is essential, and Dr Castillo discusses the “widely controversial” topic of testing for Natural Killer cells (NK cells). NK cells are a subtype of specialised lymphocytes that play a critical role in immune response, meaning the presence of such cells could affect the ability to develop a baby. The screening process consists of two tests; either blood analysis or studying tissue from an endometrial biopsy. However, Dr Castillo is keen to point out that huge technical challenges are faced when it comes to these tests, explaining how the collated results from blood and tissue can be extremely different, and cell numbers are known to fluctuate greatly during a woman’s menstrual cycle. As yet, there is currently still insufficient evidence to link this with RPL.
Miscarriage has a huge psychological effect on both women and men. However, however as heart-breaking as it is to experience recurring pregnancy loss, thanks to the wonder that is medical science, treatment and psychological support is now available.
Increased medical knowledge, and understanding, of the reproductive system and embryonic health, allows an insight into immunological conditions, chromosomal issues, and other fertility complaints, which can be factors in both conception and pregnancy loss. Fertility clinics should be there to offer help, initially in the form of tests and screening, and advise on the best plan of action for couples, whether that be a form of medication, the option of fertility treatments, and/or the use of donor eggs, in order to sustain a pregnancy and carry a baby to term.
Pregnancy loss is a highly emotional and heart-breaking moment in life. We offer below a complete transcript of the Questions & Answers from the webinar, which hopefully will shed some more light on fertility treatment for recurrent miscarriage and ways of preventing recurrent miscarriage.
Recurrent Miscarriages – Patients’ Success Stories
As we explained in our presentation, yes, we believe that it is a technique to consider. If the embryo is a factor, at least from the assisted reproductive medical point of view, the only way to be completely sure that we will be transferring only genetically normal embryos is by doing the embryo biopsy procedure. So far, in our centre, we have three years of experience doing this procedure at the blastocyst stage of the embryo. We have biopsied more than 2000 embryos so far, so this is a very well established, robust platform in our centre. However, we should also clarify that although this is a very potent technique, a very specialized technique, it is essentially a diagnostic technique. This technique will tell me whether or not there is a genetically normal embryo. However, this technique cannot turn an embryo into a good one, and, of course, patients should be aware of this.
In this specific clinical case, with all this information, I must support your decision in proceeding with egg donation as a treatment option. After a D and C, in our opinion, you should wait at least for two natural periods before embarking on any assisted reproductive techniques. So in brief, a couple of months.
Thank you so much for describing in detail to your clinical case and your previous attempts. Based on this information, it seems to be that there is an embryonic cause behind these failures, and basically, this could be associated with the advanced maternal age, a is a very important factor to consider. If we suspect that this is the most plausible cause, of course, one alternative to consider is to change the gamete, to change the egg, in this case. So by giving you donor eggs, it’s very likely that we will finally achieve our goal. With regards to NK cells, as I presented earlier in the lecture, there is still inconclusive evidence supporting the routine role of NK cell testing in an IVF scenario. Moreover, and additionally, this would be less important if we were able to identify a more important, a more clear factor, that may easily explain these failures. So in my opinion, I would say that, in this present case, I would encourage you to go for egg donation without any further testing. We already have a very clear factor that can easily explain all these failures.
Thank you so much for this additional information about karyotyping. In the vast majority of embryonic abnormalities, parental karyotyping is normal. If you remember the publication by Popescu, 67% of cases were explained by embryonic factors, but only 4% of these patients had abnormal karyotypes.
In my opinion, adenomyosis is an important factor and should be considered. In order to explore, to rule out or to confirm adenomyosis, a 3d scan is mandatory because this will give us the correct diagnosis. It’s very accurate in diagnosing adenomyosis, which can negatively impact assisted reproductive technique outcomes. This negative impact is seen in own gametes IVF, but also in egg donation IVF. If we are talking about own eggs IVF, adenomyosis can impair implantation rates, decrease implantation rates, and can increase the miscarriage rate. If we are talking about egg donation, there is a very nice publication coming from Spain, exclusively focused on egg donation treatment cycles in patients with adenomyosis and they clearly showed that in these patients, it can the rate of miscarriages. So, yes, we consider this an important topic. Adenomyosis, especially a severe degree of adenomyosis, may negatively impact the subsequent success of these treatments, including egg donation cycles. The correct treatment, in this case, is a prolonged blockage of the variant function for at least three months before proceeding with the actual treatment cycle.
I can understand how difficult it can be for you facing negative result after negative result. In this specific clinic case, I would recommend taking a break, to stop for a while and to test for additional putative uterine factors. As I presented in the lecture earlier, I would, in this case, explore, for example, acquired thrombophilia, perform a 3D scan in order to rule out anatomic factors, check for hormonal factors, and perhaps we can also consider, although debatable, immunological screening. But just in this case, I would not recommend going with further treatment, at least until we have a complete uterine exploration.
Basically, it would depend on which week the miscarriage happened and also on the procedure undergone in order to treat the miscarriage. Generally speaking, if there were no problems during the dilation and curettage and everything was uneventful, I would say that in a couple of months you will be able to embark on the next procedure.
When we treat patients who have experienced pregnancy loss, what they want are answers, because in the vast majority of cases they do not know what why they are suffering from this condition. As I told you in my presentation, it’s very important to address the psychological factors in the very first consultation. After that, the idea is to try to offer a very personalized treatment plan because every patient will be different; every patient will have their own medical background, family background and expectations, so the idea is to clarify this in the first consultation and to try to offer them a very personalized treatment plan. At the end of this extensive testing, it may be possible to provide answers so that, as soon as possible, we can focus on the correct treatment plan. We should also remember that, according to the most recent indications, in up to 95 % of cases, we will be able to provide these answers for patients. However, in 5% of patients, this will be a real challenge because we will not know the reality behind their losses.
Of course, every scenario is different. We should personalize every clinical case as not every patient has the same performance or expectations in terms of fertility. However, as a general rule, we focus specifically on patients coming to IVF clinics where the pregnancy rates after 43 years of age are a real challenge.
The short answer is no. Of course, again, every case should be personalized, but if during the previous testing panel, we have clearly identified that the problem is age-related, we would move for egg donation without any additional PGD or PGS because the realistic probability of having abnormal embryos rather low, especially if the partner sperm is optimal. So, the brief answer would be that there is no indication for PGT if the clear factor identified is age related.
Even in a perfect scenario, let’s say egg donation with normal sperm from the male partner, even after a positive pregnancy test, we face early miscarriage even in egg donation cycles. This is estimated in around 10% percent of cycles, almost in every in every centre. What we do not know clearly is the aetiology of this condition. Perhaps the important question is what, for example, is the probability of having a genetically abnormal embryo even after an egg donation treatment cycle. In our centre, this is one in five; this means that one out of five embryos produced by the egg donor may also have some genetic problems.
When we face patients with additional health conditions and, in this specific example, lupus, what we try to do in our centre is to have a very multidisciplinary approach. This means getting in touch, if possible, with the physician in charge of the male patient in order to have a complete record and current status of the condition, It’s very important to see what medication is being taken for the condition because there are some medications that may negatively impact the sperm count. We need to coordinate with the physician in charge of this specific pathology. On the other hand, we should also take into account that perhaps it is not recommended that this specific patient quit their medication because this may worsen their general condition. In this case, perhaps we can go for the cycle, assuming some risks; but as a general rule, what we do is to try to get in touch with the physician in charge, in order to have a coordinated and personalized approach.
Remember that this is happening at a genetic level and we cannot intervene, so far, at the genetic level. The short answer is no; we cannot reduce the rate of aneuploidy. This is, of course, general data, a general average. Perhaps in some subsets of egg donors, the rate will be one in eight and in other subsets perhaps it will be one in four. On average, the standard rate in our centre is one in five.
We follow Spanish law, which requires us to look for compatibility between the donor and the recipient, specifically phenotypes; typical features such as the color of the eyes, kind of the hair, skin texture and blood type. In our centre what we recommend is, if possible, for the patients to provide some digital pictures from both the male and female. These pictures then will be given to the information department, with the additional information from the form that the couple fills in containing some other specific characteristics. With all this information, the egg donation department finds the most suitable donor for the recipients. I should clarify that, here in Spain, egg donation is always completely anonymous from both sides.
Yes. We have an international department. All patients have a patient care assistant assigned and we do have native German speakers at the clinic as well. We have Dutch, Russian, Italian, and French: nine languages at the moment.
In this case, we would need to coordinate between the two centres to take a look at the feasibility. The Czech Republic is in the European Union and so it should be feasible. In this case, the coordinator of the embryology lab in our centre should coordinate with the chief of the lab from the other centre and after this, we will see if it is feasible. There are cryoshipping companies that do this kind of transport.
The short answer is yes. We should remember that we intervene at a very crucial moment, embryonic development. Remember also that we try to mimic what nature is trying to do, but, of course, we do it in a very artificial environment using the medication, using video, using techniques. I would say that yes, although epigenetics has not been proven in humans, there are studies coming from, for example, the ‘mouse model’ that show that procedures such as IVF produce epigenetics in the offspring. So at least, in theory, this is possible. However, as I said this hasn’t been confirmed in the human model. But we should remember that the first test tube baby is now 40 years old and we do not know what will happen 20 years from now. It has not been proven but, at least, in theory, epigenetics is possible.
Yes, we have partner clinics in the UK where the male partner can provide a sperm sample. You can give your sample there and ship it to a clinic, no problem. You can contact our guidance unit and we can provide you with all the information on this matter. We work with many clinics in the UK and this can be done.
In answer to the first question, with regards to the HCG level, everything depends on the lab. Every lab has their own ‘good’ levels, but generally speaking levels below 5 are not considered compatible with implantation. So, in other words, there was no implantation at all so there was a negative pregnancy test. Your second question is what you can do in order to improve your outcome. You are describing a condition within the sperm, where 99% of the morphology was abnormal. This means the spermatozoa had, for example, two heads or three tails and this is a very high degree of abnormal sperm morphology. However, we should remember that, in the vast majority of cases, and I don’t know if this was your case, we use the ICSI method in cases of abnormal sperm morphology. With this procedure, the pathologist selects a normal embryo. We are talking about 99% abnormality, a very high percent, but given the number of spermatozoa available, this means that, even with only 1% of normal sperm, I would say that, with the ICSI method, we would be able to find enough normal spermatozoa to proceed. So, in the frozen treatment cycle, after the single embryo transfer, we are looking at good pregnancy expectations of around 50% in our centre. However, bear in mind that 50% of our patients will not become pregnant at the first attempt even with ICSI. If during the first evaluation we haven’t detected any additional putative factors, I would say that this is a mere reflection of the lack of effectiveness of the technique, which is not, unfortunately, 100% percent. So at this very moment, I would just give this couple of embryos a chance and I would say that we have realistic options for a successful outcome in the frozen embryo transfer.
As a recipient, there is a consensus among clinics here in Spain that we do not proceed with any assisted reproductive technique treatment for patients over 50 years old.
In brief, no, perimenopause will not affect the outcome. In fact, this is a very common clinical presentation, at least, in our centre, and this is not relevant to the success rate. We may have the same pregnancy expectations even in women undergoing the menopause. The reason for having the same success rate is that we manage the cycle; we use medication to artificially induce the cycle, to induce the growth of the endometrial lining. By using this medication, it is us who are controlling the cycle, not the recipient. This is why it doesn’t matter whether she is menopausal or not.
Strictly from the medical point of view, after your negative pregnancy test, you can consider it straight away when bleeding has stopped after stopping the medication. This is possible without any impact on the subsequent outcome. Of course, if for any reason you want to delay the procedure, pregnancy expectations again will be exactly the same. From the medical point of view, you can go straight away as this mimics what happens in nature because nature prepares the uterus every month in order to receive an embryo.
Generally speaking, we do not recommend going for PGS in egg donation cycles. Again, of course, everything depends on the individual clinical case: not every case is the same. Perhaps, if we suspect any additional genetic factors coming from the male, for example, any translocation, PGD could be indicated. However, as a general rule, we do not recommend PGS in egg donation treatment cycles. Having said this, the strategy described in the question is perfectly feasible; we can accumulate embryos in order to do PGS. I would say, however, that this would be limited to very specific clinical cases.
It depends on the treatment, but we obviously try to make things as easy as possible for our international patients. We offer our first consultation via Skype or video conferencing, or at the clinic if the patient decides to have this first evaluation of their case with the doctor. You would then need to travel for the embryo transfer or to provide a sperm sample on the donor’s egg retrieval day. With the first consultation via Skype, you would have to travel to Spain only once. As I said before, we are available at our guidance unit to answer all your questions. You can contact us at any time and we would be happy to talk over all your inquiries regarding the logistics, procedures and everything.
Yes, of course, we can. We would need your contact details, of course, but we would also be happy to receive your request, either on our website on by email at [email protected] You can ask any questions about the treatment or costs. If you send us an email address with your name, personal telephone number we can provide detailed, personalized information.
From the first consultation to the transfer of the embryo in an egg donation cycle it would take a maximum of two to three months, everything depends on the clinical case. We need some tests demanded by Spanish law before embarking on any assisted reproductive technique, for example, we need to complete a viral screening and we need an updated smear test for patients over 40 years old. We also recommend mammography, for example. Let’s say that we have all these tests and you have everything already validated, we can do the actual procedure in a couple of months.
With regards embryo glue, every Thursday in our centre we have a clinical committee meeting and we discuss relevant topics and just a month ago we specifically discussed embryo glue extensively. Just to define embryo glue: it is a cultural medium that covers the embryo and makes it able to attach to the endometrium. It is very controversial because the medical evidence is not consistent. We have some publications supporting the use of embryo glue, showing some increase in pregnancy outcomes and, on the other hand, we have some other very good papers showing no benefit. The evidence is inconclusive. So because of this inconsistency, at least in our centre, we provide the medical evidence on this topic to the patients and we agree together on the use of embryo glue. We have the culture medium in our centre and are prepared to use it, but acknowledge that the medical evidence is conflicted in terms of a true benefit. This is more or less the same with the scratching procedure. Three years ago, in my personal consultations, we performed the scratching procedure on almost every patient crossing our door because there were early publications showing a significant increase in terms of pregnancy outcomes. However, more recent papers have challenged this concept. In fact, there was a paper published a couple of years ago here in Spain showing that, at least in egg donation cycles, there was no benefit to the scratching procedure. There are at least two very big randomized clinical trials, one in the Netherlands and one in the UK, addressing this specific topic. We expect these trials to be completed by the end of next year and, perhaps with that information on the table, we will have enough robust information to properly guide our patients about the true benefit of this procedure. At the moment, we discuss the medical evidence but do not recommend the scratching procedure on a routine basis.
Well, of course, we use proven fertility, it’s always desirable, a positive point. Previous proven fertility can be confirmed in either by the previous pregnancies of the egg donor or by previous successful egg donation cycles. Having said that, we should remember that the egg donors are usually very young women. In our centre, they average 25 years old, so this means they are young students or workers, so it is sometimes difficult to have proven fertility of the egg donor because these women are not yet thinking about pregnancy. I can say, in brief, that, generally speaking, the success rate in egg donors is pretty consistent, independent of the previous fertility status.
The cost of endometrial scratch is included, but embryo glue is an extra cost.
The doctor’s presentation touched on the issues that bother many women who are trying to conceive naturally, have done unsuccessful IUI or IVF with own eggs and, unfortunately, have experienced recurrent early miscarriage. We understand that it is a difficult topic to discuss but, at the same time, we hope we will be able to help you understand what is happening with your body and embryo before the miscarriage happens. Dr Castillo has also discussed IVF and donor eggs as a solution to recurrent miscarriages and what tests are recommended in the treatment course.