Miscarriages - How and Where to Look for Solutions?
Miscarriages statistics leave no illusions. It happens more often than we think. At age 30, one in five pregnancies ends in a miscarriage. At age 42, it’s already one in two. As the subject is not only depressing in its nature but also extremly difficult and complex in medical terms, it’s important to consult it with the best experts in the field. Dr Natalia Szlarb, Medical Director IVF Spain , is surely one of them. In this webinar, she tries to answer the question: MISCARRIAGES. How and where to look for solutions?
Dr Natalia Szlarb starts with a technical definition of a miscarriage – it is when the embryo, previously adhered to the lining of the uterus, is getting detached. All miscarriages before 20th week of gestation are called ‘early miscarriages’. Pregnancy losses that happen later on are called ‘late miscarriages’. Depending on the type, they are approached and analysed differently.
First of all, we have to be aware that women are born with certain amount of eggs in their ovaries. This amount diminishes as a woman ages. Additionally, the older a woman gets, the lower number of genetically normal embryos she’s generating. And a majority of miscarriages happen due to genetically abnormal embryos. Putting it simply, the immune cells of a woman body ‘see’ a genetically abnormal embryo as a foreign body and that’s why it is getting miscarried. So however brutal it may sound, dr Szlarb admits that when looking from this perspective, women themselves are the cause of miscarriages.
Dr Natalia Szlarb says that at her clinic (IVF Spain), every patient’s case is thoroughly analysed and decided upon. Doctors have to determine the chances of having a woman pregnant with her own eggs or – if the chances are low – make her a candidate for egg donation.The basis of such an evaluation is patient’s ovarian reserve, meaning 3 A’s: age, AMH (Anti-Müllerian Hormone) level and AFC (Antral Follicle Count). Dr Szlarb goes on to explain all of these factors in details.
Woman’s age is the most important of all the mentioned factors. Dr Szlarb admits that women are designed to generate healthy embryos and have children until they are 35 years old. Later on, women’s fertility drops dramatically and at the age of 45 women do not generate genetically healthy embryos. According to dr Szlarb, generating a genetically healthy embryo at that age is like winning a million dollars in lotto. For example, the risk of a Down syndrome in patients who are older than 35 years old is 3.5 times greater than in somebody who is 23 years old. However, thanks to modern technology that allows for the genetic testing of embryos (PGS and PGD), doctors nowadays are able to define chromosomal abnormalities in preimplantation embryos (such as Down’s syndrome, Edwards’ syndrome and Patau’s syndrome).
AMH, on the other hand, allows doctors to see how many eggs they can expect from a female patient in one cycle. For example, if AMH level is more than 2 ng/ml, it means that around 16-20 eggs can be generated at once. Of course, only the strongest eggs are going to make it through and become day 5 embryos (blastocysts). Only then the genetic testing is carried out and the number of genetically normal embryos is defined. And it is age-dependant. At the age of 20, a woman can generally generate around 80% healthy (euploid) embryos. In case of 30-year old patients, the euploidy rate is 50%. However, after 10 years, the euploidy rate is only 20% (in case of 40-year old women). With that knowledge, as well as a comprehensive embryo selection, experienced and qualified doctors are able to avoid miscarriages in IVF patients. Healthy embryos are then frozen by the vitrification method. Thanks to it, a patient can have her embryos transferred at any time in her life. Dr Szlarb admits that is common for her to do the whole family planning for her patients in just one cycle.
Dr Szlarb recalls the statistics showing that the pregnancy rate in women, who are over 35 years old and do not undergo the genetic testing of embryos, is only 18%. It happens so because, as mentioned before, the majority of embryos at this age are genetically abnormal. At the same time, when 35-year old women decide to test their embryos comprehensively with the PGS method, their accumulated pregnancy rate (after 3 transfers) is 91%. Of course, these statistics do not apply to patients who have only few embryos generated or whose embryos’ quality (due to a patient’s advanced age) is low. While the latter have usually egg donation suggested, the former are sometimes offered the solution called embryo banking. Embryo banking is offered to patients who generate good-looking embryos that are graded either A (excellent) or B (good) quality but have low AMH. Low AMH means that a patient generates only 1 or 2 genetically normal blastocysts. In such a case, cycles are repeated every 2-3 months to generate more blastocysts to find at least 20-30% of the healthy ones (determined by PGS).
Egg donation is taken into account when doctors see that there are no genetically healthy embryos left. According to the Spanish law, egg donation is anonymous. Dr Szlarb ensures that when searching for a perfect egg donor for a patient, she always tries to find the one who is as physically close to the recipient as possible. The donors always undergo a thorough assessment at the clinic, involving e.g. testing for a variety of infectious and genetic diseases as well as mental health screening.
Dr Szlarb reveals that at IVF Sparin, they always perform the so-called ‘mock cycles’ prior to an actual cycle. It means that doctors mimic a patient’s natural cycle with the use of artificial hormones. They prescribe 15 days of oestrogen supplementation, scan the uterus lining afterwards to see how thick it is and then decide whether the dose of hormones is well-adjusted to the patient’s body or not. If the results are satisfactory, the patient (as well as her donor) is put on birth-control pills for a couple of days. Then the recipient takes estrogens orally and the donor takes injections to make her eggs grow. If the sperm results on the part of a male patient are good, eggs are fertilised and the embryos are grown up to the stage of blastocysts. Then the embryo transfer is conducted.
Dr Szlarb admits that the pregnancy rates in egg donation are amazing. It is possible to bring an over 40-year old female patient to the pregnancy rates of a woman who is 20 years old. After one transfer, 70% of patients are found pregnant, after 2 transfers – 90%, and after 3 transfers – 97%.
Apart from discussing female reasons of infertility, dr Szlarb focuses on the so-called ‘male factor’ which – according to the recent research – influences around 40% of infertility cases. If there is a male factor involved, such as karyotype abnormalities or pathological FISH sperm test results, less genetically normal embryos are generated. At IVF Spain, already during the first visit, a male partner undergoes an extensive sperm workup that includes WHO criteria such as volume, motility and morphology and then also sperm DNA fragmentation testing and FertiCert™.
Finally, dr Szlarb says that in order to assure the successful implantation of a genetically normal embryo, it is important to conduct the uterus lining biopsy. By the use of ErMap (Endometrial Receptivity Map) it is possible to calculate the exact moment (the so-called ‘implantation window’) for the embryo transfer. It is especially important in cases of IVF cycles with own eggs where there is e.g. only one genetically normal embryo generated. The uterus lining biopsy is also important to identify and solve immunological issues. The latter, identified as one of the most common reasons of miscarriages, are dealt with through the use of individualised treatment protocols.
Questions and Answers from the event
I am 39 young old woman who has just experienced my 4th miscarriage in 11 years. I suffer from unexplained sub-fertility and unexplained recurrent miscarriages. Each pregnancy ends at 7.5 weeks. I have had NK cells testing, have been tested for various autoimmune issues and various clotting disorders such as lupus. Hysteroscopies have returned with no concerning results. I have borderline PCOS but this has never interfered with my cycles. Can you suggest any further issues that I could be tested for which may be causing the miscarriages?
We have to differentiate general immunology, which is called rheumatology, from the immunology of implantation. In this kind of cases we always write letters to rheumatologists to check if you are not in the acute phase of your autoimmune disease – because this can causing miscarriages. Everything else can be influenced by Prednisone. I have myself suffered from autoimmune disease when I came to Spain and I was on 10 mg of Prednisolone for 5 years. You won’t like it as you have all the side effects, you can also develop Cushing’s syndrome but sometimes rheumatology goes first. When your rheumatologist puts you on Prednisone, we have lupus and the majority of autoimmune diseases under full control. As you are 39 years old, your euploidy rate is 30%. So before you transfer anything to yourself again, please perform an IVF cycle with PGS. Please do it in the experienced lab where doctors will not be afraid to hyperstimulate you. I want as many eggs as possible out of you now because when you are 41-42, your euploidy rate is lower than now. Genetically healthy embryos that you freeze now are like gold. It’s for you forever. Then, when I know that your embryos are not only good-looking but also healthy, we can always negotiate when we transfer them to you – assuming your full immunology is under rheumatologist’s control. When you experience miscarriages despite the fact that we transferred genetically normal embryos, I’ll probably have to do the uterus lining biopsy to see your NK cells and Th1/Th2 ratio balance to apply the immunological protocol that is allowed in the pregnancy.
Is there an ideal AMH that you would like to see ?
There’s no ideal AMH. A couple of days ago I had an amazing same-sex couple that came to us to treatment in Spain. There is the so-called ROPA technique meaning that you can receive eggs of your partner. So when you have a same-sex female couple, one of the girls is generating eggs, we do IVF cycle, we fertilise the eggs with donor’s sperm and then we transfer the embryo to the other girl. Both of the girls were 27 years old: beautiful, smart, nice and well-educated. One of them had AMH = 5 ng/ml and AFC (antral follicle count) = 25. I said: ‘Wow, you could be an egg donor!’ But her wife’s AMH was 0.6 ng/ml. AMH tells me how many eggs I can expect from you when I do IVF cycle. Doctors have to know how to work with certain AMH and they have to know how many eggs to expect out of the treatment when they do a cycle. So when I have a lady who has a five-point-something AMH, I expect more than 30 eggs in a cycle. I have to work hard to do an egg retrieval properly, meaning she’s not going to bleed and that she’s going to be OK. If someone has AMH = 0.6 ng/ml at the age of 27 and I have 4 or 5 eggs out of this kind of treatment, I’ll be over the moon. And then we have to do embryo banking. A patient has to generate 2-3 embryos now and other 2-3 embryos in next 2-3 months. The age can still move the mountains. Thanks to the young age, we can generate up to 6 embryos but it has to be hard work. I know that when AMH is more than 2 (ng/ml) and the patient is more than 35 years old, in one cycle I can do entire family planing. According to ESHRE guidelines on ovarian stimulation, in Europe we do not recommend more than 300 IU of recombinant FSH (follicle-stimulating hormone). In IVF Spain, the dose is 225-250 IU. So when I apply this kind of protocol and AMH is 1-2 ng/ml, I expect 10-15 eggs. When AMH is under 1, it’s age-dependant how many euploid eggs and embryos a patient is going to have.
Can AMH differ at different months each time the test is taken? I spoke to a multiple times egg donor whose intended parents (IPs) had a child with her eggs at her worst AMH out of all the other 5 times. What is your opinion?
No, it can’t. AMH tells me about your ovarian reserve overall. It’s a typical question that you ask students when they have to become gynecologists: ‘What can negatively influence one’s AMH?’ The answer is: the treatment of autoimmune diseases. I had a patient with rheumatoid arthritis. When I first saw her, her AMH was 0.7 ng/ml. I let her recover. We waited for 6 months and when her AMH recovered, it was more than 2 (ng/ml). But this can only happen to you when you are young. When you are older than 35, your AMH can only go down. It doesn’t differ in different parts of a cycle. What differs is your FSH (follicle stimulating hormone). FSH on day 3 of a cycle is cycle-dependant. It tells me how many eggs I’m going to win in this cycle. So FSH is cycle-dependant. AMH tells me about your ovarian reserver overall and it is cycle-independent.
When PGS need be done? On blaster day 5 only? If the blaster is formed on day 6, can PGS be done? If the day 6 blaster was already frozen, can PGS be done later?
You can imagine that some embryos are like children – they’re a little bit slower than everybody else. There are some good embryos that reach the blastocyst stage not after 5 but after 6 days. And these day 6 embryos are equally good as day 5 embryos. So the answer is: yes, PGS testing can be done on day 6 embryos, too. Sometimes we even perform PGS on day 7 embryos – but these kinds of embryos are very poor and we know that majority of them will be genetically abnormal. When it comes to the second part of the question: we have a very negative experience with PGS testing on embryos that were already frozen. In a majority of my cases, it didn’t work out properly. So what I recommend is the following: transfer what you have and do the Harmony test if you are pregnant. If the results are not on your side, then you would have to decide on something. If the next cycle needs to be done, perform genetic testing on the newly generated embryos.
Do you mean it is not feasible to do PGS after the blaster is frozen? Does PGS have to be done before the blaster is frozen?
From my own experience, I wouldn’t recommend anybody to thaw an embryo, biopsy it and then freeze and thaw it again. In IVF Spain, we have best results from genetic testing of fresh embryos which later on get frozen and are thawed only once in their lifetime – 2 or 3 hours before the transfer.
Age-dependent success rate of IVF pregnancy is based on the donor egg’s age – is it correct?
Yes, it is. l always explain this to patients: if we transfer egg donor’s embryos to somebody who’s 30 years old and she’s in premature ovarian failure and early menopause, or to somebody who’s 40 years old and has poor eggs quality, or to somebody who’s 50 years old and she’s in her natural menopause – we can still make this patient’s lining grow as we want it to. Your pregnancy rate with a blastocyst is 70% per transfer if this is an egg donation. So you have a pregnancy rate of somebody who’s 20 years old.
Does a man’s age increase the risk of a miscarriage?
As long as you have good sperm analysis, you do not increase the risk of a miscarriage. I had some patients who came to us and we did an egg donation cycle. And in the first egg donation cycle, all the embryos turned out to be genetically abnormal. They went to the clinic in UK and the man got an extensive workup there. What we saw was that the karyotype of this man was OK but in his FISH genetic sperm testing there were some abnormalities. As we always want to shorten your time to pregnancy as much as possible, in a second egg donation cycle I recommended them a sperm donation. But the patient was stubborn. He said he wanted to try another egg donor, even though he had genetically abnormal FISH sperm results. I said: ‘OK, if you have so much time and strength to do it again, then I’ll do it for you and I’ll support you.’ In IVF Spain, we offer the guarantee of 5 blastocysts without any extra costs. So we stimulated another good egg donor and this man, with genetic abnormalities in the FISH sperm analysis, was able to generate 3 euploid healthy embryos. And I’ve seen two children out of this cycle. So when the sperm analysis is good, a man’s age does not increase the risk of miscarriages. The donor egg can ‘erase’ your age. And even though men have genetic abnormalities, the sperm and egg are able to correct these abnormalities. I’ve seen in my life healthy embryos and healthy children coming out of this kind of stories. But you have to be in a good genetical lab and the guys that perform the medical testing of embryos have to be very well-skilled. If you have your own pathology that you are aware of, sometimes you have to wait for genetically normal embryos to happen in your life. But it often involves more time and budget.
Do mosaic embryos happen very often?
In 2017, the Oxford paper was published and we found out that 20-30% of embryos we generate could be mosaic. But in IVF Spain I cannot confirm this number – we have less mosaic embryos than that. But we are spoiled as the majority of cycles we do are egg donations. But according to what we see, mosaic embryos from both egg donations and cycles with own eggs constitute around 10-20%.
I am 42 and I was advised to go for donor eggs. I’ve heard that miscarriage rates are 50% if I tried with own eggs… Is it also true that live-birth rates for IVF with own eggs are only 10-15% at such age?
The pregnancy rates at 42, without genetic testing, are even less than 10-15%. But I have seen a couple of cases in my life when somebody at the age of 42 had genetically normal embryos. So you need a good evaluation. You need to see your ovarian reserve. My wish list for a patient under 40 years old goes as follows: AMH = 1-2 (ng/ml) and AFC = more than 6. I can only give you a green light with your own eggs when 2 out of these 3 criteria (age, AMH, AFC) are fulfilled. You have to do homework yourself and ask yourself how many of this criteria you are fulfilling. If you are fulfilling less than 2 or none, go for an egg donation route.
I have 4 day 5 embryos from a donor. Can I test PGS before the transfer? My first transfer was without implantation.
There was a paper comparing euploidy rate in egg donation embryos from different fertility centres. The results were 60-80% per centre. If embryos are frozen, do not test them genetically now. There is a high probability that they’re healthy. What you need to do now before you transfer again is to confirm your receptivity. You have to do the uterus lining biopsy to see what was the reason that the embryo did not implant for the first time. Was the embryo too weak and that’s why it did not implant? Or maybe you have unique immunology or unique receptivity that needs 6-7 days of progesterone to open the implantation window? So I would highly recommend you to do endometrium receptivity testing.
I’m 45 and I have irregular cycles. If I go for egg donation, do you prefer to transfer frozen embryo or fresh one after using medication?
In fact, I do not care if your cycle is regular or irregular. The majority of cycles for recipient in egg donation are substitute artificial cycles. We work with patients in this way that we set up a date when they are available to come for the transfer. And then you’re just flying in for one day for a frozen embryo transfer in a substitute cycle. When it comes to patients with regular cycles, in a majority of cases we down-regulate them. We give them a medication that stops the production of female hormones in their body. We put them artificially into a menopause for 3 months so in this way we can synchronise them with the donor better. So your irregular cycles do not matter at all. With substitute hormones – 15 days of estrogens and 5.5 days of progesterone – we can move your cycles like we want to. We can make you regular.
Do you ever do cytoplasm replacement transfer with donor’s and mother’s eggs? Is this the same as a mitochondrial replacement transfer?
This kind of procedure is forbidden in Spain. According to our law, the embryo that we transfer has to be genetically from one and the same person. Transferring one embryo from you and one embryo from the donor is illegal. And it’s completely illegal to replace cytoplasm or mitochondria of an egg donor with your own one. This kind of practice it’s not allowed in Spain. However, reproductive medicine in Spain allows almost all treatments you can only dream about: genetic testing of embryos, egg donation, etc. It does not allow the procedure that you mentioned, the transfer of embryos from two different donors, sex selection and surrogacy. Everything else you can do here in Spain.
Can a couple store embryos with aneuploidies at an embryo bank?
No. The only possibilities for aneuploid embryos are either disposal or donating them for research or education of new embryologists. The decision lies with the patients, but it must be one of these three options.
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