By fertility experts from Spain.
Dr Francisco Anaya Blanes from Clinica UR Vistahermosa was kind enough to agree to be a guest on our webinar series. He spoke to us about implantation failure in IVF cycles and when patients should consider egg donation as a possible solution to the problem.
Implantation failure is a complex issue, frustrating for both medical professionals and the patients; it’s also the focus of much medical research and study as evidenced by the amount of publications devoted to the topic. Despite all this attention however, modern reproductive science is still far from being able to combat implantation failure with a 100% efficacy.
The first problem fertility specialists must deal with is the lack of consensus on how exactly to define an implantation failure. While on the surface the term seems fairly self-descriptive, failures can be caused by a variety of issues and manifest in a variety of ways. The precise definition of an implantation failure is still hotly debated amongst the medical community.
Dr Anaya’s proposed definition of an implantation failure is as follows: “an absence of pregnancy after at least three transfers of good quality embryos (fresh or frozen) in cycles of IVF or egg donation”. It is important to note, however, that in Dr Anaya’s view, some female factors (such as myomas or septet uterus) aren’t considered to be implantation failure factors, as they are separate medical issues that should be resolved before implanting an embryo in the first place. A successful implantation, after all, requires two factors: a good quality embryo with the potential to implant itself, as well as a receptive endometrium. Both requirements must be satisfied to enable a successful implantation.
The second issue is the myriad of external and internal issues which can cause implantation failure: from uterine issues to the poor quality of embryos, there are dozens of issues which could cause an undesirable result. Dr Anaya lists several of those causes, which include, but are not limited to egg quality, embryo quality, endometrial receptivity, transfer technique, incorrect endometrial-embryo interaction, incorrect support phase luted and inadequate immunological tolerance.
The influence egg and embryo quality have on implantation success is obvious – low quality oocytes can carry disorders which could negatively impact the correct development of the embryo. These disorders can be either extracytoplasmic or intracytoplasmic – based on where they are located. There are several treatments being offered that try to improve egg quality, such as Myoinositol, which increases follicular liquid, or melatonin, however, it needs to be stressed: more studies are necessary in order to fully gauge their impact and effectiveness.
Because egg and embryo quality are so important, fertility specialists often recommend egg donation as a solution to repeated implantation failure; by simply providing good quality donor eggs, we are able to raise implantation rates dramatically.
The quality of sperm is also a big factor in embryo development. Aside from the usual lab work performed on sperm samples, two important tests target the DNA carried within, which has a major impact on embryo quality and development. These tests are the FISH test (which analyses the sperm sample for chromosomal defects) as well as the DNA fragmentation test (which seeks out possible fractures of the DNA chain). There is an important relation between DNA integrity and embryo quality, as well as the fertilisation and implantation rates.
Detecting sperm defects is one thing – fixing them is another. Several treatments are in use that can avoid issues stemming from DNA fragmentation in the sperm. The MACS technique, for example, allows fertility specialists to select sperm without fragmentation, therefore improving embryo quality, which in turn improves the fertilisation rate.
There is also the PGT-A test, known until recently as the PGS test. While the primary goal of the test is to select the best quality embryo by testing for chromosomal defects, the test can sometimes also reveal causes of repeated implantation failure. There are also other options, such as testicle biopsies and medication such as Doxycycline and Diclofenac which can improve fertilisation rates.
Dr Anaya notes embryos are one of the most important factors in implantation, along with endometrial receptivity. Therefore selecting the best quality embryos is important for a successful implantation. In fact, embryo quality is the specific reason for at least half the cases of repeated implantation failure. We can even observe this in natural fertility processes – a healthy couple only has a 20 to 25% chance of conceiving naturally per cycle. This can be directly attributed to embryo quality.
Due to the importance of embryo selection several strategies are in use to improve success rates. One of the most common practices is developing the embryo to the fifth day – also known as generating a blastocyst. Usually, embryos are transferred on either day three (when they are in the so-called cleveage stage) or on day five. The difference between those two stages of development is quite simple: the embryo is much smaller, usually consisting of eight cells. A blastocyst is developed much further, to around 200 cells, which not only gives embryologist more of an idea about a given embryo’s health and prospective chances, but also lets them perform testing such as PGT-A, which would be more invasive on a smaller embryo. However, the transfer of blastocyst may not always be an option; sometimes, the number of embryos or their quality may necessitate a day three transfer.
Time-lapse systems are becoming more and more popular in embryological facilities, as they allow embryologists to observe embryo development in real time; this provides important morphokinetic data, making any developmental issues immediately apparent.
PGT-A testing allows embryologists to examine the chromosomal makeup of any given embryo. By selecting chromosomally normal – or euploid – embryos for transfer, implantation rates are increased, while the risk of abortion or chromosomal defects in the foetus are significantly lower. The PGT-A test is recommended if the patient is over 41 years old, or if they have experienced recurrent implantation failure or miscarriages. An abnormal FISH test of the sperm is also an indication for a PGT-A test; patients who do not exhibit any of these indications, however, can also have their embryos undergo the test.
Endometrium receptivity is the second largest piece of the puzzle when it comes to implantation – after all, if the uterus is not ready to receive the embryo, other factors will not even come into play. Ultrasound examination is an easy and non-invasive way of measuring the receptivity of the uterus. By measuring the thickness of the endometrial lining the optimal implantation date can be determined. Another test that can be performed concerns the microbiota within the uterus, especially the lactobacillus bacteria. By ensuring the correct concentrations of such bacteria, IVF clinics can better estimate the chances of implantation.
Sometimes, however, fertility specialists encounter unresponsive endometria, especially following surgical procedures in the uterine cavity. While uterine inresponsivity presents a challenge and often contributes to implantation failure, there are a variety of pharmaceutical treatments available for patients, such as Sildenafil, vaginal oestrogens, L-Arginine and FECG. New research seems to suggest another way – stimulating endometrial growth through a controlled local injury. This technique, referred to as an “endometrial scratch” creates a small injury within the uterus to trigger an inflammatory response, which induces the growth of the uterine lining.
A large body of studies also indicate the major role the immune system plays in fertility. Sometimes the patient’s immune system is triggered by implantation, resulting in the rejection of the embryo. The HLA system, as well as the balance between TH1 and TH2 cells, antithyroid antibodies, vitamin D levels, celiac disease and antiphospholipid syndrome, immune haplotypes and many other factors play a huge role in a successful implantation. Because of the large variety of influential factors involved, repeated implantation failure can often be traced back to immunological disorders. Although NK cells are a known factor, there are not any studies which conclusively prove a link between high levels of NK cells in peripheral blood and implantation failures or early miscarriages.
There are many ways to tackle immunologic issues in patients – from lipid emulsions and intravenous immunoglobulin, through corticosteroids, to anti-tumour necrosis factor and granulocyte colony stimulating factor treatments. Previously, a treatment using paternal leukocytes was also used, although it is no longer recommended due to the possible side effects on the patient and the foetus.
In summary, when faced with recurrent implantation failure, a variety of tests need to be performed to narrow down the root cause of the issue, as well as a professional review of previous treatments the patient received. These tests include, but are not limited to karyotype testing, hysteroscopy, vaginal / cervical / endometrial culture testing, immunological testing, FISH and sperm DNA fragmentation testing, et cetera. Once all of these tests are completed, another IVF attempt can be undertaken utilising all of the techniques and strategies aimed at improving implantation rate, such as the endometrial scratch, immunologic therapy, heparin, MACS, the PGT-A test, et cetera.
However, if this all-out assault fails, changing gametes may be the only remaining card to play for some patients. Egg and sperm donation treatments dramatically increase the chances of implantation and pregnancy in most cases; depending on the couple, the clinic may offer changing one or both gametes. If the root problem, however, lies with the patient’s immune system or their uterus, a surrogate pregnancy should be considered. Either way, after several failed attempts, or if the patient couple displays other indications, such as age or unsatisfactory test results, donation should be seen as a valid option.
Sperm donation is the recommended course of action if the couple experiences a severe male infertility issue, such as sperm anomalies or abnormal FISH test results. Conversely, egg donation would be recommended if the female side is at fault, either due to factors such as age or egg quality, or issues further down the process, such as repeated fertilisation and implantation failures, genetic diseases or ovarian failure.
Dr Anaya goes on to describe how the egg donation process is defined within the legal framework of Spanish reproductive law. Gamete donations in Spain are completely anonymous, although all donors are required by law to undergo karyotype and blood testing; they are also screened for rare illnesses. Donors are between 18 and 35 years of age and clinics are required to match donors to the patient’s karyotype as closely as possible. Fresh egg donations are commonly offered as the most successful option; donation cycles have an over 65% success rate. Dr Anaya’s Clinica Vistahermosa clinic even offers an IVF refund guarantee program because of how confident they are in the success of their methods.
The EMMA test studies the microbiota of the endometrium; its goal is to establish the percentage of the lactobacillus bacteria, which is responsible for the correct implantation of the embryo. If the bacteria is not present in sufficient quantities, we know the patient needs to undergo treatment before the embryo transfer; this treatment increases the percentage of the lactobacillus bacteria. The process is still under study; it’s not yet a sufficiently validated test.
A high level of NK cells are thought to be linked to implantation failures and miscarriages. However, a definite link has not yet been scientifically proven; this topic is still being researched. There are treatments available, such as lipid emulsions and intravenous immunoglobulin, which supress the abnormal cytotoxic effects of NK cells and help improve the chances for a successful embryo implantation.
The precise relationship between NK cells and repeated implantation failures or miscarriages is still being researched. It was established, however, that NK cell levels always read higher during uterine biopsies when compared with blood tests – in fact, measurements taken from biopsies are now preferred over those taken from peripheral blood.
PGT is a hotly debated topic – some of us believe that we should perform a PGT test during almost every IVF treatment, because it provides us with more information about embryos, allowing us to select only the euploid ones for transfer; however, the main limitation of the procedure – that is, its cost, still prevents us from achieving that goal. Also, in cases where we only have one or two embryos to work with, PGT may not be worth the effort.
We have many different guarantee programs – an egg donation program, an IVF guarantee program, et cetera. The restrictions and rules are different in every case and depend not only on the program, but also on the patient couple. It would be best to contact us to discuss a program individually – send us an email to [email protected] and we will forward your message directly to Clinica Vistahermosa.
It’s certainly a possibility – we usually measure hormone levels before each transfer. If they are not at satisfactory levels, or – if the patient has previously experienced implantation failures – we recommend a frozen cycle in order to better prepare the endometrium. The pregnancy rates for frozen transfers are comparable.
At our clinic, the first line of treatment is a course of corticosteroids. We also offer lipid emulsions. Previously, we offered intravenous immunoglobulin, however we ceased that practice because of its high cost and no real scientific proof of results.
Recent studies have shown that DNA fragmentation has a much bigger impact on embryo quality than initially thought. As such, techniques have been developed and improved in order to avoid the risk of fragmentation, which resulted in improved fertility, implantation, and pregnancy rates across the board.
Yes, we do. Because embryo adoption is cheaper than egg donation, for instance, it’s an attractive option for some patients. Embryos are matched the same way as egg donors – that is, by phenotype, which ensures both the child and the parents have the same features. Our pregnancy rates in embryo adoption cycles reach almost 50%, which makes them as good as other options.
During the last two years, our success rates for both fresh and frozen embryo cycles have been at almost the same rates, with the difference being around 1%. Even our frozen egg cycle success rates have risen to almost the same level as with fresh egg donations.
Yes. Many of our treatments nowadays are performed within the patient’s natural cycle. We’re experiencing a lot of success with this approach, however a regular cycle needs to be present; it’s crucial to the process.
If you don’t have celiac disease, it’s unlikely that your gluten intolerance is a big factor in your failed attempts.
We don’t do that. We prefer to tailor the treatment to the patient’s needs – we prefer to do the treatment with her own eggs; if, in our professional opinion, there’s no way of her achieving pregnancy that way, we offer a donor program. We don’t think it’s worth trying everything possible at once.
No, we don’t perform that procedure
We can transfer either one or two embryos; we select two or three embryos for transfer and the patient can choose whether she receives one or two at once.
Sometimes – it varies on a case to case basis. However, it’s always possible to thaw an embryo and test it if there’s a need for it.
I don’t think so – while a TSH reading of 4.3 is a bit higher than what we would consider ideal, there are several studies that demonstrate that even a TSH of up to 7 doesn’t have an effect on pregnancy. It could be lowered, of course, but it’s not the only reason for a miscarriage at 8 to 10 weeks.
No. We don’t perform procedures of this type.
No. Any fragmentation under 35% we consider normal; thus, a fragmentation of 14% wouldn’t be the reason for a miscarriage.
We simply don’t offer that service.
While your TSH level is within normal ranges and you’re taking medication for hyperthyroidism, the fact that antibodies are present could make a successful implantation difficult, were it not for your low TSH. Later on, after a clinical pregnancy is established, no complications should occur.
While it’s difficult, it’s definitely possible. We do our hardest to find donated embryos that match the patient’s phenotype as closely as possible; in some cases it’s easy and we can match the patient 100% – in others, we sometimes have to sacrifice a characteristic such as the blood group or eye colour.
If I remember correctly, when transferring two embryos the success rate is around 48%. With one, it’s around 41%.
For patients aged 42, success rates when using their own eggs are around 5% or less. For donor eggs, however, the success rates are around 70%, as long as the uterus is healthy.
The ERA test tells us the optimal time for the embryo transfer. Unfortunately, in our professional opinion 1.7 is almost the same as 0 – so it doesn’t mean anything. The ERA test doesn’t have anything to do with beta HCG.
No. In Spain, we are only allowed to transfer up to three embryos, but we only transfer one or at most two at the same time.
The low sperm count is not the cause of early miscarriages. As I said in the presentation, however, your husband’s sperm should undergo FISH and fragmentation testing, because sometimes abnormal results on those tests could explain early miscarriages.
Our clinic is located in Spain and we would definitely recommend treatment with corticosteroids and lipid emulsions in order to reduce the cytotoxic effect of NK cells.
It’s a difficult question. I think I would recommend the egg and sperm donation, because that would leave us with more embryos for transfer and for freezing for future opportunities. The other option is also good, however. It depends on the individual patient.
As I said in the presentation, NK cells are currently the subject of much debate – we’re currently trying to understand whether or not they have an effect on implantation and pregnancy as was previously thought. Each laboratory currently has their own criteria for judging the amount of NK cells, and it varies according to the testing method – for instance, values obtained during an endometrial biopsy are always higher than the ones obtained from blood analysis.
Unless your encephalitis had any side effects which impacted your hypothalamus and your productionof hormones, I don’t think it could be a cause of infertility. If you experience normal periods and your hormone levels are in valid ranges, I don’t think your encephalitis had anything to do with your infertility.