Almost all fertility patients have experienced at least one or two failed IVF cycles. When treatment fails, the most common questions asked by patients are: ‘What went wrong?’ and ‘What can be done to get better results?’ In this webinar, Dr. Nadia Caroppo (the Head of the International Medical Team at Equipo Juana Crespo) is searching for IVF failure explanations and discussing possible solutions for patients.
Saying that IVF failure was bad luck may be relieving but – in fact – it is not satisfying. Chance explains 2 out of every 3 cases of implantation failure. And what about the rest? Dr. Nadia Caroppo says that most causes are related to the so-called ‘embryonic failure’ (60-70%). Problems may also appear in reference to the way doctors perform IVF treatment (e.g. the way they stimulate patients) or the fact that they are unaware of some important causes leading to implantation failure. The real challenge is to understand where the patient’s (or the couple’s) sterility comes from. And – consequently – where more work is needed in order to be successful.
Dr. Nadia Caroppo says there are several definitions of implantation failure. Most often it is described as the impossibility of obtaining a clinical pregnancy with the transfer of at least 4 good quality embryos of at least 3 different cycles. The latter is the data from women over the age of 40. According to dr. Caroppo, embryo quality is a very important factor as it tells us about the potential the embryo has to implant. She also recollects some statistics comparing the results in natural reproduction vs. egg donation. 65% of fertile couples get pregnant in the first 6 months of trying for a baby. The same happens in egg donation programs when there are no other factors that affect implantation. So what are the other factors? Dr. Nadia Caroppo mentions the woman’s womb (uterus) as the most important factor. And this is true regardless of semen samples that do not alter the potentiality of pregnancy rates.
Dr. Nadia Caroppo describes endometrial lining as the cushion the embryos attach to. During the transfer, embryos invade it and start to scratch it to implant. There are many factors involved in the so-called molecular dialogue between embryo and endometrium, such as molecules secreted by the embryo, molecules secreted by the endometrium and – last but not least – uterine functionality. It is because of the latter that we can differentiate different types of uteruses. For example, hyper-fertile uteruses get pregnant with any embryo that passes by – even with abnormal embryos (that most often result in miscarriages). On the other hand, there are hostile uteruses that find it very difficult to get pregnant. In such a case, a thorough selection of embryos is required – just to make those pregnancies work. Unfortunately, this type of uteruses is common for couples who delay a pregnancy (because of e.g. social factors) as well as those who undergo lots of IVFs and fail.
As there are a lot of factors that account for getting pregnant, is it natural to wonder what can be improved in case of implantation failure or miscarriage. First of all, there are obvious answers, such as improving oocyte, sperm or embryo quality. Apart from that, there is also a professional in vivo lab that is of crucial importance. According to dr. Caroppo, if there is no good in vivo lab that works properly, it is difficult for a patient to get pregnant through IVF. And – last but not least – there is also uterine functionality and endometrial quality. Before starting the preparation for the embryo transfer, it is crucial to rule out any alterations that may affect one’s IVF cycle. These include altered thyroid function, diabetes, hypovitaminosis D, and inflammatory/autoimmune disorders, such as celiac disease or lactose intolerance, accounting for immunology-based endometriosis. Dr. Nadia Caroppo admits that the cases of endometriosis are very common nowadays. Unfortunately, this disease is chronic and progressive, influences embryo quality and uterine functionality and – as a result – really delays pregnancies.
One of the most common maternal factors, thrombophilia, can account for a portion of failed IVF cycles, but it is not their origin. Dr. Caroppo admits that knowing this, and knowing that a significative proportion of the population is asymptomatic, doctors have to very careful when assessing couples who have positive thrombophilia tests. Otherwise, it is easy to build up the so-called iatrogenic trap. Unfortunately, by giving Heparin/Aspirin (especially to very fibrotic hostile uteruses) one can easily ‘over-treat’ a patient and provoke a miscarriage. That’s why each treatment protocol (as well as medical care during pregnancy) has to be based on scientific evidence and careful assessment of an individual patient.
Dr. Nadia Caroppo admits that in today’s medical world, there are still a lot of things that doctors have to understand in relation to fertility treatment. There are a lot of discoveries arising and issues being studied and sometimes they’re still only the tip of the iceberg. There are a lot of things that mediate or inhibit embryo implantation and it is crucial to be aware of them in order to help the implantation process. These include fields such as immunology, genetics, epigenetics, uterine microbiome, metabolomics (the study of molecules that embryos secret and that can predict implantation), transcroptomics and psychoneuroendocrinology.
It is well known that environmental factors, related to one’s lifestyle, can influence the expression of certain genes what may alter the correct functionality of the immune system and – as a result- the implantation itself. However, as dr. Caroppo says, there are tools available nowadays that can help us deal with this problem. As we know now that a uterus is not aseptic and there are lots of bacteria that can favour the implantation, we can make sure the uterine microbiome is correctly balanced.
When it comes to oocytes quality, there are some protocols that can help to improve it before the stimulation. For example, in polycystic ovaries, Metformin (anti-diabetic drug) or Myoinositol can have positive impact on oocyte quality. In low ovarian reserve, giving androgens prior to IVF can improve the ovarian response. In the case of endometriosis, components such as Coenzyme Q10 (CoQ10) can help the ‘machinery’ of the oocyte to get better. When the very IVF treatment starts, personalised protocols are of greatest importance. Dr. Nadia Caroppo says that doctors have to understand what type of patient they are currently dealing with and on the basis of that knowledge, not to be afraid of variability between cycles. It means i.e. searching for morphological markers and hormonal levels that can be prognostic factors of egg quality.
Sperm quality can be improved as well – with e.g. zinc, selenium, DHEA or CoQ10 that work on sperm motility and decrease sperm DNA fragmentation. But according to dr. Caroppo, the key factor in improving sperm quality is an IVF lab. The impact of a very good lab that uses the latest technologies, good safety measures and quality markers is not be underestimated. It surely results in better quality embryos, better arrival at the blastocyst stage and better pregnancy rates.
Dr. Nadia Caroppo admits that a lot has changed in relation to embryo selection throughout the years of her clinic’s practice. They started with transferring day 2 and day 3 embryos, only to see in the coming years that leaving the embryos to culture to the blastocyst stage may greatly improve the chances of implantation. Meanwhile, there was a great revolution with culture media – it proved that improving culture media growth factors can lead to better quality embryos. The same refers to discovering that embryos secreted substances that made us understand how their evolution went (the so-called metabolomics). Nowadays, the most important tools available to doctors are surely preimplantation genetic testing/PGT (with all related techniques, such as FISH, NGS or aCGH) and morphikinetics (EmbryoScope or Time-Lapse technology).
Although many patients admit they have had painful embryo transfers, dr. Caroppo says that nowadays it’s possible to improve this procedure as well. There is a lot of evidence that the transfer itself does not have to entail any cramps, bleeding or discomfort. Apart from using well-known methods such as pain killers or anaesthesia, it is recommended to use new technological findings. A good example is an ultrasound-guided embryo transfer performed with a soft catheter that caresses the endometrial lining instead of scratching it. The pre-transfer essay of the uterus is also recommended to know exactly how to get inside the uterus and place the embryos correctly. Without this knowledge and without a correctly performed embryo transfer, the chances of getting pregnant are significantly decreased.
Apart from all that was said before, successful IVF treatment nowadays cannot go without the correct evaluation of uterus. According to dr. Nadia Caroppo, a patient’s uterus has to be assessed for both morphology and functionality – and there are different techniques available to improve this process in today’s medicine world. Dr. Caroppo mentions a regular 2D ultrasound (for checking endometrial-myometrial pattern), 3D ultrasound (for assessing inner morphology of the uterus), hysteroscopy (for analysing the endometrial lining) and pelvic MRI (for displaying the zonal anatomy of the uterus). Assessing quality and thickness of endometrial lining is very important. When the endometrium is more than 5 mm thick and has a trilaminar morphology, no significant differences have been found in implantation rates, pregnancy rates or miscarriages in different measurements. The diagnosis is performed through an ultrasound – sometimes in combination with a hysteroscopy.
When it comes to the success of implantation, not only the endometrium appearance is crucial – but also its environment. It is important to remember that high steroid and progesterone levels after the stimulation can result in embryotoxic environment that alters endometrial receptivity. Hydrosalpinx, a condition when a fallopian tube is blocked with a watery fluid, accounts for 50% reduction in pregnancy rates and 50% increase in miscarriage rates. That’s why it is essential to assess the fallopian tubes – as well as exclude leiomyomas (fibroids) that increase contractility, diminish blood flow and make uterine walls much harder than usual. And although dr. Caroppo admits that lots of women get pregnant despite leiomyomas, it is important to realise that the latter affect more than two failed embryo transfers in a woman. That’s why leiomyomas located in the fundal part of the uterus sometimes have to be removed surgically. Finally, in order to correctly predict the window of implantation, the ERA test is performed. It is often complemented with ALICE-EMMA test for normal uterine microbiome that can offer better implantation rates.
Dr. Nadia Caroppo concludes her presentation by reminding us that the implantation is not a passive process. The endometrium and the embryo exchange messages and that dialogue is very important. As there are a lot of factors that can interfere throughout this process, one IVF cycle rarely resembles the other. Additionally, the embryo-endometrium dialogue is favoured in a ‘friendly crib’ – meaning a functional uterus. The latter can be achieved by adjusting and adapting medical treatment to the individual characteristics of a patient. According to dr. Caroppo, personalised medicine is the most important key to the IVF cycle success.
- Questions and Answers
No, we don’t use it because we have used it and we did not see any higher success rates. Besides, growth hormones are very expensive – and IVF treatments are already very expensive themselves. So because we did not see better outcomes in our treatments using human growth hormone, we do not use it anymore.
We give CoQ10 to patients with endometriosis and to those patients who are over 37 years old. As I told you before, we see that the egg quality diminishes with age and CoQ10 has a positive impact on the machinery of the oocyte – the mitochondria. It’s the engine of the oocytes so it’s beneficial for women who have endometriosis and for women who are above 36-37 years old.
It’s always better to use fresh semen. Why? Because sometimes, when we unfreeze frozen semen samples, the quality can just be worse and we don’t have quantity to work with. So if you can use a fresh semen sample, it’s simply better. Of course, sometimes we cannot use fresh semen because of lots of reasons – and we have to use frozen semen samples. But it’s true that worse semen count and worse motility may account for worse embryo quality in the end. So if you have fresh semen samples, know that they will give you better embryos.