In this webinar, Dr Valentina Denisova, an Obstetrician-Gynecologist, and Fertility Specialist at Next Generation Clinic, located in St. Petersburg, Russia talked about all the factors that can influence your IVF chances after previous failed attempts.
The low prognosis patients are classified into 4 groups according to the results of ovarian reserve markers like antral follicle count (AFC), female age and the number of oocytes retrieved in previous cycles of conventional stimulation in cases where this information is available. According to this classification, we can divide patients, predict low response or poor prognosis and suggest some pre-treatment options and stimulation protocols. This classification aims to individualize the treatment approaches and optimize ovarian response and the number of retrieved oocytes and euploid embryos to obtain to give the highest implantation potential.
Several investigators proposed using different options to achieve euploid embryos in low prognosis patients, for example, high FSH doses, LH supplementation, double stimulation, and so. In one of the cohort studies which included more than 500 low-prognosis patients at the age of fewer than 44 years old who started their first IVF cycle and were treated with a fixed dose of FSH, and cumulative live birth rate in this group was, on average, 56% within 18 months of the treatment cycle. The variations of results are primarily determined by female age, which reflects the importance of oocyte quality.
Fruit and vegetable consumption is considered an excellent source of essential nutrients such as vitamins, and minerals that support the balance between reactive oxygen species and antioxidants. Lifestyle choices including smoking, alcohol, and other nutrition can promote chronic low-grade inflammation and oxidative stress in various organs. Therefore, lifestyle factors may eventually impact IVF outcomes and have an effect on the reproductive system in both men and women. In women, smoking, active or passive, causes an increased risk of miscarriage during pregnancy, which is potentiated by the number of cigarettes smoked per day. Smoking can also introduce perturbations in the menstrual cycle, promoting short and irregular cycles. It can also decrease ovarian reserve, which is shown by a lower antral follicle count and lower AMH level.
Several studies have demonstrated a decrease in sperm density and sperm motility in smoking individuals. Smoking has also been shown to affect sperm DNA fragmentation and some morphological parameters. Alcohol consumption should be ceased during pregnancy because it has been well-documented that it has a detrimental effect on fetal development, and there is no safe level of alcohol consumption during pregnancy. In males, alcohol was found to be harmful to sperm motility and morphology and it can impair the development and maturation of sperm, it has a detrimental effect on semen quality and the levels of male reproductive hormones.
High levels of caffeine consumption have been associated with decreased fertility. High doses during pregnancy may increase the risk of miscarriage, but it doesn’t affect the risk of congenital abnormalities. Elevated levels of cortisol, which is also called the stress hormone, leading to a greater chance of miscarriage in the first 3 weeks after conception compared to patients with normal cortisol levels.
In 2016, almost 40% of adults were overweight and among them 13% were obese. Most of the world’s population lives in countries where overweight and obesity kills more people than underweight. We need to remember that obesity is preventable. Raised BMI is a risk factor for several diseases, like cardiovascular disease, which is the main reason for death, diabetes, and even some kinds of cancers (including endometrial, breast, prostate, and liver cancers).
In women, obesity may cause some inflammatory responses, lowers the chance of pregnancy following IVF, increases the risk of pregnancy loss, and reduces rates of implantation, such women require higher dosages of gonadotropins and increased level of cycle cancellation. In males, obesity operates through different pathways. It creates epigenetic changes which can lead to some disorders in offspring, and it alters male androgenic hormones influences the host of our new hormones, and rises insulin levels. Finally, it has been linked to erectile dysfunction, causes of stress inflammation, and sleep disorder and all of these can lead to further reduction of male fertility.
Aneuploid embryos are the most frequent reason for implantation failures. Aneuploid embryos may increase the risk of first-trimester pregnancy loss. For patients under 42 years old, the overall live birth rate per oocyte was about 18%, so we need about 5–6 oocytes to produce 1 baby. For women over 42 years of age, every oocyte has only a 4% chance to become a baby, therefore, we would need more than 22 oocytes to produce a baby.
The indications for PGT-A are still arguable, and in 2018, according to ASRM (American Society for Reproductive Medicine), the value of PGT-A as a universal screening test for all patients is yet to be determined because some studies have demonstrated a higher live birth rate, however, the studies have limitations. Other important considerations about PGT-A must be addressed by further research, including costs, the role, and effect of cryopreservation time to pregnancy, etc.). It was also concluded that for patients with more than 1 embryo, PGT-A reduces healthcare costs, shortens treatment time to pregnancy and reduces the risk of failed embryo transfer. PGT-A increases implantation rates and decreases clinical pregnancy loss because the embryos can be selected.
Some investigators have expressed concerns that PGT-A adds cost to already expensive treatment and that it is an embryo diagnostic, so it never improves reproductive potential. According to this group, it’s more cost-effective to simply transfer all the embryos and let nature sort it out.
ESHRE recommendations that were published, at the beginning of 2020, suggest that PGT-A should be offered to patients of advanced maternal age, with previous recurrent miscarriage or recurrent implantation failures and severe male factor. It’s important to mention that in some cases, the only solution is egg donation.
Implantation relies on the crosstalk between an embryo and the endometrium. The optimal environment usually lasts for only a few days and begins around 6 days after ovulation. One of the possible mechanisms involved in recurrent implantation failures is the change in endometrium receptivity. One of the changes in receptivity involves the shift of timing of the window of implantation, which is previously assumed to be the same in all women. ERA test is used to identify the window of implantation, and this change is based on more than 200 genes. It was first introduced for patients with recurrent implantation failures, and so the day of the embryo transfer was changed based on the data from the ERA test, and a good pregnancy rate was achieved. However, further studies are still needed in larger samples and randomized control trials to identify its effectiveness.
Another important aspect is chronic endometritis. Among the patients with recurrent implantation failure, about 45% had chronic endometritis. This pathology can be diagnosed through histological examination, hysteroscopy, and sometimes by bacterial culture, there are some treatment options, such as antibiotics that have to be taken before your IVF cycle.
Regarding endometrial thickness, the guidelines from 2019 say that thin endometrium is commonly encountered in patients undergoing ART, and it may impact pregnancy and live birth rates in the fresh and frozen embryo transfer. However, there is insufficient evidence for the use of any adjuvants to increase the pregnancy rate in patients with thin endometrium. They also claim that endometrial thickness should be measured at the thickest portion of the endometrium. Fresh embryo transfer should be performed when the thickness is more than 8 millimetres, and frozen embryo transfer should occur when the thickness is 7 millimetres.
Other pathologies, such as uterine myomas (fibroids) and adenomyosis. Uterine myomas are the most common uterine tumours, and adenomyosis is another benign uterine disease characterized by the invasion of the endometrium into the myometrium. Myomas can lead to infertility and some reproductive problems through different mechanisms and sometimes they should be treated before IVF. There are a few treatment options, both conservative and surgical. Surgery is not always necessary before IVF. Adenomyosis may also impact implantation and even lead to some complications during pregnancy. It can be treated, but not through surgery when you are planning pregnancy.
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This is the question to some kind of another specialist like endocrinologists because cortisol levels can differ during the daytime, it can be different in the morning, in the afternoon, and in the evening. First of all, if we have an elevated level of cortisol, we have to try to find out the reason for it. And if we find the reason, in some cases, we can decrease it.
We’re talking about overweight. If the BMI is over 25, I suppose a BMI of 24 will give a better result.
When we are choosing an embryo to transfer, we take into consideration not only PGT-A testing. PGT-A results say if an embryo is euploid or probably mosaic or aneuploid. If we are talking about PGT-A results, the aneuploid embryo will not be transferred. We will discuss it with specialists in the genetic field about mosaic embryo transfer, and if we are talking about the euploid embryo according to the test result, we can say that we will transfer this embryo. We have another score of the embryo quality and this is a morphological score and we cannot deny the meaning of this score. For example, even if we have a euploid embryo but it has a very bad morphologic score in most cases, we will not achieve pregnancy, so we have to consider both results PGT-A and morphological score.
If I’m not mistaken if we are talking about these, it can be around 10 or 15 eggs to achieve a euploid blastocyst, but we need to consider a male factor because if the couple has a severe male factor, it can also influence the result. Not only the number of eggs will be important.
This is a good morphological grade, but it doesn’t mean that this blastocyst will be euploid, we don’t know if it will be euploid. For example: even when we are talking about donor embryos, which were created from donor eggs and donor sperms, they are young with good health, and only about 60% of this blastocyst will be euploid. This is normal, this is nature, so that’s why a good morphological score doesn’t mean that it will be a genetically good embryo.
All these supplemental treatments, don’t really improve egg quality, and we have only a few small, simple studies. Some of them have shown the effectiveness of these. Some of them haven’t shown anything, so we cannot recommend such supplements to all the patients. This is just scientific research, I suppose.
We have to try to find out another reason, and you’ve said that you have checked the embryos, but if you have a fresh embryo transfer. I suppose the PGT was not for 23 pairs of chromosomes, and probably you have to check the embryos by NGS for all pairs of chromosomes, and we will find the explanation. As for Hashimoto’s disease, if you have corrected your thyroid gland function before embryo transfer, it will not influence the results. When it comes to Medrol, this is the trade name of the medicine, so I need another name, to talk about it.
Actually, 8 millimeters or 11 millimeters is normal, but if they’re talking about the same cycle, it can differ because different doctors try to measure the endometrium or a different machine. When you have started progesterone, the endometrium will become thicker, and this is normal, so I don’t think this is a kind of overstimulation.
All these supplementation treatments, we don’t have enough evidence that they are working well, and I cannot say that DHEA will work as well, and you will retrieve your own eggs. Actually, at the age of 43 and with the very low ovarian reserve, we can try a natural IVF cycle and try to retrieve your own eggs, but no treatment can change the genetic changes that have happened inside the egg, so I don’t think that any supplementation treatment will help.
The mutation in these genes of conversion of folate is very common, but considering the last guidelines, there is no need to check these mutations and to change vitamin intake for all patients. Yes, the mutation is very common, but it doesn’t matter so much.
If they found a polyp during ovarian stimulation or if they found a polyp during the endometrium preparation for frozen embryo transfer, we don’t recommend performing an embryo transfer in this cycle. Usually, we recommend to recheck ultrasound in the next cycle, and if they have a confirmation of the polyp, we recommend to perform hysteroscopy and remove this polyp, and only after that, we will start to prepare for the embryo transfer.
NGS can show all the pairs of chromosomes and this is a great difference because we can only check 12 pairs of chromosomes by using FISH. Also, if we compare NGS and another method like aCGH for PGT -A, which can show, also all pairs of chromosomes, NGS can show us mosaic embryos. Other ones cannot show them, so NGS is more preferable to other methods.
AMH is a predictor. For example, when a patient comes to me with an AMH at 0.5 at the age of 30-years-old, or 0.5 at the age of 40-years-old, the chances will be totally different. I think both AMH, and AFC, and of course, age will be the predictors.
First of all, when we see such high levels of prolactin and if you had a normal level a few months ago, usually, we recommend to recheck it. First of all, there can be some laboratory mistakes or something like that or probably you have checked the prolactin level on the wrong day of the cycle. If the prolactin level is so high usually, we recommend being consulted by an endocrinologist and try to find the reason for such high prolactin, and of course, it should be compensated. As it was done on day 3 of the cycle, it’s okay. Probably, you can recheck it during the next cycle, and if it will be so high again, you can go to an endocrinologist and then this specialist will try to find the reason for such high prolactin and will prescribe you some treatment before the IVF because such a high level will influence the result of the stimulation.
First of all, I will recommend checking the embryos by PGT-A. The main reason for failure is an aneuploid embryo, and unfortunately, donor embryos created from the donor eggs can be aneuploid too. I will recommend IVF with PGT-A.
For PGT-SR, we should have indications, and if you or your partner have some rearrangements in your karyotype, it would be recommended, but as you have thrombophilia, you should receive some treatment prescribed by a hematologist. Actually, when we are talking about such a huge case history, with such a number of miscarriages, especially with the euploid embryos and if patients have thrombophilia, it’s very difficult to manage such a pregnancy, and of course, you need a preparation from hematologist before the embryo transfer. The question about PGT-SR is still open, but only if you have rearrangements you will need it, but you need real preparation from a hematologist.
Actually, there is no difference for most of the patients, so it doesn’t matter.
When we are talking about frozen embryo transfer or egg donor transfers, then the endometrium lining should not be less than seven millimeters than the prescribed progesterone. We have to try to find another reason for failure like chronic endometritis or possibly there are some hematological problems. If we are talking about a few failed transfers from donor eggs.
There are only a few scientific research works about mitochondrial transfers, and this option is not yet in everyday clinical practice. We have to receive more scientific data on this option before we can use it in our clinical practice.
That can be some kind of laboratory mistake and actually, AMH of 0.1 and 0.3 is the same. I don’t know what had happened when you were 39. Why did it increase? Possibly, the first measure was a mistake, but 0.1 and 0.3 are the same.
It is very individual and for some patients even at 42 or 43, we can find about 10 antral follicles at the beginning of the cycle. But it is possible to have a very low ovarian reserve even at 35, so it’s very individual.
The bowel removal is a very serious surgery, so this is a question for a surgeon, not for gynecologists. When it comes to endometrial scratch, a few years ago, endometria scratch seemed to be very popular, and it seemed to be effective, but right now, we don’t perform it because it doesn’t work so well. About the adhesions, you have to be consulted by abdominal surgeons.
This doesn’t indicate anything because they are both normal, so this is normal variability.
We don’t have much information about how coronavirus affect fertility because the first studies were intended for pregnancy and especially for late terms of pregnancy. I mean the first data from spring, but right now, of course, we already have data about early terms of pregnancy, but in regards to fertility overall, there is not much data right now, so I cannot answer how it can affect fertility.
In my clinical practice, the maximal age was 43, but I’ve heard that one of the doctors had an experience where a 45-year-old conceived with her own eggs. I suppose this is a kind of exclusion. In most cases, we’re saying that after 43, the chances are very, very low.
It depends on your ovarian reserve and your partner’s sperm. It can be totally different because somebody can have about 10, or even 20 follicles at the age of 40, somebody else can have 1 or 2 follicles, and there will be a great difference. Each patient is an individual, and we have to discuss the individual situation. I cannot say, on average how many cycles. Somebody can achieve a pregnancy after the first IVF cycle, but somebody else will need about 5 or probably 10 stimulations, it’s totally different.
