The ways to improve your chances after failures

Valentina-Denisova, MD,PhD
Obstetrician-Gynecologist, Fertility Specialist

Failed IVF Cycles

IVF failures and how to improve your chances
From this video you will find out:
  • What is the low prognosis in IVF?
  • What are the strategies for low response patients?
  • What is your lifestyle’s impact on your IVF?
  • What is the effect of female obesity on reproduction?
  • Is PGT-A a solution?
  • What does implantation mean?
  • Is ERA test helpful?
  • Does the ERA test really provide personalised embryo transfer solutions?


How to boost your IVF chances after a failed attempt?

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.

Low prognosis patients

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.

Impact of lifestyle changes

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.

PGT-A indications

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.

Endometrial factor

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.

Take-home messages

  • Before planning IVF, modify your lifestyle (lose weight if you are overweight, stop smoking, don’t drink alcohol, decrease caffeine intake.
  • Look for possible reasons for failures and try to correct them.
  • The main factor of success is the female’s age, so remember that egg donation might be an indication.
  • PGT-A can shorter the time of pregnancy and increase your chances.
  • Assess your chances accordingly to the current situation.
- Questions and Answers

What is the normal cortisol level? How to decrease a high level of cortisol?

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.

Would a BMI of 24 give a better result at stimulation than a BMI at 27? Or, there is no difference?

We’re talking about overweight. If the BMI is over 25, I suppose a BMI of 24 will give a better result.

Some articles say that the PGT-A testing result does not say much about the overall quality of an embryo. Why?

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.

What is the number of mature eggs necessary for a blastocyst? I am 40.

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.

Why a 5AA graded embryo doesn’t necessarily mean high quality?

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.

Do you recommend ubiquinol as a supplement to improve egg quality?

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.

I have had 4 IVF with PDG and 4 ET, fresh and frozen. All embryo’s stayed but no heartbeat. Now, I’m 43 years old, I have Hashimoto. What do you think was the cause of the failures? At 2 ET, the doctor prescribed Medrol because I insisted, any other medications you’d suggest?

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.

What does it suggest if endometrium shrinks during stimulation, for example, day 9 stimulation – 11mm, but on day 11 stimulation – 8mm thickness? What do you think? Overstimulation or something else is causing this?

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.

I am 43 and very low ovarian reserve, and even with hormones help was not able to create an egg. I am not ready for an egg donor and would like many other options before I go this route. I eat well, I am a dancer, and take some vitamins. Is DHEA good to try?

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.

I’m taking folic acid to prepare for IVF, but I have heard that 10 to 15% of the population have a gene mutation that means that they need to use Methel folate instead. Is it true that this mutation is so common?

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.

Would you recommend carrying on with transfer when during stimulation a polyp is found?

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.

How much better is NGS than other PGT-A methods, e.g. FISH? Is it worth the extra time, money, and hassle?

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.

Do you think AMH is the biggest predictor of success at IVF or AMH and AFC?

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.

I have just had day 3 blood results, and my prolactin has increased from 436 mu/L in February to 1287 mu/L in October, which is very high. What is the impact of high prolactin on IVF, and is it still possible to progress with IVF with my current level of 1287 mu/L? Both tests were performed on day 3 of the cycle.

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.

I have had a double donor transfer that failed. All day-5 blastocyst. Had ER map,(Receptive), the aqua scan was normal, KIR AB. ALICE and EMMA showed chronic endometritis. My lining was 8 – 10 on transfers. Presumed immune issue last transfer had Granocyte, tacrolimus, intralipids, prednisolone, clexane, aspirin with no implantation. Would you recommend anything else?

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.

I am 36 years, KIR BX. I have thrombophilia. I have had 4 miscarriages (before I was taking heparin and one of them IVF – euploid embryo) and 1 using heparin (natural pregnancy). After those, I got 5 transfer failures with euploid embryos. After those, they found fibrosis, I got treatment, got pregnant naturally, and I suffered in August my last miscarriage with heparin, but without PGT-A embryo. In your opinion, does it make sense to do PGT-SR + A in a new transfer?

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.

Is there a difference in starting stimulation on day-2 versus day-3 of the period?

Actually, there is no difference for most of the patients, so it doesn’t matter.

Do you have any advice on how to ensure the lining is at optimum levels for donor egg transfer? I have had 2 failed cycles and apart from the prescribed medication, I would like to know if there is anything extra I can do to help?

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.

With a low ovarian reserve, is there the option of mitochondrial transfer with donor eggs and how much would it cost? Would there be other options? My age is 42, and I had an ET but lost the embryo at week 9

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.

At 38, I had an AMH 0.1, at 39, it increased to 1.6 again, now at 42, it is 0.3. How does that work?

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.

How fast does the AMH level drop in a year at 40?

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.

Would you recommend any add-on for IVF treatment like endometrial scratch, assisted hatching, etc.? Could I have an endometrial scratch if you have adhesions? I’ve had lots of surgeries, bowel removal, etc.

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.

How variable is FSH? I had an FSH of 9.9 in February and October it had reduced to 5.26 after taking supplements. What does this indicate in terms of my fertility?

This doesn’t indicate anything because they are both normal, so this is normal variability.

Have you heard of any research yet about how the coronavirus affect fertility?

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.

What is the female maximum age where you had a pregnancy with your own eggs?

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.

How many cycles are needed at 40 to have a live birth?

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.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.