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IVF options for poor prognosis patients or with prior IVF failures

Ashim Kumar, MD
Board Certified Endocrinologist & Infertility Specialist

Category:
Failed IVF Cycles

IVF options for patients after failed attempts and poor prognosis
From this video you will find out:
  • What are the factors that need to be taken into account: uterus, tubes, sperm, etc.?
  • What are your options with low ovarian reserve?
  • What are the steps if we have multiple aneuploidy embryos?
  • What is the role of androgens, DHEA and testosterone in egg quality?
  • When should I consider moving to donor eggs?

 

What are my options if I'm a poor prognosis patient?

In this session, Dr. Ashim Kumar, Board Certified Endocrinologist and Infertility Specialist at Western Fertility Institute, Los Angeles, USA has explained options for IVF patients with poor prognosis as well as with previous failed IVF attempts.

Dr Kumar started his presentation by explaining that whenever we look at fertility, we need to always start by having a look at the oocytes, sperm, uterus, and tubes.

  • Fallopian tubes – it has been an acknowledged fact for decades that dilated fallopian tubes (hydrosalpinx) can negatively affect the chance of implantation by 50%. The removal of the fallopian tube is highly recommended as it increases the likelihood of ovarian cancer due to dilation).
  • Sperm – regarding sperm analysis, it is mainly dismissed by the doctor as other characteristics such as morphology and motility are fundamental. Thus, the freshest best sperm available is of the utmost importance. Moreover, if characteristics such as morphology are lower, a holistic approach that entails diverse and healthy lifestyle habits (healthy diet, exercise, mindful meditation, frequent ejaculation, and treatments) will be recommended rather than opting for placebo outlets.
  • Uterus – several tests can be done to evaluate the uterus, these are EMB (Endometrial Biopsy), MRI, ERA, Hysteroscopy, Thrombophilia evaluation.

Those tests are not initial evaluations for the uterus. Provided that a regular sonohysterogram has abnormal results, then those tests will be considered. In that case, an endometrial biopsy (EMB) will be first recommended, which entails the removal of cells that are sent for later testing and diagnosis. In cases of repeat failure, medical resonance imaging (MRI) will also be considered. In this way, a high-resolution magnet that provides detail-oriented results will be fundamental to identifying if the lining of the uterus is invading the surrounding muscle (endometriosis). If there is inflammation caused by endometriosis lesions, it is a fact that there might be cell factors that can negatively affect the opportunities for implantation. That being the case, a hysteroscopy would be recommended. Additionally, an endometrial receptivity assay, a test that measures what should be the duration of exposure to progesterone before embryo transfer, consists of going through a frozen embryo transfer cycle to analyze if the transfer timing should be changed specifically for the individual characteristics. Ultimately, a thrombophilia evaluation should also be considered as its main focus is on clotting disorders and these have long been associated with recurrent pregnancy loss.

Eggs – ovarian reserve issues

According to Dr Kumar, ovarian reserve encompasses these two following ideas.

  • Egg quantity: AMH
  • Egg quality: Age

First of all, from a biological perspective, a female-gender fetus will produce an average of 6 to 8 million eggs at 20 weeks of gestation and that specific amount decreases as the individual grows. Most of the eggs are lost at birth with just a million remaining. Most women will only release 400 hundred eggs over their reproductive years. Consequently, there are 1000 eggs left by menopause but of inferior quality that are unresponsive to the stimulatory hormones.

Ways to assess the quantity (Number of eggs that can be obtained):

  • Anti-Müllerian hormone (AMH) – measures levels of Anti-Müllerian hormone, which relates to your egg count
  • Antral Follicle Count (AFC) – it’s the number of antral follicles that can be found generally in both ovaries
  • FSH (Follicle-stimulating hormone) – acts on the ovaries to make the follicles and eggs grow, the higher the FSH, the fewer eggs there are

Egg quality

Looking at the woman’s age, we need to keep in mind that a 31-year-old woman with a high number of eggs is going to have a bit higher quality than one with a low number of eggs. However, in a 31-year-old with fewer eggs, the egg quality will still be far better than a 45-year-old with a lot of eggs. It is crucial to remember that age depends more on egg quality than the number of eggs, but the number of eggs plays a small role.

  • Aneuploidy

“Euploid” means the true number of chromosomes present, while the prefix “aneu” in medicine means not. What we want are euploid embryos, meaning the correct number of chromosomes in the embryo, which would be 46 – 23 from the egg and 23 from the sperm. Aneuploid embryos, on the other hand, would have an abnormal number of chromosomes or missing or extra pieces of chromosomes.

The egg starts with 92 chromosomes. All the cells in our body except for red cells have 46 chromosomes; the red cells don’t have a nucleus or chromosomes. These 23 chromosomes are from the egg that created us, and 23 are from the sperm that created us. When 1 mother cell is going to make 2 daughter cells, the DNA replicates in the cell, the DNA goes to each side of the cell, the cell pinches itself into 2, and you have 2 identical daughter cells from 1 mother cell. With ovulation, the chromosomes line up, and then they’re pulled aside, 46 to one side, 46 to the other. One set of chromosomes is thrown out, that’s called the first polar body. The 46 are lined up again, 23 pulled out on one side, 23 on the other. Another 23 are thrown out, and that’s the second polar body. The sperm comes in with another 23, and we have the 46 to make a new embryo.

This depicts the even distribution of the chromosomes so that the resulting eggs have the correct number. This kind of issue can also happen in the sperm, but it’s much less frequent. Up until age 33-34, the number of eggs is relatively stable, then it goes down rapidly. The egg quality is the inverse of that. This is the likelihood of finding an abnormal embryo. It’s relatively stable, and after age 34, it starts to increase. Aneuploid embryos are the most common cause of miscarriages.

Egg quantity

It is quite acknowledged that male hormones (androgens) increase follicular recruitment. However, having high testosterone levels or high androgen levels throughout the cycle will eventually result in retrieved poor-quality eggs and subsequently poor-quality embryos.

What is used most often for these cases?

  • DHEA (dehydroepiandrosteron), does not serve a real purpose in the body but is a placebo; it also has a very weak androgenic activity- a thousand times weaker than testosterone
  • Testosterone – unlike DHEA, has a clear purpose in the body as it binds to the androgen receptor with great affinity

According to Dr Kumar, quality is related to the propensity of the egg to generate a euploid versus aneuploid embryo. Furthermore, it is important to note that age is of the utmost importance for egg quality as the number of eggs has a small role.

Low Dose vs High Dose  – Ovarian Stimulation

In the first place, it is known that with poor prognosis patients, a much gentler approach is much more efficient rather than an aggressive type of stimulation. Nowadays, the focus on medication has slowly shifted from high doses for a low number of eggs to individualization of both the particular characteristics of the patient and the cycle based on the antral follicle count.

Egg donation

Even though opting for donor eggs can essentially be an emotionally exhausting decision to make, it is strongly suggested to consider it seriously as it might ultimately lead to the expected outcome. Deciding to opt for egg donation treatment requires thinking about all factors that need to be addressed, including the financial and medical aspects as well.

- Questions and Answers

We have MFI (Male Fertility Factor). We have had 4 failed IVF/ICSI on high dose stims [450 units HMG]. We only ever end up with 1 embryo despite 15-19 eggs retrieved. My AMH is 19 & AFC is 15. What drugs/protocol would be best for me?

When your AMH is probably 19 (pmol/L), and we use ng, so it’s about 2.6 if I’m doing some decent math off the top of my head, which is pretty favorable and appropriate with your AFC. My recommendation would be to do an antagonist protocol, and I think that you’d do better with a mixed dose with maybe, let’s say 300 units of FSH, 150 units of HMG and I would consider maybe 50 milligrams of clomiphene for about the first seven days. A little bit lower dose and this is one of those cases where the adverse outcome may be due to a few problems in the sperm itself and frequent ejaculation. This is where your lifestyle changes play a role, so a handful of nuts and berries you should be eating every day. Get those antioxidants on board, not through pills but dietary changes, exercise every day, it’s a huge benefit in decreasing the inflammation in our body, improving our body, and much more so than any pill could ever do. The third thing daily ejaculation for even a week leading up to the egg retrieval again, you only need 20 sperm, you don’t need 20 000, we don’t need 20 million, so frequent ejaculation, I think would help. So, a little bit lower dose and frequent ejaculation.

What duration do you consider a prolonged course of antibiotics for chronic endometritis? Which is the best antibiotic for this?

We commonly use Doxycycline, and we start with a two-week course, we re-biopsy, and if we still have it, we do a four-week course.

I have had 6 failed IVF cycles. The last cycle was successful however, it was a chemical pregnancy. I have thought about an ERA however, I am thinking, if I had HCG in my blood, then the embryo did implant, and I would not need the ERA?

The key here seems to be looking at the embryos because the ERA test is also used for implantation failure, and this might not be implantation failure in your mind. But in the physician’s mind, this is implantation failure, so a biochemical pregnancy, we consider implantation failure even a very early miscarriage falls into that realm of implantation failure/RPL, so recurrent pregnancy loss. It’s all kind of viewed as one continuum

When would you consider a mini IVF or flare protocol? Does this improve egg quality? Do the type of trigger used HCG versus buserelin have an impact on egg quality?

I don’t use the flare protocol at all, I think it’s a crummy protocol, it’s very aggressive, and I think it most often results in poor quality eggs. Over other protocols, I’m a strong believer in antagonists or a mini, I don’t use the flare protocol. I think the mini is going to be better in terms of equality than a flare. I use a dual trigger, I use a low dose HCG, and I use buserelin acetate, but there’s decent evidence that suggests you’re going to get maximum yield of eggs from each follicle if you use a dual trigger.

Which egg is best for fertilization? MII in anaphase II? Could MI eggs in anaphase I fertilize?

It is an MII. The MI eggs can fertilize, we do the IVM in vitro maturation, there is the success with that but it’s not the same as MII.

Do eggs grow after the trigger shot? For example: if a follicle was 16mm at trigger day, how big will it be on retrieval day?

They do grow, but it’s irrelevant. There’s no reference range for the follicles on retrieval days, so this could be 20 millimeters, could be 22 millimeters, but it’s irrelevant. Remember that we’re worrying either we do the long estimation, or we’re doing mean diameter, and it’s a gross estimate, it’s not exact, and people talk about the lining on the day of transfer versus the day you start progesterone, so the reference range meaning in our mind, are they mature, immature those kinds of things. It is for the day of trigger beyond that, it’s irrelevant.

In my last cycle in August 2020, I had 7eggs collected, 6 fertilized, and I had 4 x 5AAhatching blastocysts (2 day-5 and 2 day-6) and 1AB. Are the 6-day embryos more likely to have chromosomal issues?

Yes, slightly more likely, but I think they’re still almost as good. We’ve looked at the results meaning what percent is normal versus abnormal on day-5 versus day-6, there is a small difference, but it’s pretty small. I wouldn’t worry about that issue there, but all 4 of those embryos are good.

What could be done to increase the FSH receptor on a follicle?

We did estrogen priming for a prolonged period. This is about maybe 12 years ago. I had this idea that if we did estrogen priming, you would upregulate the FSH and LH receptors on the granulosa and theca cells. You get a better response, and what I noticed is that I was getting much more dominant follicles and dysfunctional stimulations. I think that again it sounds wonderful theoretically. Practically, speaking it’s better to get a fully synchronized good stimulation than to think that we’re going to get an extra egg or 2 or to do this miraculous supple regulation of FSH receptor by giving estrogen priming. The only time I think about this is when there’s hypothalamic hypogonadism where the woman hasn’t been exposed to estrogen for a long period, and those stimulations can take a long, long time unless you give a month or two of estrogen beforehand but during a normal IVF cycle. I think that this is hypothetically interesting, but practically it doesn’t work.

Could taking Dostinex(Cabergoline) for high prolactin affect the result of IVF Stimulation? How?

I think Cabergoline would be indicated to lower prolactin for IVF stimulation, and it shouldn’t affect either high or low prolactin. It should not affect the overall stimulation. If you think about prolactin, the way that it causes infertility is that it suppresses FSH and LH production, so potentially if you didn’t want to take cabergoline, you could let your prolactin be very high, and you wouldn’t need an antagonist or an antagonist stimulation, but in terms of it negatively affecting the stimulation, there’s no physiologic basis in that.

Does the testosterone/HGH only apply to the egg retrieval phase?

Testosterone would be before the ovarian stimulation. The HGH would be during the ovarian stimulation, we do sometimes retreat for 2 or 3 weeks, but that’s less common.

What maximal dosage of FSH will you recommend? I’m 39 years old. My AMH is 1,7, FSH is 7, and AFC is 7.

In this situation, this is where the cycle difference is a very great deal, so this type of thing you have to look at the size of the follicles if there are 3 or 4 that are a little bit like 8-9 millimeters and 2 or 3 that are 4 millimeters, then I would do a mini dose stem with just Clomid and human growth hormone. If there are 7 and all look good and uniform then I would do a moderate dose and maybe as a good high amount of Clomid with maybe 300 units of HMG rather than FSH.

My prolactin levels are high at 860, I have seen an endocrinologist, and he said he would not treat it as I do not have any of the symptoms. What would you suggest, and is this affecting fertility? I have low AMH of 3.3, secondary infertility, I have a son 16, natural ectopic after my 2nd IVF fail, a chemical on my 5th cycle, and I have just had a frozen transfer another failure. What would you suggest?

I think the vast majority of us would treat with or without symptoms. I would recommend the MRI, again the reference range is not there, and there are different units used all over the world, but it seems like it’s a pretty high prolactin level. I would get an MRI to make sure there’s not a microadenoma in the pituitary. With high levels like that again, I would incline to treat. I think the majority of the issues are related to the ovarian reserve issues and not prolactin. Even emotionally speaking, having high prolactin levels you being concerned about it makes so much more sense to treat it haven’t come down to normal, and at least that’s one less worry that you have.

What are your thoughts between medicated versus natural FET? My age is 34, secondary infertility, AMH 3.3, I have had a natural ectopic after my 2nd IVF failed. 5th transfer was a chemical after transferring 2 x 5aa hatching blastocysts, I have just had a natural embryo transfer which was negative, I have 2 x 5AA hatching day-6 embryos and 1 x 4AB day-5 embryo frozen. Would you recommend transferring 2 embryos?

I think 1 or 2 is fine. If these are untested embryos. This is one area where I would take a timeout and maybe do an HSG or even a laparoscopy and look at your fallopian tubes because the most common reason for an ectopic is that something is going on with the tubes. Given how young you are, how many embryos you’ve had transferred, and either the biochemical I would just want to check on your tubes. I’m fine with the natural cycle or programmed, but the main thing is to check your tubes before you do anything else.

What are your thoughts on calcium ionophore/Artificial oocyte activation for fertilization/embryo development?

That’s a very difficult situation because it’s a last resort type of thing. Where once we can’t figure out anything else and why it’s not happening, you can try it, but I’ve read about this again recently because we had a patient that was referred to us and the patient was having poor fertilization in the past. We’ve tried this, we’ve even tried electrocuting, shocking the egg to get it to fertilize, it’s the last resort, it’s not something that’s routinely used, and it’s not something that routinely works.

I had 5 IVF cycles till now. First, at 41 years of age last year. My AMH is 7.6 ng, 2 embryos are both fertilized successfully. I got pregnant but miscarried at 7.5 weeks. The embryos are always good till day-3 and never going to blastocyst. Last cycle, I got 8 embryos, 4 fertilized, and 3 were transferred at day-5 at almost blastocyst. We never got semen fragmentation, so not sure I should wait till blastocyst or do the day-3 transfer? I had antagonist last cycle, and I also have Hashimoto, and I worry about the thyroid levels not being the right levels.

I wouldn’t worry about the Hashimoto. Let’s get the easy one out of the way. As long as your TSH is between point 5 and 2.5. The semen fragmentation again that’s only going to tell you if you need to do ICSI or not, and it seems like that part’s okay. The most important thing, I would go to day-5 and see if you can get PGT-A done because then you know the truth. When it comes to day-3, I know some people are doing it thinking that the embryos can be better in the uterus than in the IVF lab, but if you think that, then you need to switch IVF labs because the IVF lab should be good enough to take it out to day-5. If you’re barely getting into a blastocyst, then I would stop, let them go to day-6, do the biopsy, find out what you have. If you’re putting in embryos that are not viable, then you could go down this whole path of implantation failure workup, etc. and it’s just the embryos. If you are putting in genetically viable embryos and it’s not working, then you need to take a pause, time out, do this whole implantation failure work up, figure out what’s going on. We need to know, is it A or B? You can only do that with the PGT-A.

I’m 41, AMH 4.2 pmol/L, and we have MFI (Male Factor Infertility), poor morphology & DNA Frag. We did 3xICSI cycles, produced 4-6 follicles each time, always used high dose Menopur 450. Had day-5 embryo transfer on the 3rd cycle but did not implant. Decided do Embryo Banking for the 4th ICSI cycle using high dose again, unfortunately only 1 very large follicle was produced, so switched to IUI to avoid wasting the cycle. But as predicted, it didn’t work. I’m going for the 5th cycle now. They suggested a lower dose of Menopur to the consultant, but he thinks there is no point. Do you think I should use testosterone too?

I would use testosterone, maybe a high dose of Clomid, a low dose of Menopur and Growth Hormone.

Why would you recommend HMG rather than FSH?

Most of the time, I recommend a mixed dose protocol. Mixed doses, those being FSH in the combination of HMG. In the very low dose protocols, I do use HMG in place of mixed dose, or pure FSH, and you have to drive the system meaning too low of LH, you’re not going to get anything done. Too high like the Lupron flare is going to adversely affect the outcome, but you need some decent amount of LH there to make the precursor for the FSH to work on. Remember that FSH binds to granulosa cells and converts testosterone to estradiol. Where does the testosterone come from? LH, so HMG is a combination of FSH and LH, so LH binds to theca cells and converts cholesterol to testosterone, and that testosterone is a precursor for the granulosa cells driven by FSH to work on. Without testosterone as a precursor, how do you get estradiol? You don’t. That’s why you need both FSH and LH.
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Authors
Ashim Kumar, MD

Ashim Kumar, MD

Dr Ashim Kumar is board certified in reproductive endocrinology and obstetrics and gynaecology and practices near Los Angeles, California. In recent years, Dr. Kumar has focused his efforts on those that have had difficulty conceiving and require third party reproduction (egg donor and/or gestational surrogacy). Over half of his current patients are from overseas which include Australia, Austria, China, France, Germany, India, Italy, The United Kingdom, etc. Combining meticulous attention to detail, 7-day a week work ethic, the best support (nursing & embryology) and the latest in technology, he is able to obtain the highest pregnancy rates achievable today. He has been asked to present his work across the world including Australia, India, China, and Italy and has contacts in numerous clinics that collaborate closely to provide seamless care. He completed his fellowship in reproductive endocrinology and infertility through a combined program that allowed him to work with world-renowned leaders in the field at both University of California Los Angeles and Cedars-Sinai Medical Center. Dr. Kumar completed his medical education and residency in Obstetrics and Gynaecology at Emory University in Atlanta, Georgia. Dr. Kumar has published numerous articles in peer-reviewed journals on endocrine and surgical aspects of infertility and has presented his work at the annual meeting of the American Society for Reproductive Medicine. He serves as an ad hoc reviewer for the journal Fertility and Sterility. Dr. Kumar has written several textbook chapters on management of tubal factor infertility and ovarian function including premature ovarian failure and has a special interest in hormonal and functional causes of infertility such as polycystic ovary syndrome (PCOS), tubal disorders, male factor infertility, and third party (donor/surrogate) reproduction. He is also a member of the Pacific Coast Reproductive Society and American Society for Reproductive Medicine.
Event Moderator
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.
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