Success after Failed IVF. The embryologist Perspective.

Carol Lynn Curchoe, PhD,TS (ABB)
Founder of ART Compass, Senior Clinical Embryologist, ART Compass

Category:
Embryo Implantation, Failed IVF Cycles

From this video you will find out:

Can we improve oocyte quality?
What constitutes a healthy oocyte?
How does “estrogen dominance” affects your fertility?
What constitutes healthy sperm?
What testing can be done on the uterus?
How important is the embryo transfer and the operator’s skills?

Success after Failed IVF. The embryologist Perspective.

The embryologist's insight into success after IVF failure

In this session, Carol Lynn Curchoe, PhD, TS (ABB), a Founder of ART Compass, a Fertility Guidance Technology & Senior Embryologist, has been talking about success after a failed IVF attempt. Dr Curchoe explained what is crucial to look for in the IVF lab, discussed some of the experimental technologies that can help you achieve a positive outcome, all that based on her own experience as a senior embryologist.

Dr Curchoe began her presentation by listing things that are most important to have a successful IVF cycle. These are healthy oocytes, sperm, uterus, IVF lab factors and then operator skills.

Healthy oocytes

Dr Curchoe stated that the primordial follicles in the ovary are being recruited 120 days earlier than what you have available today. It’s crucial to remember that your antral follicle count started to develop 120 days ago. It might give you hope to think that you have some control over the environment these oocytes are growing and developing in. Dr Curchoe explained that it is possible to grow and culture the embryos and gametes in the lab, but it’s impossible to improve their quality. Therefore, it starts with what you can do in your body to help the embryologists in the lab. We know, for a fact, what impacts oocyte quality is insulin metabolism, and that comes down a lot to your consumption of simple carbohydrates.

I want to encourage you to think about what you should be eating at every meal instead of what you shouldn’t be eating. If we start to think about it that way like: ‘I should eat an avocado every day, I should try to eat some tomato every day, I should try to eat one apple a day then all of a sudden we lose the craving for the bad foods.

Another thing Dr Curchoe discussed was BMI. Women of all BMIs can conceive, but when you’re having trouble conceiving, losing just 5% of your body weight and decreasing your BMI by just a little into the healthy area is so impactful for fertility and IVF outcomes. Dr Curchoe followed that if we start to make some of those healthy changes, we will see that 5% is much easier to achieve than we were previously thinking. We should also focus on are substances such as alcohol, tobacco, in a lot of areas of the United States, it’s THC, prescription drugs and also supplements. Supplements can fall into the good category, the neutral category like there’s nothing in there, or the bad category where they’re containing things that we don’t know are in there. They can contain hormones or molecules similar to hormones, but they’re disrupting what our bodies should be doing and what we need our doctors to do during our stimulation protocols. Therefore, you need to start making such changes at least 120 days before your retrieval, you want to cut down or cut out as much of your nicotine, tobacco, alcohol, caffeine just cut down on anything in your environment. Take recommended supplements, such as vitamin D, folic acid and coenzyme q10, which is helpful. Most people think cholesterol is something bad. However, you have to remember that sex hormones are made from the cholesterol molecule itself. You have to have good healthy levels of these fats for your body to make your sex hormones, it’s all-important. Dr Curchoe clarified that a lot of time, health, and wellness practitioners mention something called estrogen dominance. They start prescribing progesterone based supplements, and it’s crucial to keep in mind that those can interfere badly with fertility.

Healthy sperm

A sperm cycle is much longer than we think it is. It goes from 40 days to up to 76 days on the very long side. One of the things that we think about with sperm is something called DNA fragmentation, we want the DNA strands to be whole. We don’t want them to have been assaulted and bombarded by the environment, we need those strands to be unbroken or unfragmented to make healthy embryos. In the lab, we see that embryos fertilize, but then they arrest at day-3. That day-3 arrest comes from the quality of the sperm at the time of fertilization a lot. Two of the things that can help with DNA fragmentation and quality are temperature and the environment. Many times men have these jobs where they’re getting very hot, they have to wear a lot of equipment, or they’re working with a laptop directly on their lap. We need the testicles, the site of sperm production, to remain a couple of degrees colder than the body. Professions like construction workers, firemen, or anything where the environment can be impacting sperm quality and the temperature can be very hot or very high. When it comes to supplements and substances, it’s the same, you should start at least 80 days before. There are some male fertility supplements, and there are sometimes a lot of testosterone-based supplements and anything that contains a hormone you should be very wary of. It’s best to talk to your doctor, disclose everything you’re taking. The supplements that are very well accepted for increasing sperm quality are the same ones increasing oocyte quality, take the folic acid, vitamin D and the coenzyme q10. BMI and obesity, in general, in both men and women, has a very big impact on hormone production and gamete quality. Reducing the BMI down to a healthy level and getting low-impact exercise every day can help your insulin metabolism and help to take that glucose out of your bloodstream, which can impact gamete quality.

Healthy uterus

We can make healthy embryos in the lab, but if we don’t have a healthy uterus capable of supporting a pregnancy, it won’t matter. A couple of things that patients can look at nowadays are the endometrial receptivity tests. We want the endometrium to be synced with the age of the embryo. At times, it is necessary to take progesterone for a longer period to prepare the uterine lining and help to increase the uterine endometrium receptivity. The Receptiva DX test can tell us if there are low levels of endometriosis going on before we transfer the embryos back to the uterus. Usually, people don’t start looking at those things until after they’ve had a failed FET or a failed transfer with the genetically normal embryo. The second thing Dr Curchoe mentioned is genetics. Your set of genetic mutations. This is ranging into the realm of personalized medicine. Some mutations can cause you to metabolize folic acid differently and also make your blood clot more. Both of those things can sustain your ability to have a healthy pregnancy. Folic acid is very important for neural tube closure and defects. The clotting aspect is really important for being able to establish a pregnancy and then maintain it. Small blood clots can form in the capillaries of the placenta between the mother and the baby, and then the nutrient exchange has a more difficult time because of those blood clots. The uterine microbiome is another aspect that Dr Curchoe discussed. The uterine epithelium is consistent with the epithelium of the cervix and the vagina. Our microbiome colonizes our entire body, we have a gut microbiome, a skin microbiome, we have these organisms that live with us, have evolved with us and help to keep us healthy. Microscopic bacteria do everything from producing different vitamins to different sugars in your reproductive tract. It even produces some proteins that can help with the crosstalk between the embryo and the endometrium. We want to make sure that we’re eating a lot of healthy prebiotics, you want to eat the food your bacteria wants to digest. You can take probiotics, but we need those bacteria to be in our vagina and our endometrium. Therefore, taking them in your stomach is less desirable than eating the food that will cause the healthy bacteria to proliferate. Dr Curchoe also suggested that we should be cutting down on our antibiotic use in general. Those antibiotics in our environment, or for example, taking them when we have a virus and not a bacterial infection, can impact our microbiome everywhere in our gut, our vagina, our skin. All available literature shows that the bacteria species of Lactobacillus are the important ones to help us maintain a healthy microbiome.

IVF lab factors

In the US, we’ve switched almost all of our cycles to ‘freeze all cycles’. We’re doing upwards of 80 to 90% of PGT-A, which is the pre-implantation genetic testing for aneuploidy, and that can tell you whether the embryos we made have a normal number of chromosomes or an abnormal number of chromosomes. Part of the freeze-all strategy is to let your body go back to baseline after you’ve bombarded it with all of those stimulation medications. We will biopsy and freeze the embryos and then hopefully get those genetic testing results back and be able to transfer a genetically normal embryo to your uterus. Regarding mosaic embryos and culture to day-7, Dr Curchoe explained that she likes to have both mosaicisms reported from the genetic testing company and physicians willing to transfer mosaic embryos.

I have seen mosaic embryos go on to produce successful pregnancies, and I think that there’s ample evidence of that in the literature. I’m also a big fan of culturing embryos to the seventh day. For a variety of reasons, embryos can be slow-growing, and in general, we have seen that embryos that come back genetically normal have up to a 30% success rate. A lot of labs are not yet culturing to day-7, but I think that will become a widespread best practice.

When it comes to IVF add-ons, such as ICSI (Intracytoplasmic sperm injection), Embryo glue, Assisted hatching, which is performed at two different time points. The first is usually around day-3 or around the time of biopsy. Then the other is when we thaw the embryo, and we’re preparing it for transfer. Sometimes, we like to help the embryo to escape the membrane called the zona pellucida around it. The embryo needs to escape that membrane to implant in your uterus. Some other experimental technologies are not widespread yet but probably will be in the next couple of years. The Zymot chip is a way to prepare sperm where it swims through channels similar to how it would swim through your cervix. It is thought that separating the sperm that way gives better quality sperm at the end with less DNA fragmentation. It has been selected more naturally as it would be in your body. It eliminates the step that we do in the lab, which is where we centrifuge the sperm, and fling it to the bottom and the side of the test tube that we’re centrifuging. It is potentially causing some stress to the sperm or some damage. Another technology is called PICSI, which stands for Physiological Intracytoplasmic Sperm Injection, and it allows the sperm to bind to the dish with the same protein that it would use to bind the egg. We’ll be picking the sperm that looks the most normal, which has also bound to this certain spot on the dish.

I’m not the biggest fan of PICSI, but I know some people have used it, and again it’s hard to tell what made a cycle successful on a second or third go-round when it finally succeeds. The use of the PICSI dish could be something that people consider.

There are also a couple of different oocyte treatments. One of them helps collected immature oocytes to become mature in the lab. Those oocytes have a bit less of a success rate because they were not mature at the time of the retrieval, but it may be giving patients a chance, it probably still needs a little bit of development as well as using the Calcium ionophore (CA+) to activate oocytes. The last experimental technology that Dr Curchoe mentioned was Artificial Intelligence. The basic concept is that the computer can look at images of embryos or videos of embryos and help pick the embryo that’s going to be successful the fastest. Ultimately, we’d like this to go in the field as a replacement for biopsy. During the embryo biopsy, we pluck about 4 to 6 cells off the embryo, and it slightly damages it. Right now, it’s the best technology we have to say whether those embryos are normal or not. Finally, artificial intelligence now is all about these images and videos of embryos. However, the gold standard would be to analyze all of your data as a patient. Your demographics, your infertility diagnosis, everything about you in conjunction with the embryo images gives us tools for the prognosis and diagnosis of your infertility or your cycle. We’re not quite at that point yet where everything is connected in the realm of AI, though.

Operator skills

In the US, we start with looking at SART or the CDC, Center for Disease Control and Prevention success data. Every country has the equivalent of a governmental agency that oversees the success rates of Assisted Reproductive Technologies. The more important thing is that the clinic you go to is not falsely advertising their success rates on their website. Make sure that whatever your clinic is advertising matches the data that they’re reporting. A recent paper from Italy was released in 2020 that shows a huge difference in the operators or the people performing the embryo transfer. The embryo transfer is a key procedure for success, and it seems like once clinicians learn how to perform the embryo transfer, the number of embryo transfers that they have after that doesn’t make them better. It is probably because they learn this procedure, and then they don’t interact further with other clinicians to keep modifying that procedure after they learn it. Therefore, for embryo transfer, it’s best to use soft catheters, no bed rest, as some studies have shown to negatively impact implantation and clinical pregnancy rates. Then to use an ultrasound guide, you want to guide the catheter through the cervix and into the perfect spot in the uterus to drop the embryo off. The Vienna consensus defines the key performance indicators for both the clinical and the IVF lab, and they guide embryologists competencies.

As an embryologist, I check my statistics to the Vienna consensus. I want to know how is my fertilization rate, how is my blastocystery, and so on. The skill does matter, and I think a lot of times with picking a clinic, you as the patient are weighing a clinic that may charge more for a cycle but gets their patients pregnant faster versus a clinic that charges less for cycles, but you might need more than one cycle. Then, by the time it all adds up, that could become very costly for you.

The embryologist's insight into success after IVF failure - Questions and Answers

I froze 8 day- 5 embryos when I was 33. The first transfer resulted in my son. Since then, I have transferred 6 embryos in 4 transfers, had 2 failed attempts, 1 chemical, and 1 blighted ovum. Do you have any idea why things are going so badly after our first successful transfer?

First of all, I’m so sorry, that is so heartbreaking. You may have been struggling from primary infertility, but now it seems like you’re struggling from secondary infertility, and this is something that is not talked about a lot in the community, and a lot of people just assume once you’ve had one child, you’ll be able to have another. Secondary infertility is definitely a devastating problem, and when you’ve already been through the trauma of infertility and treatment for your IVF, it hurts even more. I don’t think that science has good explanations for this yet, and I think people have started to look toward an autoimmune problem that could come after that. Unfortunately, this question is a bit out of my personal area of expertise because it goes moreover into that clinical real, but I think a lot of specialty practices are starting to turn now to analyze the immune system for an autoimmune problem where your body is attacking the transferred embryos.

What grades of an embryo is good?

Grading is a bit of a beauty pageant for embryos, and we know that roughly success rates correlate with the look of the embryo, what we call the morphology. We also know that many good-looking embryos we biopsy are returned as genetically abnormal, and sometimes embryos that look horrible come back genetically normal, and those are the ones that we transfer first. The look, the grade, and the morphology of the embryo is not everything, it is something, but what it does is it helps the embryologist decide which embryo to transfer back first. There are grades are given for day-3 embryos typically and day- 5, or day-6, day-7 embryos, so blastocyst stage embryos. There are all different kinds of grading systems. What the day-3 grades come down to is how many cells do those embryos have. Day-3 embryos are cleavage stage embryos, so that means one cell should become two, two cells should become four, and four cells should become eight. If you see an abnormal number of cells that can be like an odd cell number, it can be too few cells, so we want those embryos to be between four and eight cells on day-3. If they have less than four cells, those are not good quality embryos. If they have high fragmentation on day-3, the quality of those embryos is a little bit lower. We want the cells to be symmetrical, and so we want to see that they’ve divided evenly, and we also want the cytoplasm to be nice and clear. The fragments can start to develop when embryos are kicking out pieces of the membrane during those cell divisions. Then they become fragments in the embryo space, and that kind of restricts the embryo from growing in the correct way when all of those fragments are there. It also reduces the area of the cell membrane, and the cells need those membranes to develop. For blastocyst grading a lot of the grading systems, nowadays, go by Gardner grading, you may have heard of that. 1 is the smallest, and 6 is the largest on that grading scale. Any embryos that are like 3,4,5,6, these are perfect embryos for biopsying. The number reflects the size of the cavity in the blastocyst. We think that this size tells us something about the quality of the embryo because it tells us a little bit about the metabolism of the embryo. The embryo has to have good metabolism to be able to develop a cavity that big. We like to go for the higher Gardner numbers, 3,4,5, or maybe even 6, and the blastocyst has two different cell types as well, so one is the inner cell mass, and one is the trophectoderm. Whenever we give a grade usually, it’s like 6AB. The first letter grade is for the inner cell mass (ICM), which becomes the fetus and the second grade is for the trophectoderm, so that’s the layer that becomes the placenta. If you have anything that’s a BB or an AA, or an AB or any combination of B’s and A’s – those are going to be better embryos. I like to push in biopsy anything that makes the blastocyst even very low-quality embryos, just because I want to give you know the patients the best chance possible.

The embryologist refused to biopsy my grade 5 blastocysts, as they were not of good quality. Do you think they should be biopsied anyway? Can a 4 CC be OK?

I would not like to disagree with an embryologist, particularly not being able to see the embryos. Some embryos are of such low quality that they literally cannot be biopsied. There are no cells available to take for the biopsy, and CCs would be very difficult embryos to biopsy. Ultimately, the morphology does correlate a bit with the normal number of chromosomes, and if it’s that low quality, the chances are it’s very abnormal. Usually, what I do is if there’s something that’s a C quality, but it can be biopsied, I’ll call it like a B-minus on the grading system. Sometimes I really push embryos to biopsy them, but then it comes back as having inconclusive results because the DNA quality wasn’t good enough to be read on the DNA sequencing machine. In that case, I start to sort of question my own judgment like maybe I shouldn’t have biopsied that embryo for that patient, but ultimately, I think what it comes down to me personally is I like to try to give every embryo a chance to be biopsy that can be. I think a lot of embryologists are like that, so if the embryologist refused to biopsy them, it probably meant that they would have destroyed the embryo by taking those cells if I had to guess.

How are you testing the uterine microbiome?

I don’t think it’s being clinically tested yet, so there are a lot of research studies that have been looking at it, but I don’t think that as a practice it’s gone into the clinic yet. That’s kind of why I mentioned this. Bacteria feed off of bad segars, the wrong kinds of bacteria feed off of bad segars. The more complex carbohydrates we provide the bacteria in our guts and our bodies, the better the quality of those probiotics or the food that the bacteria themselves are heating, and the more of the right types of bacteria we are growing overall in our bodies. I think much more is going to come out about that over the next few years.

I had 5 fertilized eggs in November during my IVF cycle, only 2 made it to day-5 embryo but were of bad quality (inner cell mass wasn’t there). I’m 42. Is there any hope for healthy embryos for me at this stage?

I do think there’s hope. I think if you’re making blastocysts and you can keep trying financially and mentally and physically, and otherwise, keep trying. Like I mentioned, the egg development cycle is 120 days long, so one of the very small studies that I was involved with as a researcher was presented as an abstract at the ASRM conference, which here in the U.S is the biggest American Reproduction Conference, so we looked at egg donor cycles, repeat egg donor cycles, so the study was kind of controlled in that way because these were all very young women with high AMH, no infertility issues and they did multiple retrievals for donor tissue to give their oocytes to egg donor recipients and what we saw is that as the cycles went on embryo quality and blastocyst number increased. This was retrospective data that we looked at, it was not the gold standard, no clinical trials double-blinded and randomized, and all of those things. We simply looked at the data that had already been gathered and was there in the medical records. I just think it’s an interesting correlation, and I don’t necessarily know if it’s being caused by the egg donors having repeated cycles, but we looked at cycles up to number 6, and we saw a very definite improvement in embryo quality between the first cycle and the last cycle. As well as the blastocyst number and the number of mature eggs that were at the time of the retrieval. I think some of that has to do with the fact that you’re administering these hormones while those primordial follicles 120 days ago were in the process of being recruited and coming into the cycle. It could also be some things that are specific to the patient, like you’re learning how to take your medications better, with more confidence, with your shots and all of those dreaded shots with your stimulations, but ultimately, I think the evidence is encouraging. If you can, keep going, then keep going and keep trying to improve some of those factors that I talked about like, insulin metabolism and healthy BMI, working out every day. Don’t go overboard because you don’t want to cause stress and cortisol in your body. Have low-impact exercise, eat healthily, get a lot of sleep, and I think you can succeed.

I have endometriosis. My first cycle was 3BB and 2nd round was 2BB. I am 36. Could sperm be affecting the embryo development as I’m discarding 3/4 embryos at each cycle (using donor sperm)?

I think you might try changing donors usually, donors are very well screened, but it’s a bit hard to say. I do think that endometriosis can impact egg quality because at 36 and maybe no diagnosis of diminished ovarian reserve or anything like that, you could try changing sperm donors. It’s a bit hard to say, but those are kind of lower quality embryos for what I would typically expect out of a 36-year-old.

How do you know which foods are good for your microbiome?

From everything I’ve read, it looks like so-called bad bacteria are feeding off of simple sugars, so any of that kind of very sugary things that we can consume. I’m an afternoon chocolate person, I love chocolate in the afternoon, and I try to tell myself that this dark chocolate it’s good for me, it’s healthy for me, but I am also a big carb eater, I love bread and everything like that, so all of those white carbs turn into simple sugars in our stomach. Complex carbohydrates cellulose and plant fiber are really the best foods for bacteria, so just increase your fruit and vegetable and take as much as you can.

In regards to probiotics – is it better to have things like kimchi or taking supplements?

I always think that micronutrients should come from food. The supplement industry is completely unregulated, and anything can be in there, or nothing can be in there, or something that you have no idea that you should have been expecting can be in the supplements. I also think your body probably processes it and absorbs it better from food rather than from supplements, so I’m not a huge supplement fan except in the case of vitamin D especially, for a lot of us who don’t get outside and see the sun as much as we want to and might not be drinking as much milk as our kids do where the milk is itself is fortified with vitamin D. I like the vitamin D, and I like the folic acid, those have been proven to be helpful. There’s slight evidence for coenzyme q10, and there’s getting to be more and more evidence on that.

Would you still recommend to freeze embryos and do the PGT-A even if you only have one embryo?

This could be kind of a complex answer, so ultimately, I think what I would recommend is to freeze it without the PGT-A, but still to freeze it and transfer it at a later cycle where your endometrium has been prepared separately. I think when you only have one embryo, a lot of times you don’t want to know the status, you want to give that embryo a chance. Most of the time, if it’s been biopsied and it comes back as abnormal, a clinic will not transfer it. There’s always some chance, there’s like 5% chance that a biopsy result can be a false positive like it will falsely diagnose the embryo as being at risk for aneuploidy or having an abnormal number of chromosomes. I think if there is only one embryo, my advice would be to freeze it. Transfer it at a later cycle but maybe not biopsy it.

What is the benefit of culturing the embryo to day-7 versus day-6?

This is going to depend on the lab specifics because sometimes, at day-6 all of the embryos it’s very clear, all of the embryos that were even approaching blastocyst have been able to be biopsied, and there is nothing left to culture to day-7. Personally, I like to check the embryos again, the morning of day-7 because I have seen a lot of embryos that were small blastocyst is or morulas on day-6 become biopsiable blastocyst on day-7, so it just kind of depends too on the environment inside the lab and how fast or how slow the embryos are growing, what time of the day they’ve done their ICSI. If it’s kind of later in the day, on the day of the egg retrieval if it’s a big lab and there’s a lot of procedures, for e ample, then those embryos might appear to be slower growing than the other ones. I think when you start to get day-7 embryos transferring them back to the uterus, the probability of them implanting is lower, but it still has up to about a 30% chance when it comes back normal, so for me I think there is a big benefit to the patient for culturing to day-7.

If my embryos were of ‘bad quality’ at day-6. Could they improve if they had been cultured to day-7?

Sometimes, what happens when you culture them overnight to day-7 is they become better quality, but a lot of times what happens is they continue to decline, and they start to degenerate, so it’s something that you can ask for, but I couldn’t say for sure, which way it would go in your case.

What’s your opinion on doing a genetic carrier screening for gestational surrogates (not traditional) even though those are not her eggs. I’ve read some details that there might be a correlation with switching on, of any carrier diseases that donor and father have? Neither have any common carrier conditions. There was no MTHFR detected in the surrogate, but I prefer folate is taken any way rather than folic acid.

In any consumer industry, you have a product that is being marketed to you, and you as the consumer are buying it, I’m just talking in general. In the human tissues industry, if you want to call it that, I feel like clinicians think it’s in everyone’s best interest to screen all of those tissues and donors and everything as thoroughly as possible. You just never know what could come up, they’re looking at hundreds of genes for the screening. As somebody who is providing you with the surrogate or with donor tissues, for example, you really want to make sure that to the best of your ability that what they’re providing is as promised, so I think if the physician is recommending that the gestational carrier be screened, and it’s not a huge expense and headache and all of those things, just go for it because the physician I’m sure is looking at many hundreds of genes and we’re thinking about is this MTHRF gene or maybe something else that we’ve read about.

Is there a risk of Down Syndrome if I would transfer a Mosaic embryo (I’m doing NGS)

Down syndrome is going to be specific for chromosome 21, so it depends on the mosaicism that the embryo has been diagnosed with. From what I’ve seen the embryos that are highly mosaic basically, just don’t implant. There hasn’t really been any evidence that an embryo, that was diagnosed with mosaicism by PGT-A has gone on to produce a mosaic pregnancy, and then the resulting child has mosaicism in their tissues. There’s only been one case of that reported in the literature, whereas there have been hundreds and hundreds of cases reported of healthy babies. I think what happens more often than not is, it either implants or it doesn’t. As far as Down Syndrome is concerned, that would be specific to the type of mosaicism that the embryo had, it would have to be in that chromosome 21.

The eggs on my 2nd round were described as being ‘a bit dark’, but I’ve not had my follow-up with the consultant yet. Can you give me any advice on this? 120 days before this cycle, I had started a low-carb diet and added in Omega-3 and CoQ-10, and I don’t smoke or drink

That’s great you’re doing all the things to help yourself, which is amazing. When the eggs look to be a bit dark sometimes, they can have something called the bullseye look, which looks like a dark spot in the center of the egg. Ultimately, I haven’t seen a lot of correlation between that dark egg look and the resulting embryo quality, so I’m not sure exactly why it happens.

If the embryo has not started hatching, should it be helped along to hatch before transfer or transfer and wait/hope it will hatch on its own? Does it matter if this is the fresh or frozen transfer?

I’m a fan of hatching the embryo because it does need to escape that membrane, which is called the zona before it can implant in the uterus. I’m a fan of helping it get out of that zona. A lot of times, what happens when we artificially hatch the embryo, and it wouldn’t have escaped on its own is we’re helping along with an embryo that is struggling. That’s really why we are applying all of this scientific knowledge that we’ve gathered over the past 40 years of doing IVF is to help you get pregnant as fast as possible. If you’re being treated for infertility, it means that your embryos probably are struggling, so it all kind of goes hand in hand. I’m a big fan of assisted hatching, I think there’s been a ton of studies done on it, it’s hard to quantify the amount that it is helping, but it’s not hurting anything. As far as fresh or frozen transfer, I think some people are of the idea that the zona hardens a little bit after the freezing, and so the assisted hatching is particularly helpful on frozen embryos, but I like to do it on fresh and frozen.

Do you get the same success rate using fresh or frozen embryos?

I’m going to answer this like across the industry, not for me personally because I can’t talk about any specifics about my clinic or my personal IVF practice, but across the industry, the rates are better with frozen embryo transfers. That’s why we are moving as an industry entirely over to frozen embryo transfers. Nowadays, we do a fresh transfer when we’re like throwing the kitchen sink at a patient, and we’re trying just anything we can, and we think that the embryo might do better if it was back in the uterine environment rather than being frozen in the lab. Now, especially in the U.S, the fresh transfer is being used as almost like a last-ditch effort to help a patient that’s really struggling. Overall I’m a fan of frozen, freeze-all cycles and frozen embryo transfers.

How many embryos would you normally recommend transferring? Is it really risky to transfer 2 embryos? I hear a lot of bad things about twins. I am 34 with endometriosis.

It’s so hard to say because this comes down to your personal risk factors, so you need to make this decision in really close confidence with your physician, your risk for being able to carry a twin pregnancy. Twin pregnancies come with a huge set of risks, so if you’ve had a lot of previous miscarriages, you have an incompetent cervix, or other problems with the uterus, your physician, I’m sure is going to recommend a single embryo transfer. Usually, single embryo transfers are recommended particularly, with PGT normal embryos. When you get into the untested embryos, you start to wade into a territory where your physician can help you decide if transferring more than one embryo is the right decision for you. I always go by what our professional society recommends, so they have a grid that they put together, and it correlates with the patient’s age, the PGT status of the embryos, so either tested or untested, and that kind of guides us on how many embryos to transfer. So the younger a patient is with PGT normal embryos, they recommend single embryo transfer, then as you start to get older, I’m talking about close to 40, then they start to recommend being able to transfer more than 1 embryo at a time. The untested embryos, it’s a bit of a different story, you can recommend transferring more than one.

Do you advise day-3 or day- 5 embryo transfer?

On day-3 a lot of embryos look good, they’re between 4 and 8 cells, but we know for a fact that only 50% of those are capable of going on to become a blastocyst. I think growing the embryo in the lab to day-5 immediately, gives you a reduction in the possible number of embryos that can be transferred, but that’s a good thing. When we were doing a lot of day-3 transfers across the industry, and we were transferring the best looking 4 or 6, or 8 cell embryo, we still had no way of knowing whether that embryo could have become a blastocyst, or not. The success rates were much lower when we were doing day-3 embryo transfers. I really like the day-5 blastocyst culture.

Does the ZyMot (Sperm Separation Devices) cost $100 per sperm sample?

The lab can buy these chips, and I believe the device itself or the chip costs 100 dollars, so then on top of that, there will be some preparation charges from the lab or from the clinic itself.

Is it worth pushing to do a freeze-all even if you only have one 5-day embryo? As I’ve heard, the embryo is not thawing correctly, and if I only have one, that’s a massive risk.

The freeze protocols nowadays should have like a 95 to 98% rate of thawing. They’re really good, so with today’s protocol of vitrification, I still would recommend freezing. The thaw risk is very low.

On my last try of the IVF cycle, the clinic mentioned that my oocytes are sticky, so the fertilizing with the sperm is not so successful, which only gave us 2 blastocysts but, which also failed after transfer. We did ICSI. What made my oocytes sticky? What does that mean? Is it my age? I am now 38.

I have no idea what that means, I’m afraid. I can see, sometimes with so-called sticky oocytes that, when you poke the ICSI needle in and then you pull it back out, the sticky cytoplasm sticks to the needle, and it starts coming out of the hole that you punctured with your ICSI needle. I think in terms of that kind of stickiness if that’s what it was specifically, that can cause the eggs to become atretic or to degenerate after the ICSI procedure. That may have reduced your number from what was able to be injected to what was able to make it to blastocyst. Ultimately, I’m speculating, I have no idea what sticky oocytes mean in this case.

3 out of 8 of my eggs were not mature on collection. How can I improve that for the next round?

That is pretty typical actually, and the way that you can get a good idea of how many eggs will be mature is how many follicles are measuring at least over 14 millimeters. The bigger, the better. If there are follicles that are under 14 millimeters, your physician still has to puncture the follicle and retrieve the egg. They can’t leave eggs in your ovaries, otherwise, it leaves you at risk for ovarian hyperstimulation syndrome. They’re going to take all the eggs out even from the very small follicles, and a lot of times, what happens is you have leading follicles that where you need to go in for your retrieval because otherwise you’re at risk of those leading follicles ovulating and you’re losing those eggs. Every retrieval is going to have some eggs that are immature and some mature eggs. 3 out of 8 sounds like a reasonable number to me, it’s well within the Vienna consensus that I mentioned. Your doctor can tinker with stimulation protocols to try to improve the maturity, but I would say that that’s in the range. There’s not a lot of room for improvement.

Can you give me more information from your opinion on why someone would need an extra ‘flush’ to get the eggs out of the follicles?

Usually, if there needs to be extra flush, it’s because the maturity of the egg is not going to be good. Inside the follicle, which is like a bag of fluid, the egg is hanging from a stalk of granulosa cells, which is called the mural granulosa and a good mature egg that has responded well to the stimulation, it’s gone through its maturation stage, it’s usually going to release from that mural granulosa pretty well, so I tend to think that if there’s flushing that needs to happen that those eggs are not going to be good quality when I’m doing the retrieval, and I can see that happening on the other side, I’m worried about those eggs.

Do you recommend Embryo Glue and Assisted hatching?

I do like Assisted Hatching. As far as Embryo Glue goes, so in your reproductive tract, you have this protein called albumin, and it helps to form a sticky matrix between the embryo and the endometrium, and Embryo Glue is very similar. It’s a hyaluronic protein that helps to form that sticky matrix between the embryo and the endometrium. There’s a lot of hot debate out there about how long to keep the embryo in Embryo Glue, how much to transfer with the embryo, and all these different things, but ultimately, I think Embryo Glue is probably not going to do any harm, and it’s something to try to help get patients pregnant faster.

Preparing endometrium for FET. What does it involve?

It can involve a couple of different things, it might involve removing any polyps or any fibroids looking for scar tissue or taking something like an antibiotic to quell a bacterial inflammation in the endometrium that can be caused by those bad bacteria that we talked about. Looking for any signs of endometriosis and treatment before the embryo transfer, but when you’re preparing the endometrium to get into that thick triple line pattern that we want to see, that’s going to be progesterone, so there are a couple of different ways to do that. One is through a natural cycle where if you don’t have any problems with ovulation at all and you know exactly when you ovulate, you allow your body to ovulate, and then the follicle becomes what’s called the corpus luteum. The corpus luteum is actually a gland that secretes progesterone, so you would naturally prime your uterus to accept the embryo just like you would in a pregnancy that happened in your fallopian tube instead of inside the laboratory. That’s called the natural FET cycle. Then you can do a couple of different types like minimally progesterone primed cycles or maximally progesterone primed IVF cycles with more than one different type of medication, and that’s all dependent on your physician. For most FET cycles, progesterone priming is a one-size-fits-all approach. You apply progesterone for a certain amount of days and then you check for the endometrial lining to see if it’s achieved a minimum level of thickness for the embryo to implant. ERA testing can help to see if the timing of the progesterone supplementation needs to be taken a little bit longer for a specific patient, or if they have achieved that endometrium that is receptive for an embryo at this kind of standard amount of days of administration. It’s mainly about progesterone priming whether you get that from a natural source like a corpus luteum or whether you’re taking that as progesterone and oil shot or a suppository.

Do frozen embryos become less successful if they are frozen for longer?

There was an ESHRE study published where they said this was true. I haven’t seen this specific study, but it’s kind of an interesting question because the longer an embryo has been frozen, the older the freezing technique was used. Nowadays, our freezing technique has become very refine and it has been changing a lot and just in the last 5 to 10 years. I don’t necessarily know how well you can control for differences in technique over a long period of years. We just had this really awesome story come out about this embryo that was frozen for 27 years and became a healthy pregnancy, so I do think that there are a lot of stories like that, and there are many people who have had their embryos and eggs frozen for more than 10 years who have been successful.

I had 5 eggs retrieved, out of which all were matured in my 1st IVF cycle this month at the age of 42.5. We did ICSI as my partner’s sperm was 99 % abnormal. 3 eggs fertilized with two grade 1-9 cells and one 1-8 cell. We transferred two 9 cells, best quality on day-3, but it failed. I have one expanded blastocyst frozen on day-6. What can I do to improve my chances of implantation on the next transfer?

First of all, having 5 eggs and then for all of them to be mature and fertilized is amazing. 99% abnormal sperm, don’t worry about it because there is 1% of millions and millions of sperm, even just 1% percent normal means that there’s plenty of normal sperm for the embryologist to find to fertilize your eggs with. My biggest recommendation is not to do the transfer at day-3 but to see which one of those embryos would have made it to the blastocyst stage, so for me a 9 cell embryo, it’s a little bit abnormal because it has that odd cell number and at the 8 cell stage what you should see is that 8 cells go to 16 cells, so having an embryo that has 9 cells is a little a bit off to me. That one expanded day-6 blastocyst probably has a good chance whereas, you don’t know with those 2 on day-3 what their actual chances were.

What is the difference between biopsy embryos in biopsy media and buffer solution? I’ve heard some embryologists prefer biopsy embryos in buffer solution.

I prefer to biopsy embryos in the culture media that they grow in. I have never done an embryo biopsy in a buffer solution, and I’m not sure what the reasons would be for doing that.

How does PGS with NGS improve outcomes compared to regular PGS?

PGS just so everyone’s on the same page, means Pre-implantation Genetic Screening, and nowadays, we are calling it PGT, which is Pre-implantation Genetic Testing, so you might hear either one of those. PGT-A is PGT for aneuploidy, so that’s simply looking at the number of chromosomes and seeing whether they’re normal or not. You can do this genetic testing with a couple of different methods, but the newest one is NGS, which is Next Generation Sequencing, so this is going to be one of these big DNA sequencing machines that cost a million dollars, and the samples are probably on a tiny microchip using like the latest microfluidic technologies, so you can load hundreds of patients on the same chip to do the screening. The NGS technology that we have these days is very sensitive, and this is how we sort of waded into this whole territory of mosaic embryos because the technology now is so sensitive that we can start to quantify this level of mosaicism. PGS with NGS has caused us a lot of questions, the PGS with older technologies wasn’t sensitive enough to detect this level of mosaicism. Previously, they would just say the embryos are normal or abnormal, so now you can kind of have at least 3 different results, normal, abnormal, and mosaic, and the whole thing that I think about with mosaics is that they have less potential and previously they either would have been called as completely, normal or completely abnormal, but that wasn’t the full picture. With any PGS technology, we strive to do is prioritize the most normal embryo for transfer first. NGS component should be just making it more sensitive and more specific to hopefully get patients pregnant even faster.

Does the thawing rate of the embryo depend on the patient’s age?

No, not so much I would say it probably depends more on the skill of the person who froze it. Some of the problems come from is the embryo cell boundaries, cell junctions can be very tight, or they can be a little bit loose. It’s just like that resulting child from that embryo would be unique and have its own unique personality, each embryo also has its own unique way of accepting those freezing solutions into the cells, so sometimes I think it’s just dependent on the embryo, sometimes it’s dependent on the skill of the operator, but I think nowadays, with these commercial protocols a lot of the variability has been taken out of the freezing and thawing procedure.

How can I ask about operator skill when I am at the consultation with the doctor?

As far as the physicians go, you want a physician who has very good rates and who practices consistently. You might not want an older physician who is not using the best methods, but you might also not want the newest physician who hasn’t had a lot of experience. That’s for the physicians. For the embryology team, what you might want to take a look at is how long the embryologists have been there, and certain kind of tricky things like is the clinic constantly advertising for new embryologists, is there a lot of turnover in their Staff, can you find them on a website like monster or next door where people who have previously worked at the clinic are actually reviewing the clinic, you want to try to see to get some insight into who is there, how long they’ve been an embryologist for, how many years of experience they have. Embryologists, we take our job very seriously, and there is a very long, slow training period, and these success rates are really important to us. There are just some bad clinics and there are some bad embryologists who bounce around from clinic to clinic. Essentially, it does matter, the length of time that staff members have been there. You do want to try to go to a clinic that has a very stable staff.

In regards to day-7 embryos. Is that counted including the egg collection day? If you had egg collection & fertilization on Monday, e.g., that would be on a Sunday?

The day of the egg collection and fertilization is day-0. Day-1 does not start until the fertilization check the next day.

I had 7 eggs retrieved, estradiol (E2) 2100 on the trigger, and only 2 were mature MII, 2 MI, 3 were destroyed. How could it be? I was expecting at least 5 mature with my E2 level.

I’m not sure what you mean by 3 destroyed, but sometimes, it means that they can be already what we call atretic or degenerating at the time of the retrieval, or it could be that when they were injected with the ICSI needle, they became atretic, so they started degenerating. It could mean either of those things. But to be honest, I am not exactly sure how it could be.

I have some eggs frozen if I get ICSI on them and fertilize, culture to blastocyst, and then freeze them again. Will this make them more susceptible to thaw failure since they have been frozen twice?

I don’t think so, personally, I don’t think so. Once the embryo has grown and all those cells have divided, it’s a different organism than it was when it was an egg.

What’s the reason why the oocyte degenerates with ICSI?

Degenerate oocytes with ICSI are the pain of my existence. If I knew the answer to this question, I would make a bajillion dollars, but it simply comes down to the resiliency of the membrane at the time of injection, and that has to do with a lot of different factors with the maturity of that oocyte. A nice egg that has a very resistant double lipid bilayer membrane and is fully mature in the cytoplasm and everything, typically will not degenerate at ICSI, but if that membrane is not stable and you inject it with the needle, that’s what causes degeneration. How we get to a place as an industry where every egg we retrieve and is mature also has that very stable resilient double layer, lipid bilayer membrane is probably more the question, and that’s exactly what I want the answer to.

Can you tell if the membrane is stable before ICSI?

No, you can’t really tell, but as soon as you touch it with your needle, then you can tell because sometimes it’s very soft, and the needle just goes through almost like hot butter, so we refer to that as basically an impact break as soon as we touch it, the membrane breaks with the needle, and you can’t tell until you touch it, unfortunately. If that does happen, I try to take the needle back out as slowly as possible to try to give that lipid membrane time to sort of healing back up.

What would be the conditions you would recommend ICSI? My husband has a very good number with exception of morphology at only 3%, would this suggest ICSI is required?

always recommend doing ICSI. Number one, when you do conventional IVF, the eggs are surrounded by cells, and you can’t tell what their maturity is or their quality, so occasionally an IVF cycle doesn’t go very well, but you have no answers for the patient because you didn’t get to see the eggs, so it’s to be able to inspect the eggs right away and see their quality of maturity at the time of the retrieval because it does impact the outcome of the cycle. It’s really instructive for the physician as well. If the retrieval didn’t go well, they can know right away. If the maturity, the stimulation didn’t go well, then they can note right away. The reason to do ICSI is to prevent something called the total failure of fertilization, and that is when you put the eggs in the sperm together and you come back the next day, and nothing is fertilized, and you have no idea why. Usually, people think like okay, ICSI was developed to solve a problem with male infertility, so we should really only be using it in cases where we’re trying to solve that problem of male infertility, and there are some theories too that the egg is attracting the best sperm and picking the best sperm. I think previously it was kind of thought that the sperm are racing to the egg and the fastest, best sperm wins this race. Ultimately, I think that there isn’t very good evidence for any of these things. When it comes down to it on a practical level every day in the lab, like I’ve said many times, I want to give our patients the best chance possible, and so for me, that means that I want to do ICSI for everybody regardless of what the diagnosis is.

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Ovarian rejuvenation and PRP – process and outcomes explained

Authors

Carol Lynn Curchoe, PhD,TS (ABB)

Carol Lynn Curchoe, PhD, TS (ABB), a Founder of ART Compass, A Fertility Guidance Technology. She's also a Senior Clinical Embryologist Board Certified in Embryology. Her PhD in the physiology of reproduction is from the University of Connecticut and a board-certified as a technical supervisor of embryology.) ART Compass is a mobile application platform for IVF cycle management, a Fertility Guidance Technology (www.fertilityguidancetechnologies.com). She is the author of The Thin Pink Line (Nova Science publishers, 2021), a critical exploration of historical perspectives and controversial topics in modern gynaecology from birth control to sterilization, to episiotomies and the “husband stitch,” to “educational” pelvic exams, shackling labouring convicts, gender-affirming surgery, human embryo research, assisted reproduction and more.

Event Moderator

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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