Fertility in the Lab
Hey everybody. I hope you all are having a great week. Embryoman, first and foremost, thank you so much for this collaboration. Second, you guys are going to see two very different videos. Mine is gonna have more of a DIY feel. His will look very professional, very well done. But hopefully both of them will get to the heart and soul of your questions. There were several good questions answered and there was actually a lot of overlap. We tag-teamed the questions and what I've noticed is there's a lot of overlap. So I am gonna highlight the ones that were assigned to me and then please follow this video.
There's going to be about 15 minutes where Embryoman does a deep dive into some of the more lab-related questions. And he does a great job. You definitely don't want to miss it. For those who don't know, Embryoman is a lab guy. His real name is Sean.
Let me start there. So Sean, aka Embryoman, has about 10 years of science research experience in addition to his degrees. Essentially his goal on social media is to keep the audience up to date on the different studies that are being published. And he tries to make it sort of, you know, non-medical, non-super technical terminology so we can all understand it. I really love what he's doing. His focus has been on IVF infertility in the IVF lab, both on social media and on his website: www.remembreo.com. So I hope you guys enjoy. Here goes answer to the first question.
Question #1: Sperm DNA fragmentation test on husband came back 13. Oxidative stress test came back high. Doctor says to do this sperm DNA fragmentation again as it's not possible for it to be that low given the high oxidative stress level. So the first thing I'll start by saying is that sperm DNA fragmentation testing is not considered a standard part of the fertility evaluation as per ASRM, which is the American Society of Reproductive Medicine. We do use sperm DNA fragmentation testing sometimes, where there is an underlying suspicion of male factor or when the couple has done IVF and poor embryo quality has resulted.
Now, the issue is what to do with this testing, and there's not really a good answer. So to this person, I would say go back to your doctor and ask the question. Let's say we do the test and let's say it were to come back the same. How would we proceed? Now let's say that in fact the DNA fragmentation test came back elevated because one of the things we know is that the test can have a lot of variability to it. What would we do differently? I think it's important for you to understand what the different management options will be before you decide whether or not to actually repeat the test. So hopefully that answer was helpful.
Question #2: Does growth hormone improve egg quality? Now, there's definitely quite a bit of literature on the use of growth hormone and its potential impact, particularly in women with low ovarian response. So you will see growth hormone, if it is used, it's generally used in women who have low ovarian response. But I should warn you that growth hormone is not a magic fix. It's one more tool in the toolkit for fertility specialists. Not everyone uses it, and you also have to be aware of the potential side effects. Many physicians have actually stopped using growth hormone because of the potential risks associated. So definitely something I would just talk to your doctor about. If it's something that you guys discuss, and you decide you want to try, then by all means, I think it's not unreasonable, but with realistic expectations, understanding that there's no magic cure and there's no one size fits all solution for low egg quality and/or low ovarian response.
Question #3: Can a day 3 FSH level help determine the quality of a retrieval cycle? I love this question because cycle day 3 FSH is a very typical hormone marker that many fertility specialists will look for. A normal FSH level done on cycles day two, three, or four in the setting of a normal estrogen level is ideally less than 10. Once it's over 10, we begin to suspect diminished ovarian reserve. So in those cases, when we have low egg reserve, we will find that the egg reserve, that the number of eggs that we are working with is going to be lower than somebody who has a normal FSH.
As far as the quality of the IVF cycle, I don't think that FSH is a good predictor of that. However, I do think that it can help guide you and your doctor in terms of what sorts of numbers should we be expecting. Now, we typically don't check FSH alone with estrogen. So we will typically check an AMH or anti-mullerian hormone as well, in addition to an ultrasound looking for antral follicle counts (Also should be done at baseline cycles day two through four). So putting all those three together, the doctor has a very good idea about the patient's ovarian reserve and can guide the patient as to what is a reasonable number of eggs to expect for their case. And as a consequence of the eggs, what is a reasonable number of embryos?
Hopefully that answers your question; I do have a YouTube video (on this). If you go to YouTube and you search Dr. Carolina Sueldo, you will find a whole video, 10 minutes, dedicated on ovarian reserve markers, where I do a deep dive on exactly this question.
Question #4: I have four failed frozen embryo transfers. Should a fresh embryo transfer be our next step? Now, to this person, first of all, I feel you, my heart goes out to you. The infertility journey is a long and hard one, and when you have multiple failed transfers, the rate of patient dropout is much higher. I always tell my patients that creating the embryos is by far the hardest step in this whole process. So if you have additional remaining frozen embryos, I always prefer to use those first. Typically, the exercise I will go through is, is there any additional testing to the embryos that needs to be performed, i.e. genetic testing? So you would unfreeze the remaining embryos, do genetic testing, refreeze them, and then once you have the genetic results, you would choose the embryo for the next transfer. The next thing would be additional testing to the uterus. Here, this might be imaging of the uterus. Think of an HSG, which you may have had at the beginning of your evaluation, a saline sonogram, or you may talk about molecular testing with your doctor, ERA, which is the endometrial receptivity assay, and the newer tests, Alice and Emma. Now, the data on all of those is very, very, what's the word I'm looking for, new. So I would definitely encourage you talk to your doctor before you proceed with any of those tests.
And then lastly, we talk about the protocol. So is it something where we need to consider changing the protocol? I'll typically go through those three things first. So embryo, uterus, and then protocol. And if we've checked all those three, then I would move forward with frozen embryo transfer next, assuming you have remaining frozen embryos.
Question #5: Is there a part of an egg's 90-day development cycle that is most important in terms of healthy behaviors like good sleep, etc.? I love this question because lifestyle component is a huge thing that I’m always talking about. So from the moment that somebody is gearing up to try to conceive, I always talk to them about three things. The lifestyle piece, which I’ll get to in a second, the supplement piece, and then the actual fertility treatment. Now, if you're just starting out, you may not be in fertility treatment, but you definitely can focus on the other two components. For supplements, most infertility specialists are going to be recommending a prenatal vitamin with folic acid. And then depending on your case, we may talk to you about additional supplementation. Also, if you are somebody who wants to add herbs into your life, that is something that I am in full support of. However, please make sure you're working with someone experienced and knowledgeable who actually understands the dynamic relationship between the different hormones at different times of the cycle.
And then the third thing I talk about is lifestyle. We talk about nutrition, exercise, sleep, stress management, there's so many things, optimization of other medical conditions. This is hugely important. And most of us talk about doing all these things for at least three months to try and optimize what we can. Now, if you're already in fertility treatment, and depending on your age and diagnosis, you may not have the luxury of the three month wait period. So if that's the case, then definitely you wanna just be doing whatever you can concurrently with the fertility treatment. Hopefully that answers your question. And then the last question, what is the percentage loss of an embryo doing PGTA, and how does age-oocyte quality affect it? In other words, when the REI suggests that the embryos won't handle the freeze-unfreeze for PGTA, is there any data to help make that decision prior or during the day 3-5 process with only a few, if any, embryos?
So the first thing you need to understand is what is your clinic's survival rate for freezing and thawing. In the current laboratory setting, for most clinics, those numbers are gonna be over 90%, hopefully closer to over 95%. So if you think about that, there's a high chance that the embryos will survive the freeze-thaw process. Now, the other question you should ask is what was the grading at the time of freezing? What is the doctor's concern? Is it just the fact that they may not survive the thaw, or was the embryo already borderline to begin with at the time of freezing?
Every clinic has a slightly different cutoff for which embryos they will agree to freeze or not freeze. And so that may be another question in addition to the clinic's survival rate. Now, specifically as far as genetic testing, the genetic testing will depend on who did the biopsy. So how proficient are they at biopsy? There's definitely a subjective component to that. And then it will depend on the lab result that we get. We know that age is the number one predictor of finding a normal embryo. So embryos that come from patients under the age of 35 have a high likelihood of at least finding one normal embryo. That said, some data from some of the big (genetic) labs, and now this data is a little bit older, but still looking at thousands of embryos, they found that even in patients who are under the age of 35, about 30% of embryos were genetically abnormal. Now, over the age of 35, that number only increases. By the time the patient is 40, we anticipate that approximately 60% of the embryos tested will be genetically abnormal. So you see, age is by far the number one predictor.
Now, as far as oocyte quality, that's a little bit more complicated. There is some suggestion in women who have a very robust response to the IVF stimulation with lots and lots of embryos that sometimes we see higher rates of abnormality or aneuploidy, is the technical term, but we don't really understand the mechanism why. So really that would be a question for your individual case. What does that mean for you? Now, if we're talking about somebody who has an average response, maybe they have endometriosis or they have unexplained infertility or tubal factor infertility, or male factor infertility, you would anticipate age to really be that primary predictor. Hopefully, that answers your question. It's definitely a lot to unpack, but hopefully I addressed all the points.
EMBRYOMAN: Hello. All right, so I am happy to be here to collaborate and answer some questions for you guys. So I'm just gonna go ahead and get started. I'll be using my website, Remembryo, to answer these questions. So if you don't know, Remembryo is a website where I review and summarize new IVF research. It's kind of like an IVF science news site. So you'll see plenty of that as I'm answering questions.
All right, so the question is, if you had a better quality embryo, but it was a day six blast, would you transfer that first or would you transfer the lower quality day five blast cyst first? So it's a question of, you know, day five versus day six. Typically day five are considered better than day six. But if the day five embryo has a lower quality than day six, you know, what do we do about that? So I'll just kind of tell you right away that it's kind of controversial. And it kind of depends on what grades we're talking about. If we're talking about like a really good quality embryo, like an AA, like a 4AA versus like a 3CC, you know, that's a big difference between like a 4AA and like a 4BB. So it depends on like the step down in quality that we're actually talking about here.
But let's look at some of the data that I have on our website here. So under this post here, I have a section on timing of blast development under that section. And there are a few studies I'll point out here. So these are a little bit older, but you know, we got these two studies here that showed no difference in pregnancy rates between day five and day six. These two studies show no difference. This study found that day five embryos performed better than day six regardless of grade. So roughly about half the live birth rate is based on this study. This study found comparable implantation rates and pregnancy rates between day six and day seven, but it was lower than day five. So there seems to be kind of a trend toward day five not being as good as day six or day seven. Then if we look at terms of embryo quality, so this study looked at good-quality embryos, live birth rate of 53%, fair quality embryos, live birth rate of 37%.
This study looked at good quality blasts, had a 41% live birth rate versus 26%. So, you know, good versus poor, it's a bit bigger of a jump. These guys didn't find as big of a jump. So C-grade embryos are 34.6 versus 39 versus 46.8. So, you know, you can kind of get an impression of how things are looking here. It's kind of hard to tell, you know, exactly what would be better. And it depends on, AA versus CC, that kind of thing. So best thing to do is ask your clinic, see what they recommend, you know, is day five versus day six, does it work better in their experience? Like we saw the different studies, they can be kind of controversial, but in their experience, you know, what works best for them?
Okay, Does the embryo scope make a big difference in IVF outcomes? All right, so with the embryo scope, it's basically an incubator with your embryos inside the incubator, there's a camera fit on top that takes kind of pictures of the embryos every five seconds or so, stitches it together to make this video or time lapse of the embryos development. So the embryologist doesn't need to intervene, change media, doesn't need to do anything like that because everything's kind of kept in there and not touched. It's just monitored by the camera. And then there's a computer software that will evaluate the embryo's development and kind of relate that to what a better quality embryo is. Like how long did it take for it to divide from two cells to four cells? How long did it take to become a areola or a blast? All that stuff is measured and calculated and chooses the best embryo for you.
All right, so when people ask, Does this work? What I like to do is go over to the Cochrane Library and check to see if they have any information on that. So this looks at the time-lapse system, so embryoscope, things like that. So what they do is they'll take all the evidence, this is up to January 2019, they included nine studies that were randomized controlled trials, so that's high-quality evidence, consisting of about 3,000 couples. And what they do is they take all that data, they put it all together, and they draw conclusions from it. They found that there is no good evidence showing that time-lapse systems is more or less effective than conventional methods of embryo incubation. So at least based on this, on those nine studies that were kind of mashed together and to draw a conclusion, they found no good evidence to show that it's more effective than conventional methods. Still, it's worth asking your clinic, see what they think. Maybe they can provide their own statistics to show you that, you know, in their hands, it does work better. But overall, based on the randomized control trials here, there's no difference.
All right, so my partner has high sperm DNA fragmentation. How does this impact live birth rates and what can be done to help? So I went and I looked for a meta-analysis for sperm DNA fragmentation current up to 2019. So this is taking all the studies or a bunch of high-quality studies up till 2019, put them together to try to draw conclusions. So they found live birth rate, there was no difference. There was a higher miscarriage rate. There were more low-quality embryos. and there was a lower clinical pregnancy rate. So this is relative risk 0.85, there's a 15% decrease in people with high sperm DNA fragmentation. Essentially, if you have a 10% clinical pregnancy rate, someone with high sperm DNA fragmentation would have 15% lower, or 8.5% clinical pregnancy rate, at least based on these studies. So it's certainly possible to have a normal pregnancy with good outcomes, but there may be some reductions in clinical pregnancy, higher miscarriage rate, things of that nature.
In terms of what can be done about it, so Supplements are an idea, antioxidant supplements. A recent study that I reviewed on remembryo did not find an improvement in sperm DNA fragmentation, but it found improvements in a bunch of different things and it did increase the antioxidant capacity in semen and reduce markers for oxidative stress. So that's, you know, positive stuff. Other things that could be done, PICSI. It's like a special dish that you could use to kind of select sperm that supposedly have lower sperm DNA fragmentation. A recent large study didn't find a benefit in most outcomes. However, it did find an improvement in miscarriage rates. So that might be worth something.
Then there's also Zymot, which is a sperm selection technique. You can get it from your IVF clinic if they offer it. Although I haven't seen any data on it that hasn't been sponsored by the company or is a big enough study to draw real conclusions from. So I'm not really sure on it, but it's worth considering if you're really worried about it.
All right. I have two chaotic embryos and the report from Igenomix says chaotic embryos may be worth retesting. What is the chance if I did that, a result would be any different? So I haven't really seen, I mean, I have seen chaotic results. I haven't seen many of them. My understanding is that it's just kind of like a mess. There are abnormalities all over the place. So, you know, normally you might be missing one copy of chromosome 22 or have like a segment of chromosome 18 that's deleted.
But with chaotic embryos, there's just a huge amount of abnormalities. And my understanding also is that it may be related to the quality of the DNA that was submitted. So, you know, the best thing I think to do is to actually ask them, call them up, say, you know, what are the chances of this not being chaotic again and see what they say.
Does it matter what lab to send your embryo to for PGTA? Like Cooper or Igenomix? Do they have different cutoffs for euploid or mosaic? I mean, with those two companies, like specifically, I think they're both like Cooper is massive. I'm pretty sure Igenomix is also very big. So they're probably going to have the best latest cutting-edge technology for PGTA.
I don't think there'd be much of a difference between them. If you're looking at like smaller companies, I'm not going to name any, but you know, if you're looking at smaller companies that maybe don't have that kind of influence, then they may have different results because the technology is not as up to date as these other companies. But I think nowadays, most can report on Mosaics pretty accurately. And it depends too, not just on the technology being used, because I think most testing labs will have the technology to report on mosaics. What also matters is what your clinic is telling you. So they may not want to report mosaics. I mean, that's something that's up to them. Or they may want to report them differently than traditionally done. So, you know, that's something to consider.
All right. And just to follow up a little bit. This is Typically, how things are reported these days with the latest technology: Less than 20% of aneuploid cells = euploid, 24% being a low-level mosaic, and so on. And I think most technologies can report their PGTA results like this. And it might be up to the clinic. Some clinics might have different criteria for what they want to report. So ask your clinic. See what they report. Do they report low-level mosaic, high-level mosaic? What are the cutoffs? What's euploid? What's aneuploid? You know, what do they transfer? Some clinics don't even transfer high-level mosaics or mosaics in general. So, you know, you want to ask about that.
Okay, Success rates for day 7 embryos using frozen oocytes and are day 7 embryos less likely to survive the thaw? For the second part, I don't think there's a difference between survival rates of day five, six or seven embryos. I don't know if there's any evidence to show that. Generally, survival rates are pretty good for thaws, usually in the neighborhood of like 95% or more. So I wouldn't be worried about that. Success rates for day seven embryos using frozen eggs. So here I reviewed a study that found no difference in pregnancy outcomes using fresh or frozen eggs. They looked at the pregnancy rates, live birth rates, and miscarriage rates, and it looks like there may be some differences, but they weren't statistically significant. There were no differences in fresh or frozen eggs. So the day seven embryos from fresh or frozen eggs should be equivalent as far as success rates go.
In terms of success rates for day seven embryos, I have a little study I found here. This study found that live birth rates from day seven are about half of day five and day six. So what 25% versus 45%? And then I have another study here. You could see that the day seven, they had about a 21% live birth rate. So yeah, there is a bit of a decrease with day sevens versus day five and day six, at least based on this study and the other study I showed you, but still acceptable, I think.
How would you judge a lab based on the number of embryos made from frozen eggs? And if it's lower than expected, how do you know if it's just bad luck or if it's an issue with the lab? It's basically a question of how do you evaluate lab quality? Yeah, so it's a great question. I don't know if there's a definitive answer. The problem is that there's just like a ton of variability between eggs, between sperm, between IVF centers, between the labs. Like in a perfect world, if we could just have a million frozen eggs and they're all genetically identical and you go around to every lab and you say, here, take these eggs, inseminate them with this identical sperm and we'll measure IVF outcomes. Um, that might be a great way to evaluate a lab's quality, but you know, that's not something that we're doing. Um, and you know, it's not really realistic unless you start cloning eggs or something. So, you know, between people, you can understand that there are differences in quality of the gametes, the eggs and the sperm, but even between, you know, the eggs that you produce yourself. So you can collect 20 eggs and, you know, maybe half of them are good and the other half aren't so good. So it's hard to really narrow down. It’s hard to use that information to evaluate a lab's quality, I think. One way you could evaluate lab quality, a little bit anyways, is if you go to the SART website. And here you can find the national statistics across the US. And every country, or a lot of countries, they'll have their own registry for success rates for IVF. So you can always look at those success rates, like the national average. And then you can compare your specific clinic's success rates to what the average is and on start you're able to look at all the different clinics and they'll give you those statistics. And you're looking for something that's, you know, around the average, I think I wouldn't, I don't know, the clinics that have like really high, like that are above the average, I kind of a little skeptical of that because I know there are practices where: some clinics won't transfer mosaic embryos, they won't transfer day seven embryos, they won't transfer poor quality embryos, you know, they don't take older patients. So they kind of cherry-pick what they're taking and that boosts their stats. Um, so if you see a clinic like that, then I kind of wonder, Hey, are you guys, you know, in it for the best interest of the patient or is it for just boosting your stats. So that's something that kind of turns me off when I see it. But yes, it's a great way to evaluate clinic and quality. That's about it. So thanks for asking those awesome questions. And thank you to Dr. Sueldo for having me along. Thank you.
*This content is intended solely for educational purposes and is not to be construed as medical advice. For personalized recommendations concerning your specific healthcare needs, kindly consult with your healthcare provider.
