In this session, Carol Lynn Curchoe, Ph.D., TS (ABB), a Founder of ART Compass, a Fertility Guidance Technology & Senior Embryologist has been talking about success after a failed IVF attempt and her view on that as a senior embryologist.
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.
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.
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.
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 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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
The day of the egg collection and fertilization is day-0. Day-1 does not start until the fertilization check the next day.
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 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.
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.
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.
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.