I’m excited to be interviewing Dr. Blake Evans of University of Oklahoma Reproductive Medicine in Oklahoma City. Dr. Evans is the recent author of an impressive paper, Mature Follicle Count and Multiple Gestation Risk Based on Patient Age and Intrauterine Insemination Cycles with Ovarian Stimulation. He is joining me to talk about when you should consider canceling your IUI.
Dr. Aimee: Welcome, Dr. Evans. Tell me about your practice, tell me about what you do there, tell us about yourself.
Dr. Blake Evans: Sure. As the name infers, it’s an academic institution at University of Oklahoma. It’s in Oklahoma City. In addition to myself, there are three other physicians, and we also have a physician assistant.
We have a very busy practice. I love being here. I started here just a few months ago, actually, and I’m really enjoying it.
Dr. Aimee: I’m sure they love having you, too. You did your fellowship at the NIH, and you did your residency at Oklahoma State University Medical Center in Tulsa, and your medical DO degree at the Oklahoma State University for Health Sciences in Tulsa as well. I imagine it’s nice to be home now.
Dr. Blake Evans: Absolutely, it is.
Dr. Aimee: Excellent. As a fertility patient, one of the most frustrating things for our patients is to be in treatment and then have someone say, “Stop. You can’t move forward. You have to cancel your IUI.” Don’t you agree?
Dr. Blake Evans: Yes, absolutely.
Dr. Aimee: That’s a huge disappointment. I feel like we need to figure out what is right for our patients.
You did a scientific study that was published in one of the most reputable journals, Obstetrics and Gynecology, in May 2020. That study was titled Mature Follicle Count and Multiple Gestation Risk Based on Patient Age and Intrauterine Insemination Cycles with Ovarian Stimulation.
Say that 10 times. I’m just kidding, don’t do that.
Dr. Blake Evans: It’s a mouthful, for sure.
Dr. Aimee: It is a mouthful, but basically it helps people figure out when should their IUI be cancelled based on the number of eggs they’ve ovulated. I want you to break this down for us. Why did you do the study?
Dr. Blake Evans: As first year fellow particularly, I found myself commonly wandering the halls with pictures of follicles from the ultrasound and wondering at what point is it okay to proceed, is this too many follicles, based off of her age, does this make a factor in the outcomes. The answer is we don’t really know.
Of course, all of my faculty have of years of experience under their belt and just have an inclination as to when to proceed, but what is that number, what’s the percentage that you can tell the patient based off of this number of follicles, based off of your age, based off of your prior cycles, this is going to probably be the risk of multiple gestation, meaning a twin or triplet, or even high than that.
That was the main drive as to why we wanted to do the study.
Dr. Aimee: What was the clinical question you were hoping to answer?
Dr. Blake Evans: Really, I just wanted to know at what point are there too many follicles and does age make a factor. At what point is it appropriate to tell the patient, “Based off of the number of follicles we’re seeing today, if you proceed, you have a pretty high risk of pregnancy?
We really wanted to see does age make a correlation. Prior studies were not really specific in regard to the patient age, number of follicles. There was a number, a general number, but there was no specific guidelines or recommendation as to how many follicles are too many to proceed.
Dr. Aimee: What is a mature follicle? For people who are listening who don’t know what that even means.
Dr. Blake Evans: Good question. A mature follicle, at least based off of our study, the definition was 14 millimeters in size or greater. A mature follicle is potentially going to have a mature egg inside. If you have a mature follicle that releases an egg upon ovulation, then it can fertilize successfully and lead to a pregnancy.
We know from doing invitro fertilization and doing egg retrievals you actually can get a mature egg in a smaller follicle, although it’s less likely than with 14 millimeters. In general, that’s around the size of when we would consider it a mature follicle. Although, during treatments we’re trying to get it a little bit larger so that we’re more certain that there is a mature egg inside of the follicle.
Dr. Aimee: Right. That’s something that you measure on an ultrasound, the pelvic ultrasounds when people go in.
Dr. Blake Evans: Correct. Yes.
Dr. Aimee: What is a multiple gestation?
Dr. Blake Evans: Multiple gestation we defined in the study as the presence of a gestational sac with a fetal pole and cardiac activity, having two or more of those present within the uterus was defined as a multiple gestation. In our study we had most commonly twins, but we certainly had a fair number of triplets and even quadruplets in some of the numbers we looked at as well.
Dr. Aimee: You should have seen my eyes when you just said that. I have patients that come in and they’re like, “Oh my god, I would love to have twins.” I’m just like but that’s not the goal of treatment. Why is this multiple gestation considered a risk?
Dr. Blake Evans: That’s a really good question. A very common misconception in our field is, “I need to have more follicles or more embryos transferred because it will increase my chance of pregnancy,” when in fact — and I’ll show you the results in just a moment — that’s not necessarily the case. Spoiler alert. Multiple gestations, although twins are very cute, we all know someone or might even also have twins ourselves, however they do come with quite a considerable risk.
There is a four-fold risk of still birth in twins, even as high as six-fold risk of still birth in triplets, and even higher, as you can imagine, with quadruplets. They also come with the risk of preterm delivery, low birth weight, and also with those come other morbidities, such as respiratory issues, intestinal issues, metabolic issues, completely aside from how expensive it is to have a baby in the NICU for weeks on end.
In addition to that, the mother is also at quite a risk, too, because there is a higher risk of preeclampsia, diabetes, cesarian section, postpartum hemorrhage. These are all things that we try to avoid if at all possible. It’s something that we really need to counsel our patients on when they’re discussing these issues with us.
Dr. Aimee: I agree. Why does age matter?
Dr. Blake Evans: Age is a very important factor in infertility, mainly because the number of eggs that a woman has, they’ve been there her entire life, even when she was developing in her mother’s womb. You can imagine that over time both the quality and the quantity of the eggs will decline.
The presumption, what we know now based off of a vast amount of literature, is that in patients who are older reproductive age typically will need more follicles or more embryos in order to have a higher success of even just carrying a singleton pregnancy. The factor of age is quite important whenever we’re considering reproductive outcomes, because it certainly plays a role.
Dr. Aimee: What is IUI? That was part of your study, as far as looking at only IUI cycles. Why does it matter that you only included people who did IUI?
Dr. Blake Evans: That’s a good question. IUI, also known as intrauterine insemination, is a process that a fertility physician or provider will place a washed or prepared semen sample into the uterus around the time of ovulation. The whole purpose of doing the washing of the semen preparation is that you get a more concentrated sample of higher motility sperm and to ideally increase your chances that those sperm will fertilize at least one egg or two eggs.
The main reason we included IUI patients in the study is because most of the time, for example, if you’re a couple that does timed intercourse at home, it’s less likely or much less commonly that you’re going to come in for an ultrasound. Although they still do, but at least when we’re looking back at our EMR, electronic medical record, we have a much more robust number of patients of IUIs to look at. Adding timed intercourse in there as well would kind of muddy the waters a bit, so we kept it just at IUI.
Dr. Aimee: That makes perfect sense. I think sometimes patients think that they have a higher risk of multiples if they add the IUI, let’s say they have more follicles. Do you think that’s the case?
Dr. Blake Evans: I don’t think so. I think that the number of follicles there, you have to assume that the risk is still going to be present, even if you’re just doing timed intercourse. In those patients that do IUI and do timed intercourse, and they’re monitoring with an ultrasound, I would still counsel them the same.
Dr. Aimee: Got it. What is ovarian stimulation?
Dr. Blake Evans: Ovarian stimulation is a process by which you take either an oral medication, such as Clomiphene Citrate, also known as Clomid, or Letrozole, also known as Femara, or even injectable medications, so gonadotropins like FSH or Follistim, Gonal-f, or Menopure. There are several different names. These will induce follicular growth in the ovary, so all of the follicles that are inside the ovary are potentially going to grow and have a mature egg inside of them eventually.
The goal is to get just maybe a couple of follicles. However, with certain medications or different doses, the patient can respond quite differently and have too many follicles.
Dr. Aimee: Right. So, we’ve basically just defined all the terms from the title, Mature Follicle Count and Multiple Gestation Risk Based on Patient Age and Intrauterine Insemination Cycles with Ovarian Stimulation. Now, what did you guys find?
Dr. Blake Evans: It was a single practice facility where this data came from, at Shady Groves from 2004 to 2017. We looked at all cycles that patients used either Clomiphene Citrate, or they used Letrozole, or they used gonadotropins, or even a combination of oral and injectable mediations. We looked at the patient’s age and we basically categorized them and broke them down to less than 38, 38 to 40, and then over 40 years of age. We looked at the outcomes, we looked at the pregnancy rates after doing the IUI.
From here, I’d like to show you what we think is the most important part of this paper. That is both provider education and patient counseling with some graphs that we had made. I’m going to pull those up for you now.
As you go down here on this graph, 38 to 40 years of age, the risk is not as dramatic, but it’s still there. The singleton rate, the blue bar, it does start to increase as the follicles change. However, the risk of multiples still increases a decent amount. Then when you get into patients over 40 years of age, we actually found that it was beneficial to have more follicles here. When you go from one all the way up to four follicles, it nearly triples the pregnancy rate, but you still have a less than 1% chance of a multiple gestation. Even when you get to five follicles, this is when we did find that it was significantly at risk to have five follicles, but it’s still overall a 3% risk of multiples for IUI.
In this graph, this is breaking it down, and it’s a little bit more of bringing the risk to real life and showing the patient if you actually get pregnant this is the percent chance that it would be either a twin, as the red shows, triplet as blue shows, or even quadruplets. Once again, all ages over here. As you go up in follicle number, the chance of twins goes all the way up to 21% per pregnancy, so it’s if you get pregnant you have a 21% chance of it being a multiple, 5% a triplet, and then a less than 1% chance of quads.
The risk is similar for patients in this age. This is less than 38 years of age. For 38 to 40, we didn’t have any quadruplets above three follicles, but this was a small number overall. Then once you get to the patients that are over 40 years of age, you still see in general less than 12% chance of multiples up to four follicles. Above that is when we found that it was a risk for patients over 40.
Lastly, this is my favorite graph that we had made. This is a heat map that we had made. This is what I commonly will show patients whenever I am counseling about the difficult decision of do we need to cancel or what is your risk if you do in fact proceed.
Let’s pick a patient, for example, that is 32 years of age. You can see that in the green, this is the higher chance of pregnancy, the yellow is mediocre, and then red is a low chance of pregnancy.
We’ll choose a 34-year-old, 15% chance with one follicle, and it goes up with two, three, four, and five follicles. But we know on the prior graphs that it’s really mainly because of a risk of multiple gestations.
This middle graph shows the green is where you want to be, red is where you don’t want to be. This is when we do the IUI what is the chance of a multiple gestation, so twin, triplet, or higher. Once again, the red zone. We can find someone, say if she is 33 and she has four follicles. If you tell her, “Well, you just have a 5% chance of a multiple,” but this is what really hits home here is the same patient, say she has five follicles, her chance if she gets pregnant is as high as about 27% if she gets pregnant.
This is where I feel like it really hits home with the patient, because they’re like, “You’re right, I don’t want to do a trigger shot. I am okay with cancelling at this point.” I feel like this is a really helpful counseling tool that we’ve been able to utilize.
Dr. Aimee: I agree. I find that patients sometimes want to take the risk, but unless they know the exact number for themselves, they’re not really made to be part of the clinical decision-making process. I think your study helps providers and patients just feel more informed for sure.
The other aspect of what you shared with us is the age over 40. I have patients that are super educated, they’ve done their research, and they understand the risk associated with multiple gestations. So, when I tell a 40-year-old I’m perfectly fine doing IUI and not doing IVF, for whatever reason, but I want to stimulate four or five eggs for you, they look at me like, “But I don’t want twins.” Your graph shows that it’s really to give them the highest chance to have a single baby with a very low chance of multiples.
Dr. Blake Evans: Exactly.
Dr. Aimee: Patients who are doing IUI without being stimulated who are over 40, perhaps they should rethink that if they have an AMH or ovarian reserve that can maybe give them more than one egg.
Dr. Blake Evans: Right.
Dr. Aimee: What advice do you have as a leading expert in our field for anyone pursuing ovarian stimulation with IUI? What kind of questions should they be asking their doctors and what should they be thinking about?
Dr. Blake Evans: I would say that IUI is a very useful tool, it’s a very helpful tool for infertility treatments, it’s very common, but one thing I would really strongly encourage patients to consider is that it unfortunately does not work every time.
As I showed you on those graphs, it’s not a perfect treatment, it doesn’t work every time. Even a couple with nothing at all infertility related, they only get pregnant about 20% of the time per month. An IUI, even though it’s not quite as high as that, it doesn’t work every time, unfortunately.
The answer, or what the thought process is of the patient, I would encourage you to not think let’s just increase the dose, let’s make a higher dose and have more follicles because that’s going to help my pregnancy rates, when in fact it really is just going to increase your multiple rate, for the most part. Of course, that is age dependent and follicle dependent.
We did also look at number of prior cycles before and how long they’ve been infertile for. That overall did not make a difference by and large. We also broke down unexplained infertility and PCOS patients, and the risk was still present there, and very similar numbers to what I showed you with those graphs.
One thing in terms of providers that I would also say as well is that these numbers are not perfect. It’s just a counseling tool, it’s an estimation. It’s something that you can show the patient a figure, you can show them this is approximately what your risk of multiples will be. In fact, that’s probably the main criticism of this paper that I’ve found, which I don’t disagree with, is that using gonadotropins, some studies such as the AMIGOS Trial, part of the RMN, Reproductive Medicine Network, that was in the New England Journal of Medicine in 2015, it showed that just using gonadotropins had higher risk of multiples as opposed to Clomid or Letrozole.
That is a big criticism of our paper. However, at the end of the day, of course we can also look at this further in future studies, but I like to think that a follicle is a follicle, two follicles are two follicles, three follicles are three follicles, and the risk in general is probably still going to be there whether it’s Clomid or Letrozole or gonadotropins. So, although it’s not perfect, I feel like this is a very helpful tool. It certainly has been great for me to show patients when counseling them as well.
The take home message is that caution should be used in proceeding with IUI after ovarian stimulation when there are more than two mature follicles in women younger than age 40 years owing to the substantially increased risk of multiple gestation without an improved chance of singleton clinical pregnancy. In women older than age 40 years, up to four follicles tripled the odds of pregnancy while maintaining a very low chance of multiples per IUI.
Dr. Aimee: How many ovulation induction cycles with IUI should a patient basically say enough is enough, it’s time to move on to something else?
Dr. Blake Evans: That’s a really good question. Typically, anywhere from four to six is when I’ll counsel a patient. At that point, if it’s not working, then we need to consider a different type of treatment after that.
Dr. Aimee: Awesome. Thank you for sharing your wonderful study findings with us. Thank you for all the research that you do. I quote and I send patients links to your articles several times a week. Thank you for all of the stuff you’re doing, and thanks for coming on and just breaking it down for us. And you’re going to come back and talk about your next study with us, too.
Dr. Blake Evans: All right, that sounds great. I’m happy to do it. Thank you so much for having me.
Dr. Aimee: Thanks, Blake. I appreciate your time.Catch more of me and topics like this through The Egg Whisperer Show. Episodes are live-streamed on YouTube, Facebook, Twitter, IGTV and Apple Podcasts . Sign up to get my newsletter. Tune in to The Egg Whisperer Show on YouTube. and Sign up for The Egg Whisperer School.