Reproductive endocrinologist and fertility specialist Eleni Greenwood Jaswa, MD, MSc, presents a practical guide to helping patients concerned about failure to conceive. After defining the common problem of infertility, she gives the first steps to determining the cause and clarifies issues related to aging. Here’s help with answering questions about oocyte cryopreservation (egg freezing) and knowing when to refer for specialty care.
my goal today is just to give you some basics that I hope and imagine are relevant to you and your practice. But really I'd like to save a lot of time for you to be able to ask your questions since I don't know exactly what the day to day looks like and what is the most useful for you? My goal is for this to be very useful and practical. So with that I'd love to begin. I'm Melanie Jasper and I'm an assistant professor of reproductive endocrinology at UCSF. I understand you all have gotten tax previously from spring and PSC. So some other fertility clinics in the Bay area. And I'm excited to be able to share UCSF perspective. And if you have any questions about what that means, our differences. Happy to address those as well in the Q. And A. But let's talk a little bit about fertility and fertility preservation. So just to begin with fertility or its counterpart infertility, bringing some of you back to your medical training. Infertility is defined as the inability of a couple to become pregnant after regular unprotected intercourse for a year. This is shortened to about six months and women over 35 years old because time is of the essence in fertility. Just some terminology recall that accountability is the probability of getting pregnant in any given month, whereas the comedy is the probability of ultimately ending in a live birth from a specific menstrual cycle. So if accountability or what most people mean with fertility, the ability to get pregnant really peaks in our twenties, probably around 25. And despite what we teach everyone in sex that really isn't that efficient in the sense that at best we probably have a 20-25 chance Of pregnancy in any given month of unprotected intercourse. So that's important to think of as a benchmark for what some of the options for fertility interventions can offer 25 maximum ability for young healthy spring chicken couple to get pregnant in any given month. Um So a little bit about the epidemiology of infertility and forgive me if this is basic, but I like to establish ground troops. So we're all on the same page. Infertility affects about is common, affects about one out of every six or seven couples. So the flip side of that means within a year of regular unprotected intercourse, the majority of couples, 85-90 will get pregnant. And when you look at how this happens, and this is the same for fertility treatments as well. You kind of see the increase the peak rates in the beginning on a monthly basis and then diminishing returns over time. So within the first month we talked about maybe 20 up to 25 chances of pregnancy by three consecutive months of trying. Perhaps 50 of couples get pregnant. And by that six month of trying, you're looking at 75%. So you're really sorting out over time as people continue to try the real fertile people initially and faster from those who might have some fertility issues After a month of regular unprotected sex, about an additional five of the population could get pregnant in the next year. So those monthly rates aren't great obviously. Uh and these are all ballpark, all comers perhaps are slightly lower now than when these studies were published because people are older or at least in the bay area in places like New York older when trying to get pregnant, which is a huge um driver of fertility and infertility. So this is just again to drive that point home that fertility these peaks accountability in the beginning months is higher. And then you experience this diminishing returns the further along you are so half of couples should be pregnant within a few months, 75%, roughly by six months. And then fewer and fewer percentages of success there after as you witness, the diminishing returns as your populations change really amongst those trying as the people who are fertile and get pregnant fall out of the denominator. So what are some basic causes of infertility? What am I seeing my patients for? Um there's a whole variety of reasons people might suffer from infertility. I like to think of it honestly as three basic ingredients. What do you need for pregnancy? You need and eggs. You need sperm and you need the ability for the egg to meet the sperm by open functional fallopian tubes. The uterus of course, is important as well. Um So when we see patients with infertility, this depends on where you are in the world, what the breakdown within this pie chart will be. But some people have an ovulation. So pcos being a common example of that. And one of my focuses of research, you aren't getting pregnant simply because you're not ovulating. You don't have a shot on goal, so to speak. An atomic issues such as tubal disease. Often um a sequel of public inflammatory disease even yours prior can cause trouble scarring and inability to get pregnant. Certainly male factor. So abnormal semen quality. What we see a lot of in san Francisco is the impact of ageing on women's egg quality. And we'll get into that a little bit more as we talk about fertility preservation options, mainly egg freezing. But ovarian aging and age related fertility decline is huge. Just for some quantitative benchmarks. We talked about a peak fertility of 20-25 month in our 20s. By the time a woman is 40 years old, that number is about five chance per month. And that's related to the impact on aid quality. Um finally, unexplained infertility probably afflicts about 40 of people we see, which means you're ovulating. The sperm looks good and the tubes are open. Our test just aren't sensitive enough or sophisticated enough to understand why you're not getting pregnant in the time that you would expect you to do. So. Oftentimes it's important to recognize that there are both male and female factors in any given couple. And it's not a blame game by any means. These are things beyond people's control for the most part, but mail it takes two to tango is the bottom line there. This is just a review. A little bit of the biology. What it takes to get pregnant again population over and pick up by a functional fallopian tube, sperm has to do the equivalent of us running 100 miles to get from the vagina to the egg. Um And then the egg has to be normal. And that means have an intact biotic spindle that's able to drive my uh my Asus initially with fertilization and then mitosis, subsequent embryo development prior to implantation. In the uterus, implantation generally occurs about a week after ovulation. Okay, so what should the what are the what are the basics of fertility testing? For example, the primary care environment? The three ingredients. I talked about eggs, tubes, and sperm. If you listen to me. Not at all. Beyond this egg, students and sperm are really the tests that constitutes a basic fertility assessment. And so how do you test for eggs? This is simply history. If someone is telling you that they have regular, predictable menstrual cycles and note when what do women think about when you say regular menstrual cycle? What a fertility doctor is talking about is a predictable interval from the first day of bleeding of one cycle to the first day of bleeding of the subsequent cycle. Now that can vary even five of seven days by you could have a 26 day cycle and then a 30 day cycle. That's fine. But as long as it's more or less regular and predictable interval between separate cycles. That is a very very high positive predictive value of a population. Um to test tubes, especially in someone with a risk factor. So pelvic surgery, prior um chlamydia infection for example, the HSG is a test that has done that stands for history of self pentagram. It's a dye test done. And typically a radiology department where they inject dye through the service in that spills out into the tubes that they are open. Take an X ray Flora Skopje and can see whether the tooth are open and lastly, a basic semen analysis should be done for any couple with infertility And when should you check for fertility issues effectively. It should be offered to anybody who either has infertility. So 12 months or six months of trying, depending on less than or greater than 35 as we discussed or even if they're just at high risk of infertility. If I see a patient whose only tried for a couple of months but has had several um, you know, abdominal surgeries for Crohn's disease, for example, that is someone who might have a risk factor for people scarring and it's very reasonable, I think, to get these data points for folks. So they know what they're working with, especially into advanced reproductive ages when they're on the clock. More or less. Um are professional societies say after 35 if we talked about six months of trying. But this can even be done much more quickly in someone who's sport er over again with the idea that time's of the essence. This is just for reference, some additional testing that can be done. And this just lists different types of imaging, for example, um, for to assess the tubes or uterus. If you're worried about the uterus, um, some blood tests that can be done, some immigrant testing for the primary evaluation. I don't know that this is needed. We'll do this by the time they come to us if you want to discern what additional lab testing may be useful um, In a woman, for example, thyroid stimulating hormone is something very tied to many bodily processes, including reproduction and should be tested really. In all women, we have a slightly narrower range where we like the TSH should be less than 2.5 for the purposes of both fertility and healthy pregnancy, which is not the same range as a normal healthy adults. So we end up actually supplementing with a lot of Synthroid and then to understand ovarian age or ovarian reserve cycle day three blood tests including a follicle stimulating hormone, which must be done with an extra dial. Those two tests without one another are impossible to interpret. So those two tests always go together. And more recently, anti malaria in hormone is becoming a really helpful index of quantitative ovarian reserve, but you don't need to worry about only if you're very interested in understanding a little bit more about how many eggs a woman has left. These are tests that we do every day, um before pregnancy, we always recommend some basic prenatal labs. So you might do infectious disease testing. But we always check are they immune to rubella? Chickenpox? What's your blood type that will become useful? Especially if they have bleeding in pregnancy for example. And then a trans vaginal ultrasound can get a good sense of what you're working with as far as uterus and ovaries go. And if there's a concern about a mass inside the cavity of fibroid polyp for something like that. A sailing sonogram is the recommended test that we use to look inside the uterus. This is just the 2010 W. H. O. Reference ranges for semen analysis. A little pearl. How did they come up with these cut offs? The W. H. O. Basically took a bunch of men from several different continents who were fertile so they had gotten their partners pregnant, were proven fertility generated a bell curve and set a cut off at the lowest five percentile. So these are all from men who were fertile but had the lowest 50% of the range. And so what does that tell you? It tells you that there's a lot of overlap in the semen analysis is not a perfect test. That said with each progressive index that I indicator that is abnormal in a semen analysis. Like if you've got low concentration and no motility that makes it progressively likely there's a male contribution to infertility. We focus primarily on four main parts of the semen analysis, which I've indicated here, volume concentration, motility and mythology. From the first three, you can calculate a total mode account which will guide us as to what fertility treatments are appropriate. Let's talk talk a little bit about variant aging just because we're in the bay Area where women tend to defer their first child bearing two later ages as compared to like some rural locations. Um. Oh my gosh. Too many. I didn't realize there's so many. We'll go there. Okay, so why is ovarian ageing an issue? We don't talk about sperm aging. Ovarian aging is an issue because women are born with every egg we will ever have a lifetime supply. So they age with the rest of our body, just like every other cell in our body. Um And so peak number of eggs, six or seven million occurs actually when women are female fetuses inside their moms at 20 weeks gestation in the mid trimester and is literally downhill from there. Um and so with aging, you have a decline in a quantity but more important for the purposes of getting pregnant, A decline in a quality. What do we mean by a quality? We mean the spindle structure that separates chromosomes from diocesan mitosis is more fragile and more prone to error, which results in abnormal Kariya types an extra chromosome 21 for example, trisomy 21 a missing chromosome here or there. That increases the risk of infertility, miscarriage and birth defects into the older ages. And so that's why we talk about ovarian ageing. We don't talk about sperm aging so much we may in the future as people get older and older. But right now we don't talk about it because every time a man's heartbeat, they literally make 1000 new sperm. And so there it's a very different biology from a reproductive perspective. By the time female hits Puberty, she has about 300,000 eggs left, which continues to decline. Menopause really is the exhaustion of this pool of eggs and functional exhaustion. And so, um, that once the number of eggs has hit a specific threshold, reproductive cycling is over. This is just a graphic again to display declines in fertility with female age. This is from a Hutterite population, I think in pennsylvania. And interestingly, when you intervene and do IVF, you see the exact same thing where success rates with fertility treatments decline with age. This is the biggest driver for much of fertility. Um this is the opposite. This is like thousands of embryos done in an IVF clinic in New Jersey where they biopsied the embryos to look at the chromosome status, was it? You employed the correct number of 46 chromosomes versus an employed and this shows you the percent of embryos by age. That is an employed as in wrong number from his owns won't make a baby And you can see it progressively increases and is over 80 by the time a woman is in her young 40s. So most embryos women make After the age of 38 or so are really abnormal Concurrent with higher uh, an employee is the risk of increasing miscarriage, spontaneous abortion with age. By the time you're 45, at least half of pregnancies result in miscarriage, probably far more than that. So if you're patient wants to know just some basics about like I am just starting to try for pregnancy. What does that mean? What do I do? Timing Is everything just like most of life? And so what is the fertile window within a woman's menstrual cycle? And what dictates that the fertile window if you consider day zero to be the day of ovulation, you are fertile If you have a single act of intercourse any day up to five days. Really prior to ovulation, the day after ovulation. It's too late. That cycles awash basically. And that's because Sperm can live in the female reproductive tract for up to five days. Whereas once a violated the egg more or less shuts down within 24 hours and can no longer be fertilized. So the most important thing is really tapped sperm on site at the time of population. Um and the peak days really are the 2-3 days leading up to ovulation. Or if you're going to pick one day a month to have intercourse, people have different ways to kind of track ovulation. Certainly the apps that can help predict. Some people are very aware of their cervical mucus, which changes to be like egg white, stretchy during the period regulatory period. Um Some people use LH pits where PM stick in the afternoon to see that LH hormone appear in the urine. Um It doesn't have to be rocket science for somebody with a normal monthly cycle. If you just start having intercourse on cycle day 10. Now cycle they want is the first day of bleeding. So you start having intercourse, cycle day 10 and have of course every other day. I wouldn't even say every day, every other day is generally adequate In cycle. They tend to cycle 20 years. More than covered your basis for your fertile window in general. For someone with regular, predictable cycles. Um This is quite a positions and practices. There's nothing there. There's no data to suggest any certain position or ritual before or after intercourse will do anything for fertility. So until there's a study, I can't recommend anything. Um Let's talk a little bit now. We talked about basic spread and better fertility, fertility workups, fertility timing, age related infertility. Let's talk about how technology can be deployed to offset the risk of future and fertility, which is fertility preservation or what most people think about as a freezing. Um The why do people freeze their eggs for exactly the reasons we've talked about with related to age decline in fertility. So this is a new England Journal um figure of how with advancing maternal age, fertility Declines and risk of miscarriage increases. So when I said that estimate of 53 for miscarriage. For people who can see that 45 or after, you can see some day that's higher as ties now 90 of miscarriage rate at 45 or older. And this is all related to a quality. So what do you do if you can stop the biology, stop the clock on the eggs at a specific age. You might be able to return to use them a decade later for the purposes of generating a healthy embryo. The main drivers that age of the egg, the uterus ages more or less irrelevant. So this egg freezing is becoming more and more common and perhaps your patients are asking about it. Um, and I hope you have some questions about it. If I'm not addressing them here, Lots of people will ask what's the best time to freeze my eggs. This is really like not one size fits all rules of thumb I talk about are generally in your 20's. It's not really recommended. And now this is for an average healthy person without any unusual reproductive risk. General Young, healthy people in their 20s. Not really encouraged only because there's so much reproductive runway ahead of you to maybe meet someone, start a family and still have time for that. Whereas by the time you're in your 40s, the cost effectiveness declines pretty significantly. So There's this trade up right. The earlier you freeze your eggs, the more likely you are to be successful with them. But the less likely you are to meet them. And so everybody has a different algorithm. This is one example of a study that is a modeling study making a bunch of assumptions that certainly don't apply to all individuals. But this study suggested 37 as the magic number for being most cost effective. I think as more women have returned to use their eggs. And we see what success rates are actually like when people freeze eggs for this, I would encourage 35. That seems to be the optimal chances of being successful with an acceleration of um decline thereafter. How many eggs to freeze against super individual and based primarily on age. Um some rules of thumb, six chance of a baby per egg frozen. This probably applies to women under 35/35. This number will be lower. All of this is to say reproduction is pretty inefficient. You can't freeze 11 eggs into some you have a family in the bank. This is one model I use with my patients pretty frequently to illustrate this concept and try to make decisions around how many eggs to breeze. We can do a pretty good job with an ultrasound looking specifically at follicles and an ovary of guessing how many eggs a certain individual might make in a certain idea of cycle. And so um the this shows you that a few things. One it's never perfect. So even though there's this ascent code at 100%, I don't think there's ever a guarantee and anything especially egg freezing. Um, so one expression isn't perfect. It's not a guarantee that live birth to egg age drives everything. So these colors falling progressively down at any given number of Eggs frozen. 20 for example, there's a huge difference if you do this at 35 versus 44 as to what your chances are of having at least one birth. Now again, this is a modeling study. It's a beautiful graphic. Obviously nature doesn't behave that perfectly. But it gives you some rough estimates or if I freeze my eggs and I have 10, what am I looking at? Do I want to do another cycle? Is this not worth it at all? To me in the first place, a lot of the data we have about success from egg freezing initially came from donor egg cycles. So these are young women donating their eggs to another individual who usually runs out of their own eggs is being unsuccessful. And just think about egg freezing. Like being your own future egg donors. So you can still use your own genetics and don't need to rely on someone else. But the data from these egg donor cycles really informed us into how successful is this technology. Um And then ultimately women are starting to come back for their eggs. So this is a technology that was declared no longer experimental by my professional society, the American Society for reproduction for reproductive Medicine. Srm in 2012. So we're coming up on the 10 year mark of this being offered in a non experimental format. And with that more women are starting to come back for these eggs. Um and so this is a study out of spain where they have been doing this for a long time and have a lot of great data. Uh and this shows you that number that I mentioned it. If you can freeze eggs by 35 that seems to be a really important cut off. Where here's the cumulative live birth rate for folks who had frozen AIDS Up to age 35 based on the number of eggs they froze versus women who froze their eggs over 35, you can see divergent trajectories of success rates. Um and so in this group, um 641 return to use their frozen eggs of over 5000. So that tells you one thing many most women probably won't ever use these days. But it also shows you in these women the 152 babies that were born to these 641 women. The success rate was, you know, two out of three women who froze less than or equal to 35 versus one in four women over 35. And so these authors included, Let's have women start freezing eggs younger and at least 10 mature age should be frozen. I'm coming to the end. I know we have we have a lot of time for questions. But this is a study now out of N. Y. U. New york is also like the Bay Area in the population, demographics and age of pregnancy first pregnancies. And so n. Y. You looked at their patients, 230 patients who had frozen. It's between 2005 and 2000 and nine in mind you these are slightly older technologies. So hopefully this under reflects success rates, but it's important to look at. Um they found that now, 10-15 years later, 38 return for their eggs. So less than half of women probably will ever come back for their eggs. Um and of those who attempted pregnancy, one and three was successful. So two out of three women who came back for frozen aids did not have a baby. Uh If you're patient has asks you and this is my final slide, but if you're patient asks you, like what does a freezing look like? What is my life look like? Um There it's generally at UCSF anyway, a two month process where you have a lead in cycle generally involving testing for population and wearing some transdermal estrogen or some other type of hormone to try to synchronize the follicles that are supporting the eggs so that they grow together. Um And then ultimately, with it's about two weeks of intense work where a patient is self administering subcutaneous injections 2 to 3 times a day for an average of 10 to 12 days, During which time they have frequent appointments with us to get transmitted from ultrasounds and blood tests. So 20 minute appointments. An average of maybe six appointments over 10-12 days to monitor the growth of the follicle supporting the eggs in time. The final injection prior to an egg retrieval procedure, which is the same day procedure takes 2030 minutes, patients are on their way home about an hour later.
