Dr. Helen H. Kim, associate professor of obstetrics and gynecology, provides a brief history of in vitro fertilization and discusses the realistic possibilities for current treatment options.
DR. HELEN KIM: OK. Hi. Thanks for staying with us this afternoon. Today we're going to talk about infertility treatment in 2014. These are my disclosures and my learning objectives. I have nothing to disclose. So this is the cover of Time magazine in 1991. This was the year that I graduated from medical school. And the cover says how a dazzling array of medical breakthroughs has made curing infertility more than just a dream. So clearly, this is hyperbole, because here we are in 2014, 23 years later, and infertility is still not cured. So magazine covers like that-- and it still happens today-- give patients an overly optimistic view of what's possible with their fertility treatment. And so today I want to focus on what are realistic expectations and review some cases that we've had at the University of Chicago. So before I get into the cases, I need to give some background on in vitro fertilization, because that's where it all began. And when we talk about breakthroughs, the first breakthrough was in 1978 with the birth of Louise Brown. So she was the first human birth after in vitro fertilization. So her mom had blocked tubes. She conceived by in vitro fertilization. She had a c-section at 38 and 1/2 weeks for preeclampsia. And Louise Brown was born. It's amazing when you go back and read the original publication, there's no information. It's a letter to Lancet. And it says, we hope to publish further medical and scientific details in your column at a later date. So in 1978, the procedure of in vitro fertilization was actually quite simple. They did an egg retrieval timed with the menstrual cycle, because there were no fertility drugs. They inseminated the egg in vitro. And they incubated the egg for 2 and 1/2 days. And they transferred one embryo into the uterus, because that's all there was. So initially after this report, there was all sorts of concerns that doctors were trying to play God, that there was a slippery slope, soon we're going to have designer babies. All sorts of horrible catastrophes were predicted. But now it's incredible that in vitro fertilization is mainstream, and millions of infertile couples have been helped by this treatment. And in fact, it's so mainstream that in 2010, Robert Edwards actually was awarded the Nobel Prize for in vitro fertilization. In 1978, Louise Brown was truly a miracle baby. IVF was not very successful. So in a natural cycle, two-thirds of the time they went and did an egg retrieval, and there was no egg. And even if they got the egg, the egg wouldn't fertilize. And even if they got one embryo, most of the time it didn't even grow. So it wasn't until we got fertility drugs that IVF became much more successful. So in 1981, the first IVF baby born in the United States was actually conceived using the help of gonadotropins. So the problem with these drugs is that you have to have injections and you have to take them every day. But if you remember from way back in medical school, when you start a menstrual cycle, there's several antral follicles that begin to grow. And then because of the drop in FSH that happens through negative feedback, only one follicle becomes dominant and ovulates. And the rest of the follicles die by atresia. But by giving these injectable fertility medications, you can take all the follicles that began to grow and keep them all growing. And so instead of having, on the left that's a picture of a normal ovary with many small follicles and just one dominant follicle here. On the right, you see a picture of an ovary that's in preparation for in vitro fertilization, where you have back to back follicles and you're able to get many, many eggs. So this is a cartoon from Infertility for Dummies. And it just says, I never realized that trying to have a baby would mean replacing the soft music and candlelight with injections and a starter pistol. So it seems kind of silly, but there's a lot of truth to this. If you're undergoing ovulation induction for in vitro fertilization, you're taking a lot of shots, and you're taking them on a prescribed schedule. So first you need shots, like I said, to get the ovaries to develop many, many eggs. But then, if you have a bunch of follicles, each making a little bit of estrogen, it's going to add up to a lot of estrogen and it may trigger your LH surge. But if you have the LH surge while the eggs are still immature, you're not going to have mature eggs to fertilize. So now we have to give another injection, either Lupron or a GnRH antagonist like Ganirelix to prevent premature ovulation. But now that we're giving a drug to prevent ovulation, when we're ready to do the ovulation, we have to give another shot to cause ovulation to occur. And then patients always ask, well, you're going to be sucking the egg out, anyway. Why do I need this final shot? And the reason is that even if we're aspirating the eggs, if we do not get that luteinizing hormone, you don't resume meiosis. The egg will never be mature. And the egg doesn't release from the follicle wall. So you actually do need that final trigger. And the next breakthrough came in 1986 with the development of transvaginal ultrasound for egg retrieval. So prior to this time, we had used laparoscopy to retrieve the eggs. And it actually wasn't very successful. You didn't get a very clear view. But with transvaginal ultrasound, you can really see the ovaries. You put a needle through the vaginal wall. So now they don't even need a real surgery. And you can aspirate the follicle fluid. And in the follicle fluid, you'll get the egg and some granulosa cells. And a final breakthrough happened more recently. So Louise Brown, her embryo was transferred back in the uterus when it was 2 and 1/2 days old because it was difficult to culture embryos past day three. Normally the embryo will grow in the Fallopian tube till day five or six and get to the uterus at day five or six and implant. So in the early days of IVF, the uterine lining and the embryo were not in sync with each other. It turns out that the nutritional needs of an embryo early in development are different than the nutritional needs that happen after day three of development. And in 1998, there's commercially available media. So now that all IVF centers were able to grow embryos to that day five blastocyst stage. And this is just, I believe, from the Atlantic, and just a couple months ago in September 2014. And it says making babies outside the womb has never been so easy. Today 1% of American kids are conceived using some sort of assisted reproductive technology. So to me, that's pretty amazing from something that people were incredibly worried about, some slippery slope and horrible things happening, to being something that's so routine that 1% of babies born today are a product of assisted reproduction. So in 2010, why are all these people having in vitro fertilization? It was developed to bypass blocked tubes. There can't be that many women with blocked tubes in the United States. And when you look, tubal factor only accounts for 7.3% of the cases of IVF performed in 2010, the year that Steptoe won the Nobel Prize. The most common reason for in vitro fertilization these days is male factor infertility. So if you add up male factor alone, and for couples who have multiple factors, there are male and female factors, almost 37% of the cases, more than a third of the IVF cases, are performed for male factor infertility. So my first case that we've taken care of is a couple that presented with infertility. He ended up having no sperm in his ejaculate. And then when he had a diagnosis, he was found to have congenital bilateral absence of the vas deferens. So in the past when there was no sperm, the only treatment available was to use a sperm donor. But with in vitro fertilization, we're able to get a lot of sperm to the egg. And you don't even need to have mature sperm. So back in 1990, there were 28 men with congenital bilateral absence of the vas deferens. And they aspirated the sperm from the epididymis. So it was not mature sperm. But within in vitro fertilization, where you can put the sperm directly on the egg, they were able to generate embryos for 21 of these couples and ended up with seven deliveries. And this is one of the first successes. It's much more successful these days. But now with in vitro fertilization, you don't need much sperm. You only need about 50,000 sperm per each egg. But since the early '90s, we have intracytoplasmic sperm injection. You don't even have to have a moving sperm. You can take a non-moving sperm and inject it directly into the egg and force fertilization. And with intracytoplasmic sperm injection and using testicularly extracted sperm, we've now opened up fertility to a whole population of men who had previously been infertile. And this is a report from the same institution, reporting two men with Klinefelter syndrome, who are 47 XXY, who are able to conceive and have babies using testicular sperm and intracytoplasmic sperm injection. And these are the initial reports showing two genetically normal babies. All right. And this is another case that we've taken care of. This is a patient who knew she would have some reproductive difficulties because she needed hormones to go through puberty. And she was ultimately diagnosed with XY gonadal dysgenesis. So her karyotype is XY, but she had gonadal dysgenesis and never developed any gonads. If you remember back to medical school, if you don't have gonads, you don't make anti-mullerian hormone. Your mullerian structures persist, so you have a uterus and Fallopian tubes. If you don't have gonads, you don't make testosterone. So you don't support your Wolffian structures, so you don't develop any male internal genitalia. So internally, uterus, Fallopian tubes looks completely female. Just her karyotype happens to be XY. But with gonadal dysgenesis, that means there are no gametes. And there are no eggs available. So the advent of in vitro fertilization allows for third-party reproduction. We can generate embryos from eggs from one person and take the embryos and transfer them into another woman. And so in vitro fertilization allows for both egg donors and for gestational carriers. So we're able to synchronize the uterus endrometrial lining and the embryo. And the first report of an embryo transfer in this way was in 1984. And in 1985 was the first report of a gestational carrier. And in 2010, of the more than 140,000 IVF procedures, about 16,000 were egg donor cycles. So more than 10% of the IVF that's done is actually some third-party reproduction. So this graph is actually from the CDC from 2011 data. But we all know that fertility declines with age. And you can see on the bottom in orange, for women who are planning to use their own eggs, that even with IVF, as they get older the success of the likelihood of having a live birth decreases dramatically, particularly after the late 30s. But if you're using an egg donor, since the fertility depends on the age of the egg, there's a consistent success rate, with about 50% success no matter how old the recipient is. So with the advent of egg donation, it allows for headlines like this, which causes kind of a stir. So this is from 2001. Lesbian gives birth to brother's baby. All right, so first that sounds kind of icky. But then when you look at the details, it's just interesting. So this whole egg donation was originally thought of as a treatment for women who had undergone premature ovarian failure. But now if you can do this for women who've gone through ovarian failure prematurely, certainly you can open this up to women who have gone through natural menopause. So these are two reports of a woman from the United States, who was 51 years old, and a woman from France, who was 62 years old. And since they were menopausal, they were going to use an egg donor to conceive and carry the pregnancy. But they wanted a genetic connection to their baby. So they asked their brother to donate the sperm. This brings up the question of is it safe to be pregnant at these older ages? And the thinking has always been, well golly, if you got pregnant on your own, your body was probably healthy enough to have this pregnancy. But what about artificially getting a woman who's very old pregnant? And the thought has always been that for all OB patients who were more than 40 years old, there's increased hypertension, gestational diabetes, and an increased incidence of C sections. But there was a study that looked at donor egg recipients who were 50 to 59 years old. And they actually compared them to IVF patients who were 31 to 42 years old. And actually when they looked at this population comparing these patients to patients who had gone through IVF, there was actually a similar rate of hypertension and gestational diabetes. But it's interesting for the women who are more than 50 years old, even if they had a singleton, more than 80% had a c-section. In this study, however, I can't say that it's the average 50-something-year-old. All of them went through an intensive screening process with an EKG, a stress treadmill test, as well as other blood tests. So they were in very good health before they had this embryo transfer. And this was like our 15 minutes of fame at the University of Chicago. This was a patient that I took care of with Dr. Yamada. The patient had cervical cancer in her early 30s and ended up having a hysterectomy. And then her ovaries were left in place. So after she recovered from the surgery and recovered from her cancer, she underwent an egg retrieval. And embryos were generated with her husband's sperm. And her mom carried the baby. So the mom gave birth to her own grandchild. And we got a lot of press. She was on the Today Show. And the AP news picked this up. But it was a really heartwarming story. And the patient's mother, the grandmother, gave birth at age 53 with no problems at all. Here's another type of patient that we've taken care of that has presented some challenges-- mullerian agenesis. So again, this was a patient who knew she was going to have issues. She was diagnosed with primary amenorrhea and was found to have no mullerian structures. And she also had no vagina as well. And so she underwent, when she was younger, a McIndoe neovagina creation. So she had this skin graft vagina made. So it sounds very simple. So she has ovaries. She just doesn't have a uterus. We should be able to use a gestational carrier. But actually doing an egg retrieval in someone who's had these procedures is actually quite challenging. This is a picture of someone with mullerian agenesis. And you can see some of the issues is that the vagina is not very pliable. It's very hard to even do an ultrasound because there's just not enough mobility. The vaginal wall is really thick. So it's hard to get the needle through. And the vagina is really short, so you can't get as close to the ovaries as you normally would during an oocyte retrieval. And you can see that there's a lot of distance between the wall where you would want to go, instead of the ovary being right there at the surface. And on the other side as well. But this is not that patient. This is a different patient who had a different uterine anomaly. And this patient here was told that she could never carry a pregnancy due to her horrible uterine anomaly. And so she got a gestational carrier. So she was in about her early 30s. And this person here is her gestational carrier. And so she had her eggs retrieved. Embryos were generated with her husband's sperm. And the gestational carrier carried the pregnancy and delivered one baby at the end of 2012. And she actually had a very close relationship with the family. She provided breast milk for this family. It was really a great relationship. But then, they had embryos frozen from their first cycle. And a couple of years later, she came back. And the couple had actually moved away to California at this point. But the gestational carrier still lived in Illinois. And she gave birth to another baby for them earlier this year. My second to last case is what about a gay couple? So again, now that we have third-party reproduction, we should be able to help these people. They're two men. They want to use an anonymous egg donor and have a different gestational carrier carry their pregnancy for them. And they both want to generate embryos. So Illinois is a great place to have a gestational carrier if you follow the rules that have been outlined. If the baby is born in Illinois, the intended parents have sole custody and full parental rights immediately upon birth. And the intended parents' names are actually entered right on the birth certificate. So there's no need to adopt the baby afterwards. But there are eligibility requirements both for the intended parent and for the gestational carrier. So the gestational carrier must give birth in Illinois. The intended parents must have a medical need for a gestational carrier. And in this case, the fact that they're both male and neither one of them have a uterus actually counts as a medical need. But one must be a biologic contributor to the pregnancy. And this is because people didn't want this idea of designer babies, someone choosing an egg donor and choosing a sperm donor and then trying to generate a particular type of infant. And you need to know who the parent is. So we would need to know which one of the men was the father. So this is not something I would recommend in this scenario. But it's something that is possible, that with preimplantation genetic diagnosis, you can actually determine the sex of the embryo ahead of time. And this is also used to screen for genetic disorders and to screen for aneuploidy. This is a picture that's a little bit old. And this is showing an embryo on day three having a couple of its cells removed. Nowadays we tend to do the biopsies more on day five at the blastocyst stage. But this is a picture of the happy couple and the happy family. They went through with an egg donor and a gestational carrier. And the gestational carrier gave birth to twins, a boy and a girl. And this is a picture from when the kids were about two years old. So it's hard to interpret, really know what the success is of gestational carriers, because that's not a separate category that's reported to the Society for Assisted Reproduction or reported separately to the CDC. And we know that there were about 859 gestational carrier cycles reported. But these are our best prognosis patients and our worst prognosis patients. Because sometimes you have people who are not infertile at all, and they just are lacking a uterus. Or you have the sickest patients, people who have horrible hypertension or kidney disease or lupus and are told that they can never carry a pregnancy. And sometimes they are older and very difficult to stimulate. This is my last case. What about this couple? And this is unfortunately the very typical patient that I see. [LAUGHTER] Yeah. But this is like the typical patient that I see at the University of Chicago. So she's 42 years old. They've been married for 18 years. Very busy professionals. Never found the right time to have a baby. And now that she's 40, they realize, oh golly, we know that fertility declines with age. Now I'll stop the birth control pills and now I'll try to get pregnant. They come in. The evaluation is completely normal. They ovulate. Tubes are open. Husband has completely normal sperm. And they're very frustrated that they can't get pregnant, because they've read every book and they've done everything right and their lives have been very successful until this moment. But the thing they always ask is with all the modern advances in medicine, with everything I've read about, with everything I see on the news, you can get anybody pregnant. How is it possible that you can't help us? But part of the thing is that fertility declines with age. And the big treatment we have to offer these people is in vitro fertilization. That's what everyone talks about on the news. And if you look at this graph, no matter how you do it, fertility declines with age. So the first number is pregnancy there on the top graph. The middle graph, in orange, which you should focus on, is live birth. And the bottom one is singleton live birth. But for any parameter, the success declines with age. And really, by the time you're over 40, we're talking less than 10% success of live birth with IVF, doing everything we can. And it's not just about getting the egg numbers. Even if we were to get them pregnant, the reason the live birth rate is so low is that there is such a huge rate of miscarriage with women who are older. And we all know this, that a good number of the embryos we get are aneuploid in older women. So what are the treatment options we have for women with diminished ovarian reserve? Well, some people have postulated what about superovulation? You give them fertility drugs. Increases your chance of getting more than one egg. And one of those eggs is more likely to be chromosomally normal. PGS, which is preimplantation genetic screening. So some have postulated that if you get a bunch of embryos, you can screen them for aneuploidy before you put them back. And then you could eliminate all the aneuploid ones and have a better chance of having a healthy baby. It sounds great in theory. But when it's actually been tested, it doesn't seem like it improves the live birth rate for every cycle that you start. So per implantation it's helpful, because you'll have a lot of embryos that are not good, so you won't even do a transfer. But for people who start, it doesn't seem to improve the pregnancy rates. So the one thing we have to offer people is egg donation. And here's another cover of Time magazine from 2002. Which should come first for women who want both, career or babies? And the harsh facts about fertility. So if this couple had thought ahead, since they'd been married for 18 years, they could have thought about freezing their embryos. So embryo freezing has been around since 1983. And fairly rapidly, by the late 1980s, there are standard protocols in place. And we can freeze at any point. So for busy couples who truly want to delay childbearing, I think one of the things to think about is whether they want to freeze their embryos now to have their babies in the future. The success of frozen embryos has gotten better and better. And now it's thought to be pretty equivalent, the success of a fresh IVF cycle versus embryos that have been frozen. And people always ask me, how long can you keep these embryos frozen? And it seems to be a long time. And this is one report of a woman who gave birth using an embryo that had been frozen for 19 years. But what if you don't have a male partner? What if you're an older woman or a woman who's not sure when they want to conceive? What are the options? Or a woman who's facing gonadotoxic chemotherapy? Egg freezing. So interestingly, egg freezing was first done in 1986 just a little bit after the first embryo freezing. But it's never really taken off. It took a long time. There's very slow scientific progress in this area. The egg is very big. There's a huge water content. It was very difficult scientifically to figure out how to optimally freeze this egg. And then after the egg is thawed, the zona pellucida became very thick and weird. It was very impossible to have fertilization occur. So the big breakthrough was when ICSI came up. And now you can individually inject a sperm into the egg. And that allows for fertilization. And so this is a slide looking at the success of egg freezing. And even though it's actually comparing two different techniques, a slow-freezing technique and a fast-freezing technique, it really speaks to how the field has advanced. In 2004, the data is shown on the left. And on the right is data from 2010. And in 2012, the American Society of Reproductive Medicine had lifted the designation of it being an experimental procedure because it was becoming to be as successful as regular embryo freezing. And even though the American Society of Reproductive Medicine cautioned people and said this is really data from gonadotoxic therapy. There's a small number. We don't recommend that this is used for routine delayed childbearing, of course that's not what's happening in the world. And this was just in the news a couple of weeks ago, that Facebook and Apple are now offering egg freezing for their employees. So this sounds very exciting. And on the first glance, it sounds like what wonderful news. But right away, there was a backlash. And here's the next day. Don't be fooled by Apple and Facebook. Egg freezing is not a benefit. And the reason this has come into play is really it's now your employer saying, we'll be happy to freeze your eggs for you. But in return, now that you can delay your fertility, maybe you want to work hard and not take a maternity leave now. And so-- And just in summary, these are my last concluding slides. For people, I think it's really important that the take-home message is that fertility declines with age. And as of right now, we don't have a treatment for that. That is the one thing we do not, as a field, have treatment for is reproductive aging. And you can see this is the graph of fertility decline. And if there was the same slope as what happened in the early '30s, we would predict menopause at age 70. But for some reason in the late '30s, there's this accelerated loss of eggs. And you end up having menopause around 50. So is there anything we can do to predict when someone may become diminished ovarian reserve and have decreased fertility? And in the olden days, we had FSH. Day three FSH was the best we had. And it really wasn't a good measure. Because by the time FSH was high, fertility had already declined and there was nothing to do. But now we have AMH, anti-mullerian hormone. So that's the same hormone that was made in the testes that caused the mullerian structures to regress. But it's also made in the granulosa cell in the small follicles. And this number, for the most part, does not fluctuate with the menstrual cycle. It does not fluctuate at all. AMH is the same every day. And it's actually a good marker of ovarian reserve. And this is a graph showing the AMH from one place, a fertility center. So it is from an infertility population. But it's showing the mean, the average AMH, and the median AMH for every single age range. You can see from the bars, there's a really wide range of normal. But we know that based on the AMH is how we dose the fertility drugs. And we also know based on the AMH how likely, how many eggs they're going to get from fertility treatment. And there's also some studies that show that you can actually use their AMH now as a measure of when they might go through menopause later. So it's a great way to predict ovarian reserve. And so I would say one of the take-home messages that I would have is fertility, we can't treat lack of eggs, reproductive aging. And maybe AMH should be part of the annual exam so people could get a sense of where they are fertility-wise and help make decisions about when they want to have their children, when they want to freeze their eggs, when they want to generate embryos. And that is it. Any questions? [APPLAUSE]
