Endometriosis Foundation of America
Endometriosis 2013 / Pregnancy Outcomes for Women with Endometriosis
Jamie Knopman, MD
Good morning, thank you for having me speak. It is very humbling to follow after these very well respected people in our field. As Dr. Grifo said I was his fellow recently graduated so he did train me well, I owe a lot of what I know to him. So, I'm happy to be with you this morning.
I am going to talk a little bit about what happened after the IVF after the embryo transfer and a little bit about fertility in and of itself without endometriosis. There are a lot of things that medically where we can assign direct modality to. We know if we smoke cigarettes we can get lung cancer. If you have an adult pap smear you can get cervical cancer. If you are obese you can get diabetes but the association between endometriosis and infertility is not as clear. We know that there is an association because this has been well established. We know patients who have endometriosis have reduced fecundity or reduced ability to get pregnant each month. Estimates in the literature suggest about 20 to 25 percent of women who are infertile have endometriosis. But the mechanism by which endometriosis causes infertility is not so clear.
Now, it is pretty obvious in a patient who has mechanical blockage or obstruction of their fallopian tubes, that makes sense, right? So the egg cannot be picked up by the tube. The sperm cannot get to the egg and there is your infertility. But what about patients who have very mild endometriosis and the fallopian tubes are fine and the ovaries look fine? What the researchers showed us is that there are other mechanisms by which infertility can be caused. One is there is a peer quality of the egg. the egg process of being mature, the process of ovulation, embryogenesis and even implantation. So we think there is even something wrong with the uterus and its ability to accept an embryo. There is also an association between immunologic dysfunction and as we said, implantation of the embryo.
It is like who is to blame? It is like if you have more than one kid, if you ask them who is responsible they will point to the other. But, is it the uterus or is it the ovary? And people who show that that there is uterine or in vitro problems in patients who have endometriosis they show that the endometrium had altered receptors. So that the receptors in the endometrium do not accept the embryo in the right way because even though it is eutopic endometrium, meaning endometrium that is in the right place, because there is endometriosis it is affected negatively.
Or, is it an egg issue? Well we have spoken today, Dr. Grifo showed us and then Dr. Hershlag also spoke about that there is a reduced egg quantity in patients who have endometriosis. We think that the endometriosis itself eats away the egg reserve and therefore the number of eggs that we have is less. We also know that the quality of the eggs are not as good. There is a classic study which people quote all the time where they took donor egg recipients who received eggs from young women who had endometriosis. The implantation rate for these recipients was less so they said, "Oh, well it must be the egg because their endometrium is fine".
When we talk about the reasons why women who have endometriosis are infertile a big thing that you will see people talk about is peritoneal factors. I do not know how you are positioned or associated with medicine but it is sort of hard - when we think about our abdomen, you know as women we are like that is our sit up area, right? That is all you think is how to get it flat but in reality that you have your stomach or your abdomen and then the bottom is your pelvis. This is what we call the pelvic cavity. This is where all the reproductive organs sit. So you have your uterus, your ovaries, your bladder, etc. But in this cavity there is space and there is space for fluid. The fluid that is in this space is called the peritoneal fluid. We all have peritoneal fluid, it's physiologic and there are a number of cells that are always in the peritoneal fluid. The amount of fluid that a woman has will be variable throughout her cycle. At the time when you are ovulating you will have a peak of peritoneal fluid.
You can have pathological peritoneal fluid in quantity and quality so if you think about a patient that has ovarian cancer they have a lot of peritoneal fluid which we will call ascities and that is where they get the big distension. Additionally, women who do IVF and can become hyper-stimulated also have an abnormal amount of peritoneal fluid. The peritoneal fluid in women who have endometriosis has been shown to have an abnormal composition of cells. The peritoneal fluid should have immune cells in a normal patient but in the endometriosis patient there is a higher number of macrophages. Macrophages are an immune cell they stimulate cytokine production. Cytokines are what causes inflammation. So, when somebody falls and cuts their knee, that knee is red, it is inflamed, the cytokines are rushing in the blood flow increasing inflammation.
Cytokines produce inflammation and these cytokines in the peritoneal fluid really have been shown to actually impact all areas of...fertility, they impact egg quality, they actually have a negative effect on sperm. The negatively impact the sperm's ability to fertilize the egg and then the subsequent development of the embryo.
Recent studies show that it is not only this peritoneal fluid that is actually bathing the ovary but an egg lives inside a follicle. So I always tell my patients you go to a grocery store you buy a dozen eggs. The follicle is the shell and the egg is on the inside. This follicle, the follicular fluid inside - in patients with endometriosis we know a higher number of inflammatory mediators. So, not only is the egg exposed to being bathed in abnormal cells it is also living in close quarters.
How is the infertility associated with endometriosis best treated? We know that medical management is not helpful. It is helpful for patients who have pelvic pain but for patients who want to get pregnant medical management does not help. Surgical management is probably helpful. I would say that if you have a surgeon who is experienced as Dr. Seckin, yes you will probably have definite benefit, but in general if you look at all comers, surgical management is plus/minus. ART, Assisted Reproductive Technology or IVF we know is definitely helpful.
I put this in because I feel like a lot of times infertility patients go crazy trying to change their lifestyle and that is not helpful. It is not that "you're not responsible" there is nothing that you can specifically change to change this process.
Surgical management for fertility: We know that there is a clear benefit for patients who have endometriosis pain related symptoms. That nobody can deny. The majority of data for infertility data is limited to mild to moderate disease and there has been shown to be a statistically significant improvement in the spontaneous pregnancy rates. They took women, they randomized they were going to have surgery for your endometriosis or you are not. Those who had surgery had a higher spontaneous pregnancy rate. This was again many of the patients who did ovulation induction so you get injectable gonadotropins or shots, then examination. But the clinically significant improvement was small. When they did a meta-analysis of the big studies, the meta-analysis where you combine studies together, they found for every 12 patients who had mild to moderate disease if they treated them surgically there would be only one additional pregnancy.
Then we move on to endometriomas. I am a couple of months late with my slides but the debate about should you take endometriomas out or not is sort of very heated. So you might be sitting here and saying, "Why should we not remove it? Why should removing it hurt"? Because you would think you have a cyst there and it should come out before try to get pregnant, right? Well, what happens is they have shown that patients who have endometriomas removed have a decrease in their ovarian reserves. So those patients wind up requiring more stimulation with IVF and higher doses of gonadotropins and it is most likely because when you take out the bad you lose the good as well. So then you might say okay so then why should you take it out at all; one is for you want to get pathological diagnosis if you are all confused. The big one is that the IVF retrieval is much easier if the endometrioma is not there. As you can imagine you have this big endometrioma that you now need to go around to get the follicles. Also, when you do surgery you obviously offer the patient symptomatic relief.
What do the experts recommend? We are governed, as Dr. Grifo was saying, by the American Society of Reproductive Medicine and in their recent Practice Committee opinion they say that routine removal is not recommended to improve fertility and it may have a negative impact on ovarian reserve and also may lengthen the time to achieve pregnancy.
Will it negatively affect a future pregnancy outcome? There have been recent studies on this and what they found was that no, there is no impact on that pregnancy outcome. You do not have a higher rate let's say of preterm delivery or...restriction.
IVF for endometriosis related infertility: We know that IVF offers the most effective treatment for patients with endometriosis. In 2002 there was a meta-analysis released by Kurt Bernhardt which has been widely quoted and what he found was that patients who had endometriosis and did IVF had a lower pregnancy rate than patients who were doing IVF for tubal factor infertility. Tubal factor infertility is sort of like a control group in a way because most of these patients are young and healthy and have good eggs.
More recently SART: SART is where all fertility centers report their data. It is a national organization. You can go online and find anyone's success rates in the country. SART pooled all of IVF outcome data around the country and what they found was actually this was now that they had noted a difference that women who had endometriosis were doing better than women who had all diagnoses for IVF. They found this to be very reassuring.
I pulled this from our data, it is not scientific, it was not a study. I just wanted to see what was going on in our center and I looked at the past 1100 retrievals. I took the patients who had between stage one and stage four endometriosis and I saw well what was their clinical pregnancy rate. This is not..., this is clinical pregnancy, which is defined as evidence of a gestational sac. What I found was similar to what SART found in that there was no difference between patients who had endometriosis and did IVF first as are all comers, which was reassuring. I then looked at it based on age and I found that - when we talk about fertility, female age, age, age, age, which I think Drs. Hershlag and Grifo were...drilled into us, it is age. The younger you are with endometriosis the better you will do in IVF.
What happens if IVF does not work? What do you do? Because we said that let's say you look at the SART data and there is a 39 percent chance of live birth per cycle, that is 61 percent of patients who will not get pregnant. Well, protocol change; recently there has been some data that has shown that maybe patients with endometriosis do better with certain protocols. You may want to try and change the protocol that you were given for the IVF retrieval. I say to patients that there are many ways to bake a cake, like I may put in more sugar, you may put in more flour, whatever it is, but possibly changing the protocol may help.
Then frozen embryo transfer: Dr. Grifo was alluding to this and these are again recent studies that just came out that patient who have endometriosis have higher success rates in a frozen embryo transfer rather than a fresh embryo transfer. Both patients were given Lupron as their down regulation so they sort of evened out the study. What they found is that maybe in the frozen embryo transfers your estrogen levels were significantly lower. This is probably better for the patients with endometriosis.
Surgical removal: As Dr. Seckin was saying it is always an option and may be a way for a patient to go who has failed IVF. Trying again because as we were saying not every patient is going to get pregnant on their first cycle. Then changing directions, there is, as we spoke last day, there are many different ways to become a parent and maybe donor egg is an option that should be investigated.
What happens after you get pregnant? Well, pregnancies that arise in women who have endometriosis appear to be at higher risk. There have been several studies that have well documented this. It is sort of hard not to believe that if you have this in your pelvis that when you get pregnant there is not going to be some negative impact on your growing fetus. But recently it came out of Sweden, and Sweden, Denmark and the Netherlands do amazing research because it is nationalized health care and when you are born you get a number and that number then follows you for the rest of your life. They did a study where they looked at thousands and thousands of babies that had been born and they found there was a higher incidence of pre-term deliveries. Specifically induced pre-term delivery so not spontaneously pre-term delivery but induced pre-term delivery. There was a higher incidence of preeclampsia, a higher incidence of C-section and a higher incidence of bleeding of placental complications. Things like placenta previa, placental rash and what pretty much is agreed upon is it is probably the same inflammation that is causing the patient's infertility associated with endometriosis, and is also leading to things such as preeclampsia and the placental complications.
Now, they did not find that there was an increase of growth restriction or still birth which had previously been shown so this is reassuring. But it actually pulled a couple of the...I asked them when a patient comes to see you and says, "I have endometriosis" do you treat them differently than a patient who does not have endometriosis? And they all said, "No". I said, "You don't treat them like they are a chronic hypertensive who comes to you and you put them in for screening every month, etc. and they said, "No". Most of them said to me, "I didn't even know that patients with endometriosis have been demonstrated to have higher pregnancy complications. I think it is reassuring because it shows that most of the people who get pregnant who have endometriosis are going to do just fine.
Do endometriomas seem to make the pregnancy situation worse? Well, as I said, in regard to IVF we think likely not, with regard to pregnancy likely not. But the size does matter because what ASRM says is most of the data has been done on small endometriosis, so 3 cm to 4 cm. When you are talking about a patient with a 10 cm endometrioma that is sort of a different ballgame. It has to be individualized for the patient.
This, I thought, was interesting. This is a study that just came out in March 2013, and for insurance "can we blame everything on our mom", which probably most of us in fact do. But there is a big focus now on early, like the early health and disease model. So now a lot of what we think is that what happens in uterus sets a person up for the rest of their life. Are they going to develop hypertension, diabetes, etc. and they think that there is in utero exposures that cause this to happen. What this study wanted to do was look at maternal exposures, what happens to the offspring. They took women who had proven endometriosis, they had surgery, MRI definite endometriosis and they polled them on what their mother's lifestyle was like. Now there is obviously a lot - this is limited because how does a child know what his mother did but they tried to limit it to simple questions like "did your mother smoke", did she drink excessive alcohol" and "did she take DES". What they found was that there was no evidence of association between in utero exposures and the development of endometriosis. While yes, the in utero environment is very important it did not seem to predispose for developing endometriosis down the road.
What does the diagnostic future hold? There have been a lot of studies recently showing that there is more chromosomal and genetic basis than we ever thought there would be. Recently we found there are specific mutations like chromosome seven that might be linked to endometriosis and then hypermethylation and hypomethylation of certain genes. When you add a methyl group to one of the bases in the genome...or adenosine this is called hyper or hypomethylation. It is sort of all alphabet soup probably. It is to me so it probably is to most other people. It really shows that this is the future.
I think biomarkers are going to really change the way that we practice medicine. To date there has not been one biomarker or panel of biomarkers that have been approved for use to identify endometriosis. There are a lot on the horizon.
This is just sort of a smattering of what we can expect. And this company I just thought was so interesting I wanted to bring it up. It is a biotech company, they are called Celmatix and what their goal is they have a two-fold goal: they sort of want to hold a crystal ball to what is coming down the road. Their primary focus is to identify women who have unexplained infertility and premature ovarian failure and sequence their genes. The hope is that one day you can come in at 21 for your first GYN visit or whatever it is. They can send the blood test and they can say to you, "You are going to have premature ovarian failure, go freeze your eggs" or "You are going to have this, go freeze your eggs".
The second half of what they want to do is they want to take all data and streamline it so that when you go to a fertility doctor we typically may start with you are going to do your three clomid cycles, then your three this, then your IVF. You would not need any of that because they would be able to say, "Oh, you need to do IVF or PGD right now.
Everyone touched on egg freezing so I am not going to go over it again but egg freezing is another sort of what we would call a preventative treatment. You go the doctor for vaccines to prevent getting some sort of a disease. If you knew you had endometriosis it might be something that you would think about, freezing your eggs at an earlier age to prevent the decline in future.
You know we go to the GYN or IC patients and you talk about things like contraception, pap smears and mammograms, etc. but your future fertility really should be a component of that discussion. I think that we should all as patients and as women we should be knowledgeable about what is out there. And as gynecologists we need to make sure that everyone is aware of what the future holds.
Novel Treatment Step Strategies: These are just a few of the various treatments that are out there now for treating endometriosis. The issue is that most of these medications have been tested in animals. There are very limited studies in humans. Most of the human data has been done to alleviate pelvic pain. It is not associated with fertility. You look at some of these and you may say, "Oh, did she fall asleep when she was making that...statins that is for cholesterol, right? But statins also have been shown to decrease cell proliferation so they may have a benefit in endometriosis. Statins are...medications we could not give it to women who are trying to get pregnant so most of what we are seeing here are drugs that would help us prevent the pain or progression of endometriosis.
Again, it is even worse alphabet soup but I think that medicine is going to go the way of you go to the store and you try on like a size 20, whatever is there, and they tailor it to you. Pretty soon we will all have our dress fitted right to size - medicine fitted to exactly what we need based on biomarkers and seeing the future.