Endofound’s Sixth Annual Medical Conference: Ending Endometriosis Starts at the Beginning
Cost Effective IVF for endometriosis
Enda McVeigh, MD
Thank you Harry for the kind invitation. As we said some are scientific talks this morning put us simple clinicians to shame. But we are sitting with the patients in front of us and we have to try to work out what we know from the scientific knowledge and how do we direct that to the patient’s bedside and to the patient in front of us? How do we take in all of the other compounding factors or co-factors which are the patient’s age and their ability and their want to conceive, etc.? What I want to try to do with this is to pull some of those things together.
If we start with some accepted starting points about IVF and about assisted conception and patients getting pregnant the most effective way, cost effective way and easiest way to conceive is at home, naturally. That is where patients want to conceive. No patient wants to enter into a fertility clinic or IVF, take what is a very personal part of their life, their reproductive capacity and sit and talk to people about it. Nobody wants to do that. Our ultimate aim should be how can we manage for those patients to conceive at home?
Endometriosis and infertility are clinically associated. We see that but it is not an absolute if you have endometriosis you are not infertile. We need to understand more about that association.
Medical treatment or the management of endometriosis with hormones is a contraceptive and therefore we are taking away that fertility aspiration at that time if we treat them that way. As we heard earlier from the last speak, surgery at any stage of endometriosis appears to enhance the chances of natural conception and I will come back to some of that.
What we need to do with patients who have endometriosis or patients of endometriosis who are trying to get pregnant is understand some of the science behind and understand how the disease might work. I say might because we have lots of different theories here at the moment floating around. Some constant messages are coming through in that understand what is going on and then what treatment modality might be the best if it is surgery or if it is assisted conception in some form. We do know the peritoneal fluid in women with endometriosis is affected and this can affect where fertilization occurs at the end of the fallopian tube where the fimbria will be bathed in this altered milieu in the peritoneum and they can affect the sperm and the eggs in different ways. Here are some of the possible ways that have been cited where through macrophages or through the interleukins it might affect sperm function and the ability of the sperm to fertilize the egg at the end of the fallopian tube.
The uterus of course is a very important part for fertility. That is where we are going to get the implantation of hopefully the blastocysts after five days. We have heard about how the endometrium may be different, different in expression of its immunological factors and also in the difference in its production of hormones internally. We need to understand how that might work and how it might affect the ability of that embryo to implant. A normal tissue for example this is in the normal endometrium if we look at the production of estradiol internally this would be the normality, however, we know in the endometriotic tissue it is changed. It results in a greater increase in the production of estradiol locally which may have an effect in the implantation process.
Surgery we have heard before does improve fertility and this is just one example of the any in the literature that will show if you do remove these minor implants through excision, not through ablation, in stage one or two endometriosis you will get an increase in the fecundity. That seems to level off after about six months and that seems to be consistent that if you have done surgery but you have not got a pregnancy after six months you probably need to think again of what your management strategy is that you do get this monthly increase.
There has been some thought process well could we in the past if we suppress the endometriotic lesions using hormones via the GnRH analogue or the contraceptive pill will that suppression then lead to a rebound in the fecundity after the patient is released from that hormonal treatment? And through this…of various studies we can see, you know, it does not work. Giving them contraceptives, giving them hormonal manipulation, suppressing the endometrium you do not get a rebound in fertility. What you have also done is during that time that you have had the patient on the hormones you have denied them that possibility, albeit small, of getting pregnant during that time.
What about using non-IVF techniques for these patients now who perhaps surgery has not worked for? We have got through that six months’ window and they are still not getting pregnant. Here are some of the things that we can do. As we have said expected management seems to be that in patients with stage one or two after that initial year the fecundity rate is about two to four percent. It is low but it does exist. There is a possibility of getting pregnant. If we do surgery we can improve that if they have not had surgery we can get it up to seven to ten percent but importantly…multiple pregnancy rate which you want to come back down to. And I said less than one so that is the average rate of twins would be one in 80 natural conceptions. If we do intrauterine insemination without any degree of ovarian stimulation we are going to get a fecundity rate that you know what, is not that different from expected management. That is not surprising because we are not really doing anything differently from what the couple is doing at home so why would we expect it to be different? Of course if we put more eggs around then we are going to increase the chances of getting pregnant. That seems natural. So if we give them Clomid or we give them controlled ovarian stimulation with exogenous gonadotropins we are going to increase the fecundity rate but you know what? We are going to end up with multiple pregnancies so we need to understand that what we want to give these couples are a healthy pregnancy, a healthy family not just a pregnancy at all costs. That is not what we should be about. If we compare this slide quickly of what we would expect in a 35-year-old who had stage one or two endometriosis, who is having IVF, having a single embryo transfer, therefore singleton pregnancy we can see we should have around about 40 percent pregnancy rate. These actually are not cost effective. They are not a reasonable way to go forward for these patients.
Staying on that multiple pregnancy risk, multiple pregnancies have been, and I think the reproductive societies worldwide now have thankfully started to recognize this and some countries are ahead of others that it is the biggest complication of IVF, is multiple pregnancies.
This is just a cost analysis of hospital inpatients for the infant or going to a child up to five years. This study, if we looked at it this is just in our Oxford area. It is about £1500 for a singleton pregnancy whereas you are up to twice, nearly three times that for a twin pregnancy. And that is just the inpatient stay of a normal child that does not take the possibility if we have got with twins a 50 percent more twins were preterm, 50 percent where physical or learning disabilities. We have a five times…risk of cerebral palsy in that second twin. If you add that into your costs of what that costs not just the human cost for that child and that family but for costs of society that is quite significant. Never mind the risks of the mother having twin pregnancies. Our aim should be singleton pregnancies. If we look at a fifth of conceptions in the UK in 2011 we were running at rates just under 20 percent, whereas in the US here you are up at nearly 30 percent. We are still having a triplet proportion of that.
This is difficult and there are many driving factors for that because when we talk about cost effective IVF for endometriosis you want to know who is it cost effective for? Is it for the patient? Is it for society? Or is it for the clinicians? Because everybody there has got a little bit of skin in the game and for different reasons they may want to do different things.
This may all depend on where you live. This shows the number of IVF centers in these different countries. If you look at the US here you have about 500 IVF centers for a population of here, where the UK are somewhere down here. We have got about 60. Or look at Japan, it has a much lower population than you have here in the US but it has a significant number of IVF. If we look at socialist countries and…we go to northern European countries we would find that about three percent of all babies born are born to assisted conception. In America you are down to about one percent in the UK we are sitting around about two percent. Two percent of all babies born in the UK are through IVF which is quite significant.
Guess what? IVF is big business. I think a lot of people know that. In the US alone it is estimated to be worth about £2.5 billion. We had last year the first IPO of an IVF group in Australia value come in at half a billion, which is now up to 700 million on current valuation. There is a lot of driving factors putting patients toward assisted conception, which may be not where they should be going.
If our patients do end up to have IVF and we have looked at all of the various reasons why we should not do it and they do end up doing it how do we do it, how should we do IVF any way differently for endometriosis patients as opposed to our patients who do not have it? And that may be on some of the protocols that we have used.
We have said that the uterus is different, seems to be different, the endometrium seems to be different in women of endometriosis. Can we, without knowledge, improve the implantation rates in any way? Well, we have said that different countries have taken different angles on this. This is the Cochrane Review looking at long term pituitary down-regulation in women with endometriosis prior to IVF and when they put it all together they decided that it was more advantageous to down-regulate a woman with a GnRH analogue for six months prior to IVF probably because you are changing the endometrium and then you get a better implantation.
If you look at some of the numbers they are pretty small. The other interesting factor is that if you look at the big databases, the SARD databases or the…databases you do not see a difference in pregnancy rates of women with endometriosis compared to women who do not have it. There is conflicting evidence there on this and I think certainly my take on this and what we do in all of our clinics is that we do not do prolonged down-regulation, not because we have to as the last speaker said because we are American, we do not do it because we believe that we are denying them that fecundity chance beforehand. You are getting a woman in front of you who wants to conceive and you are saying, “Well, I want you to take a contraceptive or GnRH analogue for six months, and you definitely won’t conceive during that time and then come and have IVF”, so we do not tend to do it. What we would tend to say is, “You know what, we won’t use an antagonist protocol because let’s just have it somewhere in between and give you antagonist long protocol, traditional way of doing IVF”, and that seems to give us the best results.
Deep endometriosis – should you remove it before IVF? Well, again there have been a few studies on this. It is all pretty low numbers and that is the problem with this, all of these observational studies are low numbers. We have one here saying that it does benefit removal prior to IVF; however, we do know that if you do remove it and they do not get pregnant you have increased their chance of getting pregnant. But it is understanding what the woman wants. Certainly when she comes into our clinics sitting in front of us which is the most important to you? I am not saying I am not going to treat both but which is most important, your fertility or your quality of life, the pain that you are having because you know what? I need to deal with maybe one before the other but both will be synergetic when we do manage them.
Something that we have not heard a lot about here is adenomyosis which can go hand in hand very much with endometriosis. And that certainly does have an effect on implantation of the embryos. We know that if we see an ultrasound or MRI of adenomyotic uterus you do not get the implantation rates. This look at that IVF cycle numbers 1, 2. 3, 4 and then the cumulative pregnancy rate so we can see if you do not have adenomyosis and you have got stage one to two endometriosis you are getting pregnancy rates of about 40 percent which we would expect. And you are getting those one after another. However, you add adenomyosis you do not get any increase it really does affect the ability of that embryo to implant. There is not a lot we can do but what we can do is set expectations for the couple in front of you right away about what your chances are.
On the ovaries should we reduce, and again we heard a little bit before. Should we remove these endometriomas prior to IVF? Well, a lot of it will depend upon the skill of your surgeons as well too. Chuck Donnez and Michel Canis are saying you know it does not really seem to affect it but you know what, they are pretty good surgeons. I think it is disingenuous if you quote figures like this if you are not that surgeon because you need to know what can you do are you traumatizing the ovary more and therefore you are damaging it and maybe you should have left it alone. Certainly the ESHRE guidelines on this would be that if you have got an endometrioma less than 4 cm leave it alone and you do IVF because you are probably going to do more harm than good. You have got to bring that into context with the patient’s wants. With a 21 year old you might be more likely to do surgery and see if they get pregnant or maybe the endometrioma as opposed to a 37 year old. Cystectomy versus that and we got there. So a summary of evidence on endometriomas is that is seems to be surgical skill and we should leave them alone if at all possible to work around.
A little bit on cryopreservation of oocytes under vitrification has changed the field for us completely. Vitrified eggs now work as well as fresh eggs. We work quite a lot with the guys in IVI, Carlos Simón and others. They have got over 100,000 vitrified eggs at the moment in their egg bank for egg donation. If you want egg donation now and you do not have a fresh donor who is running parallel with the recipient you simply ring up the bank, find out where the vitrified eggs are and move them to whichever city in Spain you want them in, the patient flies in, has her fertilization done on her transfer. They get as good results with those vitrified eggs as with fresh eggs. The technology exists to do it.
Again, this is a billion pound, a billion dollar industry; let us not push our patients with endometriosis saying let us all go and have your eggs vitrified because that is commercialization and possible exploitation and also leads to problems. Because if you have those eggs frozen then when do you put them back? “I might get that new job or I might wait to get that new house, I have got my 21-year-old eggs frozen so I have plenty of time”. It leads to a lot of problems. We are certainly seeing that now with the ability of egg donations and vitrified eggs being so common that we are getting a lot of social disturbance with this that we need to be as responsible about it in whatever way.
The key seems to be to understand the condition, understand the disease, try to implement, try to understand that patient’s needs in front of you, listen to the patients and manage it appropriately with the best input from science as possible.
As mentioned earlier this is the team that we have in Oxford and certainly the scientific team has lead and we have heard some of them already. These are the people I work with and it is an honor to be that. So, again, thank you for helping me today and thank you.