In this webinar, Dr Valentine Akande, MBBS, PhD, MRCOG, Medical Director & Lead Consultant at Bristol Centre for Reproductive Medicine – BCRM has been talking about your chances and how to improve them after failed IVF or ICSI treatments.
Dr Akande explained that if we think about the complexity associated with the embryo implanting within the lining of the womb, the most important thing that accounts for 60 if not 70% of the success is the embryo. The most significant thing about implantation or your chances of success is to do with the embryo. People talk about the embryos sticking or implanting, but actually, it is about the embryo growing because if the embryo grows it will continue to grow, and it’s very likely to implant. Many of you would have heard of something called an ectopic pregnancy which is when an embryo implants outside the womb, so it means it’s implanted in an area where it shouldn’t, and it should have implanted in the lining of the womb. That tells us that an embryo if it’s very strong and robust can implant in places that are not even conducive. Therefore, the critical thing is embryo development. Another important thing is hormonal changes, you need the right hormonal levels to prepare the lining of the womb for implantation. The right balance of hormones is important, and we know that immune responses are also important. The challenge is understanding the full immunology of fertility, and it is not as straightforward as we think, it is a challenging area, but there’s still a lot to learn about immune responses. Many of us are aware that immune response and immune factors are likely to have an impact, but how we measure that and alter it and how it influences it, is the challenge, and we haven’t perfected that yet.
Naturally, at conception, you ovulate, and very often, fertilization will occur, but then before day 7, after ovulation, over 30% of the embryos do not get past that stage. Then we wait a while longer, and before 14 days of ovulation, when you’re just about to have a period again, another 30% of embryos. This is what’s called pre-clinical, and the pregnancy test tends to be positive around this time, but very often, a lot of people who test before their pregnancy tested will have positive pregnancy tests, and then, it will not go past they’ll then have appeared and that’s known as a biochemical pregnancy. From this, about 60% of pregnancies are lost before you have the expected period. This is almost similar to what happens in IVF because when we undertake IVF, we see the embryo developing, and we put it back in the womb, and then during that stage, unfortunately, not every embryo progresses. If you go a bit further, you will see that people have a positive pregnancy test, but we then recognize that another proportion of pregnancies will miscarry. On top of that, at an early stage of conception, only 30% lead to live birth.
If we look at implantation failure, there are two things. First, it’s recognizing that there are competent embryos, and they’re then selected by the endometrium, which also has to be receptive, so you need good quality embryos, and you also need a receptive endometrium. If you have a very unreceptive endometrium, even if you have a good quality embryo, implantation chances are low. If we look at the implantation window, it’s quite short, it’s usually about 6 to 9 days, and post-ovulation is what happens naturally. When we do IVF, we are trying to simulate what happens in a natural cycle, the egg is released, gets fertilized in the fallopian tube, travels down and then implants in the womb sometime between day 6 to day 9. Typically, around day 8 or 9 when your embryos are developing in the IVF laboratory.
The thing to understand about fertility, and this is perhaps one of the most important things, is that fertility is understanding your chances or your prognosis. That is what it’s about because it’s very rare for people to be infertile.
I don’t like using the words infertility because there’s hardly anybody who is infertile. Generally, when we see people, they have a degree of subfertility, and what we’re trying to do is to increase their fertility, so technically, if you’ve been trying for a certain length of time, and you haven’t got pregnant, it means that your chances are lower, it doesn’t mean you can’t get pregnant, but it means something is reducing your chances. If you’ve been trying for 2 years and you’re 30 or 25, your chance of conceiving each month is about 1 in 20. Ideally, if you’re 25 to 30 the success rates are about 50%.
What are the factors that affect your chances? If we look at a logarithmic scale, where we have the number of eggs. When a woman is born, she has about 2 million eggs, but when she’s in her mother’s tummy at about 5 months, a woman will have 5 to 7 million eggs, and by the time she starts having periods at the age of 10 to 14, she’ll have less than half a million. By the time a woman is 37, she’s got you’ve got about 25 000, and by the time she reaches menopause, she’s got less than a thousand. Eggs are different from sperm, you are born with the number of eggs you will have, and that number continues to go down. Men can continue to produce sperm even though sperm quality can decline with age, and an 80-year-old man can still produce sperm.
Another graph presented the likelihood of pregnancy by natural conception in women aged between 20 and 30. It shows that in the first month of tries people who come off the pill, about a third will get pregnant within 3 months, about 2/3 will get pregnant and within 6 months 3/4 and if you wait a year within 12 months, about 90% will get pregnant, if you wait another year, 95%. The key thing here is that if somebody gets pregnant in the 14th month, all they’ve done is continue to try, they have done nothing different apart from just having intercourse again. This is an important concept, it’s the same with IVF, but the difficulty with IVF is that by the time you’ve had 3 cycles, you begin to wonder if there is something else going on, and there might be, but it’s still important to understand that the more times you try, you might have like in natural conception. If somebody’s been trying to conceive for 3 months and comes to the IVF clinic, the doctors will tell them to continue trying because 3 months is too soon. However, if somebody’s tried IVF for 3 cycles or 2 cycles, the doctors will wonder if there is something else wrong.
The next graph showed the likelihood of pregnancy according to age. If somebody’s 25, they have about a 90% chance of getting pregnant within 12 months, if you’re 35, your chances are 70%, and if you’re 40, it’s 50%, therefore, it’s crucial to remember how important age is.
Even when we use IVF, if we look at the data from the U.S. that was looking at thousands of cycles, if we look at the chance of having a baby from 0% to 50%, if you use your own eggs, you can see that the chances decline with advancing age. At 40, the chance of having a baby is around 25%, at 36, almost 40%, at 25, about 50%, and at 44, the chances of having a baby with your own eggs are about 4%. The challenge with this data is that you can’t get 4% of a baby or 20% of a baby, it either happens, or it doesn’t.
When we look at the donated eggs from younger women, even if you’re 60 or 70 your chance of having a baby is about 50%. This tells us that egg quality is the most important determinant of IVF success.
Somebody who’s 37 is likely to need more tries of IVF to have a baby than somebody at 31, and somebody at 40 would need many more tries to have the same chance of success. That is one way of improving your chances, the other thing to understand is the miscarriage rates which go up dramatically. Many people get pregnant, but they miscarry. The data from Scandinavia showed quite a lot of cycles, and at the age of 25, the risk of miscarriage is 12%, at 30, it’s 15%, and at 35, it’s about 20%, while at 40, you can see it goes up to 40 so, Therefore, again age is playing quite a significant effect and at the age of 45 the risk of miscarriage is about 80%, so woman’s chances are probably better with donor eggs. Sperm also is important, the quality does matter, and there is more emerging evidence that DNA fragmentation may be an important factor as well.
There is no such thing as a fertility diet, however, there is emerging evidence that a Mediterranean diet might be beneficial. The other thing is if you exercise, that’s good, but too much exercise, if you’re running a marathon, can reduce the success of fertility treatment. Smoking reduces your chance by 50%, and not only smoking but also being exposed to people who smoke.
We recognize how stressful fertility treatment can be, particularly when it doesn’t work, and it’ll be nice to get rid of all the stress, the good news is that stress does not appear to affect the chances of the success of IVF treatment apart from if you stop having periods. However, if there’s a problem with ovulation, then that causes fertility problems, but in terms of success rate, stress does not appear to have an impact.
Some other things that you can do are taking vitamins. There’s more evidence now that vitamin D, in particular, is beneficial, and folic acid reduces miscarriage, but there’s more evidence that people with lower vitamin D levels have a higher chance of implantation failure than people with good vitamin D levels.
You don’t want to be drinking more than 4 units of alcohol a week and preferably less, so that’s less than half a bottle, not more than 2 cups of coffee, and there’s emerging evidence that a Mediterranean diet may be beneficial. If you have a poor ovarian reserve, sometimes Coenzyme q10 may be beneficial, it is an antioxidant. If you have a very poor ovarian reserve, DHEA or testosterone may be beneficial but you would need to speak to an expert to discuss how that’s used or whether it is of benefit in your case, it doesn’t work for everybody, it is not a standard recommendation but sometimes if there’s no other option as long as you understand that it may not work and the side effects have been explained, it may be reasonable to use it. In terms of poor sperm quality, some male fertility supplements may improve sperm parameters, and the key thing is that they don’t always do that.
In summary, there are several causes of IVF failure. The most important is the embryo and its quality, it is determined by the egg quality, so the younger you are, the better the egg quality, and therefore better embryo quality. Sperm quality accounts for somewhere between 10 to maybe 25% of the embryo quality, but it’s mainly the egg quality. Sperm quality can be assessed by sperm DNA fragmentation test, the challenge is if you find a problem, what can you do? You can take fertility supplements and have ICSI treatment instead of IVF.
If there are problems with the womb lining, for example, if you’ve got a polyp, fibroid or adenomyosis, every clinician or specialist will be able to identify that, the challenge is where there are other subtle functional problems, such as receptivity, and there is emerging evidence that things such as an ERA test, which is an Endometrial Receptivity Array might be beneficial. We’re coming to recognize that infection can also play a part, and it depends on which studies you look at, but between 5 to 20% of women with implantation failure might have not so much as an infection but organisms within the womb cavity that can be identified as having an impact. There’s also the microbiome, meaning the organisms within the womb cavity. Some studies suggest certain viruses as well can affect implantation, so problems with the HPV virus or chickenpox virus are associated with lower chances of implantation. Sometimes there might be immune problems that are identified although the data on this is still controversial and speculative.
If you have got a severe thyroid problem, not mild, that can affect implantations. Uncontrolled diabetes, arthritis, lupus, and thrombophilia, are potential conditions, but these would need to be discussed with a specialist. If you have poor nutrition, if your general health is poor, or you have any immune problems, although the immune issues are controversial and difficult to test and treat, that can also cause a failure. Various tests can help find the cause, for example, doing a hysteroscopy, which is putting a telescope in the womb, may be beneficial in certain circumstances. Thrombophilia testing, the evidence for that is not very strong, but it can be checked. In terms of immunological testing, there is some evidence that it can be beneficial, but if you are to have immunological tests, you need to go to a centre that does it regularly and understands. Sperm DNA fragmentation testing can also be beneficial.
Somewhere between 5 to 20% of patients with chronic endometriosis where there’s mild inflammation or infection within the cavity, and this can be assessed by taking a biopsy of the womb, and there is now emerging evidence where there’s endometrial dyssynchrony and what that means is the lining of the womb is developed at a different stage from when the embryos develop so rather than being synchronized, the embryos are put back at the wrong date because the endometrium has not grown enough or too far.
Pre-implantation genetic testing for aneuploidy can be beneficial particularly in people of advanced age, with recurrent miscarriages. Another thing is endometrial scratch, which has become a bit more controversial recently because there’s a big study that suggested it doesn’t make a difference, but there have been several studies that have suggested it’s beneficial. However, in situations where the couple had more than 2 failed cycles and you’ve had top-quality blastocyst transfers, it’s probably something worth considering. Regarding aspirin, the evidence does not seem to be strong, the same thing with heparin, although heparin does not tend to cause harm apart from an increased risk of bleeding. What many people are not aware of is that aspirin increases your chance of miscarriage by about 5%, so again if you want to use aspirin, you need to understand in which situations it is used, there are certain situations where aspirin is beneficial and others where it might be harmful.
If you’re to consider immune therapy, it has to be done under expert guidance and somebody who knows what they’re doing, it is controversial, and many of the treatments are speculative. Steroids and intralipids fall under immune therapy, and if you’re to give steroids, the truth is for implantation to occur, you need some inflammation, steroids suppress inflammation, so if you suppress inflammation too much, that can counter potential implantation.
The evidence around intralipids is as controversial as is with G-CSF. There is more evidence suggesting that extra progesterone can be beneficial in some cases, and progesterone generally is administered vaginally, but also in some cases, it needs to be administered by injection, and that can result in better success rates.
The last thing Dr Akande presented was a true study, published in 2011, it was a randomized control trial where they used a clown at the time of embryo transfer, they had a hundred women randomly who did not have a clown in the room and 110 women so similar numbers, they made sure there was a clown in the room to get the woman to laugh. The success pregnancy rates were 36% where the clown was in the room and where there was no clown, the pregnancy rates were 20%. This suggests that at the time of embryo transfer we potentially should have a clown in the room, but nobody has taken this forward, and this shows how challenging sometimes doing studies in medicine can be and how sometimes we deal with the results and how do you explain as a true study like this which found benefit but has not been implemented elsewhere.
We recognize that failed IVF can be challenging both for patients but also the clinician or the expert, and it is sometimes not easy to know the answer as to why you might be having difficulty. Sometimes, it has to do with the embryo, sometimes the lining, but we have a responsibility to do our best and give you the best chances of success to make sure we’ve looked at all the possibilities. Having said that, there also has to be common sense because if you were to do every single test on yourself, it will result in enormous cost, which is not always advantageous, and sometimes it comes down to just probabilities, which means having another go and as you could see from the graphs, just having more tries is an important factor in improving your chances, and you want to make sure your treatment is personalized
The grade of the blastocyst is quite important. I’ll just give you an example if you are to run a marathon or to go through some strenuous challenge like play a difficult sports game. The younger you are and the fitter you are, the better. The same applies to embryos. If we look at people who smoke, for example, the chances are reduced. We all know that people who smoke can get pregnant, but you rarely find older people who smoke that get pregnant. Younger people do. That’s because their embryos are more robust.
The grade of the embryo is also important, particularly for freezing. The better the grade of the embryo, the more likely it is to be able to be frozen and to be thawed without getting compromised. We also know that embryo grading is dynamic. If you watch an embryo, the grade changes as you watch it. But what’s more important, as long as the blastocyst grade is good, is the genetic material or the chromosomes, and that’s why preimplantation genetic screening comes in. But the greater the embryo is, the higher the grade, the more likely the implantation will be.
I think this is a really interesting question because I’ve been in this business a long time and I’ve seen all tests or some treatments that have come and gone. Many of you would have heard about embryo glue. We used to use it, and now we don’t. Many of you might have heard of assisted hatching. We used to use it, now we don’t. I think we’re all trying to find an edge here. We’re all trying to find something new that can potentially answer why you’re not getting pregnant, and if we’re able to treat it, what would give you a better chance of getting pregnant. What is shown in the research is that an abnormal microbiome is likely to influence your chance of success, but there’s still quite a bit to do about understanding what a new, normal microbiome is and what an abnormal one is. It is also important how you do the test because to do the test of the microbiome you have to go through the vagina and the cervix into the womb.
It’s quite easy to contaminate the specimen. I think rather than testing the microbiome, it is more compelling to look for inflammation, such as when you’re testing for plasma cells or cd138. The evidence there is much more compelling than the uterine microbiome. I think we have to wait and see before we start doing normal testing for the uterine microbiome. It’s better to be looking for inflammation. The test you should do is looking for chronic endometriosis. There is compelling evidence that if you treat that, your chances can be much better.
The answer is people would do different things. There’s this question of where it is situated, or if it’s a real polyp, as opposed to a polypoid lining of the womb.
There are a few important things. One is the size and where it is situated because if it is lower down in the cavity or towards the side, it may not be as important. Also, if it’s really small it is not that problematic. However, if the polyp is big, we’ll discuss the options with the patient. Depending on what we see, we recommend you stop the cycle, and then the polyp is removed. You need to have something called a hysteroscopy. But generally, if you see a polyp, it’s not great news. You would rather you didn’t have the polyp. If there’s a definite polyp, our normal practice is to offer removal as an option.
This is a tricky one. Your age is not a real factor in fertilization, your age is more of a factor in getting to day-5. The big question here would be which center it is. Different labs have different approaches and quality standards. Certainly, this needs to be looked at in greater detail. It’s really difficult to give you an answer. This type of scenario has to be individualized. There’s no generic answer because in our center, what we do in this type of case, is we have what’s called the multi-disciplinary meeting, where all the embryologists and all the doctors get together and we go through the case in detail. It’s not a monopoly of wisdom. It’s not a single answer. Everybody puts their hand in and we go through everything that’s happened. So in this type of case, my suggestion is this needs a whole team. You need to go completely, forensically through your cycle and everything that’s happened in the lab because not having any eggs fertilizing is a concern
I think that whenever you ask that type of question in medicine, we have to believe that potentially it can be improved. For example, everybody’s getting older, but you can improve your fitness, you can improve your health. I think the same thing applies to eggs, but you cannot change the genetic content, you can change some other things. One analogy I use here is there’s no amount of vitamins, I’ll take once you start getting gray hair. Five, ten years ago, I didn’t wear glasses, and then my eyesight changed, and now I have to wear glasses all the time. There are some things you can slow down, but it’s very difficult to reverse them. To bring up egg quality is difficult, but you can slow things down. Potentially improve some stuff. For example, if you smoke, stopping smoking will certainly, improve the egg quality.
If you drink a lot, stopping would improve egg quality too. You can take CoQ10. There is some evidence that antioxidants can be beneficial. But the thing to appreciate is that when we talk about improving egg quality, you’re likely to see marginal gains, but it’s not going to improve dramatically. If you’re 40, taking vitamins is not going to make your eggs the same quality as if you were a 30-year-old. That’s the way to look at it.
I think ubiquinol can be beneficial. There is some evidence of that. It has to be taken 3 times a day ideally, and this is the important thing. If you’re taking it to try and improve egg quality, you need to take it for 4months. The question is why, for 4 months? It’s because the egg that’s collected at IVF has started developing 4 months before it has been collected. So if you want to see the benefits, it has to be taken continuously for 4 months.
There is emerging evidence that vitamin D can improve embryo quality because embryo quality is reflective of egg quality. Certainly, vitamin D can potentially help. I’ll emphasize again, it’s not going to improve it hugely.
I think it’s really important here to be very clear. If you have a vitamin D deficiency, you need to be on a high level for a certain period. Once your vitamin D levels are normal, you just need the standard supplementation, which you can get in any preconception vitamin. Overdosing in vitamin D can be harmful, as well. What is recognized, in particular, in winter where people don’t get enough sunlight, so everybody should ideally take a bit of vitamin D. If you can, get a test, either through your GP or clinic, to see if your levels are low. Then you need to take higher supplements, but otherwise, all you need is the standard dose. You can buy it over the counter, you don’t need a prescription for it. Generally, the serum levels should be above 50, although each laboratory has its set value.
If you have concerns and if you’re not taking supplements, you can request it. Most people who are taking supplements don’t need to have the levels checked. If you have a poor diet and you’re not exposed to the sun, and you’re concerned, then go to your GP and have them checked. Studies that have looked at vitamin D have looked at people who have poor nutrition, and they have seen the difference in terms of miscarriage and potential fertility rates. It’s not a test that is done routinely in fertility clinics, and you don’t need to check your levels because if you’re taking the supplements, your vitamin D levels should be fine. It’s just like you don’t need your folic acid levels checked if you’ve been taking folic acid. Only if you’ve not been taking any vitamins or preconception vitamins, you’ve got a poor diet, and you’ve not been exposed to sunlight, then get your vitamin D levels checked. There are certain sections of society where people are covered up a lot and get no sunlight at all. Those group of people needs vitamin D levels checked, but generally, if you’ve been taking preconception vitamins, you shouldn’t need your vitamin D levels checked.
People should not take Vitamin B12 unless they have been identified as having a B12 deficiency. Usually, a B12 deficiency will be identified by a full blood count, and it just shows you are anemic, then one of the tests done by your GP is B12 level. But if you just take the standard preconception, which is important, it is more than enough. You don’t need anything more. As long as you have got a good diet and you take standard preconception vitamins, there is no need to buy extra vitamins. There are studies now that show taking too many vitamins can be harmful. I’ll give you an example. Most people do not know that if men take extra folic acid every day, their risk of prostate cancer increases by 20 percent. So you just need little extra supplements, but you don’t need big doses unless you have already been identified as having a deficiency.
There’s been quite a lot done on this. Overstimulation wouldn’t have impacted your chances. I imagine that if you had 28 eggs, all your embryos would have been frozen, so that’s just unfortunate. It’s not the overstimulation that would have impacted your chances. I’m sorry to hear that the treatment didn’t work for you.
It’s a good question, and there’s one thing I always say that the advice I give you today might be different from the advice I give you in three months because we keep up to date with the latest data. In the past, we suggested that embryo glue was a good thing, so we used to recommend that patients had embryo glue, and then we stopped recommending it when we analyzed our data in patients having fresh IVF cycles. We saw, we cannot justify people taking EmbryoGlue when we looked at our data, and it made no difference, but then we found that maybe it would make a difference in patients who had frozen embryo transfers. We found there was indeed a slight difference, but then when we looked at it over a longer period, it made no difference.
So, as things stand now, we do not recommend people to have the EmbryoGlue because we do not feel it is right that you pay for something that does not confirm an advantage. The reason it probably does not work is that the culture media which we use to create the embryos, it already contains the EmbryoGlue. EmbryoGlue is a very emotive word, the company calls it EmbryoGlue, it makes it stick. EmbryoGlue is simply a hyaluronic acid.
It’s nothing more than hyaluronic acid, and you do not want it because you do not want an embryo to stick, you want the embryo to grow. In our culture media, that means where we grow the embryos, there’s already hyaluronic acid, so maybe that is why you don’t need the extra embryo glue. The answer is you can have embryo glue if you ask for it, but you will not find us recommending it to you.
This almost means I have to give you a lecture on endocrinology, and I think it all depends on what protocol you are on and the clinic philosophy. In all honesty, for most cases, measuring the hormone levels for implantation makes absolutely no difference. If you are following the protocols, and the patient is responding as expected, the hormone levels are not always the important thing. Remember that hormone levels are just measuring what the hormone is.
What is more important is what the response is. For example, let’s take the amount of rain. Let’s measure the amount of rain, and that would determine how much crops grow. If you have no rain, you have no crops, but having too much rain does not necessarily mean you have plenty of crops as well. The answer is each clinic should have its own protocols, and there will be a philosophy behind when hormones are measured. I will give you an example. We are selective about when we measure hormones. There are certain indications that things are not going the way they should, or the responding then we measure hormones.
Measuring your hormones every time there’s good evidence, which doesn’t make sense, it just potentially adds to the cost and adds to you having unnecessary blood tests. We noticed that there are many places that when they have the blood test, they pay extra for it. In our center, if you need a blood test, particularly estrogen. You do not need to pay for it. We do it as necessary, but we do not normally do it routinely for everybody. We are being selective as to who needs it and when.
We know that progesterone levels are important. We also know that if you have vaginal progesterone, you are never going to get the same levels of progesterone compared to the levels given by injections. Studies have shown that when you take vaginal progesterone, the levels of progesterone are higher. While when you give it by injection, it is high in the blood but not higher in the womb. Generally, each hospital or each clinic has its philosophy and approach. Our practice is, we only do it when necessary, and we do not tend to do hormone tests routinely, we do it as treatment goes along unless required.
The person who has done the most research on this is Jacky Boivin of Cardiff University. She is a pioneer in this area and has done quite a lot of research. The reality is, for whatever reason, it would be nice to remove stress whether you are having IVF or not, but we appreciate it is very stressful. That’s why there are counselors, and that is why we try to do our best. The good news is that as long as it is not extreme stress, it does not seem to have an impact on the chances of success. Overall, the data does not show that most people experience stress and anxiety. We know that excessive anxiety might potentially influence miscarriage. In terms of fertility, it does not seem to have much of an effect. That is good news. But we do recognize that it would be nice to remove the stress and anxiety for all.
That’s not physiological because if you take estrogen, then you’re not having a natural cycle. After all, if you start having extra estrogen, you are changing what happens to the cycle. Naturally, the estrogen will then cause what is called negative feedback and will prevent you from ovulating. So if you have a natural cycle and then start estrogen support before ovulation, it might not quite work. You either have a natural cycle, or you have a program medicated cycle. In a natural cycle, it is all right to have extra progesterone, you do not want to have extra estrogen. I think if your endometrium is six to seven millimeters, then it is worth checking in the natural cycle whether it’s thicker, because sometimes surprisingly, it is. But usually, the approach where the endometrium is thin is actually to do a program medicated cycle, where you have extra estrogen by mouth and also by patches, so you have a much higher dose. I hope that helps.
When I started IVF, the maximum age was 45, and that sounds ridiculous now, but that’s what it was then. There was a time when people couldn’t use donor sperm because of certain rules. I also remember when I used to give lectures for the British Fertility Society, and one of the sessions I used to do was ‘to treat or not to treat’. There’s a big audience, and what I’d always do, I would give those lectures for about three years in a row, and I thought well, I don’t have a monopoly of wisdom. I have my views, but actually, one needs to take a consensual approach, test the temperature of what’s going on. I used to ask people what the age limit is, and it was fascinating because you would have a range of answers. Some people would say 48, some people would say 49 or whatever, but the main question was also asking them why. What came out was nobody would treat above 50 in the UK. Now that might change, but then nobody said they would treat above the age of 51 with donor eggs or their own eggs. The reason for the 51 is because that’s the average age of menopause.
The interesting thing is, with your own eggs, the HFEA has clarified there’s no age limit at which to treat patients now. Each clinic has to take its own policy and have good reasons for why they’ve chosen a certain age. In our clinic, our approach is very simple. We would not recommend anybody having treatment with their own eggs after the age of 46. Having said that, of course, we have treated women over the age of 46, but only under very strict conditions.
This kind of case is always discussed with a multi-disciplinary group and the patient. It is very well counselled because we think it is unethical to provide treatment to somebody with their own eggs when we know that at the age of 47, the chances of getting pregnant are less than 1%. So it’s very difficult to charge somebody a lot of money when you know the chances are less than one percent. Where we have done treatment for somebody’s 47 with their own eggs, they’ve already been pregnant before or they’ve had a miscarriage or something like that, and they’ve been counselled. So 47 is just above the limit, but our limit is 46. Anybody who is over 46 has to go to a multi-disciplinary meeting for discussion. That’s the approach we take.
The fundamental point here really is that for any situation, you want to avoid medication if possible. You also want to avoid fertility treatment. It’s always that balance between what we are trying to achieve and what the risks are. You have to work those out. What’s interesting, if you look at Alistair Sutcliffe who’s done the most research in this area, and he’s looked at epidural. He’s done the epidemiological studies and what’s interesting is, forgetting about stimulation, it just seems that anybody who has fertility problems just sometimes has some high risk of gynecological problems.
There is no question that if you have 6 cycles of IVF, then your risks are higher, and it’s important to balance the risks well. What are those risks? The main risk is cancer because there’s a stimulation drug called clomiphene, which we still use, it is associated with a higher risk of ovarian cancer. But the interesting history to this is that I still remember the days when IVF was not routinely available, and the standard thing in gynecology clinics was if somebody was trying to get pregnant and they couldn’t have IVF, they used to be on clomiphene for sometimes four years in a row because there was no other treatment for them. So they were stimulating their ovaries continuously for 4years. In those days, there were more problems with cysts and cancer of the ovaries. And that’s one of the reasons why these days we don’t use clomiphene for more than six cycles or certainly a maximum of 12 cycles in certain situations.
It’s about balancing those risks. It’s not about the drugs you use, it’s actually about your stimulation, how you respond to the drugs because you can be on a very high dose of drugs. So if we gave a menopausal woman a very high dose of drugs, it wouldn’t do anything to her ovaries because her ovaries wouldn’t respond. It’s not the dose of drugs, it’s the response to drugs, that matters. So actually, we try to take measures to minimize you being overstimulated, so in our clinic, we practice what’s called appropriate stimulation. That means sometimes people get a mild stimulation.
We don’t just call it a mild stimulation. We just do that as we see fit, and we try to do what’s right in terms of creating an appropriate response, and sometimes people still over-respond. That’s the nature of people’s ovaries being more sensitive, and sometimes you find that happens. So you know, if you’re having numerous cycles, like six cycles, that’s a concern. But for most people having a few cycles is unlikely to be a major concern. That’s more of a concern if they have an ovarian cyst.
The big question here is your age. If you’ve had four miscarriages, that are now something to consider and to discuss. If you’ve had 4 miscarriages, we would hope that at least 1 of them would have been tested. If you have had 1 of the miscarriages tested and it’s shown an abnormal pregnancy, that gives a more compelling reason for you to have PGS. If you’re over 37, and you’ve had following miscarriages, then PGS is something that should be strongly considered.
One thing to mention about PGS is that it does not make an abnormal embryo normal. PGS just identifies abnormal embryos, so we do not implant them. We had a patient the other day where we had eight top-quality blastocysts, but all of them were abnormal, and that’s a tragic, really difficult situation. But at least, you did get answers. So, unfortunately, that patient didn’t have an embryo transfer in that cycle. In another case, we got four embryos, and all of them were normal.
I sometimes tend to experiment with patients. I say: Look, I have to draw my left-hand side, and you might guess that it might be pens, papers, paper clips I hold in my hand, but until you open it, you’re not sure. I think the same thing PGS testing is. Certainly, now it would be something to consider when you have had so many miscarriages because then you would have an answer. But in these circumstances, there are three things to consider. One is the technical advice, and that has to be individualized to your circumstances. The second one is the financial aspect because PGS is expensive. And the third is the emotional decision you make because people might choose to make different decisions presented with the same information.
It’s a really good question, and I will just clarify the point where I said I don’t believe in infertility, as infertility means you can’t get pregnant. I rather use the word sub-fertility. To clarify sub-fertility, or what many people call infertility is truly common in 1 in 6 couples going to the GP or hospitals for advice. And 1 in 4 couples experience difficulties, so sub- fertility. But infertility, and what I mean by infertility, is that you actually cannot get pregnant at all, is very rare. If you’ve had a hysterectomy or your testicles have been removed then you are infertile. In your case, you said at 41 you conceived ectopic pregnancy, and you had one round of IVF and a good quality blastocyst, but implantation did not occur. After one IVF cycle, it probably just is bad luck because we know you can get pregnant, as you’ve proven you can get pregnant with an ectopic pregnancy. A good quality blastocyst does not mean that the blastocyst was normal at the age of 41. The chance of that blastocyst being normal is less than 40 %. Even though it looks normal, it might still be abnormal. The answer would be most likely to try again and do PGS because most likely the problems were caused by the quality of the embryo, not necessarily blastocyst, but quality in terms of chromosomes that PGS might be able to identify. Is there a test to check the egg quality? I think my eggs are really poor. The DHEA did not help. One thing we can do is check the quantity. We can do that by scan or by an image. It just gives us an idea of the quantity. Quality is a different thing. Within your ovaries, you’ve got good eggs and not so good eggs. When you are young, you have a higher proportion of very good eggs and a lower proportion of poor quality eggs.
When you are older, like 50, most of your eggs are poor quality, and it is very unlikely for you to have good quality eggs. As you get older, there is a change in proportion. People ask this question if you can check the quality. The answer is if you’ve had IVF and created embryos that in itself is a check. IVF is a treatment, but actually, it is also a very sophisticated test because you have got the embryos and eggs in front of you. The other thing is each egg is different. Those of you who have brothers or sisters would know that very often you are different from your brother or sister.
That means you came from a different egg. If you test an egg very often, you damage that egg, so once you test an egg, that is it. There is no way to test it, it’s all about probabilities, and again about luck and that, hopefully, the egg that is fertilized that time is a good quality egg. What we need to do is optimize your chance. Your chances, unfortunately, maybe low, and biologically, there’s sometimes not much we can do about that. Therefore in those circumstances, one may need to consider egg donation, and on egg donation, your chances with donor eggs are 50%, and the chances with your own eggs might be lower. If you’re 44, the chances are less than 4%. Your chances definitely will be better with donor eggs. You’re right with DHEA, in my experience, I’ve found that in about 50% of people, it makes absolutely no difference. In some, it makes a little difference, and very rarely, it makes a huge difference for some people.
No, because eggs are fragile. Remember that most people are not aware that the average sperm count is a quarter of a billion, that’s 250 million sperm. When sperm are stressed, then they leave these little fragments of DNA, which you could test. When we do egg collection, we are only getting somewhere between zero to a maximum of 20 eggs. We aim for about 10 eggs. You don’t do DNA fragmentation on eggs.
There’s a normal range, and sometimes you have little degrees of abnormality, and it is okay. If you have a mild form of adenomyosis, that is very common. Many people have a mild form of adenomyosis. As to the abnormal shape of your uterus, if it’s only 3 to 4 millimeters. That’s actually within the normal range, and I would not recommend doing anything about it. At that type of level, which is just within the normal range. I would not be worried about it. Based on the information that you have provided here. Carry on with confidence. If it’s only mild endometriosis and adenomyosis and only three to four millimeters. I undertake surgery on the wound, but in this type of scenario, I would not.
The thing about the long protocol is quite flexible. You can be on the general spray for 6 weeks or 3 weeks,s or two weeks. Usually, you need to take it for a minimum of about two weeks to get what’s called down-regulation. I think the answer is that without knowing more about you, I cannot answer it. It might be that they’ve changed something else, and they’ve given you a flare-up protocol or something. I think this question should be directed at the clinic or to your specialist. There are many tweaks to protocols, and sometimes there’s no disadvantage, so I would not be too alarmed. You need to direct the question to them.
It’s a good question. I think green tea has antioxidants, but green tea also contains caffeine, so as long as you are not taking more than two cups of caffeinated drinks a day, you’re likely to be fine. It’s unlikely to decrease the egg quality.
It’s a really interesting question because we thought the ERA test would be a fantastic test when it came out early last decade. It’s only now that the evidence is suggesting that it might be beneficial, and I think one of the problems we have with the test is that it’s quite expensive. I mentioned to you earlier on I’ve been in this business a long time, I’ve seen tests come and go. There is some evidence that it works, and we do offer it. Yet, we’re very selective, and we look at the cases individually. For example, if you’ve had failed implantation because your embryo quality is poor. Then I would not recommend an ERA test. But if you’re young or not too old and the embryos were top quality and implantation did not occur, then you have to begin to think about the endometrium. Those are the type of instances where one might begin to look at that.
These are all interesting things, there was something about that in the past. I’ve tried it. I must say I’ve seen no difference. But again, these are tweaks, they’re not going to make huge differences. It’s not going to be harmful, but there’s no compelling evidence that mixing the two can be beneficial. There’s certainly no harm in doing both, and there has been some speculation that it might be good, but, as I said, I’ve tried it as well and haven’t noticed much much difference and now generally tend to choose one or the other. In some cases, if things don’t work, then you swap to the other the next time. Generally, they have similar effects.
I’m not a nutritionist, so I can’t comment too much about how she’s come to that conclusion. I have seen some very interesting things sometimes that patients present after consulting with some non-medical specialist, which I am concerned about. What is very clear is that if you have a lower BMI, particularly, if your BMI is lower than 19, your chances will be much lower. If it’s lower than 17, that is extreme. If your BMI is too high or too low, then your chances are affected, and sometimes it’s the microenvironment of where the egg is developing that can affect it. But also, if you’ve got a negative energy balance or you’re in a calorie deficit, it can be negative. It’s not only just the nutrients, you need a balanced diet.
There’s good evidence that you need carbs, fats, and protein. What we also recognize now is that it’s not just about your diet. Sometimes it’s actually about your genes because there are some people that, if you just remove carbs from them or even lower their carbs, they stop having periods, and some other people just remove fats from them, and they stop having periods, while for other people on the same diet there will be no change. So people’s genetics also determines their response. Some people exercise a lot, and it does not affect their egg quality or embryo quality. Other people, who exercise much less, have a poor quality of the embryos until they stop exercising, and then the embryo quality becomes better. But again, it takes four months as it takes four months for the eggs to develop. So if you make any dramatic change to your diet or exercise regime that’s supposed to affect egg quality, ideally, you want it to be for about three or four months.
That is about right. 300 UI is usually the maximum dose. There is little evidence saying that going above 2 to 5 UI confers a benefit. We do know that 300 is about the maximum dose. Some places prescribe 600. In our center, in rare instances, we go to 450, but generally, 300 is the max. There is some evidence that going to 450 can be beneficial in some patients. The thing is we don’t know which patients.
Until the studies are done, nobody knows. This is where the ERA test has come about saying that there is poor synchronization. Doing the ERA test is expensive, so it’s very difficult to know what the prevalence is. The other thing we don’t know or is if you have poor synchronization in this cycle, does that mean you’ll have poor synchronization in the next one? The next cycle might be completely normal. I think these are questions that need to be answered, but this is a new area of research, and we’re only still in the early days of it. We might have more answers in a few years. Now we simply, do not know how common it is.
When I talk about inflammation, I’m not talking about generalized inflammation. I’m talking about inflammation where the embryo is attaching, so no, that’s not an answer to take the sugar. It’s about local inflammation, not generalized inflammation. You don’t want generalized inflammation.
If you’ve got a rheumatic condition and you’re already on aspirin, then you need to take it. If you have phospholipid antibody syndrome or lupus, you need to take it. If you have a very high platelet count, which should be seen on your full blood count, or if you have a very high red cell count, those are the situations where aspirin potentially can be helpful.
At every stage, there are gradual improvements, and there will be a big leap sometimes. IVF was a big leap, and then another big leap was having ICSI. I still remember the days when there was no ICSI, and the men who had sperm problems had to use donor sperm. I think another big leap has been going to blastocyst culture because when I started, we used to put embryos back always on day two or day three, and now we tend to put the embryos back on day five. I think there is a lot of talk about the testing, like non-invasive testing, but I think that’s going to be tricky. I think epigenetics is interesting in how we can improve the quality of the eggs, and I’m not sure how that is easily achievable, especially if you think about the way the egg is structured. You’ve got the nucleus of where the center of the cell is, and then you’ve got the mitochondria. The mitochondria are like batteries. I wonder whether there will be progress in how we can deal with that. We’ve always got to be careful when we interfere in certain things of nature to see what are the long-term effects. I think it’s very exciting. There’s lots of progress, there are lots of people doing exciting research. The further we get there are also likely to be downsides, which we will find later on.
We’re just beginning to see that sometimes with frozen embryo transfers, there’s a slightly higher risk of having high blood pressure in pregnancy. These are things that are emerging with fertility treatment. Certainly, there will be more preservation, and there will be freezing more eggs. The technology there has advanced dramatically. When I started doing fertility treatment, it was not legal to treat single women or same-sex couples. That has changed. If people are about to live to 150, then fertility in 20 or 30 years will be different. People might be treated at a later age but I think in the present there’s still a lot to learn. There’s still a lot of exciting research areas. How can we improve the implantation? Many of you alluded to improve their egg quality. Most people would rather use their own genetic material rather than donor eggs.
Certainly, at this stage, we’re also not aware of things like that, we can’t create new eggs in your ovaries because that’s just physiologically not possible at the moment.
It’s not a blood test because if you have inflammation detected in your blood, that means it is everywhere, so it’s systemic, and that means you have an infection that’s affected your whole body. This is about the infection that is local and contained within your womb cavity or the womb’s lining. The lining of the womb is known as the endometrium, so when you have inflammation or infection of the womb line, it’s known as endometritis. So endometritis or chronic endometritis is inflammation of the lining of the womb, and that we can test that by taking a biopsy from the lining. Endometriosis is when the womb’s lining is outside the womb, so in the pelvis around the ovaries, around the bowel, etc. Endometriosis is different from endometritis. Endometritis is an inflammation of the womb’s lining. Endometriosis is when you’ve got the lining of the womb outside the womb. That’s causing inflammation in other areas of the body.
As a clinician, as a scientist, I think it would be helpful to wait for the evidence. We don’t know, it will be total speculation. You find it might reduce your chances, and other times you might find it improves the chances. The honest answer is I don’t know. When it comes to the vaccine, it depends on what type of response it initiates. Whether it causes a systemic response or transient, or if or it just leads to the creation of antibodies. If it just leads to the creation of antibodies, then that’s fine. That should not be a problem, but if it can cause a general systemic effect, then that might be different. The answer is I suspect that when they provide the vaccine, they will provide a bit more information on whether you should be taking it if you’re preparing for a pregnancy. But I doubt that it will affect the egg quality because it is protected and doesn’t tend to be affected by systemic inflammation.
Physiologically it doesn’t make a difference, as long as you’ve had a period after that miscarriage and you’re emotionally prepared to go through IVF. It is up to you. There’s not much evidence either way, so it is a question of being mentally prepared for it. If you’ve had a miscarriage, I’d wait at least another period before you start.
I think there are two that stand out for me. There’s one patient with a poor reserve, and she had very high FSH, and she got stimulated getting one follicle, one egg, one baby. Then she came again, high FSH, stimulated one follicle, one egg, one baby. That’s quite rare. And the other one was somebody who came to see me after 19 miscarriages, and this is not IVF, but we put her on, I can say that it was the drug regime that we used, and she then ended up having a baby after that. Those are two that stand out.
The question is: how long ago are you clear of the disease? You have to be well to proceed with IVF treatment, so each case has to be individualized because again some people have suffered ill effects of COVID-29 for months, so we would then not recommend you go ahead. But if it’s a mild case and you’re absolutely fine, then as far as we know and you’re negative, then it’s all right to proceed with treatment.
The key thing, this is not what people like to hear, but the main thing is that AMH is not a definitive test because people want to use numbers. AMH is not a fertility test. We all thought it would be a fertility test, but it is not a fertility test, and some things I’ll say now might surprise you. AMH is just a test to give us an idea of your egg numbers. That way, we can put you on the right dose of stimulation for IVF. It is not a fertility test, high AMH level does not mean high fertility. As studies have shown, your AMH level does not correlate with your chance of conceiving naturally or not. If your AMH levels are higher, it seems you have a lower chance of getting pregnant than if your AMH is lower.
I think that the reason for that is that if you have a very high AMH level, it means you’ve got polycystic ovaries because AMH just counts the number of eggs, and when you have polycystic ovaries, it means you’ve got a lot of eggs now. The most important thing about AMH is whether your levels are high, normal, or low. That’s the most important thing. The actual level is not as important. It’s a helpful guide, and we use it, but we also use your scan to decide what your reserve is. If you did an AMH level today and you repeated it in two weeks sometimes you would get a slightly different result. At 36, your AMH level probably will be in the region of 10 or thereabouts picomoles per liter, but that’s the average. You’ve got to look at a range, and the range will go from about three or thereabouts to much higher levels.
There’s a chart that’s used to look at that, but the most important thing is if you are having regular periods and your level is within the normal range, don’t be too worried about the specific AMH number itself. Lots of people tend to worry about it. Some people ask if they can have their AMH level checked after they’ve had IVF. We are very happy to do that, but it makes no difference because the most important test is how you responded to IVF.
Once you’ve had IVF treatment, we can see how your ovaries are responding that is the real test, not your AMH levels. If you’re driving on the street nobody asks you to do your driving test again because you’ve already done your driving test, and you’ve passed. What is important is whether you can drive a car properly. It is not about your fertility it’s about how you respond, and there are many studies now that have shown that AMH does not predict the chances of implantation with IVF treatment, but it helps us determine how many eggs we’re likely to get from you.
People rarely do back-to-back cycles, but it shouldn’t make any difference. The key thing if you remember is that if you have a problem with your egg reserve or there’s been an insult to the ovaries such as you’ve undertaken a marathon or you’ve had a very severe illness, you’ve lost weight and you’ve gone in a caloric deficit, then you need four months to replenish that. As long as you continue to take that replenishment, it will be of benefit to the other ones.
I don’t know the easy way to explain this, but ovaries develop in cohorts, so most of the eggs are resting, then they get to a stage almost like nursery school, where they rest, then they go to primary school, then they go to secondary school, then they go to the stage when they’re recruited. So, as long as you’ve prepared, it’s almost like if you provide education from an early stage and you continue to do that for everybody, the output is better. If for example, you have a very low body mass index or you’re trying DHEA or coenzyme Q10, then you want to have taken that at least for four months before so that it’s in your system long enough to have an impact. It shouldn’t affect back-to-back cycles for most people. The downside to four months, particularly if you have a low reserve is your chances go down. People rarely have more than three cycles in a year. It’s rare because it’s emotionally, financially, and otherwise quite challenging.
I think the answer here is that you need to have a proper consultation and all the forensic information on your case has to be taken into account. It’s very difficult to say in your circumstances which is the right test, and that’s why if you remember when I gave the presentation and listed all those tests, I said the key thing is the skill of the clinician who sees you. They have to advise you what tests to have and what not to have. You can have all of them, but it then becomes very expensive, and it might just be that if you’ve had to go to an egg donor egg, you’ve just been unlucky with this first cycle. If we look at the success after using three donor egg cycles, the success rates will be well over 70 percent, so it is more than likely that you will end up having a baby, and you’ve just been unlucky this time. So that would be the normal answer – not to have any tests after one failed implantation. But I don’t have information on what happened with your three previous failed IVFs, so that is where that forensic information is required and looking at you as an individual rather than just a generic answer.
It proved that, in a way, human beings have some systems within them that prevent them from releasing too many eggs. If you look at dogs and cats, they very often produce a litter of several puppies or kittens at the same time, while human beings have mechanisms that protect them. The ovary is quite interesting. Some people also have what’s called ovarian resistance, where they have lots of follicles and a good image, but then they don’t respond to stimulation at all. These are just physiological differences between people, and I wouldn’t worry too much about the actual AMH levels, and the same can also apply to the follicle numbers because what you’re looking for at the end of the day is a baby. It’s important to know whether it’s high, normal or low, because if it’s low, then you need perhaps sometimes a high dose to stimulate. If your reserve is high, then you need mild stimulation. As to whether IVF medication leads to increased follicles – absolutely no. The follicles are already there. What it can do is prevent those resting follicles that were asleep from growing. If somebody has a very good reserve, you need to put them on a low dose, so you only get a few of them up. If you give them a very high dose and all those follicles come up, you get ovarian hyperstimulation.
If you have a very poor reserve and you have a high dose of medication, then you’re not going to get too many follicles. During the presentation earlier, I mentioned that if somebody was into menopause, no matter how much stimulation you give them, they’re unlikely to produce any follicles.
Many people might not know that IVF medication, like Menopur, was initially produced and is still being produced from processing the urine from nuns in Italy where their FSH levels are so high because they are menopausal. That urine is collected in buckets and then processed because they have got such high FSH levels trying to stimulate their ovaries that they are menopausal. So that tells you that FSH cannot create more follicles, it can only make those receptive follicles to grow.