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.
Implantation – key factors
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.
The outcomes of spontaneous conception
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.
Managing recurrent implantation failure
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.
Effect of age – live birth with IVF treatment
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.
Diet, reducing stress and its benefits
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