Why does IVF fail with good embryos?

The first thing that we must do is check if the embryo is of good quality because that can be very different depending on the patient’s age. If the patient is young, there is probably going to be a good correlation between morphology and genetics. Any embryo with good morphology should be considered to be of good quality.

If the patient is 42-43, most of the embryos that are going to look great, such as AA, AB, BA, can still have some genetic issues. When the embryos look great, and they don’t implant, the first thing to do is to take into account the age of the patient and check whether the embryos have been genetically tested, or not.

If you are sure that the embryos are of good quality either because the patient is young or the embryos have been genetically tested, then there could be issues on the endometrium side or the mother’s body. This could mean that the endometrium is not prepared for letting the embryo implant. The patient could have some problems related to coagulation, immunology, for example,  antiphospholipid syndrome. It could happen that the endometrium’s environment is not the best because there is endometritis, chronic infection or even the endometrium microbiome may not be a perfect one. This is always going to make things more difficult for the embryos to implant.

In any case, the first thing that we need to do is to confirm that the embryos are of good quality. If they are, go and study the endometrium or the patient’s body to check if there is anything on her side that may be negatively impacting the outcome.

I wish to have an answer to this. Because if I had the answer, I would have a Nobel Prize by now. Unfortunately, regardless of techniques and advances in science, we are still not able to pinpoint exactly why it didn’t work – despite good quality embryos.
Now, what does good quality of embryos depend on? Are we talking about it just from the embryologist’s point of view? Yes, we have the scoring system and the grading of blastocysts. And everything may look fine from that perspective. However, now we are classifying things more according to what could go wrong into 3 basic categories:

1. Genetics – Are we talking about anything genetically happening with the actual embryo? The only way to address it is to have a biopsy. If you have heard about PGS (or now PGT-A), this is mainly to address this question. Despite good quality, embryos could be chromosomally abnormal. Why? Because it does not match with the actual shape of the embryo. You can have very good quality under the microscope, and still, it is genetically (or chromosomally) abnormal. And another way round – you can have a not as good quality embryo under the microscope, however, it is completely chromosomally normal. So, the only way to address it would be through PGT-A.
2. The second main element is the implantation of the embryos. We are trying to have advances in this field as much as we can. You may have heard about e.g. ERA (endometrial receptivity) testing. As you know, for the consensus about implanting the embryo, we administer progesterone for 5-6 days – and this is arbitrary. Unfortunately, we don’t know exactly what the best time is or how long we should give progesterone. But we know there is the implantation window and we try to hit this window with 5 or 6 days of progesterone. However, there are patients who have pre- or post-implantation windows and this endometrial receptivity testing has come up to address this question. Some people need more progesterone days, like 7-8 days, others need less progesterone. The majority of patients are post-implantation window.
3. The third element is immunology. Is there any other immunological factor that could impact the issues of implantation? There is a huge debate and evidence-based as well as not evidence-based arguments. I can give you two sides of the coin. Yes, there are some straightforward conditions that definitely need attention immunologically, such as rheumatoid arthritis or systemic lupus. We know that there is immunological impact and these are the most evidence-based reasons for supplementing e.g. steroids or low-molecular-weight heparins. However, other conditions are still not evidence-based but some clinics offer immunological modulation or treatment in order to overcome simple immunological derangements. When I’m talking about that, I’m talking about natural killer cells, cytokines and all these issues. So I’m not going into details in that, however, it could be a reason why good embryos would not implant.
4. And the fourth one is obvious – it’s nature. No matter what we do and despite the fact whether you’re in a good shape, genetically everything is normal, there are no immune problems and implantation happens straightforward, you cannot beat nature. Nature has its own agenda. You have a specific percentage that you cannot exceed. I cannot have a hundred couples who started IVF or a natural pregnancy and then I end up with 100% pregnancy rate success. This does not defy nature. There is a natural selection and what is allowed and what is not allowed to exceed is beyond our capacity.

So no matter what advances we are going to achieve, I don’t think we will reach the stage of 100%, meaning that every single embryo transfer will end up in a pregnancy. Unfortunately, it is not achievable. However, the main advantage now of a successful IVF treatment is to have a good number of eggs, which are fertilised and reaching the blastocyst stage, in order to allow me to transfer one or two embryos and cryopreserve the rest. If this is the scenario, you have a successful IVF treatment. Even if it doesn’t work at the fresh transfer, there are cryopreserved embryos that can be used. And this is why a successful pregnancy is built not only on the fresh transfer but there is a cumulative success rate of the fresh and the frozen embryo. So even if someone gets pregnant with the second embryo transfer, it is still considered a successful outcome of the IVF treatment. So this is the main thing – I don’t want you to be disheartened if it didn’t work from the first transfer. It is sometimes bound not to work for the first time. If we have extra embryos which are cryopreserved, that’s the main asset for you. They can be cryopreserved for 10 years so this is a luxury to have treatment within this period of time. Once you are pregnant, we can say that you’ve had a successful outcome. It can be delayed but eventually, it will happen.

They used to think aneuploidy and poor quality of embryos are the most frequent reasons for IVF failures so if we transfer good quality, euploid embryos, the pregnancy rate is much higher and it reaches about 60, 65% but this is not a 100 %. All these transformations occurring in the zygote’s falling fertilisation are monitored by all assisted reproductive clinics to determine embryo quality, morphological embryo quality. Embryo quality is assessed on the basis of several parameters: morphological, developmental, genetic and metabolic. The quality of an embryo is dependent on the quality of the oocyte that created it and while many studies have described the relationship between oocyte and embryo quality. Several of the embryo quality parameters have also been influenced by paternal factors. Clinically it has been observed that the transfer of euploid embryos results in an implantation rate about 60% while almost 40% of embryos remain unaccounted for. Although some losses can be accounted for by endometrial factors so the residual loss could be partly accounted for by paternal factors. Those factors like obesity, alcohol consumption, stress, severe male factor of infertility, advanced paternal age and some gynaecological problems itself may have influence on IVF outcomes. What counts and among these factors we need to especially pay attention are gynaecological diseases. We need to work with our female patients and it is well known that several types of uterine fibroids, endometriosis, pelvic inflammation may influence IVF outcome so once a person has any of these diseases, we need to prepare her for the embryo transfer just to optimise chances for success.

We must take into account that we transfer embryos in accordance to the morphological characteristics and that we have certain pregnancy rates per transfer. Nevertheless when we transfer two or three good quality embryos and there is no pregnancy, we are talking about implantation failure and this is when we must review the study to identify the reason for implantation failure.

It can be the option and it cannot. It’s difficult to say how a pregnancy is progressing. I can tell you from my experience: when you put a top quality day 5 blastocyst into a healthy uterus, then the implantation will happen 100% because the embryo will hatch in a few hours: one, two, three, five hours and will implant. I’m saying that because when the embryo has progressed outside very well for five days, I cannot find any reason why it will stop for the next two, three, five hours. This actually is very important before I will assess the immunological problem. When you have a bad embryo at the beginning then, it’s not nice to think, it’s not sensible to think that the problem is with the house that you put this embryo to live in but you have first of all to be sure that this embryo can live as long as you want in order to have a successful pregnancy.

Maybe in such cases we can have a perfect embryo, euploid blastocyst 5AA or 6AA for example and there is no implantation in the uterus. So in this case it might be that the endometrium, thickness of the endometrium is an important thing, the age of the patient, the previous failed cycles and the medical history of the patient can impact outcome.

Why doesn’t a very good-quality embryo implant? There are two reasons. It can be a low-quality embryo with bad genetic information inside. It may look like a very nice embryo, morphologically nice. But it may contain the incorrect number of chromosomes. The embryo development stops. The other reason is the implantation window, the best timing for embryo transfer. 20% of women are not receptive 5 days after the first intake of progesterone. If we have, for example, two or three embryo transfers without implantation with negative HCG, it is necessary to think about the implantation window and about testing it. So it depends from case to case.

In women after 45, it is necessary to think about chromosomal abnormality inside of the embryo. In younger women, very often, the reason is the bad timing of embryo transfer. But individually, it’s not possible to say why it did not work. It’s only a general answer, but there is no individual answer. It is necessary to do many tests, and sometimes we can’t find the reason.

We can consider three factors here: the gynecologists, endometrium/uterus, and the embryo. For an inexperienced gynecologist, if you want to get the perfect embryo and they cannot properly do the embryo transfer, you can have a negative result. This is on our side.

Secondly, as a gynecologist, during the whole process, I have to follow up on two things: the eggs, and the endometrium. As for the endometrium, during every ultrasound, we check and note down the thickness and the shape of the endometrium. If the endometrial lining is not fulfilling the criteria, we don’t do the embryo transfer, we freeze all embryos, we prepare the endometrium, then we do the transfer. This is the second side.

Thirdly, according to studies, in infertile couples, even with the best embryo, on the 5th day, 40% of those very good-looking embryos are genetically abnormal. On the embryo’s side, a genetically abnormal embryo can cause IVF failure. These are the important things. When there is a failure after an IVF attempt, we call the patients to ask two things. First, if they’ve done a radiological exam to see her uterus and tubes, to see if there is a problem inside, and secondly, we check the chromosomal structure of both partners because if there is any chromosomal abnormality in one of the partners, we have to check on the embryo level – if there is any chromosomal abnormality then we choose the best one and the healthy one and then perform the transfer.

This is an extremely difficult question to answer. In fact, I don’t really have an answer. But what I can say is that there are different factors in achieving a pregnancy. And one of them is the embryo, and the quality, the good quality. And even good quality or good looking embryo doesn’t mean that the embryo is actually competent or able to implant.

So we have to think that even if we transfer a perfectly looking blastocyst, perfectly developed, then we don’t really know the actual inside of the embryo. We know that  around 30-40%, it depends on the age of the patient. 40% of the embryos are actually not able to implant despite them looking fine, so that could be already a reason.

Then other factors affecting implantations are the importance of the lining of the womb to be coordinated or synchronized with the stage of the embryo. There has to be what we call the window of implantation. It is a time frame where the embryo is most likely to implant. If we get that window implantation wrong, then the embryo is at a certain stage, and the lining is at the stage that could be either bit behind the embryo or a little bit forward compared to the embryo. If that happens, there is no perfect synchronization, and the embryo is not going implant, and so that’s another important factor. That leads to the hormonal environment, which again has to be perfectly precise, and the thickness that we already discussed. We take into account the endometrium thickness, the whole environment, the glands, the substances, and the stuff inside the uterus, the receptors. So there is a micro world or microenvironment which is all in that thickness, in that lining and that is what has to be perfect for the embryo implant.

There’s no real way of discerning what a perfect embryo is or how many compounding factors that can impact on the day how an embryo will behave or grow, adapt in vitro like in the little plastic dish or as a transplanted back and there are many reasons as to why a really good quality ambient has been graded as a high quality embryo and fails to produce a pregnancy. That can be down to the receptivity of the endometrium that means that the lining of the womb doesn’t pick the embryo and attach the embryo well enough; it could be down to if the embryo itself, the outer cells of the embryo that are implanted to endometrium may not be functioning properly either. So, there are many factors but because this whole happens inside into uterus, is very little is known as to why that may be caused but there are lots of research using mouse embryos and using other different animal models and human embryo models in vitro to be able to kind of find out the causes of these. There’s lots of interesting research going on.

A difficult one and in some ways it’s the million dollar question and the way I think of it is there’s like a funnel with IVF treatment and if you think of everyone going into the top of the funnel starting off treatment most of them, some 90% of them will go on and have a 90% plus or go on and have an egg collection, of those 95% and nearly all of them will have embryos to transfer. So most people who start out on IVF will have an embryo transfer. The next step is when you get this funnel and essentially from an embryo transfer, only about 30 to 40% of women will become pregnant. So there’s this huge kind of drop off after the transfer and then after a positive pregnancy test about 70 to 80% of women will go on and have a baby. So really IVF fails the most between embryo transfer and pregnancy test. Now the reason behind that you can probably put into one of four categories, as part of a jigsaw puzzle, so the first thing is: it a problem with the embryo and we you’d ask the questions about good quality embryos and embryos is quite difficult to grade and even the conventional grading looking down a microscope, is not that reliable. Even putting back the best quality embryo probably only has about a 50% chance of a pregnancy and that’s putting them the best quality back. Some people will do genetic testing of embryos and even putting back a perfect embryo doesn’t alter those statistics still, so it’s probably something more than just the embryo but perhaps the embryo perhaps accounts for at least a third of those failures. The other three things to think about: is it the transfer process itself that has been difficult or tricky and you can use ultrasound to put an embryo back inside the womb but we still know embryos are not sticky and move around. You can put it back, you can see it’s back in the uterus and still end up with an ectopic pregnancy, so ultrasound isn’t always that reliable. Is it to do with immunology? Is it the immune system that’s attacking the embryo or doesn’t allow it to implant? There’s lots of research happening in that area but we’re still not really much further to understanding that and then finally it is about the endometrium, the womb lining itself. Is the problem with the receptivity or not? Selecting a good embryo or even there’s some thought perhaps if there’s a problem with the endometrium you accept an embryo that’s abnormal then that leads to miscarriages. These are still areas that are very much the focus of research. There are some supplementary tests that can be added on to look at endometrial receptivity but the science backing them up at the moment is a bit unhelpful in that it is not very easy and sort of affects how you do the treatment. So many places don’t necessarily offer those tests at all. So ultimately you don’t really know the honest answer is no one can tell you why that failed in your circumstances but they’re the four factors that probably have some influence on why it doesn’t work.

One of the most important factors for the embryo to implant is the window of implantation. Embryo needs to be completely synchronised with the uterus which is hard to do as an embryo is made outside of the body and then brought inside of the body. Second reason why it is not always easy is that even with good embryos there is a failure. is that not every embryo that is made in the lab is normal. Recent studies proved that most of the embryos that are made are abnormal. Could be sometimes 40 % of embryos that are abnormal and by abnormal I mean that they don’t have the right number of the DNA that an embryo should have. In most of the cases, the embryo will just not implant.

First of all, to answer this question, I think the more important thing is doing a little bit of introduction on fertility age. I always explain to patients that fertility is very dependent on the age of the patient. We know that we have a certain ovarian reserve that we’re born with. This ovarian reserve is going to decrease with age in terms of numbers, but also in terms of the quality of the eggs that we have. So actually, what we can test is the ovarian reserve, in terms of numbers, but not the quality of the eggs we have. And that’s why we are always talking about eggs and fertility.

What we do know is that for example, after the age of 35-37-40, it’s more difficult to achieve a pregnancy. We know that after 40, it’s trickier to become pregnant. There’s a higher risk of having a miscarriage. And also, there are higher rates of having embryos with problems in the chromosomes and all of this is related to the quality of the eggs which is then related to age.

The other thing that I want to say is, a good embryo in terms of morphology, isn’t necessarily related to the good genetics of the embryo. So we can see a very beautiful embryo, but this is not going to tell us if the embryo is a euploid embryo or not. Euploid embryo means that the embryo has the correct number of chromosomes and their good disposition. It is also a very important thing to know. When we talk about good embryos, we have to consideration morphology and also genetics which is very important. And the third thing is if we are transferring good quality eggs that have been tested and we know that they are euploid, they have the maximum possibility of implantation when we are using euploid embryos, we know that the success rate is 70% more or less. So we know that not all of them will implant and this can be because of statistics. We know that not all of them will implant. We would like to give a 100%, but it doesn’t work like this.

On the other hand, if we have several implantation failures, then we need to check if there’s something else that is affecting it. Because the first thing that we have to check is if the embryo is correct in terms of genetics and also that the karyotype of the parents that are giving the eggs and spermatozoid is correct. But if this is confirmed and still doesn’t work, we have to rule out, e.g. thrombophilia factor, a predisposition of having blood clots and problems to become pregnant, or repeated miscarriages. We have to study the uterus to make sure that everything is correct with the hysteroscopy or biopsy. We can also study the endometrium to see if there’s a problem with the receptivity of the endometrium or, or we can also test microbiota. And also we can test some immunological things that would be responsible for this bad outcome.