Uterine factors that impact on blastocyst implantation

Obviously, it looks like a long-standing fertility problem. I assume all tests results came back as negative. There is evidence that hydrosalpinx can affect the endometrial environment. So if any of the embryo transfers and the pregnancies occurred while there was still hydrosalpinx, that could be a contributing factor. If hysteroscopies have shown that the uterus is normal, that has nothing to do with abnormalities. What’s interesting is the presence of endometriosis. Endometriosis has been considered a cause of the abnormal endometrial environment. Some years ago, myself and my colleagues in America published a number of papers showing that women with endometriosis have delayed endometrium. Normally in my practice, we don’t do a natural cycle in women with endometriosis.

We do prolonged down-regulation so we suppress the pituitary gland, we stop the cycles completely for three months before restarting the endometrial activity with high doses of oestrogen and then progesterone. So what we like to do – according to the evidence that we’ve published – is to actually reset the endometrial clock in women with endometriosis. The endometrium in women with endometriosis is likely to be disorganised – so although a biopsy can show it to be in-phase because of progesterone exposure, deep inside the endometrium may not be ready for the pregnancy. My recommendation will be not to do a natural cycle but instead to down-regulate the pituitary gland to stop the cycles and then restart it on a hormonally controlled cycle.

This is a very good question. It is still unknown but what we know as a fact is that it takes time for the endometrium to absorb progesterone. So for the same reason, could you achieve in one day what you normally achieve in five days, just by giving the same dose of progesterone? Well, the answer is: no. There is a ceiling effect with receptors in the uterus. And there is evidence that prolonged progesterone administration may be better than high doses of progesterone within a short period of time. It is because the receptors for progesterone may not be able to respond to the doses of progesterone as well as if progesterone was given over a longer period of time. I have had cases of women that have had an endometrial biopsy for the endometrial receptivity assay – so to determine the implantation window – and after five days of progesterone, they still had the pre-receptive endometrium. It means they needed another day of progesterone or another day and a half. And you cannot overcome that by giving a higher dose in the five previous days. So I think 800 milligrams of progesterone in the form of pessaries (for instance, 400 milligram pessaries twice a day) is a good standard dose but the length of the progesterone administration may differ.

Well, you can’t do it. The test is available in our clinic but if the test is not available in a specific clinic, then you cannot test it. Normally, it’s done by taking a biopsy of the lining of the womb, called endometrium, at specific time. The biopsy is sent to the lab and there they will be looking for the presence of bacteria, confirming if lactobacillus is the main bacteria within the endometrial cavity or if there are other types of bacteria. Then perhaps you should consider antibiotics or probiotics. What we need to know is whether perhaps there are the cases of bacteria within the uterus that cause chronic endometritis, which is inflammation that will affect the embryo implantation. So the test has to be done in order to determine the presence of bacteria – otherwise it will be a silent problem.

This is the same as in the previous question. It can be tested by a biopsy and normally, there is treatment with probiotics or antibiotics, which is normally recommended based on the test results. Then obviously a second biopsy is needed to ensure that the normal endometrial environment has been restored.

This is a is very frustrating and indeed confusing and perhaps challenging for the physicians looking after you. But as I mentioned in my presentation, if the fibroids were affecting the junctional zone, they could cause abnormal contractions of normal vascularity. I have no information about the ultrasound findings or indeed operation notes in relation to your surgery, so it is difficult for me to say whether it was actually the cause of you previous miscarriages or not. But it could potentially have been the cause of your miscarriages. You also need to bear in mind that women of your chronological age have probably 70-75% chances of producing abnormal embryos. That per se is another contributing factor to miscarriage. So I think that at this point in time it is difficult and I wouldn’t worry about the cause of your previous miscarriages if you haven’t got any more fibroids. Instead, I would embark on IVF with a plan to create embryos that can be cultured to blastocysts and be genetically tested. Because on a balance of probabilities and based on published evidence, there is more chance than not that your embryos are genetically abnormal – just because of your age, which in turn may be the cause of miscarriage or implantation failure.

Any surgery, especially laparoscopic myomectomy or open myomectomy, can cause adhesions within the uterus and within the pelvis. And if the adhesions are within the pelvis, it is a possible cause of tubal blockage – or it may not be tubal blockage, so the tubes are open, but abnormal tubal function. So anyone that has had surgery is at an increased risk of adhesions. Hence why, before offering a surgery for any problem, we need to look at what are the possible consequences and complications of surgery for somebody trying to conceive. I do perform surgery regularly: from laparoscopic myomectomy to laparoscopic hysterectomies, to tubal surgery, to ovarian cysts, to removal adhesions or to removal of endometriosis – and I always make my patients aware that one of the possible consequences and the risks of a surgery is the presence of adhesions. And adhesions in women seeking pregnancy and in women who have got tubes and are planning to conceive naturally, could cause blockage. It could also cause abnormal tubal function – so the tubes are not blocked but they’re not contracting and not functioning properly because adhesions may stretch or alter the normal anatomy and the relationship with the ovaries.

Well, implantation is a problem obviously. Maybe again there is a line and the same underlying problem between failed implementation and ectopic pregnancies. You’re from France so France is a country where the technology is available. I would suggest that you have a hysteroscopy to look at the inside of the uterus to exclude some abnormalities. And also, if you’ve had two ectopic pregnancies, you will need to be seen by a gynecologist with expertise in a reproductive surgery and possibly by a fertility physician as well to see if the underlying causes for your ectopic pregnancies could be adhesions. Sometimes it could be damaged tubes and in some cases, it is necessary to remove the tubes to reduce the risk of other ectopic pregnancies – in case, obviously, the tubes have not been removed already. But if you are attempting to conceive, you will need to consider having a hysteroscopy in order to assess the inside of the uterus. And if you were to embark on IVF treatment and you have had ectopic pregnancies, I would probably consider clipping the tubes before doing IVF in order to reduce the risk of damage. I know you said your tube is blocked – and that’s the problem. If the tube is blocked, you can have fluid accumulating within the uterus. The fluid within the uterus becomes toxic and that is the reason why embryos may not implant or that’s the reason why you can have an ectopic pregnancy. So blocked tubes, in my opinion, are current evidence suggesting they should be removed or should be detached from the uterus at least before embarking on IVF treatment. That’s what we do in my clinic all the time.

Again, it’s very difficult. I don’t have any information about the fibroid or how close the fibroid was to the endometrium and whether there was an impact on blood supply, etc. So generally there are a lot of factors. A laparoscopic myomectomy normally improves the endometrial performance. I am not entirely sure about the reason why the doctor told you to wait for three months. There is certainly no evidence and no published recommendation that says you have to wait for a certain number of months. Provided that there is normal endometrial environment, so provided that four weeks after the surgery the endometrium looks good, homogenous and there’s no free fluid within the cavity, then you don’t need to wait. Some surgeons may be anxious about the fact that you have had myomectomy and that is because of the risk of uterine rupture. But realistically, the uterus doesn’t rupture when you have a three-month pregnancy. The uterus ruptures when you are 9 months pregnant, when you’re 38 weeks pregnant. And before that, there would be a long wait. So in my practice, I normally perform myomectomy and a scan four weeks after the myomectomy. If the endometrium looks good and there are no problems within the cavity, then I would advise you to start trying to conceive naturally or to have an embryo transfer.

Yes, as it was mentioned already, depending on the size and whether they are close to the junction zone, they can cause abnormal contraction, inflammation or abnormal blood supply. However, the definition of subserosal (which means on the outside of the uterus), intramural (which is in the middle layer of the uterus) or submucosal (which means on the inside of the uterus) is very much operator dependent. What may be an intramural fibroid for a gynecologist (who is not very familiar with the subject and doesn’t see it every day in his practice) could be a submucosal type II fibroid for somebody else. So you can see that the definition of the side of a fibroid may vary between different gynecologists. And indeed, the surgical approach, the recommendation and the consequences of the fibroid on future pregnancy outcome are dependent on the presence of the fibroid as well as the side and the size of the fibroid.

I find it difficult that you’d been told that if you had 18 fibroids, those were not affecting the uterus. The fibroids within the uterus or within the layers of the uterus would have certainly affected the normal uterine activity, contractility and the blood supply. So the fibroids per se would have been a cause of your subfertility. What to do now? I think the recommendation for you now is to have a diagnostic hysteroscopy to ensure that the removal of fibroids hasn’t caused any adhesions within the uterus. That is a consequence. You’re 44 now so your age per se is a problem. You have raised BMI which again is an issue. If a hysteroscopy comes back as normal, I would recommend you have the endometrial combined test which includes the ERA test (so the endometrial activity assessment) and then also the test for bacterial infection and the test for chronic endometritis. The test for bacterial infection is called EMMA and the test to exclude chronic endometritis is called ALICE. So a diagnostic hysteroscopy first and then the combined endometrial tests.

Of course you’ve got number of issues in the uterus, you have fibroids. As I said in my presentation, you do need to have the fibroids that are close to the endometrium removed. There is a risk of you forming the adhesions, both within the uterus and outside the uterus – but it’s a matter of balancing the risk of you forming adhesions and the risk of you not getting pregnant because of the fibroids. So the surgery has to be performed by a skilled and experienced surgeon, possibly a fertility surgeon and not just a gynecologist. After the surgery, I would advise you to take some oestrogen in order to build up the lining of the womb and avoid forming adhesions within the cavity.

We are talking about two different things here. One is the protocol to stimulate ovaries, so I agree that if you have low AMH and lower ovarian reserve, it will be much better for you to be on a short protocol. But you can have a short protocol to stimulate ovaries, collect eggs, fertilise eggs and create embryos which can be frozen. And then, in the frozen embryo transfer cycle, you can be down regulated because the embryos are already being created. So there is no impact on ovarian reserve. And in that case, if you have a history of endometriosis, down regulation will be – in my preference – the best option.

As as I said in my presentation, the presence of a fibroid and the fact whether it is a subserosal, intramural or submucosal fibroid is very much an individual diagnosis. It depends on the surgeon and the person that does the scan. I think the question here is: if the fibroid is very big (and 7 cm is a large fibroid) and intramural – so close to the endometrium- does that fibroid impinge on the junctional zone? If it does, then yes, you need to have it removed. Performing a hysteroscopy and a laparoscopy at this stage may not be the best approach because if the fibroid is not submucosal, you may not be able to see it by a hysteroscopy and a laparoscopy will only confirm where the fibroid is. It will be more appropriate to have a 3D ultrasound scan or to arrange an MRI scan of the pelvis to see where the fibroid is in relation to the junctional zone – which will be my preference. Or, assuming that it is close to the junctional zone, remove it before your next transfer.

We normally do that bacterial analysis, or the biopsy, together with the endometrial receptivity analysis and around day 20 of the cycle – that is during the implantation window.

There is no harm in doing it at all. But you don’t know whether that probiotic treatment is what you need in order to increase your lactobacillus.

The best way to test for chlamydia and other sexually transmitted diseases will be through some swabs taken from within the cervical canal and within the vagina. Chlamydia can also be diagnosed on a urine sample which is a quite reliable test by a technique called PCR.

If you have just had the endometrial receptivity assessment test, then I would recommend you also have ALICE and EMMA tests to exclude chronic endometritis and any bacterial abnormalities within the endometrium because they can be a cause of an implantation failure. They can also be a cause of problems throughout pregnancy as I presented during my very short lecture. So you have been exposed to pregnancy and you were very unfortunate when you had the stillbirth in December 2019. That could have just been bad luck. But I understand that a hysteroscopy was performed in 2017 which showed everything was fine and the polyp was removed. But again, I would recommend perhaps another hysteroscopy just to make sure that there have not been any adhesions or abnormalities within the uterus that could have occurred since then. And then, if that hysteroscopy is normal, do the endometrial assessment to exclude bacterial vaginosis, abnormal bacterial environment and chronic endometritis. And if all of that is negative, then yes, you could carry on with another embryo transfer – but perhaps have the embryos genetically tested as well.

Ideally, they should be done during the implantation window. We normally do them around day 20 of the cycle. You can do them on a natural cycle or you can do them on a hormonally controlled cycle. If you’re planning to have a frozen embryo transfer and hormonally controlled cycles with oestrogen and progesterone, then yes, it would be better to do them while on oestrogen and progesterone.

A hysteroscopy should be done at the beginning of the menstrual cycle so just after the last menstruation is finished. If you do it too late in the cycle, it may not be easy to see abnormalities. You may not be able to see if there is some adenomyosis and if there are some patches of abnormal endometrial development because the thick endometrium may obscure the normal view of the uterus as shown at the time of a hysteroscopy. So I would recommend that it is done straight after the menstruation has ended. And yes, you can do it while you’re on oestrogen but if you’ve got very thick endometrium because of oestrogen, then I wouldn’t suggest you to do it.

Yes, of course you can do a hysterocopy at the same time as egg collection. We do that very frequently and because we like to freeze embryos – obviously after genetic testing – we do several cycles in our clinic. We don’t do fresh embryo transfers. We collect eggs, fertilise them, do genetic testing and freeze the embryos – meanwhile we investigate the uterus and we often do a hysterocopy at the same time as egg collection. But not many clinics do it because you need to have special equipment to do a hysterocopy. It’s a gynecological procedure. I’m aware that in England, where my clinic is based, other fertility clinics do not perform a hysterocopy because they do not have the facilities to perform that procedure. But in theory, yes, it can be performed.

Well, you only have one sedation for the procedure. You obviously have only one hospital admission and you can assess the endometrium. Obviously, you’re not going to do an embryo transfer so you combine the benefit of the egg collection with that of endometrial assessment.

Obviously, this is out of the scope of tonight’s webinar. However, I do not believe in natural cycle IVF. I think that IVF per se has to be done with the ovarian simulation. There’s been lots of publicity around some clinics offering natural cycle IVF. This is not what I do. I like to personalise the stimulation protocol and Pergoveris is one of many medications we can use to induce ovarian stimulation – but it is not the only one. I would not recommend a natural cycle. I’d look at everything you have had and what can be done differently in the subsequent cycle. But of course, if you have a very low ovarian reserve, if you have very low AMH and if you only have few antral follicles, then it might be that there is very little that can be done in order to induce ovarian simulation.

It looks like the problem was in creating embryos or perhaps in embryo quality. So looking at the endometrium and looking at the presence of NK cells or even endometrial scratch is ,perhaps, irrelevant. Before we assume that there might be a problem with the endometrium,
you have to have good quality embryos to be transferred. I would recommend pre-implantation genetic testing and if you have had poor fertilisation or poor embryo formation, then I would recommend also sperm DNA fragmentation tests. There is an indication and there is a benefit in
using Metformin if there is polycystic ovary syndrome (PCOS). I would also recommend that Clexane is an adjuvant and should only be prescribed and used in certain conditions and cases. You’re not going to have Metformin and Clexane to overcome problems with embryo quality. They can only overcome problems with implantation. But again, you need to have a good quality embryo before you can assume that there is a problem with the endometrium.

I would definitely recommend that you have the ERA test to assess the implementation window. I would also like to check for the presence of any abnormal bacterial environment as well as excluding chronic endometritis. I think it is certainly important. Because you have had the laparoscopy for fibroids, it is possible that you’ve got some adhesions within the uterus. So I would also recommend to do a hysteroscopy because the HSG doesn’t rule out the presence of adhesions within the uterus.

I agree, it’s a good option.

No, I don’t think you should be concerned about it, providing you don’t have other symptoms. As I said before, endometriosis is a chronic condition and you will have it for most of your life, at least reproductive life. I think you should just live the life you live now and be healthy. You’ve got normal body mass index, you’ve got a normal healthy diet, you take probiotics so I wouldn’t recommend to do anything.

No, I really wouldn’t test the endometrial microbiome with menstrual flow. You would like to test the endometrium itself so it means the biopsy has to be taken when there is no period.

There is no evidence that HCG injection after transfer improves the implantation. There have been some very weak and not controlled studies suggesting that there may be some improvement in some types of patients with some types of stimulation protocols but I cannot recommend that you should have HCG injection on the day of the transfer in order to improve implantation.

Yes, we do ALICE and EMMA tests. Our clinic is in Cheshire which is South Manchester, about 10-15 minutes from Manchester Airport and between Manchester, Liverpool and Chester. If you go onto our website, you can find the exact location of our clinic there.

I assume the embryos that were genetically tested came back as normal. I’m not entirely sure whether there was any test done on the microbiome or to exclude the presence of abnormal endometrial environment. Hysteroscopy and laparoscopy don’t give us information about endometritis. They don’t give us information about abnormal endometrial environment. Especially if you have had a laparoscopy to block or clip the tubes because you’ve had fluid, then it is likely that there was a problem with the endometrium. Fluid in the endometrium from the tubes is toxic and can cause abnormal endometrial environment.

That could be a problem because it could affect normal endometrial environment. If you have not been menstruating and having normal endometrial development, that itself is a factor that could impact on implantation potential. Providing clinical finings are still valid, nothing should have changed in your hysteroscopy results since December.

Well, there is no evidence and I don’t use it to help implantation.

There is some growing evidence that growth factors within the uterus improve implantation. I think this is still under research and it’s not routinely performed in clinical practice. I wouldn’t recommend it to you or to anyone else until there is robust evidence suggesting that it is effective and safe.