Uterine factors that impact on blastocyst implantation

Luciano Nardo, MD MRCOG
, Consultant Gynaecologist, Subspecialist in Reproductive Medicine & Surgery, UK

From this video you will find out:

If embryo quality is the most important factor in successful implantation?
Why uterine and endometrial investigation prior to IVF is crucial?
How intramural and submucosal fibroids impact on fertility performance?
Whether it is always necessary to remove fibroids and polyps?
What the worst-case scenario of intrauterine adhesions is?
How endometrial receptivity array(ERA) is performed?
What risks are associated with abnormal vaginal microbiota?

Uterine factors that impact on blastocyst implantation

Embryo implantation and uterine facotors

Uterine factor infertility relates to abnormalities of the uterus that can make it difficult to conceive or carry a pregnancy to term. In this webinar, Prof. Luciano Nardo, MD MRCOG, Consultant Gynaecologist & Specialist in Reproductive Medicine, explains the uterine factors that have an effect on embryo implantation in IVF treatment. It is a fact that successful embryo implantation is dependent not only on how good the embryo is but also on the normal endometrial and uterine environment. In this case, implantation failures are similar to miscarriages – some factors could be shared between both of them. To minimise the risk of an implantation failure or an early pregnancy loss, it is very important to prepare for upcoming IVF in a thorough and individualised way. Before using any assisted reproductive technique (ART ), one should investigate a few issues related to their reproductive health. These include ovarian reserve, semen performance/analysis, normal appearance of the uterus and ovaries and embryo quality – both in a morphological and a genetical sense. In prof. Luciano Nardo’s opinion, investigating the uterus is as important as investigating everything else we do before commencing a cycle of assisted conception. In his practice, he always individualises the diagnostic tests offered to patients with a plan to minimise unnecessary risks and the time to pregnancy as well as to maximise the chance of success in the shortest possible time.

Defining recurrent failure

When conducting fertility treatments, doctors and patients are often faced with the dilemma of something being unexplained. It can be highly frustrating as fertility issues are hard enough to deal with when we understand what’s causing the problem. Prof. Luciano Nardo says that doctors need to be in a position to explain why subfertility occurs, why the transfer failed or why a miscarriage took place – and the only way to explain it is by looking into the possible causes. One of the most important technological developments and significant progress in the field of reproductive medicine is surely the possibility of investigating embryos, from the early stage to the blastocyst (day 5 or 6). Data published in the literature demonstrates that pre-implantation genetic testing for aneuploidies in embryos increases the chances of live birth and reduces the risk of miscarriages. However, relying entirely on this improvement may entail some surprising consequences. Prof. Nardo admits that – if the embryo test results come back as normal – there is a tendency to assume that everything is fine and patients may embark on an IVF journey. And it is often wrong as IVF itself doesn’t help to overcome the underlying infertility problem.

The importance of uterus assessment

Prof. Luciano Nardo does not share the view that everything that is not successful is unexplained. He says that at his clinic, they always start with investigating the uterus at a very early stage of the fertility program to ensure that it is possible to shorten the time to pregnancy, reduce the risk of miscarriages and increase the chances of successful embryo implantation. There are a lot of gynaecological problems known to impact on normal endometrium environment that, in turn, will affect the ability of embryos to implant.

Fibroids and infertility

One of the most common gynaecological problems encountered in women trying to conceive is the presence of fibroids. These are generally benign lumps that can grow within the uterus, in the layers of the uterus and outside the uterus. Prof. Nardo admits that the impact on fertility and implantation is significantly different depending on the fibroid’s location. While the subserosal fibroids (located on the outside of the uterus) are of no importance to conception and pregnancy, fibroids within the uterus and those within the layers of the uterus will affect normal fertility performance. In early pregnancy, they are the causes of miscarriages and in women trying to conceive, they can lead to subfertility. It is enough to say that fibroids can impact tubal patency and normal endometrial activity and they may also cause abnormal blood supply to the uterus as well as inflammation. Fibroids that are present within the uterus and inside the endometrial environment are called submucosal. They can easily be seen on a transvaginal two-dimensional ultrasound scan. They are divided into type 0, type 1 and type 2, depending on how much of the fibroid protrudes within the endometrial cavity. Submucosal fibroids have to be removed in women trying to conceive. And, what prof. Nardo stresses heavily, it is not to be done after a failed IVF cycle or a miscarriage but proactively before first conception attempts. There is strong published evidence that fibroids within the uterus cavity significantly affect the success of IVF treatment. Surprisingly, removing fibroids is sometimes enough to conceive naturally, without the need of starting an IVF treatment cycle at all. According to prof. Luciano Nardo, it is equally important to look at the fibroids that are not within the uterus but which are within the layers of the uterus and may be close to the endometrium. These are the intramural ones and they are close to the junctional zone – the area between the endometrium and the myometrium. There is evidence that fibroids affecting or impinging the junctional zone cause inflammation, affect blood supply and induce contractions. Therefore, they should be removed to give the uterus the best chance of success. The best way to assess if fibroids are impacting the junctional zone will be by an MRI scan.

Polyps

Polyps, being another common type of benign lumps, can be the result of prolonged hormonal treatment. As they are considered to be foreign bodies within the uterus, they can cause spotting and bleeding as well as impact the ability of a blastocyst to implant successfully. Polyps are generally soft and fleshy and can be very easily removed by hysteroscopy. Doctors can differentiate them from fibroids with the use of ultrasound scans. Prof. Nardo says that polyps, just like fibroids, should be removed before a woman’s conception attempts, before starting IVF treatment or in any case when there is a history of miscarriages.

Adhesions

When looking for causes of subfertility, miscarriages or implantation failures, one cannot ignore intrauterine adhesions. They usually occur following intrauterine surgery or curettage, insertion of coils or previous sexually transmitted diseases. They are often associated with painful periods and can be diagnosed and treated with a hysteroscopy. According to prof. Luciano Nardo, the worst-case scenario of intrauterine adhesions is Asherman’s syndrome (AS) when there is the complete obliteration of the inside of the uterus by what looks like cotton wool. In such a case, surgery is challenging and can only be performed by experienced surgeons. It should be followed with at least eight weeks of hormone therapy to induce a rapid and significant growth of the lining of the womb. There is scientific evidence that the removal of adhesions improves fertility, the ability of an embryo to implant and the pregnancy rates.

More uterine abnormalities

Congenital uterus abnormalities are something that women are born with – and the septum is the most common example of them. It is like a partition wall within the uterus and it can occupy either the entire cavity of the uterus (a full septum) or a proportionate percentage of the cavity (a partial septum). There is some evidence that a septate uterus can impact the ability of a blastocyst to implant and can cause a miscarriage, a pre-term delivery as well as increase the probability of a caesarean section. The presence of a septum will also affect placentation, reduce the size of the uterine cavity and harm the presence of growth factor receptors which are important for normal endometrial function. Prof. Nardo says that removing the septum improves the outcome: lowers the miscarriage rate and improves the pregnancy rate of women with unexplained infertility.

Assuring the best endometrial environment

Prof. Nardo admits that only recently doctors have acquired information about how important the endometrial environment is for successful embryo implantation and pregnancy. In women with a history of recurrent implantation failures and – at the same time – good embryo quality, it is recommended to analyze the endometrium. It is a genetic test called endometrial receptivity array (ERA) which is performed after taking a biopsy of the endometrium. It uses the latest genetic technology – next-generation sequencing (NGS). The biopsy is performed at a certain time in the cycle and gives doctors information based on the analysis of some gene expression of the endometrium. Generally speaking, it provides data about the best time when to transfer the embryo. It defines the endometrium as being either in the pre-receptive phase (not ready), the receptive phase (ready) or the post-receptive phase (past the optimal state). In prof. Nardo’s opinion, the information gained from the ERA test is extremely important to personalise the time of the embryo transfer. What doctors do next is to conduct the so-called ‘mock’ cycle which means mimicking what happens during a frozen embryo transfer either in a natural cycle or a hormonally controlled cycle. It helps them to see whether there is an adequate endometrial environment to support successful blastocyst implantation. In case the endometrium seems not to be prepared, the decision about prolonging progesterone exposure is made. Apart from the ERA test, there is also the ALICE test that identifies the abnormal endometrial environment. It is known that up to 40% of patients undergoing IVF treatment present abnormal vaginal microbiota. Unfortunately, the abnormal microbiome in the uterus is not symptomatic – unless, of course, we take the implantation failure as a symptom. Prof. Nardo highlights that bacterial vaginosis (BV) is not only responsible for implantation failures but it also increases the risk of late miscarriage and premature rupture of membranes, so premature labour. The most important bacterial species within the endometrium is called lactobacillus. The lack of lactobacillus or, on the other hand, the dominance of others types of bacteria will affect the chances of an embryo to implant successfully.

A lesson to learn

Prof. Luciano Nardo admits that fertility patients are often told that their subfertility is unexplained. However, what he claims is that ‘unexplained’ is not the right word it means that the patients’ inability to become pregnant has not been investigated enough or the causes have not been found. Embarking on the IVF journey is not the right solution in such cases as the treatment itself is not going to overcome the problems, such as e.g. the abnormal endometrial environment or the presence of a fibroid or a septum. It will only move patients from the problem of unexplained subfertility to the problem of an unexplained implantation failure. The administration of the right medications or surgical removal of infertility causes before IVF treatment may significantly increase the ability to achieve a successful pregnancy and live birth.

Embryo implantation and uterine facotors - Questions and Answers

I’m 35 years old. I had PGD on a blastocyst and the diagnosis was: implantation failure. I have had two biochemical pregnancies (one of which was from a natural conception) and many negative transfers. ERA, EMMA and ALICE tests were performed. Laparoscopy to remove hydrosalpinx has been done. I’m going to have my fourth hysteroscopy in a few weeks. I have endometriosis and insulin resistance treated with preventive immune treatment. Do you have any suggestions? This time the transfer will be in a natural cycle. All previous transfers have been in a substituted cycle.

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.

When preparing the endometrium, does the dosage of progesterone matter? For example, if you give someone 600mg vs 800mg pessaries or if you add in SC injections as well? If the test result comes back as “pre-receptive”, is it only a matter of not enough time exposed to progesterone or is it possible that the P4 dosage may have also been too low and or the body is not absorbing it efficiently?

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.

How would you test the levels of bacteria if this test is not available?

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.

You talked about vagina bacterial environment. How can this be tested and treated?

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.

I had a 9-cm broad ligament subserosal + 3cm fundal subserosal fibroid which were removed laparoscopically last year. Prior to surgery, I miscarried first time at 7 weeks and second time I had a missed miscarriage at 12 weeks (heartbeat detected at 8 weeks). Could the fibroids have been a cause of my miscarriages? I did all the recurrent miscarriage tests and everything came back normal. Also I have been trying to conceive since August 2019 but I only got 1 biochemical pregnancy. Should I start IVF? I am 38 and time is not on my side.

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.

Can laparoscopic myomectomy cause your tubes to get blocked?

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.

What are the test or ultrasounds I can do in my country to ensure successful implementation? I’ve had 2 ectopic pregnancies before and my tube is blocked. I’m from France.

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.

I had a laparoscopic surgery with a myomectomy. The fibroid was in the wall of my uterus. My doctor says not to do a transfer for at least 3 months. Why is the wait so long when the embryo isn’t very large at first?

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.

Can intramural (posterior & subserosal) fibroids prevent one from conceiving / IVF success? Also, can it cause a miscarriage?

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’ve had 3 embryo transfers using donor embryos. Everything up to the transfer was fine, yet there was no sign of pregnancy. I have had fibroids removed (between 2nd and 3rd go) – 18 in total and up to 8 cm. They were within the myometrium and I had been told they shouldn’t have been an issue… I also had a cystectomy prior to starting IVF. I am 44 now and I have a BMI of over 30. What tests should I explore now?

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.

I’m 41, I have 3 myomas: one around 4 cm, transmural, with endometrium contact and 2 more of 15 mm and 19 mm – these are intramural and touch the endometrium. I was operated for adhesions and suffer as well of adenomyosis. Would you advise me to perform treatment before starting IVF process? And what would be my chances of implantation afterwards due to several issues in the uterus?

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.

You mentioned that your clinic prefers to do long protocols and down-regulation for longer. But if a patient had low AMH & low ovarian reserve, is it still appropriate to down regulate? My consultant inquiries why my first clinic chose to down regulate. He said that, as I have low ovarian reserve, it is better not to bring me on premenopausal state.

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.

I have a 7-cm subserosal/intramural fibroid, my clinic advised me to not touch it as it has no effect on cavity. What do you recommend? To get it removed or not? I’m also thinking to get a hysteroscopy and a laparoscopy done as I have not done them yet. I have one failed transfer and I am waiting for my next transfer. I have 3 embryos frozen. I’m 39.

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.

Which day of the cycle should the bacterium test be done (the biopsy)?

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.

Would you suggest it is no harm to add L.acidophilus to a diet, for example through probiotic yoghurts?

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.

Is it possible to diagnose chlamydia or any other uterus infection through testing menstrual blood?

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.

I was able to get pregnant via IVF and donated egg last year but unfortunately, this ended in a stillbirth in Dec 2019. Now I have had two embryo transfers but no pregnancy. What tests should I have done? Originally, I have had a hysteroscopy where one polyp was removed in 2017. Tubes were not investigated as I was about to have IVF and doctors said the tubes wouldn’t be needed – thus, there was no investigation of them. Overall, I have had 11 transfers, although probably only two embryos have been of very good quality. No other pregnancies. The hysteroscopy in 2017 showed there were no other polyps and the view of the tubes was clear. But they didn’t check whether the tubes were open. I’m seeing my doctor next week to decide whether we have an embryo transfer this cycle or further tests. I am using both own eggs and donated eggs. The ERA test has been done.

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.

Which day of the cycle ALICE and EMMA tests should be done? Are they done when you’re on oestrogen and progesterone as in the embryo transfer?

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.

And which day of cycle a hysteroscopy should be done? I am now on oestrogen – can I do a hysteroscopy?

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.

Can you do a hysterocopy during the same time as egg collection?

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.

What is the benefit of a hysteroscopy during egg collection as compared to the end of a cycle?

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.

If I did not respond to the Pergoveris treatment, do you think the egg collection during the natural cycle is an advantage?

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.

We are about to go for our 4th ICSI cycle. Last cycle was the furthest we got: a day 5 transfer, not quite a blastocyst. I’m thinking if should we go for the ERA test, PGS, the sperm DNA fragmentation test, the NK cell test and endometrial scratch. If costs are an issue, would you prioritise one over another? What’s your view on using medications such as Metformin or Clexane to help implantation?

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 am 49 years old, I have had two failed implantation using sister’s eggs with PGT embryos. I was treated for adenomyosis with Lucrin for 3 months. I’ve had a laparoscopy for fibroids. All other tests were good. HSG test ruled out fluid in the tubes, even though they are blocked. I am due for my next cycle. The ERA test not done. What other things can I do now considering my age? The previous transfers have been very painful and my new doctor says she will put me under for this transfer.

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.

The IVF clinic I have had a mini consultation at suggested I do PGS testing on my embryos as I have had recurrent miscarriages.

I agree, it’s a good option.

Finally, after 10 IVFs with my own eggs as well as donor eggs, miscarriages etc., I will be using a donor and a surrogate but my question is about my own health. I’ve had intramural and subserosal fibroids taken out twice, endometriosis all my life and other problems. Should I be worried about my own future health and should I be doing anything to generally be healthy? I eat Mediterranean organic diet. My BMI is 19.5 -20. I have organic probiotics (80 billion, 34 strains) every day, organic flax seed oil as well.

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.

Can you assess microbiota test with period blood? Will that permit to see the overall state of the uterus?

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.

Does HCG injection on the day of the transfer improve implantation rates? Or is this still not proven?

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.

Where is your clinic in the UK? Do you do ALICE and EMMA tests there?

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.

Before my 8th IVF (for which I prepared about one year), I did PGS, DNA, NK cell test and a genetic test for which two eggs of AA and AB quality were collected. Few months before that I also did a laparoscopy when the tubes were clipped and a hysteroscopy. The implantation did not occur. What do you think went wrong?

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.

I had a hysteroscopy in December – do you think the results are still valid now? At the moment of a hysteroscopy I was having a long cycle but no menstruation for the last 5 months.

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.

What do you think of Gonapeptyl to aid implantation?

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

What about Neupogen (G-CSF) to improve 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.

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Authors

Luciano Nardo, MD MRCOG

Prof. Luciano Nardo, MD MRCOG, is a Consultant Gynaecologist, Subspecialist in Reproductive Medicine & Surgery, UK. He trained in Italy, London and Manchester before being appointed as a consultant in gynaecology and reproductive medicine at St Mary’s Hospital, Manchester, where he worked full time until 2011. His clinical and academic interests are in infertility, assisted conception, gynaecological endocrinology, pelvic pain, menstrual disorders and hysteroscopic management of uterine abnormalities. He has expertise in gynaecological ultrasound scan and management of early pregnancy problems including recurrent miscarriage. He has vast experience in advanced laparoscopic surgery for the treatment of endometriosis, adhesions, fibroids, ovarian cysts, tubal surgery and other benign gynaecological conditions regularly performing complex laparoscopic procedures such as hysterectomy, myomectomy and reversal of sterilisation as day case procedures. Luciano is a Member of the Royal College of Obstetricians and Gynaecologists and an associate member of many other learned societies. In July 2017 he was appointed as Visiting Professor to both Manchester Metropolitan University and Catania University, in recognition of his long term commitment to research and teaching alongside his clinical career. He has published in excess of 100 papers on many aspects of gynaecology, reproductive medicine and surgery and is regularly an invited speaker at national and international conferences.

Event Moderator

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.

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