My IVF cycle has failed. What to do next?

Nadia Caroppo, MD
Head of the International Medical Team at Equipo Juana Crespo, Equipo Juana Crespo

From this video you will find out:

how to define implantation failure?
what types of uteruses there are?
what factors affect implantation success?
which treatment methods improve chances of pregnancy?
why uterine functionality is crucial for successful IVF treatment?

My IVF cycle has failed. What to do next?

What should I do if my IVF cycle has failed?

Almost all fertility patients have experienced at least one or two failed IVF cycles. When treatment fails, the most common questions asked by patients are: ‘What went wrong?’ and ‘What can be done to get better results?’ In this webinar, Dr. Nadia Caroppo (the Head of the International Medical Team at Equipo Juana Crespo) is searching for IVF failure explanations and discussing possible solutions for patients.

Saying that IVF failure was bad luck may be relieving but – in fact – it is not satisfying. Chance explains 2 out of every 3 cases of implantation failure. And what about the rest? Dr. Nadia Caroppo says that most causes are related to the so-called ‘embryonic failure’ (60-70%). Problems may also appear in reference to the way doctors perform IVF treatment (e.g. the way they stimulate patients) or the fact that they are unaware of some important causes leading to implantation failure. The real challenge is to understand where the patient’s (or the couple’s) sterility comes from. And – consequently – where more work is needed in order to be successful.

Implantation failure – what is it?

Dr. Nadia Caroppo says there are several definitions of implantation failure. Most often it is described as the impossibility of obtaining a clinical pregnancy with the transfer of at least 4 good quality embryos of at least 3 different cycles. The latter is the data from women over the age of 40. According to dr. Caroppo, embryo quality is a very important factor as it tells us about the potential the embryo has to implant. She also recollects some statistics comparing the results in natural reproduction vs. egg donation. 65% of fertile couples get pregnant in the first 6 months of trying for a baby. The same happens in egg donation programs when there are no other factors that affect implantation. So what are the other factors? Dr. Nadia Caroppo mentions the woman’s womb (uterus) as the most important factor. And this is true regardless of semen samples that do not alter the potentiality of pregnancy rates.

What happens during embryo transfer

Dr. Nadia Caroppo describes endometrial lining as the cushion the embryos attach to. During the transfer, embryos invade it and start to scratch it to implant. There are many factors involved in the so-called molecular dialogue between embryo and endometrium, such as molecules secreted by the embryo, molecules secreted by the endometrium and – last but not least – uterine functionality. It is because of the latter that we can differentiate different types of uteruses. For example, hyper-fertile uteruses get pregnant with any embryo that passes by – even with abnormal embryos (that most often result in miscarriages). On the other hand, there are hostile uteruses that find it very difficult to get pregnant. In such a case, a thorough selection of embryos is required – just to make those pregnancies work. Unfortunately, this type of uteruses is common for couples who delay a pregnancy (because of e.g. social factors) as well as those who undergo lots of IVFs and fail.

What influences embryo implantation

As there are a lot of factors that account for getting pregnant, is it natural to wonder what can be improved in case of implantation failure or miscarriage. First of all, there are obvious answers, such as improving oocyte, sperm or embryo quality. Apart from that, there is also a professional in vivo lab that is of crucial importance. According to dr. Caroppo, if there is no good in vivo lab that works properly, it is difficult for a patient to get pregnant through IVF. And – last but not least – there is also uterine functionality and endometrial quality. Before starting the preparation for the embryo transfer, it is crucial to rule out any alterations that may affect one’s IVF cycle. These include altered thyroid function, diabetes, hypovitaminosis D, and inflammatory/autoimmune disorders, such as celiac disease or lactose intolerance, accounting for immunology-based endometriosis. Dr. Nadia Caroppo admits that the cases of endometriosis are very common nowadays. Unfortunately, this disease is chronic and progressive, influences embryo quality and uterine functionality and – as a result – really delays pregnancies.

One of the most common maternal factors, thrombophilia, can account for a portion of failed IVF cycles, but it is not their origin. Dr. Caroppo admits that knowing this, and knowing that a significative proportion of the population is asymptomatic, doctors have to very careful when assessing couples who have positive thrombophilia tests. Otherwise, it is easy to build up the so-called iatrogenic trap. Unfortunately, by giving Heparin/Aspirin (especially to very fibrotic hostile uteruses) one can easily ‘over-treat’ a patient and provoke a miscarriage. That’s why each treatment protocol (as well as medical care during pregnancy) has to be based on scientific evidence and careful assessment of an individual patient.

A new era of the IVF world

Dr. Nadia Caroppo admits that in today’s medical world, there are still a lot of things that doctors have to understand in relation to fertility treatment. There are a lot of discoveries arising and issues being studied and sometimes they’re still only the tip of the iceberg. There are a lot of things that mediate or inhibit embryo implantation and it is crucial to be aware of them in order to help the implantation process. These include fields such as immunology, genetics, epigenetics, uterine microbiome, metabolomics (the study of molecules that embryos secret and that can predict implantation), transcroptomics and psychoneuroendocrinology.

How to improve chances of pregnancy

It is well known that environmental factors, related to one’s lifestyle, can influence the expression of certain genes what may alter the correct functionality of the immune system and – as a result- the implantation itself. However, as dr. Caroppo says, there are tools available nowadays that can help us deal with this problem. As we know now that a uterus is not aseptic and there are lots of bacteria that can favour the implantation, we can make sure the uterine microbiome is correctly balanced.

When it comes to oocytes quality, there are some protocols that can help to improve it before the stimulation. For example, in polycystic ovaries, Metformin (anti-diabetic drug) or Myoinositol can have positive impact on oocyte quality. In low ovarian reserve, giving androgens prior to IVF can improve the ovarian response. In the case of endometriosis, components such as Coenzyme Q10 (CoQ10) can help the ‘machinery’ of the oocyte to get better. When the very IVF treatment starts, personalised protocols are of greatest importance. Dr. Nadia Caroppo says that doctors have to understand what type of patient they are currently dealing with and on the basis of that knowledge, not to be afraid of variability between cycles. It means i.e. searching for morphological markers and hormonal levels that can be prognostic factors of egg quality.

Sperm quality can be improved as well – with e.g. zinc, selenium, DHEA or CoQ10 that work on sperm motility and decrease sperm DNA fragmentation. But according to dr. Caroppo, the key factor in improving sperm quality is an IVF lab. The impact of a very good lab that uses the latest technologies, good safety measures and quality markers is not be underestimated. It surely results in better quality embryos, better arrival at the blastocyst stage and better pregnancy rates.

The importance of embryo selection

Dr. Nadia Caroppo admits that a lot has changed in relation to embryo selection throughout the years of her clinic’s practice. They started with transferring day 2 and day 3 embryos, only to see in the coming years that leaving the embryos to culture to the blastocyst stage may greatly improve the chances of implantation. Meanwhile, there was a great revolution with culture media – it proved that improving culture media growth factors can lead to better quality embryos. The same refers to discovering that embryos secreted substances that made us understand how their evolution went (the so-called metabolomics). Nowadays, the most important tools available to doctors are surely preimplantation genetic testing/PGT (with all related techniques, such as FISH, NGS or aCGH) and morphikinetics (EmbryoScope or Time-Lapse technology).

Embryo transfer experience

Although many patients admit they have had painful embryo transfers, dr. Caroppo says that nowadays it’s possible to improve this procedure as well. There is a lot of evidence that the transfer itself does not have to entail any cramps, bleeding or discomfort. Apart from using well-known methods such as pain killers or anaesthesia, it is recommended to use new technological findings. A good example is an ultrasound-guided embryo transfer performed with a soft catheter that caresses the endometrial lining instead of scratching it. The pre-transfer essay of the uterus is also recommended to know exactly how to get inside the uterus and place the embryos correctly. Without this knowledge and without a correctly performed embryo transfer, the chances of getting pregnant are significantly decreased.

Uterine evaluation as the key to success

Apart from all that was said before, successful IVF treatment nowadays cannot go without the correct evaluation of uterus. According to dr. Nadia Caroppo, a patient’s uterus has to be assessed for both morphology and functionality – and there are different techniques available to improve this process in today’s medicine world. Dr. Caroppo mentions a regular 2D ultrasound (for checking endometrial-myometrial pattern), 3D ultrasound (for assessing inner morphology of the uterus), hysteroscopy (for analysing the endometrial lining) and pelvic MRI (for displaying the zonal anatomy of the uterus). Assessing quality and thickness of endometrial lining is very important. When the endometrium is more than 5 mm thick and has a trilaminar morphology, no significant differences have been found in implantation rates, pregnancy rates or miscarriages in different measurements. The diagnosis is performed through an ultrasound – sometimes in combination with a hysteroscopy.

When it comes to the success of implantation, not only the endometrium appearance is crucial – but also its environment. It is important to remember that high steroid and progesterone levels after the stimulation can result in embryotoxic environment that alters endometrial receptivity. Hydrosalpinx, a condition when a fallopian tube is blocked with a watery fluid, accounts for 50% reduction in pregnancy rates and 50% increase in miscarriage rates. That’s why it is essential to assess the fallopian tubes – as well as exclude leiomyomas (fibroids) that increase contractility, diminish blood flow and make uterine walls much harder than usual. And although dr. Caroppo admits that lots of women get pregnant despite leiomyomas, it is important to realise that the latter affect more than two failed embryo transfers in a woman. That’s why leiomyomas located in the fundal part of the uterus sometimes have to be removed surgically. Finally, in order to correctly predict the window of implantation, the ERA test is performed. It is often complemented with ALICE-EMMA test for normal uterine microbiome that can offer better implantation rates.

Understanding the cause

Dr. Nadia Caroppo concludes her presentation by reminding us that the implantation is not a passive process. The endometrium and the embryo exchange messages and that dialogue is very important. As there are a lot of factors that can interfere throughout this process, one IVF cycle rarely resembles the other. Additionally, the embryo-endometrium dialogue is favoured in a ‘friendly crib’ – meaning a functional uterus. The latter can be achieved by adjusting and adapting medical treatment to the individual characteristics of a patient. According to dr. Caroppo, personalised medicine is the most important key to the IVF cycle success.

- Questions and Answers

I’d like to know when is the best day for the embryo transfer?

First of all, we have to follow the days of life of the embryo. If I have day 3 embryos, the progesterone I have to have in my body has to be three days old. I cannot go ahead and transfer a 3 day embryo in the endometrium lining prepared for a day 5 embryo. We have to follow the days of evolution of those embryos. If we have day 3 embryos, then three days of progesterone. If we have day 5 embryos at the blastocyst stage – five days of progesterone. The ERA test sometimes assesses the perfect timing – but we see that even with not following exactly the days and the hours dictated by the ERA test, meaning if it’s pre-receptive or post-receptive endometrium, we have gotten most patients pregnant. That’s why I told you about the implantation window – that we are standing that and we see that embryos themselves can open the implantation window and we can manage it. So the most important thing is to follow the days of progesterone – and they have to match the days of evolution of the embryo.

What is thrombophilia and can it be treated?

Thrombophilias are a group of alterations coming from the coagulation cascade that can alter the functionality of that coagulation cascade. So one can develop micro-thrombosis and that micro-thrombosis can have a negative impact on what will be the placenta of the baby. They can create blood clots and alter the blood flow between the baby and the mother. So sometimes heartbeats can stop because of micro infractions that are caused by those blood clots – they just obturate the arteries and veins of the placenta. Thrombophilias can also cause e.g. heart attacks, brain ictus, palmary from thrombosis. So we can have thrombophilias that have other manifestations, not only related to pregnancies. Sometimes we have women who miscarry because of thrombophilia – but those are very little proportion of the population and they can be treated with Heparin and sometimes with Aspirin. Thrombophilias are generally treated with Heparin – it’s a drug that prevents those blood clots from forming.

Are there any techniques or changes that can be made to everyday living to improve fertility of women over 40 when all fertility tests come out positive with no problems?

Age is the best prognostic factor of IVF cycle. We know that as we age, embryo quantity and quality diminishes. The cut-off age is very arbitrary but we see that from 35 years old, women tend to have worse quality eggs – and therefore, worse quality embryos. Unfortunately, we cannot change our age. Of course, we can live a healthy lifestyle and sometimes just take those pre-IVF treatments: myoinositol (MYO), coenzyme Q10, Omega-3 and diminish lactose or gluten intakes – that can help us. But if we have problems in our 40s, our embryos may not be healthy. We have to assess why you do not get pregnant. If you have never got pregnant being 40, we have to not only study embryos with PGT-A to discard chromosomally abnormal ones but we also have to study them in the lab. The reason is that abnormal embryos do get you pregnant – but with babies that are affected by Down syndrome. So if you haven’t been pregnant, you have to be assessed for other factors that may account for your infertility.

Do you use human growth hormone (HGH) in your protocols?

No, we don’t use it because we have used it and we did not see any higher success rates. Besides, growth hormones are very expensive – and IVF treatments are already very expensive themselves. So because we did not see better outcomes in our treatments using human growth hormone, we do not use it anymore.

Are there any tests that can let me know if I have a hostile uterus or the tests to know good or bad quality of eggs?

I’ll start with the second part because it’s easier. We do not know what quality eggs we’ll have until we have them in the IVF lab and we see how they are fertilised and how their evolution goes. So there is no chance for us to know their quality beforehand. We can have some markers just by looking at the morphology of the follicles. Follicles are the houses of the oocytes and this is what we measure when you are under a stimulation protocol. We see that if we have abnormal morphology (being a very elongated follicle or an irregular follicle), probably those eggs won’t be top quality. So that is one thing we have to take into consideration. If you have a hostile uterus, first of all, measure the walls and assess the endometrial lining in the pre-ovulatory stage with a 3D ultrasound. If we have a suspicion of adenomyosis and endometriosis, we just perform a pelvic MRI. Those things can give us a lot of information. Sometimes during the first consultation visit, when patients come to get some information, we also do a hysteroscopy when we see that the cavity is not normal or when some women did undergo past hysteroscopies or interventions and there is a suspicion that the cavity is not okay. So they have to assess your uterus a little bit more and eventually – the fallopian tubes.

Is Coenzyme Q10 beneficial in those patients who do not have endometriosis?

We give CoQ10 to patients with endometriosis and to those patients who are over 37 years old. As I told you before, we see that the egg quality diminishes with age and CoQ10 has a positive impact on the machinery of the oocyte – the mitochondria. It’s the engine of the oocytes so it’s beneficial for women who have endometriosis and for women who are above 36-37 years old.

Are there any benefits of DHEA? Who would you recommend it to?

I’d recommend it to low responders or to the women who have a low ovarian reserve. We tend to give DHEA in 75 milligrams dosages daily about 2 months before the start of the stimulation and throughout the stimulation. We do not give it to all women with a low response but only when we see that the final results in the egg count are lower than expected.

How do you prevent an asynchronous growth of follicles? Do you do estrogen priming or some other kind of pretreatment?

We can give contraceptives before the treatment. We do give them for a very short time before we start the stimulation. We do estrogen priming or we use analogues and we change protocols. The best protocols to assure synchronic stimulations are long protocols. We see that lots of clinics are a little bit afraid of long protocols because sometimes you can get hyperstimulated. But if you take all the precautions, hyperstimulation is very rare nowadays. We just have to adjust doses correctly. So using analogues before, along with long protocols, is the best way to avoid asynchrony.

Do you use Time-Lapse incubators at your clinic?

No, at this time now we do not use them. We have very powerful biologists in our labs and they do a lot of quality checks, they check on each other and do interobserver checks. And we see that what they tell us about the morphology of the embryos accounts for the same results as with Time-Lapse technology. We did many tests in our lab and we did not see any differences between using Time-lapse incubators and using the regular way. So we do not use Time-Lapse at our clinic now.

Is the ERA test the same as a uterus biopsy? Can a hysteroscopy be done on the same day as the ERA test? I’m very scared of the ERA test without anesthesia – is there any other way to desensitize a patient?

The ERA test is a uterine biopsy. We sometimes do a hysteroscopy, just to check on the endometrium lining, and after that, we do the biopsy. It’s like a scratch – yes, it hurts, it’s like a very powerful menstrual cramp but it lasts literally two seconds. If you do not tolerate a hysteroscopy, mild sedation can be done or paracervical anaesthesia can be injected. And that can help with pain tolerance. We sometimes use Atropine or and other painkillers, too. But pain is very subjective so we have to see what you tolerate and what you do not tolerate. Just don’t be afraid of that. Believe me, it accounts for just one minute of your life – and that’s it.

When it comes to egg donation, which embryo grade should I expect as the best for the transfer?Should I request assisted hatching as well?

Here in Spain, we classify embryos with letters: A, B, C and D. First of all, in a good egg donation program, you have to have a good arrival to the blastocyst stage. Your goal should be top-quality embryos – A and B quality embryos should be the gold standard for egg donation. Those gradings will give you a pregnancy. My advice is not to do assisted hatching. It’s like doing the holes in the embryos’ shell – like pinpoints. So lots of embryos – which are not top quality – do not benefit from that. So no, we do not perform assisted hatching at all. My advice is not to do it if you undergo egg donation. Just get to transfer day 5 embryos (blastocyst stage) – that’s the goal.

Do you suggest a day 3 embryo transfer in egg donation process?

No, I don’t. In our clinic, we do the blastocyst stage transfer. We have a very good arrival to the blastocyst stage and for egg donation programs, we have never used day 3 embryos – except for very few patients who get pregnant with day 3 embryos. But they account for a very low percentage of our patients. But the general rule is to get to the blastocyst stage.

Is it possible to increase sperm morphology? How is it possible? Our doctor suggests using sperm microchip as it is finding the best sperm for treatment. Is this solution enough? Do you have any additional advice?

We cannot change the sperm morphology. What your doctor suggested – the microchip, Fertile Chip or annexin columns – is a way to select sperms that do not have fragmented DNA because of the oxidation process that sperms undergo from when they are formed till when they are ejaculated. So DNA fragmentation in sperm count accounts for worse quality embryos which are more fragmented. But you can use the microchip, Fertile Chip or annexin columns only in sperms with normal count and normal motility – because if you have one of those two parameters diminished, then you are not a candidate for doing any of those. The best way to select sperm with single-stranded DNA fragmentation is just by doing intracytoplasmic sperm injection (ICSI) during which a biologist chooses the best sperm you have. That already diminishes DNA fragmentation. Double-stranded DNA fragmentation is much more complex and we do not know yet which type of test is best in that case. When there is high fragmentation of DNA, some doctors suggest a testicular biopsy. We personally do not use Fertile Chip often – we do not see any differences between using it or not using it. Personally, we use it in very few patients.

After 6 embryo transfers resulting in three failures, 2 early miscarriages and one cournal ectopic pregnancy, would you recommend having the ERA test done? Or is this not needed due to the implantation occurring three times?

This is a very powerful story. First of all, a cournal ectopic pregnancy is very rare. When you have ectopic pregnancies of any origin, it means that the embryo escaped your uterus because your uterus was not correctly prepared or that the fallopian tube of that cournal ectopic pregnancy was not correct and not healthy. Your early miscarriages also talk about your uterus. So I don’t suggest to do the ERA test because the problem does not lie in the understanding of the embryo with your endometrium – if they attach correctly – but in studying your uterus from another point of view. Maybe you have adenomyosis or some uterine malformation that can account for the two early miscarriages and the cournal ectopic pregnancy. So my advice is not to do the ERA test because it is not useful for you. It’s not a problem of attaching or adhesion of the embryo – your medical history has to be seen from another point of view.

I have had four implantation failures. I had 1 early miscarriage at 6 weeks. I’m on an immune protocol even though there was no immune issue identified. I had ER Map, endometrial scratch. Would you do any further testing? My current doctor said we should keep with the same protocol.

It’s another powerful story. In case of immunity – as dictated by immunologists nowadays – we do not have any type of agreement on what works and what does not work. Immunologists tend to use Heparin, Aspirin, lots of patients also receive corticosteroids. But the problem is that we do not know what we are suppressing – if this is a good immune system or the immune system that does not account for good implantation. So endometrial scratching is not my advice – there’s no evidence right now that it helps. The ER mapping test is not useful either – you had a miscarriage so your embryos got to stick. I think that you have to be studied from another point of view – from the functionality and morphology of your uterus, your fallopian tubes, etc. Do not stay with the same protocol because if you failed a few times already, it’s just doing the same thing to fail again. You have to search for some advice just to understand what they have to change in order to make everything work. Of course, I’m not for or against your immunologists – please don’t misinterpret me. But we have some things that we do not agree with and in lots of international congresses, they do not have any consensus either. So yes, we have to take immunology into consideration but the thing is that nowadays we do not know what works and what does not does work. So you have to get studied from another point of view.

Do you use culture media with growth factor added? Does your clinic use media such as EmbryoGen + BlastGen (sequential culture media with Granulocyte-macrophage colony-stimulating factor (GM-CSF))?

No, we’re not using EmbryoGen + BlastGen and culture media with granulocyte-macrophage colony-stimulating factor. We are currently testing the culture media we have in terms of quantity of amino acids, glucose, oxygen levels, carbon dioxide levels, pressure, temperature, etc. and comparing them with the blastocyst stage arrival and embryo quality.

How is the ERA test performed?

The ERA test is a biopsy that is performed when we are in the luteal phase just right after the ovulation. It can be done in a natural cycle or in a substitute cycle with estrogen and progesterone. It is performed to see if the endometrial lining expresses some receptors that may imply that the window of implantation is occurring and when it is occurring.

I’m planning a hysteroscopy and the ERA test. Does it make sense to do a 3D ultrasound as well?

You can plan a hysteroscopy the same day just to see how the endometrium lining is. Of course, the assessment of the luteal phase endometrial lining is not the same as the pre-ovulatory endometrial lining. What we assess with a hysteroscopy is the pre-ovulatory endometrial lining and its morphology. If you do it in a post-ovulatory phase – in the luteal phase – the assessment is much more difficult because we do not know what is normal and not normal. You can do a hysteroscopy – maybe your doctors want to assess your cavity. Afterwards I’d performed the ERA test. And yes, it does make sense to do a 3D ultrasound – they are complementary tests. We always do a 3D ultrasound when a patient comes in from the first consultation – just to understand how the inner cavity looks like. But that is not ruling out factors to perform a hysteroscopy – a hysteroscopy sometimes has to be performed to assess other things, not only the cavity.

If the tubes have been clipped, is there any chance that there is still some hydrosalpinx in the uterus?

Clipping of the tubes is done when we have very difficult surgeries to be performed, for example, with deep endometriosis, and we cannot do a salpingectomy (taking away the tubes). Then you just clip them from the beginning of the tube – the so-called proximal part of the tube. Yes, of course, if you have clipped the tubes, you can have hydrosalpinx in the distal part. But if you’ve clipped it correctly, the chances for that fluid to go back and reflux inside the uterus are very low. However, sometimes we see it. And how do we see it? We see it when you have a continuously slight quantity of liquid inside the uterus in the ultrasound. And sometimes, after you got pregnant and you had your tubes clipped when your uterus stretches that clipping can just go away. And if you had hydrosalpinx, you could have a new manifestation of it. But if it does not bother you, then it’s not a problem.

If, by any chance, the tubes have been stretched, does it mean hydrosalpinx might be the one that contributes to the failure of the implantation?

Yes, of course – hydrosalpinx means that liquid is retained in the fallopian tubes. Normally that liquid has to spill to the belly – if, for some reason, I have a distal blockage of my tubes, that liquid will drain inside my uterus. And that liquid is toxic. So if it is toxic, it can alter the implantation and kill my embryo. So yes, if you have hydrosalpinx, it’s mandatory to resolve it – either by clipping or by taking away the fallopian tubes.

So clipping or taking away the fallopian tubes would be the solution? How can I verify this?

Clipping of fallopian tubes means performing a hysterosalpingogram – injecting the liquid inside the uterus and doing some shots of RX to see if you have hydrosalpinx or not. That’s the traditional way. Sometimes you can do a hysterosonogram that can only indicate if you have blocked tubes or not. It’s very difficult to see if you have hydrosalpinx unless it is very noticeable. But the most important test to do is a hysterosalpingogram.

How would you open the implantation window? Is that possible to do?

We have some studies going on and we have very good preliminary results. We are using different types of protocols in natural cycles and we are seeing that women get pregnant even if we do not use triggers to make the ovulation occur. So yes, it can be done and we are going to present our results in the Spanish Fertility Congress and afterwards, we will present them in the European and American Congress as well.

What type of probiotics would you recommend?

We use probiotics with high count of lactobacillus. Here in Spain we have one that is called DONNAplus Flora íntima. We use it before and throughout the endometrium preparation to make sure that we have a good flow of lactobacillus. So it would be best to choose such probiotics that include most types of lactobacillus.

Do frozen transfers also follow day 3/day 5 embryos rule?

Yes, for frozen embryos, we have to follow the rule of the days of progesterone, too. If I have a day 3 embryo, I have to have three days of progesterone. When it comes to day 5 embryos, you can transfer them regardless if it’s six or seven days of progesterone – but you have to have at least five days of progesterone. We have to follow that rule – you cannot transfer a day 5 embryo into the endometrium lining prepared for a day 3 embryo.

Is a frozen transfer more successful than a fresh one? And if yes, why is that?

It depends on a lot of things. It depends on the cause of sterility. If the cause of sterility is e.g. a male factor and we have perfectly healthy embryos and the uterus is also perfect in the assessment, we can go ahead and have a fresh embryo transfer. Frozen transfers just account for a small part of the population – those who have hyperstimulation or who have to undergo different surgeries to correct uterine defects or fallopian tube defects. In such cases, we have to freeze embryos. There was a trend some time ago to freeze all the embryos because we saw different studies saying that there were better results with frozen embryos. But today we know that fresh and frozen embryo transfers have the same pregnancy rates. They may of course have different implications throughout a pregnancy, e.g. frozen embryo transfers can give you a high rate of preeclampsia, etc. But in terms of pregnancy rates, they are the same.

What is the best egg donor’s age? Is it better when a donor has her own child or not?

All our donors are under 30. If they have had a child of their own, they are proven donors – regardless of the fact if we can assess their ovaries and see if their follicles are regular, have good count, etc. If a donor has a good body mass index (BMI), she leads a healthy lifestyle etc., most probably her eggs will be of good quality. Of course, some donors don’t have good quality eggs – but we will know that eventually when we create the embryos. Although egg donor programs permit donors until 35 years of age, we do not include donors who are over 30. The only exception is very good donors reserved for international patients who have to undergo egg donation programs – and only because they have had all the live births the Spanish law dictates.

How is your egg donor database during the Covid-19 period?

We are doing strict protocols with PCR testing in all our donors when they start the stimulation and before they undergo the egg pickup – just to make sure that we do not put them in a risky situation. We haven’t had any donors affected by Covid-19. Today we know that coronavirus, Covid-19, does not live inside follicular liquid nor in sperms, and it does not affect the embryo and does not cross the placenta. So that’s good news for all couples or women who have to undergo egg donation programs.

Is it possible to perform a hysteroscopy in the same cycle as an ultrasound? I have had the ERA test but no hysteroscopy. I would like to transfer a frozen embryo this cycle if possible, but I would like to do all the necessary tests, too. Which tests would you recommend? I now have cycle day 3 and I will see my new doctor on cycle day 10 for a first long appointment and an ultrasound. I had 11 embryo transfers and the ninth one led to a pregnancy – but unfortunately, it resulted in a still birth in week 36. Now I’m proceeding to the 12th embryo transfer.

You can do a hysteroscopy and you can go ahead and do the embryo transfer on that cycle. But we have to make sure that we do not damage the endometrial lining. So if no damage is done, then yes – you can go ahead. The ERA test in the same cycle as the embryo transfer is not possible because your endometrial lining is going to be scratched. It will provoke bleeding – and blood plus an embryo is not a good combination. I think that day 3 evaluation of your cycle is good to see things such as e.g. the uterine muscle. Day 10 is the best to assess the uterus, as in the pre-ovulatory phase you can assess endometrial lining quality, the myometrium, your fallopian tubes and if there are any signs of adenomyosis. Adenomyosis is the first thing that accounts for the loss of uterine functionality. Unfortunately, most stillbirths do not have a cause. I think that your doctor has to assess your uterus in a 3D ultrasound, eventually in a pelvic MRI and decide if something has to be done to treat the uterus to bring back its functionality.

How is the fallopian tube test done?

The fallopian tube test is done by injecting an oily contrast and doing some X-ray scans of how the liquid passes through the fallopian tubes – to see if it has free spill inside your belly or not. It’s a bit painful but it’s useful if you have never undergone a hysterosalpingogram – that is how it’s called. It can also be done with gel. The fallopian tube testing is done just after you finish your period – not in the pre-ovulatory phase because you can have false positive tests. You can have the results showing your fallopian tubes being blocked and that may not be the point. It may be so just because your endometrial lining is thick and the liquid cannot pass through the fallopian tubes. If you are not going to undergo any oocyte retrievals anymore and you’re opting to open a new window with egg donation, first of all, please check on your uterus. Because otherwise, even in an egg donation program, you can fail again and that’s not the point. So please just make your doctor investigate your uterine functionality a little bit more.

Is there a big difference in success rates between the frozen transfer of an embryo created with fresh semen and with frozen semen?

It’s always better to use fresh semen. Why? Because sometimes, when we unfreeze frozen semen samples, the quality can just be worse and we don’t have quantity to work with. So if you can use a fresh semen sample, it’s simply better. Of course, sometimes we cannot use fresh semen because of lots of reasons – and we have to use frozen semen samples. But it’s true that worse semen count and worse motility may account for worse embryo quality in the end. So if you have fresh semen samples, know that they will give you better embryos.

Do you suggest NGS for all cases? And what about EmbryoGlue?

We do not use EmbryoGlue because we did not have different success rates using it. When it comes to next generation sequencing (NGS) – no, we do not suggest it for all cases because it’s not useful. If I know that a 35-year old woman will have normal embryos, the only thing that NGS will allow me to do is to shorten the cohort and get to a normal healthy pregnancy before the cohort I did not test. So we don’t always use it. We also have to know if we have a good cohort of healthy embryos to test. Maternal age is one of the most mandatory factors that requires applying PGT-A – as well as recurrent miscarriages or recurrent implantation failures of lots of embryos. Then we will use it. But otherwise, we do not believe that all patients have to undergo PGT with NGS.

If I’m doing egg donation + pre-implantation screening + intravenous immunoglobulin, isn’t this too much to also ask for EmbryoGlue? Does EmbryoGlue really work or is this more a gadget like tool?

It’s just something else that we can offer. But as I told you before, we do not use it. Our success rates are already high and we do not use it. Intravenous globulins are very discussed. There is no scientific evidence that they work. They are very expensive and they have lots of side effects. Mortality cases were reported from using intravenous globulins so just be careful about that. Make sure to get assessed if you are going to use it. If you have a good uterus, you will get pregnant with egg donation. It’s really not useful to do all those things. If you’re failing with egg donation, check on your uterus and your fallopian tubes. Their functionality is very important. I’m sorry but I will be like a broken telephone, talking about this again and again. We’ve seen lots of patients who have failed like 17 embryos in egg donation treatment and their problem was in the uterus. When we fixed it, they got pregnant the first time. So that’s why it is mandatory to do.

Did you say that women over 40 with low ovarian reserve should decrease or increase lactose intake?

The advice is always to decrease lactose and gluten intake. But we do not suggest it for low ovarian reserves – we suggest it for patients that have a history of endometriosis or adenomyosis. Not all patients are candidates to diminish lactose or gluten intake and it’s not mandatory for all women over 40. We suggest doing that because we see that there is a correlation between the inflammation provoked by lactose or gluten intake with inflammation occurring around the uterus because of adenomyosis and endometriosis. So if you have been diagnosed with adenomyosis or endometriosis, then yes – I suggest you do that regardless of your age.

Do you recommend Melatonin for low ovarian reserve patients? Is 1 milligram a day worthwhile? Can it interact with any of the protocol drugs?

We give Melatonin because we have some products that include it. We include myo-inositol, chiro-inositol, zinc, selenium. Yes,1 milligram a day is worthwhile – not only for low ovarian reserve patients but also for polycystic patients. We give Melatonin to all our patients who will undergo a stimulation protocol. And no, it does not interact with any other drug.

I gained 4 kilos after each transfer in a short time. I started exercising a lot now. How many weeks before the next transfer should I slow down?

You can exercise normally just till the day of the embryo transfer. After the transfer, you can have a normal lifestyle – just make sure you do not do heavy exercises. There is no indication to rest unless you have a very pathological uterus. Then bed rest is then suggested. However, it happens in a very little percentage of our patients. Generally, there’s no need to stop exercising, you can go ahead and have a normal life until the day of the embryo transfer. Afterwards, if there is no contraindication, you can continue with exercises – but maybe a little less heavily.

I am using donated eggs. Should I still have my fallopian tubes investigated? And would DHEA be of any help? I do not have high testosterone.

If you are not undergoing a stimulation protocol, then DHEA is not helpful to you. In such a case, I don’t suggest you to use it. And yes, investigate your fallopian tubes. If you have undergone egg donation, have failed it and have never been tested for the fallopian tubes, then yes – get tested.

I have been taking CoQ10 and DHEA for three months. Do you think it will make a difference in my AMH which is 0.02? I’m 44 and I’d like to use my own eggs.

No, they won’t make a difference in the AMH count. They can make a difference in the quality of your eggs. But remember that at the age of 44, you will need a huge amount of eggs to have a normal embryo. So if you want to use your own eggs, my suggestion is to get tested for abnormal embryos – in order to discard chromosomally abnormal embryos. You can go on and take CoQ10 and DHEA but remember they can help you with your eggs’ quality and not with AMH count. The latter won’t be altered. Unfortunately, the lower AMH count is the product of ageing.

I tested positive for rubella IgG (67.3 IU/ml). Can it be treated before IVF? Prolactin level is 39.5 µg/L . Is there any danger for the treatment?

If you tested positive for rubella IgG, it means that you have been vaccinated. So that’s good and you don’t have to do anything. If you had negative IgG results, our suggestion would be to get vaccinated. Your prolactin level is not very high so no there’s no danger for the treatment. Prolactin is a stress hormone that can be elevated because of many factors. So if you had a high level of prolactin, we would suggest repeating that test after one month. We’d suggest you to just be calm before the test and if it does go down, then it’s ok. If the prolactin levels are increased or very high, then we have to study you to see if the gland that produces that hormone in our brains is not increased in size. That can account for alteration during the pregnancy. But now, before going for IVF treatment, that value you have is not very high.

I am scheduled for a frozen embryo transfer (FET) in 5 days. I have a (very) retroverted uterus and my age is 44. Is there anything you would or would not recommend to me? E.g. ultrasound-guided embryo transfer?

Retroverted uteruses are a big challenge because it’s very difficult to see them through an abdominal ultrasound. Transfers can be very difficult. Sometimes retroverted uteruses are challenging because their functionality is a little worse with respect to anteverted uteruses. So yes, doing ultrasound-guided soft catheter embryo transfer is mandatory. Most clinics offer it nowadays. You don’t have to experience any pain, any contractions and you don’t have to be uncomfortable that day. That’s my only suggestion.

Is an ultrasound-guided embryo transfer vaginal?

No, it’s through the belly. Sometimes we have to go inside the uterus with the catheter blindly because it’s very difficult to see a retroverted uterus. Of course, it happens for us to have the catheter placed inside the vagina but it’s better not to do it when we do the transfer. Why? Because we can damage the endometrial lining by doing so. So even if we are not able to see anything, it’s better to go in blindly. But of course, in order to do that, first we have to essay the embryo transfer before to know exactly how many millimetres we have to get inside.

I had one failed IVF with one embryo implanted (blastocyst). I did a vaginal ultrasound, a hysteroscopy, my fallopian tubes were fine, my uterus was normal with a 3D scan and my endometrial lining was ok. What other problems could there be and what other tests should I do to rule out other factors that prevent pregnancy?

First of all, one failed IVF with one day 5 blastocyst stage embryo is not something that you have to worry about. Maybe the uterine preparation was not correct, maybe your doctors have to change the way they prepare you. I don’t know your age and that can also account for implantation failure. I don’t know the quality of the blastocyst they transferred. I don’t know if the transfer was painful or if you had bleeding after the transfer or not. There are of course some other things to assess, too. But if everything seemed normal, just give yourself another shot with another embryo transfer and with a different preparation. If you fail two or more embryos of good quality, then maybe you have to be assessed from a uterine functionality point of view – maybe with a pelvic MRI or maybe by seeing the characteristics of the endometrium lining with hysteroscopy in the pre-ovulatory phase. Those may be the things for your doctors to study and investigate a little bit more.

I have had five ICSI – one embryo each time. One failed, three miscarriages (at 5, 7 and 13 weeks) At 13 weeks the heart stopped (male normal karyotype). My hereditary thrombophilia screen was normal. A hysteroscopy was normal but with a retroverted uterus. In March, I did a cycle and got one top blastocyst but I was forced to freeze it due to Covid-19. With only one embryo, I can’t afford trial and error with the implantation window. Would you have any recommendations?

Three miscarriages talk about your uterus. First of all, get screened for your fallopian tubes. Secondly, get screened for your uterine functionality. If your cycles are painful, they talk about the functionality of the uterus. Retroverted uteruses generally mean that you have retrograde menstruations that go inside your belly through the fallopian tubes. That may be a factor contributing to the appearance of adenomyosis. Retroverted uteruses tend to age worse than anteverted uteruses. I think that before you go ahead with the embryo transfer, we have to understand how your uterus works. Three miscarriages out of four embryo transfers are not a problem of your embryo not attaching to your endometrial lining – it’s a problem of the embryo not getting the right blood flow. And that may be because of a hard uterus. In a hard uterus, myometrium (the muscle) is not functioning correctly. So I think that you have to be assessed from another point of view. Get tested for the fallopian tubes and see if you can do a pelvic MRI and get a consultation just to see what is happening. This is very important and you cannot afford to fail once more. It’s very difficult psychologically to undergo another miscarriage or get negative results. That’s my advice.

Can DONNAplus Flora íntima be used during the natural cycle prior to the potential egg collection? Just some clarification: my body did not respond to Pergoveris – the treatment had to be stopped. Before that, also after Pergoveris, I had only one good follicle which was empty. But as a result of the natural cycle, I had two embryos (which did not implant). The doctor recommended not taking any medication but returning on day 7 for an ultrasound because my body responds better without hormonal stimulation.

I think that you have a very low ovarian reserve. And low ovarian reserve ovaries are very difficult to manage with stimulation. Pergoveris is a very potent medication but if the protocol is not used correctly, you won’t respond to it. We just have to see the timing that your ovary has in terms of waking up and just potentiate that waking up and push it a little bit more. DONNAplus Flora íntima does not interact and does not contribute to a better response or to a higher quantity of eggs. It just helps the uterine flora microbiome to be a little bit better. And if you have a very low ovarian reserve, some cycles will be good and some cycles won’t be that good. You can have empty follicles or sometimes the instructions that we give to trigger the ovulation do not reach the ovary properly. And that may be the cause of an empty follicle. But if you are planning to go on with a natural cycle to retrieve eggs and that works for you, that’s ok. Just remember that DONNAplus Flora íntima is not going to interfere with that or make it better.

What do you mean by ‘pushing the timing of the ovary’?

Very high FSH levels show us that the ovary is not functional enough. If you have very high FSH levels and I give you Pergoveris or other medication in top dosage being e.g. 450 units, you won’t respond to it. So we have to see when your ovary wakes up in terms of FSH levels and estrogen levels. And when it starts to wake up, we push it with a little bit of medication. If you have a normal body mass index, you don’t need very high dosages of the medication just to have the same results. It’s a protocol that is very personalised. We have to play with hormonal dosages just to make sure that we know exactly when the ovary wakes up.

At which point is it recommended to change a doctor or a clinic? I did three embryo transfers in one country, then three other transfers in a different country, then three more in yet another one. Now I’m doing a new transfer in the fourth country. Do you usually recommend following the same doctor and/or clinic?

It is very difficult. You have to be comfortable with your doctor. You have undergone lots of treatments so if you don’t see that someone can offer you another view of your problem, I think you have to search for different opinions. Because if you go ahead and do the same things regardless of the country that you’re in and regardless of the clinic that you are in, it won’t be useful and you will fail again. Unfortunately, we sometimes have patients that have no chances of getting pregnant (because e.g. they have a very hostile uterus) and we have to tell them to stop going ahead and stop trying with one IVF after another. I think that your story has to be assessed from a different point of view. So before you go ahead with another embryo transfer, another IVF cycle or donor cycle – I don’t know which type of treatment you are now undergoing – make sure you get a different opinion. You know that something is not ok – you are the first one to know it. So if you don’t get another investigation or if it is not a turning point in your history, I think there’s no point in going ahead and doing the same things all over again. Of course we may fail – all of us can fail because fertility is not absolute science. We are always in the grey area of fertility, there’s not only black or white. But it’s important for you to feel that your doctor is doing something different each time to understand what might have gone wrong and how he or she can work around it. As a patient, you have to feel comfortable and believe in your doctor and know that he or she is doing something different just to offer you a better solution to your problems. Sometimes they just have to tell you: ‘Look, we will run some other tests but I see that all you’ve done and all that my colleagues have done is ok – so maybe we have to opt for other treatments.’ It might be a subrogate uterus (if you can undergo it in your country) or adoption or something else. I don’t know exactly what you underwent and I will be glad to evaluate your case if you want me to. You can always contact us if you want another opinion just to see if we can do something different for you. I hope you have a bit more of luck this time.

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Authors

Nadia Caroppo, MD

Dr Nadia Caroppo is a gynaecologist and the Head of the International Medical Team at Equipo Juana Crespo, an IVF clinic from Valencia, Spain. Dr Caroppo has 8 years of experience and speaks Spanish, English, Italian, and French. She has obtained her Bachelor of Medicine (Hons) from the University of Buenos Aires and an expert in Gynaecology and Obstetrics. Her residence was at the Italian Hospital in Buenos Aires, Argentina. Her qualifications have been recognized in Spain and Italy. An expert in reproductive medicine both for patients and egg donors. Co-author of numerous scientific publications and an international conference speaker, a specialist in lower genital tract and colposcopy.

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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