Good embryos and poor outcomes. What to do?

Raul Olivares, Dr.
Medical Director & Owner of Barcelona IVF , Barcelona IVF

Category:
Failed IVF Cycles

What to do when we have poor outcomes even though we have good embryos
From this video you will find out:
  • Why good embryos do not always guarantee IVF success?
  • What factors can reduce uterine receptivity?
  • How important is the endometrial microbiota for successful implantation?
  • What is the relation between vitamin D depletion and egg quality?
  • Should patients get tested for NK cells?
  • What is the role of immunotherapy in IVF?
 

Why high quality embryos sometimes may not result in a pregnancy?

In this session, Dr. Raul Olivares, Medical Director & Owner of Barcelona IVF talked about various reasons for failed IVF attempts, he also explained what can be done if we receive good embryos but there are still poor IVF results.

Why high quality embryos sometimes may not result in a pregnancy? - Questions and Answers

When doing FET with down-regulation, is it an issue to find a dominant follicle at the baseline scan?

In some cases, we will recommend down-regulation. Usually, when you are doing a frozen embryo transfer, patients undergo a treatment with oral estrogen to build up the endometrium. Once they have the right thickness, then we start the progesterone, and on day five of progesterone, we do the embryo transfer. In cases like adenomyosis, which is a level of endometriosis in the muscle of the uterus, it could be good to try with a strong down-regulation.

We don’t work with down-regulation as a standard procedure because the doses of estrogens that we use are enough to avoid any dominant follicle but having a dominant follicle at the baseline scan, well, if you have a dominant follicle, and you’ve taken the downregulation, you just have to wait until the follicle vanishes, and then you can start preparing the endometrium. If you have that dominant follicle in the first scan because the down-regulation has not been fully effective, you can add the progesterone, and then probably you would have to schedule the frozen embryo transfer sooner than expected, but as long as the patient has not ovulated, as long as the progesterone levels are not high, there is no issue with that. You can just move forward and carry out the embryo transfer.

What is the healthiest BMI for someone going through IVF? Is a BMI of 27 OK for fertility?

It should be under 25. That is the ideal BMI, we know that the normal BMI is between 18 and 25, and if you have a lower BMI, you may have ovulatory disorders. If your BMI is over 25, you may start having problems, like hyperestrogenism. However, I would say that if you are below 30, the impact of the BMI is not going to be that high. Once you are over 35, it becomes a problem once you are over 40, we do not treat patients. We recommend them going through a diet or going through surgery to reduce the BMI. If it is under 25, it’s ideal.

Between 25 and 30, it’s not such an issue, and there are two studies carried out in Sweden and in the Netherlands that showed that patients with BMI between 25 and 30 that went on a diet for six months and lost between 4 and 7 kilos, I think if I’m not wrong, they show the same pregnancy rates.

The main problem with BMI is how you manage it. If you are 30 years old, and you have a BMI of 33, probably it’s better to invest some time to lose weight and then go with IVF. If you are 41 or 42 and your BMI is 35, you cannot invest six months losing weight because probably what you are going to do is make your outcome worse. Remember those graphics and how fast they reduce the live birth once you are over 40. In these cases, since BMI seemingly affects receptivity, it is better to undergo IVF, then freeze the embryos, lose weight, and then transfer them. That’s the main issue, the approach depends a lot on how old the patient is, but if it’s possible, keep the BMI level below 25 and if it is not possible, under 30.

Would an ERA test help? Due to having a chemical pregnancy, would you still recommend an ERA?

The company claims that it’s useful, and probably some chemical pregnancies may be due to abnormal implantation. This abnormal implantation can be because the embryo cannot get deep enough into the endometrium. After all, it’s not fully receptive. The theory is that yes, it could be, but I think that the problem has more to do with the tool but not with the theory.

The window of implantation is clear, my only concern is that I don’t feel that the ERA is an efficient tool to work out if the window of implantation is opened or displaced. That’s my issue with the test, so as I’ve said, I would recommend ERA only in cases in which the natural cycle cannot be done because the patient is either menopausal or has very irregular cycles. You have to do the same when you’ve done the ERA.

You have to do the same, you have to mirror the cycle to be effective. All the ERA tests that I have done in natural cycles were receptive. The window of implantation was normal, so why do you have to go through an expensive and invasive test if we can switch and work with the natural cycle, fewer hormones, yes more scan because you have to monitor the follicle and trigger the ovulation – that’s all. It’s advisable only in cases where HRT( hormone replacement therapy) cannot be avoided.

How often do you see hydrosalpinx? Flow-through of my tubes is delayed, which I know from a laparoscopy, and I have endometriosis. Should I further investigate hydrosalpinx?

The current knowledge is that you only must treat hydrosalpinx if you see it on a scan. If you do hysterosalpingography and you see that you have a lack of spill into the peritoneum, but you do a scan, and you see that everything is normal, it is not necessary to remove the hydrosalpinx. If you do a scan and you see that there is something wrong with the tubes, it’s better to remove it surgically or either by putting a clip or maybe by removing the tubes.

It is accepted that hydrosalpinx reduces the implantation rates either because this fluid may go back to the cavity and be toxic for the embryo. Also, this is a liquid, which is a very inflammatory liquid that may also increase the inflammation at the endometrium making it more difficult for the embryo to implant. Whenever you see hydrosalpinx in a scan, don’t go ahead with transfers, remove it, and then treat it. If you only see it on hysterosalpingography, but you cannot see it on the scan, I wouldn’t recommend removing it at the very beginning. I would go for some embryo transfers, but if the patient does not get pregnant, I would still consider removing the hydrosalpinx.

I have one 16-year-old, I had a natural ectopic after my 2nd failed IVF cycle, I had 5 fresh transfers, 1 FET, and transferred 9 embryos in total, and I only ever had a chemical pregnancy, I am just preparing for another FET. Would you consider any tests? I have had HSG, Hysteroscopy, I have endometriosis and low AMH. I am preparing for FET, I have been taking aspirin for 2 weeks, but my consultant says to stop aspirin 5 days before transfer as it affects implantation. I have only heard of taking it throughout and not stopping it, not sure what to do? I am 35.

There are two different things. One thing is that you’ve had an ectopic pregnancy. If you’ve had an ectopic pregnancy, this could have been due to any kind of inflammation or problem that was affecting the tubes, so if you have an inflammation, this could have been created by chronic inflammation, and once more, we have the ALICE and the endometrium biopsy to check if the environment in the endometrium is okay, or not.

As I’ve said, you may have a problem with the embryos, or you may have a problem with the receptivity. As you are 35, initially, the idea that the embryos can have the problem is not relevant. Because of the ectopic pregnancy, which demonstrates that your tubes have some kind of problem, I would suggest, in your case, to do a biopsy to see if the ALICE and the EMMA tests are okay, just to check your microbiota and discard any chronic symptomatic endometritis. Despite having a normal hysteroscopy. Hysteroscopy is very subjective when you want to diagnose this. Second thing, I don’t know if all your transfer had been using hormones, using estrogens, and using progesterone. If you’ve been through this kind of cycle, another option could be switching to a natural cycle. Let the endometrium prepare with the natural hormones and see what happens. If you had natural cycles, I would recommend to keep on working like that.

Regarding the aspirin and that it could be useless if there is no implantation failure, the main problem is that it’s usually recommended in the wrong way. The aspirin needs 3 to 4 weeks before the embryo transfer to have a full anticoagulant effect. If you started at the beginning of the treatment, if you started when you were doing the embryo transfer, or once you had the positive pregnancy test, it’s going to be useless. You need to start it in a previous cycle and at least 1 month or 3 weeks before the embryo transfer, and you should not stop it during the treatment. If you stop it 5 days before, the embryo transfer is not going to be effective. The effect of the aspirin lasts for 1 month if you have been taking it properly. When patients are going to deliver, they stop the aspirin 1 month before the due date to avoid any rash, so if you stop it five days before, I can’t see the point, it’s not going to have any impact. It’s better to continue it in any case because you are seeking that anticoagulation. Probably, before giving you aspirin, what I would have done is checking the thrombophilias, the antiphospholipid syndrome to see if there is anything that deserves to be treated with heparin or aspirin, but I would focus more on ALICE, EMMA, keep going ahead with a natural cycle and an aspirin.

You must look for something that has changed, you were successful 16 years ago, now, you are not. The only thing that could have changed is this kind of inflammation that has damaged the tubes, and that has caused the ectopic pregnancy. Try to check if this is also affecting the endometrium.

Can you use the vaginal probiotic suppository without having the EMMA and ALICE test? When should you start, how long, and what brand is recommended?

Yes, this was the classical approach before we had the EMMA an ALICE. Before those tests, the only thing that we could do was an endometrium biopsy and carrying out an endometrium culture. We did not have an option to do a histopathologic or a pathologic study. It was just to carry out an endometrial culture, and if the culture was positive, we treated the patients, and then we gave them vaginal probiotics. The problem was that most of the bacteria that the ALICE detects do not grow in the standard cultures medium, so then the endometrium biopsy to carry out the culture is not as efficient as the ALICE because it is not a culture, they detect the DNA of the bacteria.

This is the problem with ALICE. Since we don’t do culture, they recommend an antibiotic, but they don’t have the antibiogram to confirm that the bacteria is going to be sensitive to that antibiotic. The idea is that whenever we have an abnormal ALICE, we give antibiotics, then after the patient finishes the antibiotics, we recommend vaginal probiotics, and then we repeat the biopsy to confirm if the bacteria is there or not. If it is there, we give another course of antibiotics with a different antibiotic, and we repeat the whole treatment. I had patients that needed up to 4 biopsies until we have eliminated it. I’m doing the endometrium culture in the first biopsy these days. If I’m lucky and the bacteria that detects the ALICE grows in the endometrium culture, I will have the antibiogram. If the antibiotic that the lab recommends is one of the antibiotics to which the bacteria are resistant, I can switch it and be more effective from the very beginning. Whenever I do an EMMA and ALICE, I take a sample with the same biopsy, and I put it in a conventional culture to see if something grows.

The idea of giving a course of antibiotics and then giving a course of vaginal probiotics without doing the EMMA and ALICE, well, first of all, we don’t know if you need it, I think that it’s also positive for the patients to get that information, it is not the same undergoing treatment if you think that this could be the problem or compared to that you know there is a problem, and you’re treating, or you have treated that problem. It makes more sense also from the psychological perspective to carry out the test to confirm that there’s something wrong and treat it. It is also helpful to understand what could have been the problem in the previous negatives. If it’s difficult for you to have the test done, then yes, but don’t take the vaginal probiotic, first take a course of antibiotics, a general antibiotic, white spectrum like Amoxicillin, every 8 hours for 1 week and then follow the vaginal probiotics. It’s very important to know that vaginal probiotics should not be mixed with progesterone when it’s taken vaginally.

Ideally, what we do is that we give a course of antibiotics, and then in the cycle that the patient is getting ready for the embryo transfer, in the first phase of the treatment, we give the probiotics, and they stop it as soon as they start the progesterone. If you mix probiotics and progesterone, the vagina is going to be a mess, and you’re not going to get any benefit from any of them.
Doxycycline is a good antibiotic, it’s a white spectrum and should cover chlamydias, urea plasmas. It may not be useful against streptococcus, which is one of the most common bacteria causing chronic endometritis. If you have been tested for chlamydia, mycoplasma, ureaplasma if any of them is positive, I would recommend taking Doxycycline. These are bacteria that are much easier to test than chronic endometritis. As an empiric treatment, it makes sense taking a course of antibiotics and a course of vaginal probiotic, it is not going to cause any damage to your body, but if it’s possible, I would recommend doing the EMMA and ALICE because it’s going to give you very useful information, it could also help us to understand what has happened and it would be much more specific to carry out the correct treatment.

Would you recommend taking probiotics before embryo transfer until birth (and after)?

No, I don’t think that they are going to be useful. If you mean vaginal probiotics, taking probiotics can be useful for other things. I’m just now focusing on obstetrics and gynecology, and we only carry out these tests when we think that there is an implantation failure. We do not do endometrium biopsies in all our patients. We assume that in the majority of our patients, the microbiota in the endometrium is going to be okay. In terms of improving live birth taking vaginal probiotics is not going to have any significant impact. During the pregnancy, well, it’s not going to do any harm at all, and it may help in other aspects, in other parts of your body, but with regards to the obstetrics, I don’t think that they are going to make any significant change.

I am working with a healthy surrogate, how likely would PGS normal tested embryos produce a baby with Down Syndrome or other known genetic disorders. Does it ever happen?

Theoretically, it could happen because there is no single test in medicine that gives you 100% efficiency, but the risk is very low with the new techniques. With the NGS, we have a sensibility of a 99.8%, so there is theoretically a 0.2% risk of having some kind of issue that the technique cannot detect, and the same happens with amniocentesis, which is not 100% efficient. You can even have a normal amniocentesis and a very low risk that the embryo can have a problem, especially things that we call mosaicism that means that not all the cells are affected by the genetic issues.

There are Down Syndromes in which only 10 or 15 or 20% of the cells have the trisomy, not 100% of the cells, and in these cases, since the number of cells that you study is limited and is much more limited in the PGS in which you often study 4 or 5 cells that not in the amniocentesis where you can study 25 to 50 cells, so there is a slight difference in terms of sensitivity, but in all cases, the tests have limitations. The number of cases that I’m aware of within this new technology, the NGS is that so far no embryo classified as healthy has produced any issues in the baby, so we can consider that w so far we have a 100% efficiency, but theoretically, it could happen. This is a very low percentage of cases.

If you do a PGS, that’s the best you can do to reduce the risk to the maximum. There’s always going to be a residual risk, but it’s going to be very low.

Can taking an aspirin when there are no known issues cause a problem in having successful implantation, pregnancy, or live birth? I have had IVF once with failed implantation with a good quality untested embryo. I was advised to take aspirin, and I have no known health conditions.

It’s true that taking aspirin once a day, it’s even recommended in cases of patients who have cardiac problems because it thins the blood, it’s like a blood thinner, but my way of understanding the medicine is that if you just have a patient, and you give to the patient everything that you have, the aspirin, the prednisone, the heparin, the probiotics, the antibiotics, in Spain, we have an expression that says that you are killing flies with cannons and that’s a bit of that. It’s like we are over-treating a huge amount of patients. I think that medicine is related to deciding what kind of things can be useful for that particular patient, and if not, you become a machine that gives products without treating everybody and giving medicines to everybody without knowing if they need them.

This is not the medicine I like, so I would add aspirin only if I think that the patient should have gotten pregnant and she is not, and in those cases, despite having normal thrombophilias and a normal antiphospholipid syndrome, a normal folic acid, normal homocysteine and I may still recommend it because, for example, in the thrombophilias, which are caused or could be caused because of mutations in the coagulation factors. Since the initial studies in the mid-90s, we find a new mutation that can cause a problem. We cannot discard that there are other mutations yet to be known, mutations that may also cause thrombophilia and that are going to be discovered in the future. It makes sense that even if all the tests come out normal, you may give aspirin and heparin to a patient who has a recurrent implantation failure, but to any single patient who is about to start an IVF, no I don’t recommend that.

Can belly fat be bad for hormone absorption during stimulation? My BMI is 26.7.

With this BMI, I wouldn’t say so. It’s true that when the BMI is over 30 and especially when it’s over 35, the patients may need higher doses to get the same stimulation because, when you just give a shot of hormones, the volume of the body is important, and the distribution of this armor inside of the body is also important. It is not the same to treat someone whose weight is 55 kilos and someone whose weight is 122 kilos. The effects of the hormones are going to be different. It’s better to have a normal BMI because probably the stimulations are going to be much more effective. The majority of the hormones are going to go to the receptors in the ovaries and are not going to be stored in the fat all around the body.

What is natural IVF? Is it not too invasible to retrieve only one or two eggs every month and freeze/bank them?

I don’t think that it makes sense. In my opinion, the results of natural IVF are not that good. Understanding natural IVF just following your cycle with a very low amount of hormones and then going for the dominant follicle and retrieve that follicle. It is the standard concept for natural IVF. The advantage of the natural cycle can be found in some cases of patients who have a low ovarian response. Giving them hormones is not going to make them produce many follicles, it could be useful. I would recommend doing an IUI rather than natural IVF.

The main reason for this is that up to 25% of the cycles, you do not get the egg. In another 20-25% of the cycles, the egg is not of good quality. When you’re doing natural IVF in patients over 38-39, on the other hand, there are the patients that most commonly have a lower ovarian reserve. Natural IVF, in my opinion, makes sense only in young patients who have other factors that make IUI useless, like a male factor, blocked tubes, if not, it is worth to obtain more oocytes. I had a lecture about IVF in patients = older than 40, and it’s clear that the more eggs you have, the best the prognosis is.

Taking hormones is not bad at all, as I always say if the stimulations were risky for women, it would be very controversial from the ethical point of view to treat egg donors that can go through 1,2,3, 4, up to 6 rounds of IVF. We do that because the evidence is that taking hormones is not going to cause any mid or long-term effect on your body. Don’t be afraid of taking injections to try because if you instead of 1, you take 4 eggs, you are significantly increasing your chances of having a baby, so why do you have to go through 4 rounds, 4 months, let’s say that you are 41. to get 444 eggs, you need to invest 4 months, this time can be crucial, and the quality of the eggs that you are going to get in the 4th attempt could be worse than the first one. If you take a stimulation and you get those 4 eggs in a single round, you may improve your outcome.

I can see the point and take into account that it’s usually recommended in patients who are over 38. I prefer to give a mild stimulation or even a strong stimulation because I know that if I get 3-4 eggs, I’m improving your life birth, not that pregnancy rate, your life birth.

In your opinion, what dose of vitamin D should be given before and during pregnancy? What is your view regarding good quality fish oils eg. Carlson’s and organic folate, and prenatal vitamins?

Vitamin D depends on the levels. If the levels are below 20, you should treat them with high doses. I’ve got patients that I’ve treated with 50 000 units per week, so that means more than 7500 units every day because I wanted them to recover very soon. These doses are contraindicated during pregnancy. In pregnancy, vitamin D is the only one, which if you take too much, could have a toxic effect. You have to be very careful, and you can take thousands of vitamin C, thousands of vitamin E, vitamin B, B12, and nothing is going to happen nothing, but too much vitamin D can be harmful to you. During pregnancy, the maximum recommended dose is 600 units per day.

We usually give such a dose for patients who need to recover the vitamin D levels, we treat with 25000 units per week. They are available in small bottles here in Spain. You take the bottle once a week, and then you have enough vitamin D for one week, so it’s a very easy treatment, and in cases of severe deficiencies, I give two bottles of 25 000 units, so that’s a maximum. Fish oils, folate, and others, well these kinds of things, honestly in terms of improving live birth, there is no evidence, at all. I prepared a lecture about diet and IVF outcomes, and then all the studies confirm that these kinds of things do not improve the quality of the egg, which is the main factor related to better live birth.

In any case, they are all going to help you start the pregnancy in a better condition, and that’s also important. We do recommend to have a good diet, we do recommend taking different vitamins like CoQ10, DHEA, Omega-3, Omega-6, folate, and all these kinds of things. In all cases, if we are successful, you are going to be pregnant, and we prefer to look into the future and not focus on being successful and forget what happens afterward, we want to go ahead.

What is the name of the blood test that can check the genetics of the baby during pregnancy?

There are two types. There are non-invasive prenatal tests, which are the tests that are usually done on week 10 and that consist of taking some blood from the mother isolating the DNA of the baby, and then you can do a limited amount of genetic testings of them. Then you have the CVS, which is an invasive test in which you take cells out of the placenta, it is usually done around week 11-12. Then you have amniocentesis, which is the standard test that is done around week 15. You put a needle into the sack, and you obtain the amniotic fluid. Then you study the cells that are floating.

The most efficient is probably amniocentesis because you are testing cells from the baby. Then, the CVS because you are testing the cells of the placenta, it is known though that some genetic abnormalities are limited to the placenta, and the baby may not have them. The less efficient in terms of results is a non-invasive prenatal test, but it has the advantage that it is non-invasive, so it means zero risks for you. The other ones are invasive, and they may cause a miscarriage. The risk is between 0.51%. It is not very high depending on the expertise of the doctor, but they are invasive and they have risks, so you have to decide which one suits your case.

I’m waiting for my second FET. I had one fresh ET with a very good embryo (extended blastocyst). I have regular ovulation. My endometrium at the time of ovulation is usually fairly thin (cca. 7mm). What kind of cycle do you recommend to perform my next FET – natural cycle, moderate natural cycle, or stimulated cycle? And why?

The problem is that, in some cases, patients or even doctors tend to think that transferring a pretty embryo means that the embryo is good. That’s not always true especially as you get older. Having an expanded blastocyst if you are 42, the chances of that blastocyst to be genetically normal is 11%, so 1 out of 10 are going to be really good embryos. If you are 32, more than 70% of these embryos are going to be genetically normal, and then there will be a really strong correlation between morphology and genetics. In any case, I would say that an endometrium of 7mm is normal.

Last year there was a very big revision about the concept of thin endometrium carried out by the Canadian Fertility Society, and they concluded that as long as your endometrium is around 7 mm, that’s fine in an IVF that means that you’ve been stimulated. Our cut-off point is 6mm when we do embryo transfer, so to me, your endometrium is normal. It has probably more to do with the fact of using hormones or using natural cycle but not because you’re going to get a thicker or thinner endometrium. It’s probably more related to how good that endometrium is going to be from the functional perspective. If you have tried hormones and it does not work, try to change to a natural cycle.

We do use some stimulated cycles in some cases of patients with really thin endometriums that are between 4 and 5 millimeters. We try to stimulate, we give higher doses of estradiol. In some cases, pills do not work, and then the endometrium responds to the estradiol, so in these cases, we use stimulated cycles, but we usually work with hormone replacement therapies or a completely natural cycle. The only thing we do is that trigger the ovulation to schedule the embryo transfer.

My first gynecologist saw on ultrasound scan that position of my uterus fundus is a little bit lower than recommended (cca. 4-5mm). She refused to do a hysteroscopy. My second gynecologist saw on ultrasound scan ‘cat’s eyes’, and she is sure, that I have septum or mild form of the heart-shaped uterus. Would you recommend hysteroscopy or not? I already had one unsuccessful fresh ET with extended blastocyst.

Nowadays, if you can have a good 3D scan, that should be more than enough. The hysteroscopy is only going to let you see the shape of the cavity, but if you have this kind of heart-shaped uterus, it could be because you have a septum or because you have a bicornuate uterus, which means that the uterus, the whole uterus have this kind of shape, you may have a normal uterus with a septum, or you may have a bicornuate.

If you just see the inside of the cavity, you are not going to know if the external part is normal or not. In this case, a good 3D scan can help. In some other cases, a magnetic resonance, an MRI (magnetic resonant imaging) can also help to get a better idea of the external shape of the uterus. In this case, for example, you see that there is something wrong with the scan, it could make sense to do a hysteroscopy because you’ve seen something wrong.

I think that other tests are probably not so invasive and easier than hysteroscopies like a 3D scan or MRI, but the hysteroscopy could help you to get a direct view of the cavity and confirm whether you have this kind of hair-shaped uterus or not.

What is your view on what the surrogate could do that would be a bit different to a mother carrying her own or her donor’s egg in pregnancy to ensure a healthy birth of the baby.

I would say that there should not be any difference at all. The main problem is that surrogacy is illegal in Spain, so my experience in this field is zero because we can’t do that here. I’ve got some patients that have gone through surrogacy, they flew to other countries to have this treatment, and I don’t think that anything different should be done. They should have as healthy a life as possible and probably the best advice I could give is just to do what you would do if the baby was yours, so continue with a healthy life, doing some sport, all the things that you would recommend to any other woman. Once she’s pregnant, the body is going to react to this pregnancy the same way. If she’s a surrogate and has gone through IVF with her eggs or you have used other eggs coming from an egg donor to transfer the embryos to a surrogate, I think that’s how they should behave during pregnancy.

Does progesterone level affect the implantation? Do you recommend progesterone injection on top of the pessaries?

It’s now becoming trendy, I would say. We did a study in which we tested 255 patients, and we were checking the progesterone levels on the day of the embryo transfer. Other studies suggested that if on the day of the embryo transfer your progesterone levels were below 9.2, that could be a lower implantation rate and a higher miscarriage rate. In those cases, it was suggested that adding injected progesterone but not intramuscular, subcutaneous progesterone could revert this effect, and the results with that in those cases were promising.

The thing is that the incidents of these low levels are very different when you compare different clinics. I can tell you about two clinics that are here, in Barcelona, our clinic (IVF Barcelona) and Dexeus Mujer clinic. They have published a result and study in which they have tested progesterone, and 30% of their patients had low progesterone levels, that’s incredible because, in our group of 250, only 9% of the patients had low levels of progesterone, which is the difference. They probably work with the different protocols of progesterone, and they use 400 milligrams every 12 hours.

We work with 200 milligrams every 8 hours. We may probably get steadier progesterone levels throughout all the day, and they may have peaks in the morning and the evening, and when you test the progesterone, which is usually done the midday when most of the transfers are done, you may have abnormally low levels. Our experience is that if you give some subcutaneous progesterone when the levels are below 10, I would say 9.5-10, the outcome is going to be better, and you are going to rescue cases that otherwise would have been negatives.

I don’t know if it’s because of a lack of implantation, because of an early miscarriage, or because the levels are not good enough to let the embryo going but in any case, it’s useful. Another issue that we have is that the levels are different. Some clinics suggest 10.4, other clinics initially consider 9.2, and now they have recommended 8.7, we work with 10, so it’s a bit of a mess. In these cases, I recommend the clinic to test their patients to know exactly how often that happens in their population. According to their protocols and then determine this cut-off point and decide when subcutaneous progesterone should be added to the vaginal pessaries.

Should the progesterone level be checked and monitored after the ET? What is a normal level on transfer day, and how much should it increase? 1-week post-transfer, what is the normal level? I sit better to have a higher level than lower?

The idea is that progesterone in excess is never an issue. If you have to choose, it’s always better to have higher levels. The main problem is that the cut-off point is still controversial. Clinics consider that the progesterone level should be close to 9, other ones 10 or 10.4, so basically, you should check the levels that lead to a significantly lower pregnancy rate in your clinic and then correct that. I don’t think that the population that the different clinics are treating are different, also the ethics or the patient’s age, so if you want to check the progesterone levels, they should be checked on the day of the embryo transfer.

Now, I have a case of a patient that had normal levels on the day of the embryo transfer, and 6 days later, the levels were extremely low, but this is probably the first case that I’ve had after doing a lot of research but it could happen, this is medicine, so I would say check your levels on the day of the embryo transfer. If they are good, you should not modify the treatment. If they are low according to what your clinic considers low levels, then add one subcutaneous progesterone a day, and that should be more than enough to recover the normal pregnancy rates.

Would you recommend a natural IVF cycle for women over 40?

I would recommend it only in very specific cases. The chances of doing the whole cycle and losing 1 month for nothing are probably up to 50%. If we just take into account the cases in which we do not get the egg and in which the egg is not of good quality to be fertilized, so for me, it’s very low. Now, some treatments drugs are very comfortable that you take one shot and they stimulate you for 7 days, so why do you want to go through 3-4 rounds of cycles in which you have low chances of getting an egg, it’s better to just go through 1 round and produce 2-3 three eggs, it’s better. Only in very specific cases, the natural cycle would be advisable especially in patients over 40.

Does using intralipids increase the implantation rate?

There is no evidence, as I’ve said, The American Society considers that the evidence is of very low quality. The intralipids may have important side effects, they contain sodium, which’s very allergenic. There has been described severe side effects in patients, some of them even have been admitted to the hospital, so it’s not like you’re taking something that is not going to cause any problem. In my opinion, the effects have not been proved at all and taking into account that the benefits do not outweigh the risk, I do not recommend them, and we never use them.

My TSH is on the low side, 0.18 picomoles. Can that also affect the implantation?

This level is on edge. It could be that you have slight hyperthyroidism, but this kind of problem is not going to have an impact on the implantation. It’s always worse to have high TSH than low TSH, and probably if you go to the endocrinologist, he’s not going to give you anything, he’s going to say okay go ahead, and then if he gets worse during the pregnancy, we would treat it, but I wouldn’t be worried about that.

During a short protocol, I had 7 follicles and only 3 eggs retrieved, it has been recommended to try a long protocol to increase follicle synchronization with Suprefact injection for 7 days before the period start date. I have heard of varying lengths of the down-regulation treatment. Is this dependent on the type of medication? Or, does this seem short?

No, that’s the standard long protocol. When you retrieve these eggs, it could be because the size of the follicles was different, and in this case, it makes sense to work with the long protocol and the standard is to start any drug that you use like Suprefact, Gonapepty, Decapeptyl one week before you have your period, that’s a standard protocol. I wouldn’t recommend down-regulating for longer than that because these drugs may also reduce the response afterward, so you should stick to the days that we recommend, which is 7 days, and try to use the lower possible Superfact dose. We start with a stronger dose to cause the downregulation, and as soon as the patient is starting with the stimulation, we reduce the Suprefact dose to avoid this negative effect on the ovaries. If you’ve only got 3 eggs because the follicles were too big and too small, long protocols make sense.

What is the lower dose of Suprefact, and should I start low?

The idea is that if you start with the Suprefact at whatever those you recommend, it’s better to reduce the dose to half. When we’re trying to down-regulate the patient, and another thing is when we try to keep the patient down-regulated, so if we work with Superfact if I’m not wrong is like zero, Superfact is not available in Spain, so I’m not very familiar with it, but I think the dose is 0.5, then you should go to 0.25 whenever you start the stimulation.

I have had several good embryos but failed transfers, I do not smoke, I have lost 12 pounds, my diet is good, I removed gluten, we can’t figure out wh. My physician is not familiar with EMMA or ALICE. What advice would you have for me? I am 44. I was on aspirin and heparin. I was taking 40 mg of heparin.

As you are 44 and you are using your eggs, I’m sure that unfortunately, the main problem is the genetics of your embryos. I would suggest doing the PGS since you are lucky enough to produce a good number of embryos. Statistically, at 44, only 1% percent of the embryos are going to be genetically normal. As you’ve already done PGS, two different things may impact your case. One thing is that genetics is the most important thing that age affects because it’s related to an increased risk of genetic abnormalities. The age may also affect other parts of the egg that also play relevant roles in the early stages of the embryo development like, for example, the mitochondria, which are the structures that produce the energy that the embryo needs to continue dividing, and in some cases, one of the things that we have observed is that when we do PGS the implantation rates remain very similar until the patients are 43, the results of the genetically normal embryos tend to be better than when they are older than 43. We think that this is because these other structures may be also too old. If the mitochondria have failed to produce the energy that the embryo needs, this may cause a failure in a genetically normal embryo. That could be one specific factor that, unfortunately, cannot be tested. This is just a theory.

There could be other factors related to your uterus. Having an abnormal microbiome or having thrombophilias and antiphospholipid syndrome, should be tested. If you are transferring genetically normal embryos at your age, you are transferring the best embryos that you can produce. If these embryos do not work, it’s because either they have other problems that we are not going to be able to solve like mitochondrial issues or there could be something wrong on your side.

We have not discussed the doses of heparin. The standard protocol with heparin is 40 milligrams a day or 4000 units of enoxaparin, but I’ve got patients that have needed up to 100 milligrams, a huge amount of heparin to have an ongoing pregnancy.

I’ve got cases, but these cases are probably mostly related to recurrent miscarriages in which I’ve increased the dose from 40 mg to 60. It’s becoming more and more common to work with 60 milligrams. Seemingly 40 milligrams, in cases of patients who need heparin may not be enough, there is this kind of a trend. 60 milligrams is a strong dose that should be monitored by hematologists, not by gynecologists.

EMMA and ALICE would make sense in your case because that would let us know if there is anything wrong with your size. Checking thrombophilias to decide if you need higher doses of heparin could also be another good thing, and that’s it.

I have 4 failed ICSIs with 2 biochemical pregnancies and one missed abortion. I am 40 years old. No PGT-A was ever done so far. What would be your next steps?

You’re already answering the question considering PGT-A. Our current approach is first to be sure whether the embryos are of good quality or not. Before deciding to start changing things, then we do an IVF, we check the genetics. If the results of the genetics suggest that genetics are not the problem because most of the embryos are genetically normal, then before transferring these embryos, we consider carrying out all the tests to discard problems on your side. The main problem that you’ve had so far is the genetics of the embryos, so I don’t think that you could also have something wrong with the endometrium or in your body, it would make sense to transfer this embryo. The PGT-A somehow is going to help us know if these embryos, apart from being pretty or morphologically good were also genetically normal, and based on the results that we get from the PGT-A, we can then decide to carry out further studies on your side or not.

We’ve just experienced our first IVF-ICSI cycle with a 5AA grade hatching blastocyst – we are both just 30 years old. Is it likely that it failed due to egg quality? And should we be aware of any changes to our protocol for when we commence FET? My TSH was 5.6 before the transfer, but I’m on 50 mg thyroxine daily to bring it down. My progesterone level wasn’t checked before transfer. We do have a male sperm morphology issue. Should we try to transfer 2 blastocysts next time?

I think that you’ve been unlucky, I don’t know what has failed but even in cases like this as you are 30 years old, there should not have been any problem getting pregnant. 5.6 is slightly high, it’s higher than 4.4, and if there’s anything that everybody agrees is that having a TSH over 4.4.

If there is a male factor, I don’t think that the egg is going to play any role. This TSH is high, it could have made things more difficult for the embryo, but even if we transfer the best possible embryo, in the best possible environment, we are never going to get a 100%. I would probably consider transferring another embryo before starting to carrying out tests on your side to see if there is anything wrong. So, correct the TSH, that’s for sure. I would recommend transferring 1 blastocyst, not transferring more. If you transfer more embryos, the pregnancy rate of the transfer is going to be higher, but the embryos are individuals, they don’t affect each other, they do not help, they do not disturb, so if you transfer 1, the implantation rate is going to be the same that if you transfer 2.

If you have several embryos, I would still recommend transferring 1 in your next attempt, and as I’ve said, without considering any investigation at this level. Even when we are doing an egg donation, we do not have a 100%. With 1 good blastocyst, you should expect to have 65% chances, so there’s still a 35% of the patients who are not going to get pregnant, this does not mean that there’s anything wrong or that there are any problems that should be treated. I would just move forward and consider a second transfer, and if that second transfer fails, then yes, I would consider doing some research to see if there is anything that should be treated.

I am 41, I have unexplained infertility. I had 5 miscarriages (natural) in 18 months. I had 3-day 5/6 euploid embryos out of 7 that fertilized. First, IVF failed. Is there hope for the last two to work? What else should be tested or done? My last embryo miscarried, and it was chromosomally normal.

You had seven embryos, and 3 were tested and genetically normal. These are probably one of these cases in which you’ve been lucky having 3 embryos, out of 7. It would be a good idea not to wait too long to consider some easy tests like thrombophilias, antiphospholipid syndrome, and things like that to discard any issues. These embryos are very valuable. Since you’ve been pregnant 5 times naturally, whenever you want to transfer the frozen ones, use the natural cycle.

Rather than using hormones and work with hormone replacement therapy, I would recommend using a natural cycle. You’ve been pregnant 5 times, so why do you want to try something different. Now that you are transferring good embryos, try to work with the natural cycle.

These miscarriages could have been due to some yet to be known issue. I would also consider taking aspirin and heparin despite having normal thrombophilia and normal antiphospholipid.

Unfortunately, other factors may also cause a miscarriage that is not genetics like abnormal development, abnormal implantation, we know that when we transfer a genetically normal embryo, there are still some problems that could happen, and we are reducing the risk of miscarriage by 70%, but there is still a 30% of cases in which you may have another problem and some of them are isolated. Because of the information you have given to me before, I would recommend considering heparin and aspirin. You should start taking aspirin one month before the embryo transfer. Heparin you should start taking on the first day of the cycle, in which you start the preparation for the embryo transfer, so do not start it on the day of the embryo transfer but a couple of weeks before.

I am 44, I had a couple of failed IVF with my own eggs, it never ended as a positive test, using different protocols. I had my first DE transfer last month, which also failed with 5 AA embryos. A year ago, an HSG showed blocked tubes, the doctor said I have hydrosalpinx and suggested to remove the tubes. 2 months after, I had HyCoSy done to double-check, and the tubes were patent, hydrosalpinx was not seen. I took Doxycycline for 2 weeks. Do you recommend to do an EMMA, ALICE, or to check the tubes again?

In cases like yours, after the Doxycycline, you should take some vaginal probiotics. I don’t know if you did that because the Doxycyclin, the antibiotics kill the good and the bad cells, they also kill lactobacilli, so it’s useful to use the vaginal probiotics to recover the normal flora. I’m not fond of oral probiotics, I prefer vaginal probiotics because the vagina is close to the uterus, so whatever you put there is easier to get to the endometrium.

There is not a single study using oral probiotics that have proven to recover the vaginal microbiome, so the endometrium is much more difficult. I would recommend using vaginal probiotics.

In any case, EMMA and ALICE, despite taking the antibiotics, could make sense. As I’ve said, there are cases in which patients needed up to 2-3 or even 4 biopsies until we have been able to completely clean the endometrium of bacteria. Doxycycline may have been useful or not, depending on the bacteria that you have.

The EMMA, ALICE is also going to help to see if you had the hydrosalpinx if this had somehow affected the endometrium. If there is anything wrong at that level, you may probably have dysbiosis, or you may still have a kind of chronic inflammation, so I would recommend that. That being said, unfortunately, you had only had 1 good embryo transfer so far, the last one at 44, which should not be taken into account because the genetic quality of those embryos has probably been very poor, so probably, if you have more transfers, what I would suggest before considering EMMA, ALICE is to go for another round, and if after 2, you will not get pregnant, then consider them.

I had a natural ectopic pregnancy in the right tube treated without surgery or medication. Some months later, I had HyCoSy where the liquid passed through the tubes without requiring additional pressure, however, could not be seen in the right tube. I’ve heard the liquid in HyCoSy isn’t suitable to check for clear the tubes, and that HSG should be done. Would the EMMA / ALICE test be more useful, or should I do both? Does this still matter if going for IVF rather than trying naturally?

The HyCoSy is helpful, it’s a scan that allows in an easier way to check for clear tubes, I don’t think that HSG is going to improve as long as the doctor who performs the HyCoSy has good expertise, the results are very similar.

You may have an ectopic pregnancy and still have a patent tube, that’s something that could happen but in any case, what I can tell you is that this tube is not going to work fine. One of the main problems that we sometimes have is that we can only diagnose a tubal factor when there is an atomic abnormality, but the tubes are not passive structures, they are active, they transport the embryo using kind of a contraction and in some cases, they may not work as expected and behave as if there was a real tubal factor that cannot be diagnosed.

If the tube was not damaged before the ectopic pregnancy, it is now damaged. I wouldn’t be confident with this tube. In regards to EMMA and ALICE, those check something different like changes in the environment in the endometrium, but they do not check if the tubes are patterned or not. They may help if you think that these tubes have been damaged by an infection or an inflammatory process because this inflammation may also be in the endometrium. If the tube has been damaged, for example, because of endometriosis, EMMA and ALICE are not going to shed light on your problem.

I would consider them only if you think that the tube was damaged because of an infection.

I would say that IVF is probably the right treatment when you think that there is a tubal factor, so I don’t think that you should do EMMA, ALICE at this stage. Just do the IVF, check the embryos, transfer them and if you don’t succeed, then consider any treatment as if you had a recurrent implantation failure. Even if you are trying to conceive naturally, I don’t think that EMMA, ALICE makes any sense if you think that this tubal problem is not caused by infections or inflammations.

We have had 1 unsuccessful donor egg transfer and have 2 frozen embryos left to transfer. Is there any benefit of transferring both at the same time, or would the best route be to transfer one at a time and have 2 further attempts? My wife is 40.

Two different concepts sometimes are misunderstood. The pregnancy rate per cycle and the pregnancy rate per transfer. The pregnancy rate per cycle means the chances that you get pregnant with any of the embryos that you have created after a single retrieval, or after a single egg donation, after a single cycle. Let’s say that you have 3 embryos, these embryos should offer you, let’s say 80% chance of getting pregnant either with the first, the second, or the third. This 80% is going to be achieved the same if you transfer 3 times, 1 embryo or if you transfer all 3 together, so transferring embryos together does not increase the overall pregnancy rate of the cycle, it just shortens the number of attempts that you need, and this may mean fewer attempts, less money, but in terms of results, it is the same to transfer 3 embryos together or 1 by 1. The main problem is that if you transfer 3 together, you may have triplets, which is a bad outcome.

This is why I always tell my patients that there is no medical reason for transferring more than 1 embryo at a time because it’s not going to improve the performance of the cycle. If you transfer 2 embryos, you may be increasing the chances of the embryo transfer. When this does make sense? When the risk of twins is not that high because it could be very demanding psychologically and emotionally for the couples.

Let’s say you had 7 embryos to go for 7 rounds of 7 transfers with 7 negatives apart from the money, it can be devastating for you psychologically, emotionally. Your wife is 40, indeed, the risk of having twins at this age is not that high, so considering transferring 2 embryos is a good idea but not because this is going to improve the live birth of your cycle, just because it’s going to shorten the number of attempts that you need.

I’m 48-year-old without menstruation since September. I just started to take progesterone after my GP.suggestions, and I hope my menstruation will come back. My AMH is at the moment 0.28. Do you think if I can’t get pregnant during the 3 months of treatment, I should try IVF with my eggs?

I don’t think so. Most of the time, when we do recommend egg donation, it is not that the patient cannot get pregnant, it is because we think that IVF is not going to add any benefit to the chances that you may get trying to get pregnant on your own. With this low AMH, if you go through any stimulation, you’re probably going to produce one follicle. At 48, your chances of having a baby are going to be in the best scenario at 1%.

If you go through an IVF with this AMH, your chances are going to be 1.5%, so it is worthless to go through this process to just improve your chances by 0.5% or 1%, it does not make sense at all. If you can get pregnant on your own, another scenario would be if you were a single woman with no partner, and your only option was IVF. If you have a partner and everything else is normal, the main problem is that IVF with this AMH is not going to improve the chances that you have at all. If you want to get pregnant with your eggs, my recommendation would be to keep trying naturally. Whenever you want to do a treatment, consider egg donation but do not consider IVF, it’s going to be a waste of time, money, among other things.

What made the subcutaneous injections better than the intramuscular injection for progesterone?

The side effects. Intramuscular injections are painful because it’s an oily solution, the subcutaneous injection is a water solution. There have been described severe side effects from intramuscular progesterone. Some of them are severe like pneumonia and eosinophilic pneumonia, apart from local abscess and problems with the injections.

The subcutaneous injections can be self-administered like any other drug during IVF. The effect is the same, so I can’t see the point of using intramuscular progesterone nowadays if you have subcutaneous injections available.

What about a mild form of adenomyosis in the backside of the uterus. Is this a really big problem for implantation and further pregnancy? I’m very worried about this.

Adenomyosis is one of these kinds of things that is also very controversial. Sometimes, you see adenomyosis on the scan, and you see all the typical signs of the endometrium that is going inside the uterus. Such us: hyperechogenic myometrium, asymmetry of the uterus. In these cases, it may make sense to down-regulate patients before transferring the embryos. In these cases, the data suggested, although it is still controversial, it has been suggested that the implantation rates can be lower.

If you have adenomyosis and it has been easy to diagnose, is it via a scan, then if you are going to transfer embryos consider down-regulation before, not a long down-regulation. I remember one case that I had, I down-regulated the patient for 3 months because the uterus was awful in terms of all the things that she had, but those are very specific cases. Usually, down-regulation from the prior month is enough to keep this pseudo-endometriosis at a low level, and then, it is believed that it may improve, at least it’s not going to cause any damage and in cases of the adenomyosis may make sense.

Authors
Raul Olivares, Dr.

Raul Olivares, Dr.

Dr. Raul Olivares began working in assisted reproduction in 1996. In 2003 he created one of the first Spanish international Departments in the Institut Marques, and was its Director until 2010. He became the medical director of Barcelona IVF in 2010. Dr. Olivares says: "I would describe myself as a vocational doctor. As far as I can remember from my childhood, my dream was not to be a doctor; rather it was to bring children into the world. Firstly I made it come true in the delivery room, where I thoroughly enjoyed myself, and now before conception. I am one of those who believes that while the end result is essential, it is not the only thing that matters. That is why I have always defined Barcelona IVF as a philosophical programme because, when we started it, we gave up many amenities in trying to fulfil our dream of successfully performing the medicine we like. I truly believe that assisted reproduction should be like this, a strange combination of idealism whilst keeping our feet on the ground. The speed in which we acquire knowledge is dizzying and this leads to our results improving; however, we must of course always try to ensure that the entire process is worth it, without losing sight of the fact that our end goal is to fulfil the dreams of those that trust us."
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry, and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her traveling, biking, learning new things, or spending time outdoors.

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