Why was your attempt unsuccessful and what to do next

A very good question. A very tough one to start with because there’s no easy answer for that. This has been discussed for years and years and the rules have been shifting. We need to realize that there are many forms or types of fibromas, the ones that grow outside of the uterus, the subserous myomas or fibromas fibroids. They’re not that problematic. Then, there are the ones that grow inside the uterine cavity, the submucous fibroids – these are a big problem and should be removed possibly via hysteroscopy. But here we’re actually discussing the ones that grow in the wall of the uterine cavity and the rules have been changing, actually, over the years. The “rules of four” have been there for quite some time. If there’s more than four myomas fibroids, operate first and then perform the transfer or then another one was when the fibroma is larger than four centimeters in diameter, then operate. But, currently actually, the experts in the field usually say when it’s in the wall of the uterus and is really large, it might play a certain role but it shouldn’t play a substantial role and do not operate try and perform the IVF cycle and first as long as the patient doesn’t have any substantial problems, any pains, any cycle irregularities, irregular  bleedings, so, yes, they might play a certain role but we don’t operate until the patient has actually specific problems.

A very good question. I take it the high quality of these embryos was probably just based on their morphology, on their development and, hopefully, through day 5 of the development because day 3 is inconclusive. But if these were high-quality embryos on day 5, yes, this is something you might want to consider especially if you have doubts about the next possible IVF attempt, if you should keep trying with your own eggs or is there maybe an underlying problem that’s not showing even though the karyotypes are okay? Once again, I do have to mention the age and I’ll get back to that in just a moment. I also have to mention that while the PGT-A procedure, the genetic testing of the embryos, is very helpful, it mainly serves as a method of embryo selection for the transfer. It’s especially helpful when you have multiple embryos. There are cycles sometimes where the patient or the couple have 5-8 embryos and when the patient goes through seven frozen embryo transfers unsuccessfully that gets very frustrating. In a situation like this, it’s definitely a good idea to do that. When there are just one or two embryos, it gets a little questionable and it’s especially tough to decide when the patient is around 40 or over 40 because they usually don’t have so many embryos and, yes, the PGT-A with a poor result might actually prevent you from repeating the IVF cycle with your own eggs again because it shows that there’s a very little chance. I have had patients that came from another country. She was 40 with very good AMH, successful stimulations 9-11 oocytes and after a five-day cultivation, they had 4-5 or even 6 blastocysts. Guess how many transfers? None. Why? All the embryos were aneuploidy. That’s in a situation where it might actually give you a clear suggestion. Generally, I would say, yes, that’s perhaps a good idea but you have to take into account everything else plus the price of the test, of course, as well.

Thank you very much for the question and the specification that is actually very helpful. I think you’re on the right track because the donor egg treatment is definitely going to work here. Fortunately, the ability of the uterus to take care of the pregnancy remains very strong until high age so the fact that you’re 45 does not play a role here, not anymore. The quality of the egg is important or decisive and, of course, the quality of the sperm cells, eventually, and the right micromanipulation methods and everything else. Pointers or tips for success for you personally? If it’s a mock cycle, the preparation cycle, definitely an ultrasound to check on the height of the endometrium and then based on that the dose of the estrogen hormones can be adjusted for the actual transfer cycle so that might be very helpful. Otherwise, stay positive, eat your vitamins and hope for the best. There’s just nothing that you can really do at this point to try and increase your chances. Of course, there are the things like I mentioned before vitamins: folic acid or folate but every clinic does that. I’m quite sure you’re taking these already; otherwise, there are no real tricks that should be mentioned here unless, of course, there’s a problem on the ultrasound check, if there’s a  sign of a polyp or a cyst in the ovaries, then you might want to reconsider and maybe postpone the treatment but I hope this is not going to be the case. Good luck!

This is a very tough one and I’m sorry but it’s actually exceeding my expertise. If you do have blood coagulation issues, then you might be at risk while taking estrogen hormones or during the stimulation. You’re definitely a candidate for the low molecular weight Heparin injections. But as far as the question of the hemangioma goes, then you will have to talk about that with your specialist. They have to see and possibly monitor the treatment and say if a low molecular weight Heparin application is strictly forbidden, a contraindicated or if it’s possible but you’ll have to be monitored closely or if it’s no problem at all. If they can also suggest the right dose so this may be of course a tough issue and it’s one where you’ll have to actually cooperate with both sides, with both your reproductive medicine specialist or assisted reproduction specialist but also your practitioner, your internist or your hematologist, whoever actually does the follow-up on the hemangioma. That’s a very tough one and needs to be solved carefully so that you can stay safe. That’s always the number one point in any treatment.

This is a tough one, of course. When everything is seemingly perfect and still no success, if there was the PGS, the pre-implantation genetic screening, which is an  older label for PGT-A, performed that usually means that both partners had a karyotype examination and it was probably normal because otherwise you would have mentioned that. So genetics is out of the question here. I would wonder about possible hematological issues. Many blastocyst transfers sound like repeated implantation failure. I’d suggest, at least, a blood test for the  hereditary thrombophilia factor two and factor five, at least, those two and possibly, eventually, when you get a positive pathological result and discussing this with the hematologist, maybe low molecular weight Heparin could be applied. Another option is to discuss this with an immunologist but it’s tough to find a specialist for reproductive immunology and to have the perfect tests suggested. I couldn’t even do that and I turned the few immunologists that I  know and respect and I’m in awe of because it’s a very complex field. Last but not least, hysteroscopy, perhaps, unless it was performed, of course. But it says that the uterus looks good. This is probably based on the ultrasound. But after more than 3-4 unsuccessful transfers I would perform or have the diagnostic hysteroscopy performed and check for signs of chronic endometritis or chronic inflammation of the uterine cavity.

Laparoscopy is fine but that’s when you look in the uterine cavity, in the pelvis.  Usually, hysteroscopy is a part of that so I take it you probably had a hysteroscopy. I don’t mean to be rude but 38 is a slightly higher age from the reproductive point of view or the point of view of reproductive health. Once again, nature is quite tough here in that regard. I might not have mentioned that. I did mention it many times in my previous talks. It’s different in men who, generally, produce fresh sperm cells throughout their life. The woman is born with all the eggs and the eggs grow older with her and that’s why the quality of the eggs is best between 20 and 29. It’s good until 35 and it’s acceptable until 40 but in this group, 35 through 40, some literature actually states success rates around 14%. We have been luckier or more successful and we are usually looking at better numbers than that. But this shows you that the quality of the cells can be poorer if you have a very good response of the ovaries and many eggs and good development of the embryos, yes, I would try again, possibly with the PGT-A with the genetic testing of the embryos and I would look into the hematological and possible immunological factors.

A very good multi-layered question. There is not one rule, not one recommendation as far as the number of IVF cycles goes, that would fit all. Age is important here. Being 42 and one failed attempt you can try again but the success rates as I have mentioned are very low, somewhere between 1-5% so out of a hundred attempts 1-3 successful ones. These are very poor chances so that may be the major problem. The age certainly does influence the minimum number of cycles. If the patient is 32 and there’s no other major issue like no response from the ovaries, then recommend going ahead and we’ll try to work on the protocol, we’ll try to improve the protocol so two three four cycles still make sense. In somebody who is 43, it’s questionable whether the one cycle really makes sense. In your case, perhaps, I would try one more time with a better and improved protocol, maybe genetic testing of the embryo; however, if there’s one good embryo, I would just transfer it and give it a chance and if you fail again then it’s probably time to think about egg donation.

They have been actually mentioned or partially answered in the talk. The first one – what are the success rates? It depends on the age. I have mentioned that in the group where the woman is between 40-45 with own eggs 1-3% success rate, with donated eggs 55-60%. So it’s a different world. Of course, if it’s the patient’s own eggs and she’s 28, then the difference would not be that huge because with her own eggs if there’s a good response from her ovaries, there’s basically still that about 50% chance that she’ll get pregnant from the transfer of one embryo. The success rates with own eggs in the group 18-35, the success rates with own eggs are 50-55% so very close to the ones with donated eggs. Age plays a very important role and it’s in those higher age groups where the difference shows. How do we check the quality of the eggs? There is really hardly any way how to check for the quality truly. It’s based on morphology. The eggs are actually examined after the oocyte pickup; they have to be placed in a special maturation medium for a while and then they’re cleared of everything else so that sort of group of support cells, the cumulus all photos,  and when the egg is naked, hence the name denudation, then the embryologist looks at the egg and there’s actually a list of parameters that they go through. Is it regular? Are there fragmentations? Is the polar body well specified? But there is no easy or no simple way to just check for the quality of the egg. A polar body diagnostic might be mentioned here. When you take the polar body from the egg and you examine the polar body, in the meantime the egg is fertilized and can develop into an embryo. But this is a rather expensive method that is not very frequently done because it has been pushed aside by the testing the PGT-A the testing of the embryos themselves.

Once again, they have been listed in the presentation. It’s karyotype, all blood tests, blood tests for karyotype so the chromosomes have to be in order, for cystic fibrosis, for muscular atrophy and for hereditary deafness. So these four are actually given by the law. If you wish to actually ask for another, an additional genetic test, such as the fragile eggs, you can always inquire about that, you can ask the coordinator during the preparation phase and it can be examined in the donor. But in that case, the cost of the examination goes actually to the patient but there can be extra tests performed from these blood tests. But these four that I mentioned are the rules and they have to be part of the examination of the genetic consult without those the geneticist wouldn’t give the green light.

7 mm is good. 8-10 better. Natural cycle, basically, yes, it depends. The follow-up questions would be do you have a regular cycle possibly and what’s the state of not only the uterus but the ovaries as well? One thing that’s important the native cycle or the natural cycle, I take it we were talking about embryo transfer here so possibly frozen embryo transfer. Yes, I like the natural cycles for the transfer, especially of the cryopreserved embryos, the frozen embryo transfers very much. As far as the success rates go, they’re actually the same in both groups. I have heard at the congress colleagues from  France, Spain and Germany mentioning the same and it was fun and interesting to hear the same experience. They all said the same thing: in the natural cycles, the success rates are slightly higher but it’s not statistically significant. It doesn’t really matter. I’d say if it’s a frozen embryo, then, yes, let’s go with the natural cycle, let’s take a look around the L11 or 12, let’s measure the endometrium,  evaluate its structure, let’s take a look at the dominant follicle in the ovary which produces the estrogen that’s the fuel that actually pushes the endometrium higher. If everything is perfect, we might step in and time the ovulation and then eventually the transfer. However, if it’s a cycle with egg donation where a donor is stimulated in there it’s not really possible because the timing of certain crucial steps is given by the ovaries of the donor so in there the endometrium has to be prepared with estrogens. But the success rates are about the same; they’re very similar; statistically exactly the same.

A straight answer – unequivocally, yes. Go for the frozen embryo transfer because as far as I know your body mass index does not really have a significant influence on the ability of the uterus to build up the endometrium, take the embryo in and on the chances of the embryo to implant. The influence of the higher body mass index is usually felt in the regular cycle with a higher weight, it might become irregular, problematic, it might have an influence on the ovulation, it might have an influence on the response of the ovaries to a stimulation. But if you have cryopreserved embryos, it shouldn’t really play a major role and I would just go for the transfer. Good luck!

The age is favorable here but the ovarian reserve seems to be low. I wonder how low the AMH. Is it low as in one nanogram per milliliter or lower than 0.3? OK, 2.5. Is that picomole per liter or nanogram per milliliter? That’s very important. If you happen to know the units they might play a major difference here because if this in nanograms per milliliter, it would still be actually fair, that would be a  normal level. So I take it this is probably in picomole per milliliter in which case it is lower. How to help the maturity of eggs? I would have to take a look at the stimulation protocols, see what the development was, how many follicles in total, why only some of them were growing. Sometimes a different protocol can help to even it out. There are other tricks such as estrogen priming – it’s not very popular but it’s something that we can try. Estrogen towards the end of the previous cycle prior to the stimulation to even out the follicles before we start to stimulate them and then this could eventually lead to a more balanced growth of the follicles. Generally, if this is a question of a low ovarian reserve and that can happen at 35, unexplained low AMH and follicle count, I’m afraid that this is something, that she’ll have to struggle with. 450 Meriofert – yes, this is a very high dose of the FSH. The maximum dose regularly uses 300 units per day. 450 is really high and I don’t think there’s anything else you can try. There have been ways tested how to try and increase the ovarian reserve and some of them have been even partially successful in getting more eggs or more ripe eggs but ultimately the take-home baby rate, the parameter that’s the really important one for us, it always stays the same. We cannot turn back time and there’s nothing that we can really do to improve the ovarian reserve. Unfortunately, the answer there is no; there’s hardly anything that you can really do and if repeatedly the stimulations are unsuccessful or if the AMH grows or drops further it might be time to think about egg donation.

If it is what I think it is that’s the testing of the blastomeres on day 3. It has been pretty much abandoned so NGS is definitely the right answer here. That’s the better method. Testing or biopsy on day 5 and NGS – that’s very good because the NGS does actually give the lab a chance to see not only the major chromosomal problems but also balanced translocations and there’s hardly any other method that would be able to show that. I see that another question jumped up asking what NGS is. Let me tell you exactly – it’s next-generation  sequencing – your geneticist will know or your physician will know. It’s a specific method for the analysis of those cells that we gain via the biopsy. Next generation sequencing it’s a type of pre-implantation genetic testing.

The NGS is the one to go with. I would look no further for the PGT-A. NGS is the method of choice.

Long story and tough. Basically, you would be interested in her previous history but if there were any miscarriages you would know, right? In that case, we might want to look at the hematology but we cannot possibly give her a low molecular weight Heparin just to make sure. It’s not indicated and the hematologists would go crazy and rightly. Vitamins, the right lifestyle and a little bit of luck but, basically, that’s it. There are hardly any simple suggestions that I could still give you. I understand that this is very stressful and I’m really sorry that it hadn’t worked previously but just look at her history, talk to her or better have her talk to the gynecologist. If she was through previous pregnancies, were there any complications in those pregnancies? Did she carry the term successfully? I take it, yes, because, otherwise, she wouldn’t probably do this and in that case, there’s nothing else specifically that I would recommend. Just a good follow-up during the pregnancy but this is pretty much standard in most of the European countries including perhaps Greece or I don’t know where this one goes on. So tons of good luck and I hope it works!

Historically, the quantities given were up to 10 milligrams per day but there have been some studies that have found that problematic and, usually, it’s recommended to not to go over 5 milligrams of folic acid per day. Nowadays, I have to admit that I usually recommend some pregnancy vitamins rather than just purely folic acid. It also depends on what the situation is in the specific patient. If there’s a form of hereditary thrombophilia that is the MPHFR factor mutation, then usually higher doses of folic acid are recommended. Usually, these first trimester vitamins such as Femibion One are a good choice or a sure option because there’s not only folic acid in them but also the methylate, the metabolite already. I’d say the minimum should be 400 micrograms per day but usually, you want to go a little higher than that. I’d say to stay on the safe side safe side no more than 5 milligrams per day.

That’s a tough one because you have been through a lot and you have listed pretty much everything that we have mentioned including the ERA test, hysteroscopy, thrombophilia, NK blood test, biopsy. I did have a patient who has been through 19 cycles including some with egg donation and the spermiogram looked perfect. It was normal and, eventually, because there was no other answers, she said “well, what can you recommend?” and I said “well, the only actually binding issue putting all these cycles together is the sperm cells. They were always the same and even though this spermiogram looked really strong,  we performed a DNA fragmentation test and it showed actually a very high level of DNA fragmentation. Back at that time, we didn’t have the MACS  test to sort out the sperm cells prior to fertilization so I recommended donated sperm and she got pregnant and carried successfully to term. That was the game-changer, eventually. But, here, this is too simple of an answer and it doesn’t really hit it correctly. Five donor egg transfers – grade 1 embryos, one embryo each time. This is really tough. We’re looking at the two frozen embryos, of course. At 48. I don’t really recommend usually in a natural transfer cycle a native frozen embryo transfer cycle even if the cycle is still quite regular. I would give those two remaining embryos a chance and then eventually think about adoption. I’m sorry, it’s really tough but I don’t see any loopholes here I mean you have done everything right. I’m very sorry and it hurts but I don’t have an answer. The one with termination doesn’t really play a role. The natural pregnancy with the same partner that ended in miscarriage doesn’t really change it. At 45, everybody’s saying okay, the major suspect here is the quality of the eggs and, yes, rightly so. But the sperm quality can also play a role and the fragmentation can be a part of that so that’s maybe something to look into. But it’s not going to play a role in the transfer of those frozen embryos, you’re not going to change anything there so I would just give them a chance and that’s it.