IVF & embryo transfer – how important is it to prepare a woman for transfer?

Constantino Dino Demetroulis, MD
Director at Biogenetic Center for Human Reproduction, Biogenetic Center for Human Reproduction

Category:
Embryo Implantation, Embryo Transfer, Failed IVF Cycles, Success Rates

From this video you will find out:

IVF & embryo transfer – how important is it to prepare a woman for transfer?

IVF & embryo transfer – how to prepare?

Watch the webinar on the topic of “IVF & Embryo transfer -⁠ how important is it to prepare a woman for transfer? What’s the proper procedure of preparing the endometrium for embryo transfer?” Our guest speaker was Dr. Constantino Dino Demetroulis, a Director at theBiogenetic center for Human Reproduction in Greece. He is also an experienced Obstetrician and Gynaecologist with a subspecialty in Human Reproduction, IVF and Reproductive Endocrinology. Dr Dino was raised in a medical environment, spending a lot of time in his father’s lab, and later in the IVF unit that he had set up – Biogenetic for HR which was the first IVF center in Greece in 1984. Dr Demetroulis has gained his experience at University Hospitals in the UK, The Royal London Hospital, St Bartholomew’s Hospital and Newham General Hospital of London. Dr Dino’s motto is:

A baby for every couple.

Preparation before an embryo transfer

It is widely understood that a healthy, top grade embryo is more likely to result in a positive pregnancy outcome, but is that really the case, or is it the endometrium which decides whether implantation will occur? In this webinar, Dr Dino Demetroulis, Director of Biogenetic Centre for Human Reproduction, Greece, discusses the importance of the embryo transfer, outlining the correct procedure and advising how patients can prepare themselves to receive their incredibly special cargo. Since the birth of the first IVF baby in 1978, in vitro fertilisation has been a great support to infertile couples. Over the last 40 years tremendous advances have been made, yet the knowledge surrounding the embryo transfer still remains uncertain, leaving fertility specialists to regularly question how they can work with patients to fully create the most conducive environment for implantation.

On average, the embryo is circa 60-80% responsible for implantation, with the endometrium counting for around 20-40%.

Whilst this figure is indeed less, it is still a major determinant in providing a successful outcome following IVF. It is therefore imperative that the body is properly prepared and that the procedure is performed correctly.

Embry transfer – the most important stage of an IVF

The embryo transfer is the final yet most crucial stage in the IVF process. By this point couples have been though numerous investigations, tests, money and anxiety, whilst waiting for results and a diagnosis. Drugs have been administered, ovarian stimulation has taken place, followed by surgery to collect the eggs, fertilisation and the cultivation of those hugely valuable embryos. It has been a long journey for patients to reach this last step; a procedure that only takes between a couple of seconds to a couple of minutes. It is essential that nothing goes wrong during this shortest part of the treatment.

The three greatest factors, which are known to affect pregnancy rates, are the embryo quality, uterine receptivity and transfer efficiency.

However, within these determinants are numerous variables which can either have a positive or negative effect on the outcome. These include; the day of transfer, the transfer medium, catheter choice and placing of the embryo/s in the uterine cavity; all aspects heavily linked to the transfer process.

Embryo transfer – how to make it right

Dr Demetroulis outlines the most significant considerations, he believes, affect embryo transfer success. Transfers must only be carried out by experienced personnel under ultrasound guidance. In his opinion, a soft type of catheter is usually best, and there should be no blood, in the catheter, following the procedure. It is also advisable for vaginal swabs and tests to be conducted before the transfer to check for any infections. The placing of the catheter is also of high importance as it must not touch the uterine fundus; if contact is made this can cause the uterus to contract, which may lead to a rejection of the embryo. Ideally, transfers are atraumatic (free from any trauma), with an absence of pain or bleeding.

Endometrium comes from the Greek words Endo (inside) and Metra (uterus), it is the host of the embryo and the place where life grows, develops and lives until birth.

During pregnancy, the glands and blood vessels, in the uterine lining, grow, increasing in size and number. Vascular spaces fuse, becoming interconnected and forming the placenta which, once a pregnancy is fully established, supplies oxygen and nutrition to the baby. Implantation does not just happen at any time during a woman’s menstrual cycle, it can only take place during a specific timeframe, which is medically referred to as the window of implantation. During this window, the uterus is at maximum receptivity. To establish an endometrium which is optimal to receive and accept an embryo, several specific determinants, such as hormonal or immunological factors, need to coincide.

Endometrial receptivity and uterine lining

Endometrial receptivity can be assessed via ultrasound, hysteroscopy (biopsy) and hormonal receptors, checked through blood and uterine analysis. ERA (Endometrial Receptivity Array) testing can also help infertility specialists understand further receptivity information, especially in patients whose cycles have repeatedly failed following the transfer of a good quality embryo. By using a small sample of endometrial tissue, the ERA test can help medical teams establish the best day for transferring the embryo.

Endometrial thickness also plays a role in helping to achieve a successful pregnancy outcome.

Dr Demetroulis explains that a woman’s uterine lining should be between 8-12mm, advising that thickness improves blood flow to the uterus whilst also providing a suitable place for the embryo to implant. With IVF one approach does not suit all and it is the same when preparing the uterus; the endometrium is complicated. Within the body there are around 20,000 protein coding genes, which are expressed in human cells, circa 70% of these are found within a normal endometrium, finding one treatment to fit everyone is impossible. Doctors must ensure they have fully investigated the patient’s medical history, looking at what previously went wrong and trying differing regimens to find the most optimal treatment protocol for everyone. When preparing for an embryo transfer it is important that the female is regularly scanned. Conditions such as OHSS, endometrium polyps, uterine fibroids or a thin endometrium can all have an adverse effect on implantation. For patients suffering from any of these issues, then a freeze all cycle may be the most beneficial option. In women who have suffered from recurrent implantation failure then medical teams might also want to check for hydrosalpinges. This is when the fallopian tube/s become inflated with water. If the fluid passes down into the uterus it has the potential to affect the embryo. Fallopian tubes can be drained of any liquid which could hinder implantation.

Doctors should discuss all available options with their clients who, in turn, must never be afraid to ask any questions or challenge medical teams. The aim of every fertility specialist is ultimately to make every couple happy, and they should never be offended by patients who question.

So what can patients do to prepare the endometrium and aid implantation?

Dr Demetroulis explains that, in all honesty, the answer is variable and individualised to each woman. There are many myths surrounding implantation and, whilst the internet can be a great source of information, it is also a confusing place. Mothers-to-be should take vitamins, such as folic acid and vitamin b alongside their clinic prescribed medications, and not be afraid to use all types of treatments available, such as acupuncture or reflexology. Body shape has an impact on pregnancy and therefore patients should ensure they are neither under or overweight. Finally, couples should remain positive and let Mother Nature take over; for couples not undergoing IVF, they do not even think about the endometrium or implantation, yet natural pregnancies do happen. The goal of any IVF cycle is to achieve a successful pregnancy to live birth and, in order to accomplish this, it’s important to choose a well-experienced and caring team; neither gynaecologists or embryologists nor nurses can make a pregnancy happen on their own; it’s imperative that clinics work together. Medical staff also need to recognise that every patient and every cycle is unique. Whilst there will always be similarities no two situations are ever the same. Infertility specialists should look at all the varying parameters so that they can do the best for each couple.

From his own experience, Dr Demetroulis has seen successful pregnancy outcomes from lower quality embryos, advising that chances are chances, percentages are merely a number and it’s the pregnancy test which tells patients whether they have been successful, not the statistics.

You may also be interested in reading: How to prepare for IVF Embryo Transfer, before and afterwards – Patient’s perspective

IVF & embryo transfer – how to prepare? - Questions and Answers

I have difficulties with embryo transfer. It is very painful for me and the doctors found the transfer difficult to complete. What can I do? Can I use painkiller prior to the transfer?

Yes, you can use a painkiller, but we have to find the reason why it’s painful for you. Is it the speculum that is painful for you? Is it the anxiety of the procedure? Have you had a hysteroscopy before? There is a possibility to do it under anaesthetic if it’s too painful for you otherwise. If the painkiller doesn’t help you, then you can do it under anaesthetic.

Does food or drink affect implantation?

Well, hopefully not. But drink, of course, you shouldn’t be drunk because of the anxiety – it’s not a good idea to have three or four whiskey’s or to have two or three cups of coffee because coffee stimulates the uterus and you can have contractions. Eating any kind of food you want – that’s no problem, also if you want to have a glass of wine or a glass of whiskey or whatever before the transfer because you’re anxious about it, then that’s fine, no problem.

We have had four cycles of IVF. Two times I have started bleeding before the pregnancy blood test and then two times it all seemed to be okay, but I am getting a negative result. Two times we have had to do the transfer whilst I am sedated, as I find it painful. What do you think of this – is this the correct approach?

If you’re asking me about being sedated not to feel the pain, yes, it is the correct approach, but the reason you’re not getting pregnant is something else. As I said in my talk, the embryo transfer should be automatic – it’s a procedure that takes seconds and this is a procedure that can be detrimental, or give a negative result. So, you need to be relaxed, the doctor should be relaxed and not under pressure, and if all of you work in harmony, then you increase the chances of getting a positive pregnancy test. So, if you feel that you’ll be more relaxed if you are sedated, is not a bad idea. The drugs that we use for sedation do not affect the pregnancy rate.

I had a miscarriage in week 8 with IVF using an egg donor. Was it most likely something I did wrong or not? I used vaginal Crinone gel once in the morning and once at night, but within a two-hour window. Is that wrong? Does it have to be administered exactly the same time?

Okay, it’s very important because you reached the eighth week and worked with a donor, so that means the donor was a young woman. So, it’s very important to know the reason you miscarried. So, a chromosomal analysis should have been done on the embryo that you miscarried to make sure that it was chromosomally normal. Now regarding the vaginal Crinone, it’s not very important to use it at an exact time. What is important, is that you have the correct amount of progesterone in your blood system. So, if you use only Crinone, and this is something important, when we measure progesterone and we use vaginal progesterone, the test result is not measuring the progesterone that is used vaginally, so maybe the progesterone that you used was not enough. Regarding the time, not to worry, it doesn’t have to be exact – it’s the amount of progesterone that is in your blood system that is important because you were using donor eggs, which means that your ovaries are not functioning, so your ovaries are not producing progesterone. Maybe, the amount of progesterone in the Crinone was too little for you.

I had my hydrosalpinx removed a few years back, but you said they should be blocked only and not removed? Why?

Thank you for that question, it’s very important. With the ovary, we see lots of vessels, like the ovarian vessel and the fallopian tube vessel. So, if you remove the tube, you are affecting the vascularity and the blood supply to the ovary, and that can affect the ovary regarding egg quality and the number of eggs. So, the best thing to maintain the vascularity of the ovary is not removing the tube, but to block the tube as close to the uterus and remove also a small piece. That means there is no plume from the tube going down to the uterus, so there is no toxic material affecting the embryos, but the ovary would not be affected at all.

Is prednisolone indicated? If yes, what dose?

Well, we always use cortisone in order to decrease the immune system, though most studies suggest no, you should not use cortisone. Now, sometimes we have to use things that research says is not useful, and it does help. Your doctor has to see your history in order to decide if it should or should not be given to you. Five milligrams once a day is fine, but it’s not mandatory to take it. If you ask me, do I give it to my patients? Yes, I give it to every patient. Is it necessary? No, it’s not necessary, but it doesn’t do any harm.

I had a first IVF which was successful but miscarried. After this I had 4 that I had frozen transferred and all failed. Do you think that this is due to the embryos being frozen?

No, it’s not because the embryos were frozen. It all depends on how old you are and what quality of everything you had. And the other thing, after you miscarried did you have a scrape? Did you have a D&C? How is your endometrium? I recommend that before you do another IVF, if you have any more frozen embryos, definitely do a hysteroscopy.

Is it okay to drink a cup of coffee during IVF treatment, or should we stop drinking coffee?

No, you should drink coffee and definitely not decaffeinated coffee. You should enjoy your life. You should be living a normal life, you should never stop your habits, only bad habits. A bad habit is smoking, like smoking one pack of cigarettes or drinking more than three or four cups of coffee. Instead of drinking one glass of wine, a bad habit is drinking four or five glasses of wine. Live your life normally, but don’t overdo it.

There is ERA (endometrial receptivity analysis) – have you heard of this? Is it worth doing before implanting an embryo?

Is it worth it? Yes, only if you have recurrent implantation failure, that means if you are young, and you have good quality embryos – when I say young, I’m talking about not how you feel or how you look, I’m talking about how old your organs are. If you are less than 35, and you have repeated implantation failure, definitely you have to do it. It will help, but there are other things to do before you do that. You have to do a scrape of the uterus, you have to do a hysteroscopy, and endometrial scratching we now do quite often. The other thing is, if you’re older than 35 and you have good quality of embryos, that is, after discussion with the embryologist you know your embryos are fine, you have a great endometrium, meaning you have eight millimetres of endometrium, I can’t understand why there’s no implantation and of course, you’ve excluded semen problems and there is no problem with the sperm, then yes it is worth it.

I have an extremely stressful job and have deferred my IVF cycle several times as a result. I am 48 and don’t want to defer for any longer, but I can’t leave my job yet as I need the income. What can I do?

In life, we see what is important. Of course, the job is important because of your income, but what happens when you’re ill? Do you go to your job? No. What happens if you have an accident and you break a leg and you have to be in the hospital? Do you go to your job? No. Of course, you don’t have to see it like that, but family – you have to see how important it is for you to have a child. It’s not like, “Oh I don’t have milk in the house, when you go to the supermarket, get a bottle”, “Let me go and have IVF to have a child.” No, you should not see it like that. You have to see how important it is for you is to have a child. If it’s very important then you say, “This time, I will spend more time with my specialist to find the solution for me to have children.” Well at the age of 48, the best way to achieve a pregnancy is to go with donor eggs. So, what you should do is to find a centre, you talk with the doctors, you continue with your job, you don’t have to stop your job, you just have to spend a little bit more time regarding your infertility problem and less time with your job. You don’t say “Oh, I’m stopping my job now that I have to look after having a baby” – no, just have more time with the infertility problem and less time for your job.

Do you recommend egg transfer during the same cycle as egg collection?

This is normal, this is what we do. We have the embryos, and then according to the number of embryos or the quality of the embryos, we decide at which stage to do the embryo transfer. We will do it on day 2, day 3, day 5, unless there is a problem either with the endometrium or if you have recurrent implantation failure, or you have hyperstimulation, or there is a polyp in the endometrium – then you don’t do an embryo transfer. You have to make sure that there is a harmony, that means a good embryo and a good endometrium, then you do the transfer. Otherwise, if you don’t have a good endometrium, no, you don’t try to do the transfer because you will increase the chances of failure. It doesn’t mean you definitely fail, you will increase the chances of failure. If you succeed, everyone is happy, but if you fail then you would know the reason why you failed and this is not good for you to know the reason why you failed, and you went ahead.

What is the correct dose of progesterone?

There is not a correct dose of progesterone. We have three ways of administering progesterone – one is vagina, one is intramuscular and the other is by mouth. Now, the absorbance of progesterone is different in each of the ways you give it, so the best thing is to measure progesterone and to know that we have at least 20 nanograms per ml of progesterone in your blood system. Anything above that is good, anything less than that and you have to think of giving more progesterone. The research suggests that giving progesterone vaginally means it is absorbed better through the uterus and straight to the embryos, rather than giving it by mouth, but sometimes the level is not at the right number so we might have to give intramuscular progesterone. So, the correct dose does not exist. What exists is the right amount of progesterone in the blood system, and the progesterone intravaginally, which we cannot measure.

Should only excellent embryo blastocysts be implanted or will good quality also result in a successful pregnancy?

Well, if you have perfect blastocysts and a nice endometrium, you should be pregnant, otherwise, there is some other problem that we didn’t find, so you need more investigations. Well, blastocysts, in order to go to blastocyst state, you must have a lot of embryos, otherwise, you lose a lot. It’s those that you lose that might be normal, so if they were transferred inside the uterus maybe they will have survived, whereas in the laboratory, even though assistants today are very good, they are not perfect. They are not like the uterus, we don’t have a man-made uterus – we have instruments that resemble the environment but it’s not a uterus. So, it’s very important to decide what is best for you, and it’s best for you to go for blastocyst transfer if you have enough embryos or we have previous failures of implantation, which means you need to see if those embryos will end up as blastocysts. You should always be ready to hear the words, “I’m sorry, we will not be doing a transfer because we don’t have any embryos” and this is because none of the embryos went to blastocysts. But if you were to put any of those embryos that didn’t go to blastocysts earlier into the uterus, could there have been a pregnancy? Yes, there could have. So, it’s very important that there is not one thing to do in infertility, you have to see all the aspects. Consider fertility as a big puzzle; every part plays a role in it, and the most important part of the puzzle and the biggest part of the puzzle is the egg.

Can poor quality sperm cause miscarriage?

The answer is yes, but as I said, the egg plays the most important role in forming a human being. A good quality egg can cover a bad quality sperm, but the straight forward answer to this question is yes. But, when we do a semen analysis and we see a bad quality sperm, you don’t say “Okay, bad quality sperm, let’s do IVF” but we try to find out why the sperm is bad, and if we find the reason, most of the times we don’t, we have to treat it. Also, if we have a bad sperm, we should help the sperm by giving antioxidants to give vitamins – we cannot do much help to the sperm, but if you give all these medications and vitamins to a male for 3 months at least, definitely he will have better sperm when you do IVF. The sperm also plays a role in miscarriage. We can have a good embryo, but it can then end in miscarriage because the chromosomes were not normal on the sperm, so yes you should always make sure that you have done the best to help a bad sperm before you do ISCI, the intracytoplasmic sperm injection.

Can egg transfer be done in the natural cycle? I mean that the patient does not take medicine.

A natural cycle is a natural cycle. It’s sometimes more difficult to do because you have to do a lot of monitoring, and you have to find the moment when the endometrium is the most receptive, you have to find the endometrium window, so the implantation window. Yes it is possible, but if you don’t do it under natural cycle, then you have more control – you know exactly how the hormones work. But if you feel that you don’t want to take any medicine, then yes it is possible to do it under a natural cycle, and this is up to you to decide. But, if you and your doctor decide to do it under natural cycle, you have to be very careful with measuring the hormones like estradiol, LH and progesterone.

I just joined, apologies if the information has been given – what is the recommended preparation protocol before returning frozen embryos from egg donation?

When we have embryos from egg donation, you should prepare your endometrium – is very important to note that when we transfer these embryos, which are good embryos because the donor is a young donor – now, we talked about the sperm on the question from the previous attendant, it’s important to know that also the sperm was good, so you have a good embryo because you have a good egg and a good sperm. So now, you need a good endometrium. So, in order to prepare the endometrium, you can, of course, do it under natural cycle or you can do it by preparing the endometrium, that is by stopping the ovaries from working, and then by controlling the endometrium with estradiol, meaning with tablets either by mouth or intravaginally, or by patches, and then you are sure that you have a good endometrium, and then you give progesterone. Whereas, with the natural cycle, it’s a little bit more difficult because you have to know exactly when ovulation will happen and that’s when progesterone starts, so you might lose the implantation window. You can have an embryo transfer of good quality embryos, you know they have a good quality embryo if you have a good quality egg and a good sperm. So, if you have a good quality embryo and a well-prepared endometrium, the endometrium can be prepared by having an injection of GnRH analogue which will stop your period. That means there are no hormones produced by your ovaries, so you take the hormones by mouth, vaginally or by patches, and then you observe the endometrium and when you reach a normally sized endometrium of about 8 to 10 millimeters then you give the progesterone. So, you know exactly that the endometrium is normal, and you know exactly when you give progesterone. You can do it also in the natural cycle, but with the natural cycle you have to be careful that you lose the LH surge that means you have ovulation, and then progesterone rises up, so you lose the implantation window. You get a better implantation window if you control the endometrium by not having the hormones produced by the ovaries but controlling it by giving hormones externally. So, I would say when you do egg donation, and you do a programme with embryos from egg donation, don’t find try a natural cycle.

We had a one-time failure to implant, and second-time donor cycle – no implantation. I previously had a big fibroid removed. What investigation would you recommend – age 44?

Well definitely, I recommend hysteroscopy – definitely that because you need to see how the uterine cavity is after the myomectomy after the fibroids have been removed, so that will also help you to know if there is any problem in the uterus, and to solve this problem. If there is nothing in the uterine cavity is completely normal, then you should have done what we call endometrial scratching, and that would increase the chances of you getting pregnant. But again, was this embryo a good quality embryo? Was the sperm good? Were the eggs good, from a young donor? And you had good embryos? If the answer is yes, the embryo was perfect, then a hysteroscopy will definitely help you, and I wish you the best next time.

We used egg donors for three embryo transfers. The doctor says there might be unseen donor issues. What do you think the unseen issue could be? Could it be an old donor being used?

Well, this is what I said in my speech – never be afraid to ask your doctor any question you have. You should challenge your doctors, three embryo transfers and if all these three were with eggs from an egg donor, that means that you have good quality embryos, there must be a reason why you’re not getting pregnant. You need more investigation. As I said again today, there is no couple that cannot have a child; every couple should be able to have a child even with a surrogate mother, for example. But in your case, I think you should put everything down – the sperm quality, the egg quality, how old the donor was, was this donor matching your blood type? As I said again, is your husband’s sperm all normal? Also, your uterus: is your endometrium of normal size? Is everything well? Do you need to take any other medicine? Like, do you need to take aspirin, or do you need to take some anticoagulants? Was your progesterone normal? Were you given the right drugs after the transfer? Was your endometrium prepared well? So, you just have to sit down with your doctor and say, okay, let’s see all the parameters that affecting me getting pregnant. Have we checked everything? Have you done everything? Then you can say yes, there is the possibility that you were unlucky, but you should make sure that all the parameters have been checked correctly.

Do you recommend 3 day transfer or 5 day blastocysts? I have small fibroids and am 47 years old, using donor eggs.

Well, it all depends on how many eggs you have from the donor. If you have a lot of eggs from the donor, that means more than eight, I definitely recommend day five blastocyst transfer. Regarding your fibroids, you say ‘small fibroids’ but how many of them are there? Three, four, five? The other thing is, definitely before I do my next transfer, I would do a hysteroscopy about three to four weeks before I start preparing my endometrium for the embryo transfer. So, if you have fewer eggs, and therefore fewer embryos, I would recommend day three, and with the rest of the embryos, you can wait to see if they go to blastocysts, and if they go to blastocysts, then freeze them. If they don’t grow, don’t worry that you will not get pregnant as that doesn’t mean anything. As I said before, not all of the embryos reach blastocysts, and if they were put back to the uterus they probably would have survived, so again don’t worry about that. So, it all depends on how many eggs you have, but definitely, next time, do a hysteroscopy before you do any transfer, and if again we don’t get pregnant, then yes, you should remove your fibroids.

I had two failed IVF cycles and I’m thinking of going to Greece for an egg donor, preferably in Thessaloniki. Which clinic would you recommend? Even though I am Greek, I am nervous to do it alone, any suggestions? I am hoping to do a two embryo transfer – would you recommend it? I am 46.

Well, two embryos are correct really, – the law allows a maximum of two embryos to be implanted. This is your decision – if you’re afraid of twins, then we do one embryo transfer. Regarding which clinic, there are many clinics in Thessaloniki. All of them have good results; you just have to visit them, see which doctor matches with you and to see which doctor you trust and that is all you will do. You just have to trust your doctor but you have to decide, even if your friend tells you “Oh, look I went to that clinic, it’s the best clinic, you should go there”, okay, accept that, but it doesn’t mean that you have to stay with that, you have to go to them yourself and you have you to have to decide if this doctor is good for you and if you can trust him to help you in your infertility problem. Otherwise, you don’t have to go. It’s simple to go and visit two or three units in Thessaloniki and then you just decide which one you want to go. It’s your decision, mainly yours, but also your husband.

Do you offer a first Skype consultation? If yes, how much does it cost?

Yes, our Skype consultation is free.

Are there more risks to transfer two embryos than one embryo?

There’s no risk – the only risk is that you have a multiple pregnancy, so twins. I love twins because always when you have one child, you always want to have a second one, and if you don’t want the second one, then the child says “Oh I want a brother or I want a sister” and then you have to go again through the whole process. So, having twins might be a difficult pregnancy, yes true, you have premature labor, it’s more difficult to raise two children simultaneously. But, I love twins because with one procedure, you get two children and with one delivery you get two children. When you change diapers, you change the diaper also for the second child – because after three or four years when we have the second child, then you have to go back again, again through IVF, again through delivery, again through changing diapers, again breastfeeding, you know. Everything is so tiring, so having twins is the best thing for all of us. I don’t have to worry again when about if you will get pregnant or not. With having twins, you finish your family, but if you want a third charge that’s different. But we always want a second child so twins are the best – two embryos give you better chances of getting pregnant, of course, it also increases the chances of getting twins, but it’s very nice to happen as you finish once and for all.

How can we know that there is a possibility of overstimulation?

Well, hyperstimulation is a risk, and today, the chances of having a patient with hyperstimulation stimulation are decreased quite a lot. For one, because we know the ovaries before like if they’re polycystic ovaries, we know the hormone AMH is high and that this patient is high risk for hyperstimulation. So, we monitor the patient more closely, we don’t give too many drugs, so the amount of drugs they take is minimal, and then we don’t do egg transfer, and then we have other medications like Cabergoline or Dostinex that decrease the chances of hyperstimulation, so today, the percentage of hyperstimulated patient has decreased quite a lot. Another drug is GnRH antagonist that also helped not to increase estradiol, so you decrease the chances of hyperstimulation. So, if your doctor knows that you have polycystic ovaries or high AMH, he will control you much better and I’m almost sure that you will not end up with severe hyperstimulation – maybe minor hyperstimulation, but definitely not major hyperstimulation if you are looked after well, and I believe every doctor today looks after his patients very well.

How can I improve the quality of the endometrium?

Well, sometimes, we cannot. This is your endometrium – why is it like this? We would have to check your history. One is after scrapes, after D&Cs, after miscarriage. Now, we can help with a lot of things. We can check if you have adhesion in your uterus, which makes a bad endometrium, by doing a hysteroscopy. The most important thing today is to assess the endometrium and thank God, with the hysteroscopy, we can assess very well how the uterus looks inside, and if there are any adhesions, we can break them. Now, we use viagra in order to increase the vascularity – that means the estradiol, the oestrogen that we take, to go to the uterus and affect the endometrium. By scraping the endometrium, we can increase the implantation possibility, but if you have a good quality of embryo you have high chances of getting pregnant, even with a bad endometrium. A lot of things we say about the endometrium, for example, if it’s less than 5 millimetres, usually there’s not a pregnancy. Well, this is a word that we use, “usually” – it doesn’t mean that you will not get pregnant, it means that you have a very low possibility of getting pregnant. We know the ectopic pregnancy, which means the pregnancy is in the ovary or in the fallopian tube or outside in the intestine. Is there endometrium there? No, there is no endometrium in there, but how come we have a pregnancy? There is a possibility. So, again, the endometrium… A lot of things need to be straightened out about this endometrium – now, it all depends on what the problem is of your endometrium, and then we can find the solution.

Should the egg and sperm be mixed on the same day? If yes, what should be the timing after this sperm is produced?

Well, it all depends if you do ISCI or normal IVF. Well, it all depends on the quality of the eggs and the embryologist would have to decide on that, according to the quality of the eggs. The husband has to produce the sperm at the time of egg collection and the sperm is prepared accordingly, and after you have the prepared sperm, then you have to check the eggs and we have to know that ISCI is done only on mature eggs, when they are in metaphase 2. If you don’t have a mature egg, then you cannot inject the sperm inside it. Now, if you do IVF, you don’t strip the eggs, that means you don’t take the cells out of the eggs in order to check them if they are mature. Those cells are the ones that give [inaudible], I’ll say it in simple words, to the eggs that are not matured, they can later mature, so that means we can have a better egg to get fertilised. So, the timing is in accordance with which procedure you do. It’s not a problem, of course, it has to be done on the same day.

What should be done to avoid miscarriage as an older patient?

Well, miscarriage is hard, and any woman, I guess, has a chance of getting a miscarriage. Well, an older woman has higher chances of getting miscarriage, so in order to avoid you have this, you have to exclude things you can control, like give the patient anticoagulants so she has better circulation or hormones to feed the pregnancy. Then, the other thing is, you have to make sure that the hormones that feed the pregnancy, like estradiol and progesterone are at the right levels, so if you do all this then you decrease the chances. However, we have to know that 80% of miscarriages are due to a chromosomal abnormality, so the older the woman is, the higher the chances of having an abnormal embryo implanted, meaning a higher chance of miscarrying. So, you just have to make sure if you miscarry, it’s very important to do a chromosomal analysis of the embryo that was miscarried in order to make sure what was the cause of the miscarriage. If the cause was a chromosomal anomaly of the embryo, then you’re more relaxed and you don’t have to worry, but if this was a normal chromosomal embryo, then you have to do more research to find the cause of the miscarriage.

I have a bicornuate uterus and am using embryo donation – is there anything I can do about the uterus being this shape to help improve my chances?

Well I’m sure that she had a hysteroscopy, and I’m sure that we had a laparoscopy to make sure that this is a bicornuate uterus, not a septate uterus because if it’s a septate uterus you can fix this uterus, but it’s bicornuate, you have to do a hysteroscopy to see which of the cornua is bigger, and this is where you do your transfer. The recommendation, in this case, is that you transfer one embryo, not two embryos, and again, it’s a good idea to do a scrape or a pipette biopsy, or even better, a hysteroscopy, before to do an embryo transfer with a donor egg. Don’t worry about the bicornuate uterus, even though it’s an increased chance of miscarriage, but using donor eggs from a young girl, that means between 22 to 28 years old, you have very good chances of getting a pregnancy, but you have to be careful because you are in an increased possibility of miscarriage -not an early miscarriage, but a second trimester miscarriage, so you just have to take it very easy and to speak with your doctor.

Do you recommend blastocyst transfer or 3 day embryo transfer? For example, if I have three embryos at day 3, do you recommend to wait for blastocyst stage or transfer these embryos?

If you only have three embryos, so if at day two it says that three embryos have fertilised, and there are two or four cells then I will not wait for day three, I would put those three embryos back at day two. It depends also on the law of the country that you’re doing the embryo transfer in because if you are at the age of 32 we can only transfer two embryos in Greece if you are more than 38 years you can put three embryos back. So, I will put them on day two, and I would not wait until day three. Day three is better if you have five or six embryos, to see which are the best two to put back or the best three to put back. Blastocysts are what you do if you have about eight to ten embryos because you will lose a lot of them till day five. So, with fewer embryos, day two is better, with more embryos, day three, more embryos, around eight to ten, then blastocysts.

Can you have low/poor sperm count and a good egg and still have a good grade quality embryo?

There’s a lot of parameters that we check now about the sperm, it’s not only the count but also the quality and morphology of the sperm. It’s also the movement of the sperm, the motility of the sperm, but now we also check the DNA fragmentation – the percentage of how many sperms have fragmented DNA or the increased oxidative stress of the sperm. So, what I want to say is, you might have a low count sperm but a good fragmentation index, and you might have a high count sperm and a low fragmentation index, so one parameter, meaning low sperm count, doesn’t mean a lot. You have to check all the other parameters in order to make a decision if you have a good or a bad quality sperm, and if the sperm is a bad quality before you do your IVF, you should take anti-oxidative drugs and vitamins for at least three months is to make it at least a slightly better quality sperm to increase your chances of getting a good quality embryo.

I had IVF with donor eggs and was advised 3×400 utrogestan and Lubion once a day, and I had a miscarriage at 8 weeks. I previously had 3 cycles with 2×400 cyclogest, 2 biochemicals only. Is 1200 utrogestan and Lubion too high?

It is important that you’re getting pregnant but unfortunately, the pregnancy does not continue. Now, progesterone is one reason. I wouldn’t say that your miscarriages were because of progesterone -you have to measure the progesterone and you have to do blood tests of progesterone when you get a positive pregnancy test. When you take the positive pregnancy test there are three major hormones that we need to check: estradiol, progesterone, and TSH. TSH is begun in your thyroid. Now, too much progesterone can be detrimental for the pregnancy so there must be about two to one of estradiol to progesterone ratio. It is very important to have this ratio, so by telling me all these different doses of progesterone means nothing – the most important thing is that at the time when your pregnancy test was positive, what was the value of your progesterone? If it was low, and then you increase the doses, what was the value? Again, I’m saying the progesterone that we used vaginally, cannot be measured in the bloodstream – only the progesterone that we take by mouth or intramuscularly. So, it’s very important to measure the progesterone levels when you get pregnant, and then every four or five days in order to make sure that the progesterone levels are normal, so the dosage on its own means nothing, the amount of progesterone in your bloodstream means a lot.

My embryologist said “The other embryo was slower: 2-cell on day 2, only 3-cell on day 3, small compacted morula on day 4 and fair quality early blastocyst 1B on day 5. In my opinion, this embryo has a low chance to start a pregnancy.” I have to travel far to get this IVF, and after hearing this, I feel like I need a new doctor. Do you agree?

Well as I said, the most important thing is to trust your doctor. You have to challenge him, you have to ask him what is his expert opinion and if you’re not happy with the answers then yes, you can change the doctor. I would not say I agree or disagree, I have to leave it on you – you have to make the decision if this doctor is good for you. You have to see you trust him. You have to see if he is honest. You have to see if he talks to you and explains things to you. In infertility, there is nothing right or wrong; it’s not black and white – it’s a rainbow of many colours. Even as I said to you, you might have a bad embryo and you can be pregnant with a normal pregnancy, or you can have a perfect embryo and miscarry or not get pregnant. It’s only chances – a good embryo has high chances of getting you pregnant, a bad embryo has lower chances of getting you pregnant. So, every embryo and how it progresses from two to four, to morula, to blastocyst is different – also you have to know something important: what time fertilisation was at, and what time the embryo was checked because you can do ICSI on one egg at one o’clock, and then do to ICSI on another after half an hour or after one hour, so you have to make sure of the timing when you check the embryos and when you do the fertilisation. I would say you are the one to make the decision about your doctor – you have to feel comfortable with your doctor and you have to trust. If you lose the trust, then you change, otherwise, stay there.

What did you mean by “does donor blood fit your blood”?

Always try for the donor to have a similar blood group either with your husband or with you, because that will make it easier for you regarding the possibility of a child in the future. They may ask you “Mother, what is your blood group?” or “Father, what is your blood group?” – if theirs doesn’t coincide with yours, they may ask “Well, how did I come to life?” so that gives questions. Regarding pregnancy possibility, no, it doesn’t play a role. If you use a donor from a different group, it does not change the possibility of you getting pregnant – it’s only in the future if you don’t want your child ever to know that it comes from a donor egg then you should have an donor that matches your blood group, because otherwise if the child’s blood group is one that doesn’t coincide you with you, it’s a possibility they will question you about that. That’s the only reason I mention the blood group.

In what cases should aspirin be given?

Well, in the case of a disease called Systemic Lupus Erythematosus, that’s when you give aspirin. Or, some women don’t want anticoagulants by injection, so they will not like to do injections on themselves, then yes, we will give aspirin. All these anticoagulants, either aspirin or heparin, do not allow the blood to clot easily, so all the hormones that feed the pregnancy will go to the uterus much easier, especially when women have a bad endometrium or they have fibroids, or their vascularity is affected. You want to make the blood thinner, so the blood can travel much easier to the vessels, or you have an older woman trying to get pregnant with donor eggs, it means the vascular system is not functioning well because the vessels are not as good as when they were young, so like, 20 years old. So, aspirin or heparin will thin the blood so the transport of all these hormones that feed the pregnancy will travel much easier to the pregnancy.

Is it recommended to have a hysteroscopy if the test was normal before the first pregnancy?

Well, after your pregnancy you don’t know if something has changed after the pregnancy in the uterus. No, it’s not recommended – only if there is doubt about the quality of your endometrium. If there is doubt about the quality of your endometrium, even though you were pregnant and even though you delivered, then it’s recommended, otherwise no, it’s not recommended.

What do you think about the Ukrainian donation programme? Do you have any information about the results of the Ukrainian clinics?

Well, I don’t believe the numbers. If I see a unit that says they have a 60% pregnancy rate and another that says they have a 30% pregnancy rate, I will go to both of them, but the number would not make me make the decision. Why? Because what happens if I belong in the 40% in the 60% pregnancy rate unit that has a 40% failure? The other one has 30% pregnancy rate and 70% failure rate – what happens if I go there and I become the 30% that get pregnant? What I have to check is not the numbers, but the person that will look after me, how people treat me, how they will explain things to me, how they will investigate me, how I feel, do I trust this person with my infertility problem, are they looking after me? Are they spending two minutes with me and then saying “Okay, go to do this test and come back after a month”? How much time are they spending explaining things to me? That’s the important thing. So any unit in this world that deals with infertility is a good unit, but the most important thing is: is it a good unit for me? I have to decide on that, not the numbers, not the fancy lab or the fancy waiting room. I just have to see the people that work there: how good are with me, how it will help me, and then I have to see their experience, then I have to see the lab, how good their lab is, but numbers mean nothing. So, answering your question: what do think about the Ukrainian programme? Perfect. If you want to go there, you just have to visit them and then just say yes, they’re good for me and find it, and then if you’re not happy, then you have to try something else. You make the decision.

Can MRI show the shape of the uterus?

Yes, MRI is very helpful – it can show the shape of the uterus, especially when you have fibroids, as it can give you give you a lot of information about how the weight of the fibroids affects the uterus. But again, MRI is just one tool, but the golden tool for the uterus and especially for the cavity, where the embryos are implanted, the endometrium, is a hysteroscopy. An MRI will help you, but don’t rely only on the MRI – definitely have a hysteroscopy when you have a question about the uterus or when you have a question about your endometrium. Again, think of what I said on my talk: the most important role in pregnancy is the embryo – if you have a good quality embryo you have higher chances of getting pregnant.

Our last cycle was in Greece by a donor. We were told once where the sperm was collected that the egg collection would be done the next day. The process used was IVF – is that the right way to do IVF?

So, your question is asking if it was correct that your husband gave the sperm a day before. Well, the sperm should be given on the day of the egg collection of the donor – that’s the correct way. If you didn’t get pregnant, could that be a possibility of why you didn’t get pregnant? Yes, it is a possibility that that’s the reason you didn’t get pregnant. But again, it all depends on how good the sperm was. Now, is this something wrong? Yes and no. Why I say yes? Because having a fresh sperm is much better than having a 24-hour waiting prepared sperm because definitely the sperm was prepared. From my experience, a good sperm is when you prepare the sperm for either intrauterine insemination or for ICSI or IVF – it can be alive and put into the incubator for two or three or four days, so it depends on the quality of the sperm. But again, it’s better to give the sperm on the day of the egg collection, and again, it’s not something wrong.

What do you do to prepare your endometrium?

I prepare artificial cycles, I prepare cycles that I can control. I don’t like natural cycles because natural light cycles can give you problems – that means you can have an early rise of progesterone and you can lose the implantation window. So, by artificial cycles, you can control the endometrium – you are sure that you have the right size and you know exactly when you will give your progesterone and then you know exactly the time that you will do your embryo transfers, so having artificial cycles is much better, and give you better chances of having a successful pregnancy. Natural cycles are good, but he can be sometimes detrimental with their premature rise of progesterone.

Is the number of embryos available for transfer the only reason to decide on which day to do the transfer? Can there be a reason not to wait for blastocyst transfer, even if we have a lot of embryos available?

Well, it depends on quite a lot on the history: if this was your first IVF attempt, or if you had other previous IVF failures. The number of embryos is the major reason to decide on which day to transfer because if you have enough embryos, you are not afraid of ending up without an embryo transfer because a lot of embryos will be lost in your system when you culture them. Whereas, if they go back to the normal environment, they will probably survive, so because you don’t want to lose too many, you must have many in order to do blastocyst transfer. Now, can there be a reason not to wait for blastocyst transfer if we have a lot of embryos available. Well, the other reason is that you wanted to have more embryos to freeze, so the best thing you could do is a day three transfer – you choose the best of them and then if you want to see if the rest of the embryos become blastocysts, then you wait, or if you don’t want to wait to lose the embryos again, then a day three freezing, so if you don’t get pregnant, you have more embryos to manipulate with, when doing the next transfer.

I have had three chemical pregnancies. What do you suggest I do to prevent this?

Well, the most important thing is your age, and the other thing is, you’re getting pregnant but this pregnancy does not continue. Well, if you are young, that means you have to do a lot of investigation regarding your chromosomes – if there is some kind of disease that you have that doesn’t allow the embryos to continue to grow. If you are older, you’re very likely that you’re getting pregnant but unlucky that the pregnancy does not continue. So, the most likely reason is that you have chromosomally abnormal embryos implanted, so that’s why they don’t continue to grow. The other thing is, you have to make sure that you have a good endometrium. Are you sure you have a good endometrium, so if you’re placing good embryos, is your endometrium good enough to keep them there? The other thing is, if you have a good endometrium, you just have to try donor eggs and trying donor eggs, you will see you do get pregnant, and you don’t have a miscarriage and you don’t have a biochemical pregnancy. A biochemical pregnancy means that you have a positive HCG, but this did not continue to see a sac or an embryo with a fetal heart, so what I suggest is that you use donor eggs.

Does frozen sperm decrease the quality of embryo? We gave a sperm sample three years ago and are doing a cycle in January with a donor egg.

I wish you the best – you will get pregnant. It’s fine, you can have a child even after 12 years of cryopreservation of sperm, so don’t worry about that. The most important thing is that the sperm quality was good at the time of freezing it, so if you had a good sperm quality at the time of freezing, even if you do it after four years or five years or six years, don’t worry about that. Your good quality eggs from a young donor, even you have a minor sperm problem, will cover it, and you will be pregnant, and you will have a successful pregnancy, so go ahead and use it, and I hope I hear from you that you’re pregnant.

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Authors

Constantino Dino Demetroulis, MD

Dr. Constantino Dino Demetroulis is a Director of Biogenetic Center for Human Reproduction in Greece. He's very active in medical research: he was a co-investigator in the study of the fallopian tube cell biology and metabolism and studied the incidence and significance of necrospermia in fertile and subfertile males. He is also interested in the studies on the effect of stress on the male partner in infertile couples, polycystic ovaries and diabetes and misoprostol for the treatment of miscarriages. He is a member of numerous international academic societies, among others European Society of Human Reproduction and Embryology, American Society for Reproductive Medicine or International Society of Gynecological Endocrinology.

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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