In this webinar, Dr Arianna D’Angelo, MD, Consultant in Assisted Reproduction at Wales Fertility Institute, ESHRE UK Clinician National representative; and a member of the ESHRE Ethics Committee has talked about how the ovaries are stimulated and prepared for egg collection as well as explained how the embryo transfer is done.
The ultrasound scan is the first step of your fertility journey, and you’re going to see one of the doctors at the clinic. After some personal questions, such as your sexual life, how many years you’ve been trying to conceive, what you eat and what you do during your life. Later, the doctor will do some examinations that involve an ultrasound probe, which can scare some patients as it is an intimidating instrument because it’s long and big, and it goes down below.
The actual procedure is quite intimate, and it does require a bit of preparation, nevertheless, the good thing about the internal ultrasound scan is that it’s very useful for doctors. This is because, in the past, doctors used to do internal examinations with their hands, but this instrument is like having an eye on the finger. Since they can’t see what’s going on inside the body, this instrument is useful because the doctors, and you can discover what might be the problem, and they can do something about it.
A few things the doctor asks before she starts with the ultrasound investigation is whether you have any latex allergy because, at most of the clinics, they use a cover over the probe, which is made with latex. Nowadays, for instance, in the UK, they all use latex-free covers and latex-free equipment. Nevertheless, the doctor needs to know if you have a latex or rubber allergy because that can be quite dangerous.
She then applies some lubricant on top of the probe, which is water-based, very liquid, and not toxic. This must be friendly for conception because after you have the consultation with the doctor, you might want to try conceiving naturally, and if she applies something toxic to the sperm, then you won’t be able to conceive.
After, you’re asked to go to the toilet and empty your bladder, as it’s the best way to look at the inside of the womb and ovaries. If the bladder is full, the majority of the image will be covered by the bladder and also be quite uncomfortable for you.
It’s also important to give verbal consent for the examination. As this is an intimate examination, you have to make sure that you’re fully aware of what’s going on, and your doctor needs to have your approval before doing anything, even if it’s an examination.
The scan, explains Dr D’Angelo, is very well tolerated even if the probe is long. As a matter of fact, its thickness is like a finger or a tampon, so it’s not very big at all. Moreover, the probe will go in only for a few centimetres, thus it doesn’t go inside all the way through and this is something the doctor has to manoeuvre. Therefore, the length of the probe is not too bad.
Once the technology is set up, the doctor looks at what they’re interested in, which are your internal organs, primarily your reproductive organs. Therefore, the doctor will look at the womb and the ovaries, which normally the woman has one womb and two ovaries. They will also look at your eggs.
On the right side of the video’s screen shows the inside of the vagina and the internal organs, such as the belly, spine, bowel, and bladder. When the probe goes inside the vagina, they can see the neck of the womb, which is the place they take the smear test (pap test), the womb and its length, and the uterus. By looking at the uterus, they want to make sure it’s nice and regular; therefore, they examine it in many views to not miss any abnormalities.
Sometimes, some people have two uterus, others have a uterus which is split in 2, or they have a small uterus. So, everything is looked at in detail. In addition to this, pathologies (lumps and bumps) are also looked at, such as fibroids, polyps, or things that can affect your fertility.
Then you can see the endometrial cavity. The sonographer is measuring the thickness of the endometrium, which is the cavity where the baby develops. Therefore, it’s very important that the lining of the womb or the endometrium is nice and regular.
Dr D’Angelo then shows three lines, which are usually suggestive of an endometrium in the middle of the cycle. Thus, that’s usually the picture they get when a woman is fertile, and they must acquire all of this information from the ultrasound scan to make sure that the place where the pregnancy is going to develop is healthy and ready for the embryo to go back or for the pregnancy to develop.
I always tell my patients to think about the uterine cavity as a hotel room, it’s the hotel room for the baby, so if there’s someone in the hotel room, surely you don’t want to share a room with anyone else, that’s your room, and that’s what we want to make sure that the hotel room is nice and empty and comfortable.
Therefore, by following the doctor’s example, if there are polyps, fibroids, or anything unusual such as adhesion or scarring, inside the ‘hotel room’, it needs to be sorted out before the embryo transfer because it will make the environment hostile and uncomfortable for the pregnancy.
The following video shown by Dr. Arianna is of the ovaries. Not only is it important to look at the uterus, but it’s important to look at the ovaries as well because they’re like a “bank”, says Dr D’Angelo, that contain eggs. She has to make sure that there are both ovaries which contain eggs.
The video shows the bladder and, by moving the probe inside, the uterus can also be seen. If the probe is moved up and down, you can see the right and left ovary. Moreover, you can also see some black areas inside the ovaries which are called follicles, more specifically, antral follicles and they contain the eggs. The doctor counts them and makes sure that each ovary has at least 4 antral follicles, which is considered normal. Some people have less, and some have more.
Dr D’Angelo emphasizes that these findings are very important for them as well as for you because they have consequences on the way they’re going to stimulate your ovaries and on the way they’re going to attempt to get you pregnant.
In the image of a normal ovary with lots of nice, little follicles, the doctor measures the ovary and makes sure that it’s healthy and that there are no cysts or other signs of pathologies.
They also look at the position of the ovary just to ensure that’s very close to the probe because, eventually, they’re going to stimulate the ovary and get some eggs out of it. Therefore, the doctor explains that she doesn’t want the ovaries to be up in the belly because it would mean that the vaginal procedure is going to be almost impossible and very difficult to collect the eggs for IVF.
According to Dr D’Angelo, the egg reserve is very important, which may be a quite controversial topic. She explains that a lot of patients ask her how to increase their number of eggs if they have a low egg reserve, and the problem is that women are born with a set amount of eggs that stay with them all their lives; therefore, it’s crucial to protect the eggs since they can’t regenerate as the sperm that it’s produced every 3 months as freshly new produced sperm.
Later on, the ScanTrainer shows the measurements of the ovaries. Following this, Dr. D’Angelo mentions another important aspect they look at during the ultrasound scan, which is the area near the ovaries, the fallopian tubes. These aren’t normally visible because they’re quite small, they’re only visible if they are injected with some dye. Thus, it’s possible to inject some contrast media and do an ultrasound scan to check whether the tubes are opened or blocked.
Dr D’Angelo showed what you can expect during the first part of the appointment; however, during the IVF treatment, the ultrasound is used almost every day because with IVF they aim to stimulate those little eggs, those little follicles in the ovary, with injections to monitor and make sure that the follicles are growing and that the egg could mature to then be collected.
Dr D’Angelo now focuses on the follicle size. She’ll make sure that those follicles are increasing every day, 1.5 millimetres a day, roughly until they reach maturation, meaning a good size. This is the time when they aspirate the eggs, which are then mixed with the sperm in the tube to create little embryos. These embryos can grow in the lab up to day 5 to 6 and then be transferred back to the womb.
In the stimulation phase, different protocols can be used. Dr. D’Angelo shows a list of drugs that are usually given subcutaneously, which can provoke some side effects, like:
During the hormonal stimulation, which is done during the egg growth, people can feel:
Moreover, the use of progesterone, meaning the pessaries or injections that help the embryo to implant in the womb, can also give some potential side effects, like:
The image shown by Dr. D’Angelo shows an ovary. She explains that they aim to recruit 5–15 follicles during the stimulation phase and that the ultrasound scan is used almost daily to monitor their growth.
The following image of the ovary is what they expect to see during the stimulation phase.
This ovary is quite big, it’s almost two, or three times the normal size and it contains lots of follicles. Each of these follicles is measured by the doctor who also takes the average measurement and plots it on a grid so they can monitor how these follicles grow. This is crucial because if the follicles don’t grow the way they expect, it’ll have consequences on the success rates and sometimes the treatment must be suspended if they feel it’s not going in the right direction.
Therefore, once they look that the follicles reach around 18, 19 or 20 millimetres, the egg is expected to be matured to be collected. However, because the stimulation is very artificial in the body, they need to prepare for the egg collection in such a way that the egg has matured completely before being collected.
The doctor gives an injection to the patient that will require 36 hours to be completely active and this is the time the egg needs to complete the maturation.
This final injection is called a trigger shot, and the patient must stick to the rules in terms of time because if the eggs are retrieved too early, if the injection has been taken too late or if they go too early, there will be a risk of the eggs being immature. Moreover, if the injection is taken too early and the doctor acts too late, the risk is that you’ll ovulate. For this reason, it’s important that the timing is right.
Dr D’Angelo explains that the average is 36 hours but between 34 and 38 hours is reasonable to have matured eggs.
The egg collection is usually done under sedation or strong painkillers because otherwise is quite painful.
For this reason, “IVF is a teamwork,” assures Dr. D’Angelo.
She also provides some instructions before the egg collection, such as:
Dr D’Angelo shows another video, this time, about egg collection. In this video, you can see a dotted line, which is the needle guide, where it’s inside the follicle. The follicle is reduced until disappears, and the block shown in the video is the follicle fluid which has been sucked out and given to the embryologist. Furthermore, the long line that can be seen, which is pulsating, it’s a big blood vessel.
Because of this, the procedure must be done in safe hands because the needle is very close to the big blood vessel and there are potential risks if the operator isn’t fully trained. It’s also very important that you’re informed about the risks which are mainly potential vascular injuries, bleeding or infection. However, these risks are very rare and, according to Dr D’Angelo, it’s probably 0.03%.
This procedure, once again, must be done by operators who are fully trained and qualified because it does carry some risks.
Once the eggs are collected, they’re inseminated with the partner’s or donor’s sperm to create an embryo. The embryo shown by the doctor is called a blastocyst, meaning it’s an embryo that’s been already cultured for 5 days in the lab and it’s almost on its own as a small pregnancy because it’s the internal inner cell mass that will become the actual baby. There’s also some fluid inside the embryo.
After the embryo is transferred, it will hatch from the membrane and then implant in the womb. However, it’s not always the case. Furthermore, the embryo is transferred by using a ‘funny’ instrument for the smear or pap test, which is not very comfortable and that women unfortunately have to go through. Nonetheless, the procedure isn’t painful but rather uncomfortable and it’s usually done without sedation unless there are some complications or problems or if the patient is anxious.
The instrument is positioned inside the vagina, the neck of the womb is cleaned, they remove all the mucus, and they gently pass the catheter. It looks like a needle but it’s a very thing straw. Then, they inject the embryo inside the womb and, this time, with the full bladder because the ultrasound is done on the woman’s belly, meaning it’s external.
The bladder works like a window for the doctor, so through the blood, they can see what happens inside the womb. She states that it’s very important to have a full bladder because the doctors and you can see what’s happening, and also because the bladder will make the womb straight which will make the procedure very easy to perform as normally the womb is flipped when the bladder is empty, either backwards or onwards. Therefore, when the bladder is full, the womb is straight and it’s easier to pass the catheter.
Dr D’Angelo proceeds to explain the image, where you can see the neck of the womb, the cervix, and the catheter that goes all the way inside almost 1 or 1.5 centimetres below the top of the womb where’s the right place to put the embryo. The embryo can’t be seen with the naked eye because it’s microscopic, it’s tiny; however, the embryo is contained in a drop of culture media which will be visible during the ultrasound scan like little white dots. Most of the time, they take a picture or video to give to the patients as a memory and as proof that everything is going well and that the embryo is there.
When we say the patient is virtually pregnant, also called PUPO pregnancy (unless proven otherwise), and that’s the start of the 2-weeks of wait before the pregnancy test takes place.
Dr D’Angelo talks about some of the risks associated with IVF or ICSI procedures, such as:
Dr D’Angelo remarks that:
These are all complications that can happen and it’s important that you’re told all these things before starting your treatment.
These three types of pregnancies are abnormal ones and can be life-threatening; therefore, they need to be dealt with quickly.
I always said to my patients to think about the constructive side, so let’s go through the cycle together and find out if there’s anything that we could learn and we could do differently. So, it’s always important to reflect on the cycle and then try something different.
It very much depends on the stage of the embryo when you had your embryo transfer. If you had an embryo transferred on day-5, the embryos at the blastocyst stage, then it takes around 48 hours for the embryo to implant. So, after 10 days, if you have a blood test, you will have some evidence for pregnancy. If you had an embryo transferred on day-2 or day-3, then perhaps it will need a couple of days more. With the urine pregnancy test, we suggest waiting 14 to 16 days. Some of the urine tests are not as sensitive to pick up the pregnancy. The blood test definitely after 10 days will be fine.
Normally, as part of the IVF treatment, we offer an early pregnancy scan, and that is usually a viability scan just to make sure that the pregnancy is in the right place, is diable, and there is a baby’s heart. After that usually, we refer the patients to the obstetrician, there are a series of blood tests and an early screening test that can be done even at 10 weeks of pregnancy like the Chorionic villus sampling (CVS). The scan usually, in the first trimesters around 10-12 weeks would identify some problems. It depends on what birth defects we’re talking about because the spectrum is quite broad. In terms of genetic defects, the best thing to do is either have the blood test for the non-invasive genetic test or associated with the nuclear translucency measurement for the identification of Down Syndrome, and then obviously, if you want to have more precise answers, it’s the Chorionic CVS between 10 and 12 weeks, otherwise, wait for the second trimester, but it becomes more invasive for the pregnancy in a way and the mother as well because finding out about this while the pregnancy is advanced can have quite a lot of consequences emotionally. The problems with herniation or hydrocephalus can be identified at 10-12 weeks, but obviously, these kinds of defects are a little bit more advanced. Normally, there would be an ultrasound scan done at 20 weeks, and that is the anomaly scan where we look specifically at each organ inside the baby’s body, at the brain, blood, a heart, so some defects can be already found at the 20 weeks scan.
The gas we don’t tend to use. We do the embryo transfer very close to the lab, and we don’t know if this gas is toxic for the embryos and eggs, so I don’t think it’s recommended. The general aesthetic we don’t use either. For sedation, we usually give some Propofol or Morphine. Some Morphine or a little bit of Valium, and so it is called conscious sedation basically, the patient is awake and can tell the anesthetist if she requires any more painkillers. The whole idea is really to relax the pelvic area, and we find that when the patient is relaxed, the only instrumentation that we use, like the speculum, goes in nicely, and it makes the procedure easier from a technical point of view as well. Some anxious patients, so tend to contract the pelvic floor muscles, and that is even something that they can’t control, then they will benefit from having some conscious sedation. Occasionally, we also prescribe some Valium to take perhaps the night before or the morning of the embryo transfer just again to relax a little bit before the procedure takes place.
The future is going to be artificial gametes, which I’m not going to talk about because I don’t know much about it, but we hope in the future, we’ll be able to create eggs and sperm in the lab so that we don’t need anything else, but that’s a little bit far future, and we just have to be realistic. Two things are very important. First, is education, we have to start educating our young generation that it’s very important to look after your eggs, so don’t smoke, don’t drink too much, think about these things because the eggs stay with us for all our lives, and when we reach age 40-44, the eggs have been there for 44 years, so they are the reflection of what we’ve been through in our life if we’ve been having lots of nights out, lots of drink, lots of smoke, lots of drugs also, so unhealthy lifestyle, unhealthy diet, these are all things that day by day are seen in the eggs.
That’s why it’s important to do fertility education, which is something that is happening more and more now, and I’m really glad to see that happening also in high school alongside family planning. The second thing that we can do is also to start thinking that things that we see in the press are not always through, so all these celebrities that are getting pregnant in their late 40s-50s having children at any point in life, most of them are having egg donation, which is a perfectly acceptable option when you don’t have eggs when the eggs are not of good enough quality, but they don’t tell that. Obviously, the message goes out there that you can get pregnant at any point in life, but unfortunately, when we are not at the stage that we can have an egg on demand in a way, we need to do some more research. My message to all women is just to look after their eggs as much as they can.
That’s quite a lot of supplements. I can see that they are all very useful supplements, so I don’t think they will be too much or contraindicated. What is evidence-based is the folic acid, so the folic acid, it’s a must, we all have to advise our patients to start taking folic acid the moment they want to start conceiving because that is being proved that it does reduce the incidence of spina bifida, so neural tube defects in the baby. There is also more and more evidence about vitamin D, so it’s very important to take that as well. These prenatal vitamins I believe that means that they all contain all the vitamins that are required in pregnancy like vitamin B, D, C, iron, the ferrous sulfate iron is important. In regards to fish oil and probiotics, I don’t know, but I think they are all good for a healthy lifestyle. If you’re a vegetarian or vegan, and you don’t get much intake of proteins, perhaps that is why you need more supplements.
It depends on the experience of the doctor as well to make sure that we go at the right time, and that’s one of the challenges of our job to make sure that we don’t go to collect the eggs when it’s too early or when it’s too late. Sometimes, this is a bit of a learning curve, each woman is different, each patient is different, and the difference is not just between the patients, but it’s also between the same patients in different cycles, so some patients react to a drug in a certain way, and then the same patients react to a different drug or the same drug differently. There is a minimum number of days that it would be advisable for stimulation and to go too early with the stimulation. It’s not just a problem with the eggs, it’s also a problem with the endometrium. Don’t forget that those eggs produce hormones, and the hormones will prepare the lining of the endometrium for the pregnancy, so there must be enough exposure to the endometrium to the estrogens, otherwise, we end up having an embryo, which goes into the endometrial cavity, to an environment, which is not synchronized with the age of the embryo, and that is one of the reasons why embryos don’t implant if the endometrium is not well prepared. There have to be at least 10 days of stimulation to allow the good maturation of the lining, and then the decision is usually taken together, it’s not just the follicular size, but it’s also the thickness of the lining and the appearance of the lining. Once we get those eggs out, we expect some of them to be immature, so not all the eggs are mature maybe, 20-10% of the eggs can be immature, very rarely they are over mature, but sometimes if they are over matured possibly, it’s because we left it too late to collect, and in some protocols, this can happen because they don’t get released. After all, you’re taking the drugs to stop you from releasing the eggs, nevertheless, they pass that stage, and they’re just not good enough to be fertilized.
There is non-invasive fetal testing, which usually is done in the first trimester. It’s the sampling of the cells in the maternal blood to see if there is any problem. That can also be associated with standardized tests that are usually done around 14-15 weeks. Then as I said, there could be other tests, but they are invasive, so I wouldn’t recommend it and then a series of scans to check the baby’s growing well associated with the doppler study as well of the vascular, of the cord, and just to make sure the baby is feeling well. This is done as part of fetal medicine. I don’t do obstetrics, so I don’t have any specific details, but there is a blood test, a non-invasive blood test that can be done to find out about genetic abnormalities, and then a series of scans through the pregnancy. When we do the PGD, we usually advise doing some antenatal testing to make sure that the actual PGD was right so they will look at the genetic abnormalities like Down Syndrome, Turner Syndrome, or monosomy, anything that can be genetic just, to confirm the PGD.
Pergoveris is a bit different, it’s the same make as Gonal-F left, but the actual drug is different. Gonal –F is the only follicular stimulating hormone, which means that it just contains one type of hormone to stimulate the follicles. Pergoveris contains two hormones, so it’s partly follicular stimulating hormone and part luteinized hormone, so LH activity, which is always very good to give. There is no enough evidence to say which one works best, but there are some protocols that can be given to people who had perhaps several failures or a low egg reserve, which implies starting with Gonal-F the first week and then from day 8 onwards adding the Pergoveris, so switching to Pergoveris, so that you add that LH activity which is that extra hormone that might just give the eggs that extra boost to become more competent and more mature. This is called a sequential protocol, so it’s a combination of the two drugs. These are different drugs, so I wouldn’t say that Pergoveris is better than Gonal-F, I would say that they are different, and it can be used either as an alternative from the very beginning of the stimulation or in an addition to the Gonal-F in the sequential protocol.
Sometimes, we withdraw the FSH injections, so the stimulation drugs even for more than 18 hours, even for 2 or 3 days if there is a high risk of hyperstimulation sometimes, we do something called casting, which means withdrawal of the FSH until the trigger is done, and normally, it’s to allow the reduction of the hormone level to a safe level so that the risk of hyperstimulation is reduced. However, I have to say that recently the new protocols with the antagonist have the possibility of using a trigger shot, which is the agonist. By giving that, we reduce the risk of hyperstimulation quite dramatically, so that’s a rescue way. It depends on which protocol has been used, in this case. If it is a long protocol, sometimes the FSH has to be stopped because if the risk of hyperextension is too high, then that is the only option to reduce the exposure to the estrogens. Sometimes, we also don’t give the stimulation in a short protocol, it depends on each case, but perhaps the follicles were already quite big, and they didn’t want to grow them too much, so that is when you don’t take the FSH injection and take the suprecur or the drugs to stop you from ovulating and then have the trigger shot.
If two cycles are fresh, so you’re going to stimulate the ovaries again. Then we usually recommend having a couple of periods to give the time to the body to reset a little bit, and then you can start again. If you had a fresh cycle, and then if you have some frozen embryos, you can go back even the following month. Between 2 frozen cycles, there is no need to wait. When we’re talking about frozen cycles, you can go for one after the other, but some cycles are quite intense emotionally, as well. Not just for the woman, but also the partner. Sometimes, it’s better to have a bit of a break, but it is very much depending on how you feel. A couple of periods should be enough.
