In this session, Dr Zane Vītiņa, a Gynaecologist Reproductologist, the Director of Clinic EGV, Riga, Latvia, has been discussing various reasons for failed IVF attempts and what can be done to improve your chances.
Dr Vītiņa started by explaining how important is the investigation done before the first IVF cycle. When it comes to women, the investigation includes an interview. Patients are asked if there were any diseases in the past, also inherited diseases. It’s also important to ask about reproductive function, pregnancies in the past. We ask about when the menstrual cycle started, how regular are they. If there is any specific discharge from the vagina, if there is any discomfort during sexual intercourse, how many partners the lady had and when she started her sexual life. We evaluate hormonal status, especially Anti-Müllerian Hormone (AMH), which gives us an answer on how big a possibility is to get pregnant with the patient’s own eggs.
We evaluate FSH and LH hormones as well as Estradiol, which comes from ovaries. The thyroid gland and all four androgens are also checked. Any disturbances in hormonal status can lead to no-ovulation. We also check if there were any infections in the past, especially Chlamydia. Around 25% of women do not know that they had Chlamydia in the past, there may not be any symptoms, but the tubes can be blocked and closed, and a new tissue can appear in the abdomen. We check for Toxoplasmosis and Rubella IgG. If a woman didn’t have Rubella or she’s not vaccinated, she has to be vaccinated before a planned pregnancy. Toxoplasmosis is an infection that can infect the baby only if the woman was exposed during pregnancy. We perform pap smear and check for infections, especially sexually transmitted infections, not later than three months before stimulation.
When it comes to men, we ask almost the same questions. The andrologist performs an ultrasound examination and evaluates testicles just to be sure that there is no varicocele. We check spermogram, we look at concentration, motility and morphology, this is included in every spermogram.
We also perform an HBA test (hyaluronic binding assay) to check the maturity of sperm cells in fresh semen. MAR (mixed agglutination reaction) tests immunological status, checks for antibodies of the IgG and IgA. The oxidative stress test is the only test that shows whether men should use antioxidants before treatment.
Guidelines say that we need to evaluate everything more in-depth after two failed attempts, especially if there were good quality embryos and good endometrium.
After failed cycles, we use 3/4D ultrasound. Sometimes, we use it before the first cycle, but even if the 2D ultrasound doesn’t show anything after a second failed attempt, we always use the same evaluation, and it is nearly as effective as MRI (magnetic resonance imaging).
Two types of pathologies can occur: congenital and obtained uterine pathologies. The most important for implantation failure, which can be detected with 3D ultrasound, are congenital pathologies.
The uterus and genital tract develop during the 5th-9th week of pregnancy, when a woman is still inside the mother’s uterus. In the beginning, two ducts go together, there are two uteri, afterwards, the middle part that fuses dissolves. A septum can be formed after the two uteri halves join to form a normal uterus but fails. The septum can be very tiny and thin, and with ultrasound, we do not see it, this could affect implantation. If the septum appears, it is very often covered with the endometrium. It could also be a reason why missed abortion occurs.
We perform hysteroscopy for diagnostical aims when we don’t see any pathology with ultrasound. During hysteroscopy, we take a little piece of the endometrium for histological evaluation as well as the microbiome. If we find a problem, we treat it. We can also find polyps, which can be removed during this procedure.
Implantation can fail due to altered timing of the window of implantation (WOI), which we can check with the ERA test (Endometrial Receptivity Array). To achieve pregnancy, we need chromosomally normal embryos and a receptive endometrium. In 30%, the endometrium can be non-receptive. Endometrial Receptivity Window means the time when the embryos can implant. It usually occurs on the 5th day of progesterone, the 5th day after ovulation, it can be changed, though. It usually lasts approximately 24 hours, typically, it is only 8 hours. How do we detect this pathology? We usually prepare a patient for embryo transfer, but when we would normally put the embryo inside the uterus, we take a little piece of the endometrium and evaluate it. The evaluation is based on morphological changes after the progesterone and 238 gene expressions during the period of window receptivity.
The most frequent male reason for failed cycles or absence of blastocyst developing or miscarriages is DNA sperm fragmentation. The major contributing factor for sperm DNA fragmentation is oxidative stress, and it can be associated with:
If two embryo transfers fail, it is mandatory to do karyotyping. If the couple is older and would like to be treated with their own genetical material, we perform it before the first attempt. In this situation, it is also mandatory to evaluate Thrombophilia. There can be congenital and obtained Thrombophilia. It is a group of pathological blood coagulation that increases the risk of thrombosis. The smallest vessels are in the placenta.
At the time of pregnancy, first, the implantation may not occur at all. The second thing is that very often pregnancy doesn’t develop further than chemical pregnancy. Thrombophilia can cause infertility, miscarriage, spontaneous abortion, premature delivery, Intrauterine Fetal Death (IUFD), Intrauterine Fetal Growth Retardation (IUFGR), placental abruption, preeclampsia, maternal thrombosis or tromboembolia.
If in previous cycles Embryoscope, the time-lapse incubator hasn’t been used, we recommend using it after failed cycles. Normally after fertilization, we need to evaluate fertilization after 18 hours, and due to that, we need to take out this embryo from the incubator and evaluate it under the microscope. The embryologists check if there are any crucial problems, however, taking the embryos out can reduce the possibility of live birth.
We can transfer a day-2 embryo, which consists of between 2 and 4 cells, day-3 consists of 8 cells, as well as a day-5 embryo which is a blastocyst and consists already of approximately 100 cells. Around the embryo, there is a sort of shell, called zona pellucida. At the end of the day 5-6th, an embryo goes out from this shell and hatches in the endometrial wall.
We can perform the transfer on the 2nd and 3rd day, but it is always better to transfer a day-5 blastocyst.
The hatching is happening naturally. However, in some situations, it is mandatory to make a little hole in this shell. This method is called assisted hatching. It increases implantation chances, it can be done via laser, mechanically or chemically, but it is best to use a laser.
Another thing that is recommended if there are failed cycles is to screen the embryos for aneuploidies. It can be done by taking the polar body, one or two cells from a day-3 embryo are taken. However, it is much better to take approximately 10 cells from the blastocyst. PGT-A can help us choose a euploid embryo and transfer only healthy embryos.
PGT-A is indicated in the advanced maternal and paternal age, habitual miscarriages, previous aneuploidy pregnancy, previous failed implantations, and severe sperm pathology.
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At the moment, I would not say that for sure you need to use the blastocyst. Usually, it is evaluated, and researchers say that in most of the cases when blastocysts do not develop, it is not connected with the women factor if the problem was visible already at 2-day and 3-day of the embryo’s development. If the problem appears at a 4-day embryo, then you need actually to evaluate the partner’s sperm DNA fragmentation. If you were 40-42, then for sure, you need the donor eggs.
Poor embryos at day-1 usually mean that the problem is with the eggs, but you could change the type of stimulation or medication, which you use during stimulation. For example, in the previous cycle, you had a long cycle GnRH agonist cycle, next time maybe, you can try the antagonist cycle. There are a few options, in most cases, we use Gonal F or Bemfola, which is a folitropin alfa, but you can also try to use follitropin delta like Rekovelle. Maybe this can help, sometimes we see such situations, and changing something in the stimulation can also help to get better eggs.
You need to detect anti-chlamydia IgA, IgGand if it is elevated, then you had it. If it is not heavily elevated, then you never had Chlamydia. From time to time, this infection occurs without any symptoms, maybe some urinary problems, and that is all.
I suppose you need to try either with donor sperm or donor egg or try one more cycle. You could try as you are quite young, but you could try to use just to fertilize some eggs with the donor’s sperm with the next try, and some sperm from your partners could be fertilized with the donor eggs, at least to understand if it happens with other genetic material.
You should evaluate all the possibilities, which I’ve explained before, karyotyping, thrombophilia, DNA fragmentation. You don’t need an ERA test because you had implantation. If you would have 2 miscarriages, then it would be recommended to evaluate also the genetics of embryos.
The possibility of natural conceiving is only 8%, but with IVF and ICSI, the percentage increases to 33-40%. At our clinic (EGV), the percentage is from 59-70% success rate of implantation, but nobody can promise you to be pregnant after the first try. You need to understand that in those 8, 10, 14 days that you already were pregnant, and this is like losing the pregnancy, but yes, it can happen, and it doesn’t mean that next time it will not implant.
I am not sure about your AMH exactly, but if it is low and you’ve been trying for 4 years now, you are 40, therefore I would recommend trying donor eggs.
The researchers say that there is a little bit higher monozygotic twin possibility, but actually, this is the only thing that can happen. We never had anything like this after assisted hatching, but the researchers said that there could be a little bit elevated risk. This is the only risk, which has been found with this procedure.
You can try with the next cycle, you don’t need to wait for any cycle. In most cases, if the IVF cycle does not end with the implantation with a fresh cycle and if there are no embryos left, then you need to wait for two cycles. If this is a frozen embryo transfer cycle, then you don’t need to wait.
At the beginning of each menstrual cycle, some antral follicles appear, and it is connected with a lot of things like your age, time, stress, etc. Age is the most important but also the way of the stimulation, for example, if you use a short protocol, agonist protocol, you always will have a smaller amount of eggs compared to the long cycle.
I would give you a smaller dosage and for a longer time. If you have multi follicular ovaries, you don’t need that, but if you do, then the short protocol is recommended. Looking at your story, perhaps it’s time to try another way of a protocol with GnRH and agonist protocol with a lower dosage.
BMI 29 is a little bit over 28, which is recommended. We choose the dosage of the stimulation based on the age, body mass index, antral follicle count at the particular cycle, as well as AMH and FSH. With your AMH level, 13, taking Gonal f 300iu would be too much, I would recommend taking 200-225 units per day.
TSH level should be lower than 2.1 to get good quality embryos. I would recommend evaluating karyotype, thrombophilia for sure, also DNA fragmentation of male sperm. Perhaps, you could do hysteroscopy with diagnosis, or do a 3D ultrasound, maybe you have septa. This is what I would do in your case. As you’ve had pregnancies, for sure you have implantation at the right time, so you don’t need to check any other things like the ERA test.
If the endometrium is at least 6.5, then the implantation with the assisted reproduction technique can happen. If you would like to have a pregnancy naturally conceived, then six millimeters is enough. I would recommend having a stimulated cycle with estrogen starting from the second day of the menstrual cycle, 2 milligrams 3 times per day, and the ultrasound monitoring at approximately 10, until the 12th day of the menstrual cycle. Then, evaluate whether to reduce this dosage or increase and afterward add the progesterone as you had a little bit thinner endometrium than usually in a natural cycle. The researcher says that the best possibility of conceiving is if the endometrium is between 8 to 12.5 millimeters.
I don’t think that you need hysteroscopy. With your adenomyosis and a thin endometrium, it would be better to wait for one cycle. Then, try again with frozen embryo transfer. Mild adenomyosis is not a big problem of infertility. Doctors certainly know what to do. A heart-shaped uterus is just a shape, not a problem.
Hydrosalpinx is a very severe problem with pregnancies. If you had it two years ago, then for sure you need to remove those. The best diagnosis of the tubes is laparoscopy. The oldest woman I ever had who got pregnant with her own eggs was 44 years old. Even if the AMH level is good when you turn 44, even if the pregnancy appears, they always have miscarriages. The first thing, which I would recommend is removing the tubes. The second thing, as you already did the donor eggs transfer before, you should try again. Even with the donor eggs, there is no 100% guarantee that you’ll get pregnant.
Usually, we use such a big dosage only in the situation when AMH is very low and when you are very thin, and when you have a bad prognosis of having eggs at all.
BMI 27 is okay, but maybe you have a few problems with hormone index with insulin resistance. BMI 25 is perfect over 28 is too high. According to your AFC for a particular cycle, I would say 8 eggs are expected. Follicles don’t guarantee that there is an egg inside. AMH is good, so we wait, we would be happy with 8 eggs in this particular case.
