During this OnlinePatientMeeting, Marta Wojciechowska, Senior Embryologist, Head of Embryology Laboratory at InviMed Gdynia, Poland, answered patients’ questions about failed IVF due to embryo quality and revealed what can be done differently after IVF failure.
Embryo quality is determined by two main factors: the paternal and the maternal factors. This means the sperm and the oocyte. To produce good-quality embryos, we need to have good-quality oocytes, and with good-quality embryos, we have a higher chance of achieving a successful pregnancy.
The main enemy in reproduction is age because ageing oocytes have lower potential. All women are born with a fixed, limited number of oocytes, and the number declines with age. The oocyte quality also declines with age, oocytes from older women have a higher probability of having chromosomal abnormalities. This can cause a greater risk of aneuploid embryos and, in effect, lower chances of having children. Ageing oocytes have a lower chance of successful fertilization and normal embryonic development, and if pregnancy happens, there is a lot higher chance of miscarriage.
The sperm factor is very important because when the patient has no sperm, there is nothing that can be done. Sperm quality is affected by many factors: the environment, the toxins that surround us, the medications the patient takes, congenital factors, and genetic errors that may lead to poor sperm quality. There are also doctrinal factors, immunological, oncological, and even infectious factors. Lifestyle factors, such as drugs, smoking, and anabolic steroids, all impact sperm quality. Last but not least, recent data shows that age also matters in the case of men. Normally, we know that men can produce sperm and become fathers at a very late age; however, the quality of the sperm declines with age as well.
We have to take into account how we assess embryo quality. To choose the best embryo for transfer, an embryologist needs to take it from the incubator, place it under the microscope and asses as well as measure some parameters: cleavage, how the embryo divides, if it’s clear, correct, or abnormal, the pattern of cleavage, and if the number of cells is appropriate for the time of development. If there is some cytoplasmic fragmentation, which is also a bad sign and a sign of poor quality, the presence of multinucleation is a bad sign as it can lower implantation potential. The quality is assessed according to certain rules, and top-quality embryos mean the best of the best. The embryo is then selected for transfer, or if the transfer is postponed for some reason for freezing and use in further cycles, is a top-quality embryo on day 2 of culture. Two days post-fertilization, it should have 4 to 5 cells, and on day 3, it should have 6 to 8 cells with no multinucleation and less than 10% of fragmented cells.
The assessment is performed according to these morphological criteria with different grading systems. At InviMed a perfect embryo is graded 1. When an embryo has 8 round cells at day 3 with no fragmentation and normal multinucleation, it can be graded as a blastocyst grade 1. This embryo would be chosen for transfer.
A possible reason for IVF failure due to poor embryo quality is also related to paternal and maternal factors. Age affects the quality of oocytes, which can prevent the production of viable embryos. In the paternal case, it’s the activation of the paternal genome that matters. If the sperm quality is seriously poor, the embryo may even stop development and will not progress to the blastocyst stage, which is the stage that implants in the uterus.
However, together with the doctors, there are several techniques to first select sperm and then perform successful fertilization using techniques like ICSI, PICSI, and IVF. These techniques allow us to increase the chances of infertile men to have children.
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The embryo does not divide well, an embryo with bad quality, with a lot of fragmentation, when it fails to develop to the blastocyst stage, it cannot implant. The second questions depend on the patient medical history, like the number of previous cycles, number of associated illnesses which also can affect embryo quality. As an embryologist, I look at the quality of oocytes and the quality of sperm, I need to look at what I see under my microscope.
The pre-implantation genetic diagnostics it will not improve the embryo quality, it’s strongly recommended that if there is a risk of genetical disease or patient is f. e. carrier of translocations that will affect pregnancy, it can cause miscarriage. In our clinic, Invimed genetic analysis of embryos is performed at the blastocyst stage, so we need to perform full blastocyst culture, observe it during the five or six days. We need to obtain good quality embryos to make the analysis, but if during the analysis we will obtain results that some healthy embryos, we will transfer those embryos and see if it has implanted. Possibly, a previous implantation failure was due to genetical errors.
I cannot say that it will have an impact, but it’s a very useful tool for the embryologist to choose their best top-quality embryo for transfer or freezing or genetic analysis. In the time-lapse analysis, we can observe every step of development from the very beginning, from fertilization until the development of blastocyst. There are various parameters that we consider f.e., the time of the cleavage created, cleavage to 4 cells, then to 8 cells etc. Thanks to this, we can be sure that our chosen embryo is that embryo that will end up in the pregnancy.
In our laboratory and many clinics that perform it, we have several techniques that help us to choose the best sperm. We perform sperm preparation techniques like swim-up, density gradient centrifugation and lately we are also using more advanced techniques for selection of the sperm, like microfluidic techniques or the FertileChip. It allows us to choose the best sperm, and then we use more sophisticated techniques to inject the sperm to increase the chance of successful fertilization. IMSI is a selection of sperm under the high magnification on a microscope, in our clinic, it is MIC6600. PICSI allows us to choose the sperm that are functionally mature, it is based on the attachment of mature sperm to the hyaluronic acid, when the sperm attaches, the embryologist chooses the right sperm, it really can increase the fertilization rate.
It all depends because paternal genome activates on day-3 so the embryo by itself starts to manage its own development. On day-5 which is the blastocyst. In our clinic, we have good results with transfers on day-2-3 and day-5. Recently we transfer day-5 embryos almost every time transfer, at the blastocyst stage transfers. In most cases, there is a higher chance of implantation. As an embryologist, I can say that I love blastocysts because they are very beautiful, and I love how they develop, how they behave.
Modern techniques like vitrification that we are using nowadays do not impact embryo quality because it’s almost 100% of survival of embryos after verification technique. From my experience as an embryologist, I can tell you that it’s a safe method and allows our patients to keep their material for the moment that it will be needed.
I would also point out the sperm factor would be involved because if the embryo does not develop beyond day-3, we need to consider the sperm factor. If it’s genetically abnormal it would be hard to check it as we examine the embryos that are fully developed. The answer would be to check these embryos at day-3, however, in our clinics, all the biopsies of embryos are performed at day-5.
Regarding other techniques, the point is that we do not use them just to check if they work. We need to have a strong recommendation to use any additional techniques. F.e. assisted hatching – when the embryo has some problems with hatching from the zona pellucida we perform assisted hatching, we cut the zona and, after the transfer, the embryos can easily go out. We have to have a strong indication to perform that. There are other techniques, of course, each clinic has its own cultural system, and there are optimized to ensure the best conditions to the embryos.
If it’s your first cycle, I think that the clinician would recommend trying again because failure in the first cycle does not determine that the chance of success is zero. The number and quality of the eggs and the embryos generated from these eggs can be markedly different even when the stimulation protocol would be the same. Sometimes, the doctors could consider the alteration of the stimulation protocol, but it should be discussed strongly with the doctor. Moreover, if the patient is under chronological control, it also should be consulted. Techniques I’ve mentioned before for a sperm selection allow to improve the effect of fertilization, so if it’s the first cycle I would say that it’s worth trying once again to see if the reaction of the organism would be different.
You had tried it three times, and well as I said at the beginning, the age is our greatest enemy in reproduction. After 35 years of age, our fertility declines dramatically. In our clinic, specialists recommend considering egg donation program after two or three failed IVF cycles. As I am an embryologist, I cannot say, you should move on to the egg donation, it must be an independent decision of patient and with the clinician. With three failed cycles, with low fertilization rate because two eggs from nine mature eggs is a very small number and none of them reached the blastocyst stage, even with using donor sperm. I would say that perhaps it is time to consider other options.
As far as I know, there is evidence that the endometriosis can affect egg quality because of the constant inflammation process in the organism. The oocytes are that are affected by endometriosis are under constant stress, and their functions can be impaired after fertilization. As an embryologist, I often had the opportunity to see oocytes extracted from the ovaries that were affected by endometriosis. These oocytes were markedly changed. I couldn’t assess the quality as good. I must say that yes, endometriosis and uterine inflammation affects the egg quality.
The quality can be markedly different even when using the same protocol, and I was looking at some papers recently, and I couldn’t find any strong evidence that similar protocol affects its markedly. I’ve seen that mild stimulations are more beneficial, but as an embryologist, I cannot speak about stimulation protocols with 100% certainty. I would rather address this question to the clinician.
We draw immature oocytes and allow them to run through the maturation process in the laboratory. The laboratory conditions are created to mimic the natural environment, but it will never be perfect. In my experience and my lab, we use in vitro maturation techniques, and we had embryos that reached the blastocyst stage, and they successfully implant. The oocytes quality is what we are born with, and good oocytes will correctly mature in the culture and after fertilization will produce a good embryo.
No, because it’s designed in the way that it would not affect embryos. First of all, embryos are not taken out from the incubator, and they are placed in an incubator after the moment of fertilization, after that they are taken out for the embryo transferred, after three or five days. The camera does not affect the embryos by some radiation or something like that. The only thing that determines the quality of the embryos is the genetical material of the parents that created it.
I would say that, yes. Social freezing is considered by many women when they are close to reaching 35 years of age. They have plans to have children, but later on in life, it’s all personal, I will not interfere with that. According to Polish law, vitrification of oocytes is allowed only in oncological cases. When a 38-year-old woman has frozen oocytes that she vitrified 10 years ago, and she’d like to use them, she will have a high chance of getting pregnant.
We do not expect any microbes in the sperm, so if there’s any inflammation or bacterial fungi or even virus, the semen quality will be impaired because the organ is moved to defend against this inflammation process. In our clinics, in certain cases, we recommend the bacteriological analysis of sperm just to eliminate the possibility of an adverse effect of microbes on the sperm.
I must admit that I would like to have these questions to be sent to me because I’m not an expert on PGT-A so I would like to check it with my colleagues. I don’t want to give false answers. From the experience of my colleagues, the reliability of the test is very high, and I did not hear about this false-positive or false-negative result.
We don’t use EmryoGen media. Our system includes one-step media and time-lapse system. It is hard for me to advise and recommend it, as we do not use it.
There are two methods of assisted hatching that we use in our clinic, it’s mechanical, just cutting with a sharp laser under the microscope and most popular is the laser methods we make a small hole in the zona pellucida of the embryo, just to facilitate the exit from the shell. The laser method is faster, however, an experienced embryologist will be able to cut the zona very quick and without possible harm to to the embryo.
We are born with the oocytes, this definite number of oocytes and those will create our embryos. The diet is very important, in our clinic, we have a special person to advise wich diet and what types of food you should eat. There are so many protocols of diet that will influence the overall well-being of the patients. It would also increase the chances of becoming parents. I’ll be happy to connect you with a dietician that we work with to provide you with all the details.
The fact is, when the blastocyst survives the process of thawing, it will be ready to implant. If they survive and it looks good, the embryo should be transferred because blastocysts are very resistant to freezing condition and they behave quite nicely after thawing.
The latest research data show us that in men that reached a certain age, men who turn 50, they have a higher percentage of sperm DNA fragmentation. If the sperm DNA fragmentation is beyond some safe level, it can cause fertilization failure. If the embryo will be created and the pregnancy would happen, it will increase the chances of miscarriage.
