Another side of IVF
All over the world the method of IVF (in vitro fertilization) is considered as the main method of treating infertility. It is effective in all its forms. Besides, IVF is often the only solution for families in which a man is sick.
In vitro fertilization is a relatively young method of infertility treatment. It was first applied in England in 1978.
The main point of IVF (in vitro fertilization): spermatozoids are met with ovum in a test tube, and then they are placed in the uterus of an infertile woman or a surrogate mother. With a favorable outcome of the procedure (pregnancy) there are frequent cases when test-tube fertilization leads to multiple pregnancies: twins or triplets are born, because several ova are involved in the in vitro fertilization attempt. At the request of a woman a reduction can be made (removal of excess embryos), but it happens that this leads to the death of the remaining and to the subsequent miscarriage. The success of the IVF procedure is approximately 35-40%. Thus, we face two possible problems:
1. Multiple pregnancies;
2. Low probability of success with a high cost of IVF procedure.
Multiple pregnancy
In order to increase the chances that such an embryo “from a test tube” will take root in a woman’s uterus, they are usually attached a few. That is why twins or triplets are often born after IVF. All this of course is also a lottery – you never know how many embryos will take root, not one, one, two or more. Therefore, for many years from the date of the invention of IVF, women who never wanted to have twins or triplets immediately had to go to such conditions and be ready, that the “many children” option is the place to be.
During all these years, little has been said that multiple pregnancies are actually quite risky for both mother and babies. What was the use of talking about it if there was no other way out?
Risks of multiple pregnancy:
For babies:
• infants are more likely to be born weak and require resuscitation;
• low birth weight;
• increased risk of miscarriage: for a period of 20 weeks – the probability is 2 times higher;
• increased risk of intrauterine infection;
• increased risk of prenatal death of one of the fruits;
• increased risk of stillbirth or death of the newborn in the first week of life;
• increased risk of disability of children during childbirth (cerebral palsy and other developmental pathologies);
• increased risk of placenta previa, as well as its premature detachment;
• increased risk of entanglement by umbilical cord and knotting on it.
For mother:
• increased risk of eclampsia, preeclampsia;
• increased risk of preterm birth;
• increased risk of anemia and diabetes;
• three times higher risk of preeclampsia;
• premature rupture of amniotic fluid is noted by 20% more often;
• more often a weakness of uterine and abdominal contractions is diagnosed (necessary processes during labor);
• atony of the uterus and bleeding in the postpartum period are more common.
Embryo quality assessment in IVF programs
The results of in vitro fertilization depend on a huge number of factors, but it is the embryological stage of the procedure that has the most important, practically determining result, value.
Manipulating microscopic human embryos is a complex area of medicine. Therefore, in the process of work, doctors use complex terminology.
First day
Immediately after fertilization, the doctor checks for signs that the ICSI, PIXI or IVF procedure is successful. To do this, it looks like pronuclei look and evaluates them:
• availability;
• quantity;
• internal structure;
• symmetry;
• look.
Pronuclei are the germ cell nuclei (male and female) that have not yet merged. Studying their appearance, one can evaluate the prospects, quality and livelihoods of future embryos.
Standard criteria:
• there should be two pronuclei;
• they should be close by;
• their sizes should be the same;
• the nucleoli (pronuclei) should be visualized inside;
• “nucleoli” must have the correct location and quantity.
At this stage of embryo development, many pathologies can form that lead to their death. For example: the presence of one pronuclei instead of two (fertilization does not take place); the presence of three pronuclei (the embryo is not viable, since it will have a triple chromosome set).
Bad embryos are immediately discarded. It makes no sense to replant them. Even if they do not die at the stage of cultivation, the woman’s body itself rejects such embryos. As a result, if the pregnancy occurs, it is very quickly interrupted. This happens in the first weeks of gestation.
Gestation, gestational age of the newborn (from Lat. Gestatio- bearing) – the number of full weeks of pregnancy between the first day of the last woman’s menstruation and the time of umbilical cord cutting during childbirth.
Second day
On the second day of cultivation, the cell divides into two. Blastomeres are formed.
Blastomeres are embryonic cells at the cleavage stage. A fertilized egg divides into two daughter cells called blastomeres. Each blastomere is divided into two new cells, which are also called blastomeres.
The quality criteria of the embryo at this stage are his:
• dimensions;
• form;
• degree of fragmentation (volume, which is occupied by non-nuclear elements of the cytoplasm inside the embryo);
• The more blastomeres inside the embryo and the smaller the degree of fragmentation, the more qualitative it is considered. Such an embryo has a great potential for further normal development.
Many embryologists use a classification that reflects the quality of embryos using four letters of the Latin alphabet.
Here is the classification:
• A – there are no nuclear-free fragments, high-quality embryo;
• B – fragmentation up to 20%, medium quality embryo;
• C – the content of cytoplasmic nuclear-free elements is more than 20%, but does not reach 50%, the embryo is of satisfactory quality;
• D – the number of anuclear (non-nuclear) fragments of the cytoplasm exceeds 50%; such an embryo is considered to be of poor quality.
This classification also uses numbers that reflect the number of blastomeres. The more of them, the better the product of the fusion of male and female germ cells. For example, the embryo “4B” is rated higher than the “3C”. After all it has more blastomeres and less fragmentation.
Third day
A normal embryo on the third day of development has from 7 to 9 blastomeres. It is already starting to implement the genetic program laid down in it.
At this stage, many embryos cease to develop. This is due to the presence of defects in genetic material.
“Development block” – this is how embryologists call the phenomenon, which provides natural selection. The breeding process is very complicated. DNA breakdown often occurs. “Broken” embryos stop developing.
Evaluation of their quality is the same as on the second day. A similar classification is used. Only blastomere becomes larger. Therefore, they are described, for example, as 8A.
Fourth day
If the embryo develops naturally, it would have entered the uterus on the fourth day after fertilization. Until that time, it is in the fallopian tube.
On the fourth day, the embryo consists of 10-16 blastomeres. It becomes more compact – takes up a small amount relative to the number of cells. Its surface looks smoother than on the third day.
Morula – the so-called stage of development of the embryo at this stage. In translation, this means “mulberry”. So embryologists called him precisely because of their external resemblance to this berry.
This stage ends with cavitation. This is the process of formation of the cavity inside the embryo.
Fifth day
On the fifth day of development, the embryo reaches a stage called the blastocyst. This means that the cavity inside the embryo has already reached 50% of its total volume.
Unlike previous stages of development, the blastocyst consists of different cells:
• Trophoblast. It is outside. This part of the embryo is responsible for its implantation (implantation) into the uterine lining. From it, the placenta and other extra-embryonic membranes will develop.
• Embryoblast. It is inside. Organs and tissues of the fetus will later be formed from these cells.
It is at this stage that in most cases doctors transplant the embryo into the woman’s uterus. They can also be frozen. This is done to save the “extra” embryos for the next cycle.
The entire embryo is surrounded by a shiny shell. After transfer, this shell is broken. The blastocyst comes out and is embedded in the wall of the uterus. This process is called hatching, which means “hatching.”
Some couples are given preimplantation diagnostics for the early detection of chromosomal and genetic mutations. In this case, PGD is done at this stage, when a part of the cells begins to protrude beyond the outer shell.
At this stage of development, the criteria for embryo quality are:
• size of the internal cavity;
• degree of embryo penetration beyond the shell;
• number and density of cells.
• The size of the internal cavity is estimated in numbers, the other two criteria – in letters.
Based on the size, there are six degrees of maturity of the blastocyst:
1 – cavity inside the embryo less than 50% (early blastocyst);
2 – cavity inside the embryo more than 50% of its volume;
3 – the cavity occupies the entire volume of the embryo;
4 – the cavity increases, and the shell of the embryo becomes thinner (expanded blastocyst);
5 – trophectoderm (outer layer of the blastocyst) penetrates the shiny sheath;
6 – the blastocyst “hatch” and leaves the envelope.
The cells of a quality embryo must be grouped. Imagine tennis balls that are packed inside a soccer ball. The more of them, and the denser located, the better the embryo is.
This parameter is reflected in the letters:
• A – tightly packed “soccer ball” with a large number of cells;
• B – the average number of cells inside the blastocyst;
• C – a small number of cells.
The trophectodermal layer is also evaluated. Continuing the analogy, we can compare it with the leather from which the football is sewn. The smaller the segments (cells), and the denser they are located, the better.
This parameter is also estimated by the letters of the Latin alphabet:
• A – many cells;
• B – the average number of cells;
• C – few cells.
The trophectodermal layer is also estimated. Continuing the analogy, we can compare it with the leather from which the football is sewn. The smaller the segments (cells) and the denser they are located it is better.
This parameter is also estimated by the letters of the Latin alphabet:
A – many cells;
B – the average number of cells;
C – few cells
Accordingly, the general characteristics of the embryo are displayed in numbers and two letters. For example, the 4AA record means that the embryo is in the extended blastocyst stage, many cells are contained inside, and the outside of its trophectoderm is also represented by a large number of cells.
The process of embryo development is very complicated. The IVF procedure is considered successful if at least 40% of them attained the good quality blastocyst stage on the fifth day of development.
The success of IVF procedure
Perhaps one of the most important conditions for pregnancy in IVF is the selection and transfer of a high-quality embryo. And here it should be noted an obvious technological breakthrough.
Time-Lapse technology, known under the commercial name as EmbryoScope®, Primo Vision ™, Geri®, Esco Miri®, or EEVA ™, is continuously monitored for embryonic development, which allows you to record videos about their evolution without resorting to microscopic observation. That is, there is no need to get the embryos from the incubators and this ensures stable growing conditions during their development up to the blastocyst stage. Using this system, embryos are constantly monitored and images are taken at intervals of 10 minutes.
Before performing embryo transfer, special software restores all captured images and allows a specialist to view and analyze the development of embryos in order to select the most suitable one for transfer.
Thus, observations with the help of time-lapse provide an opportunity to analyze new development parameters, which can improve accuracy when choosing embryos with the greatest potential for the development of pregnancy. A major breakthrough was made in classical values performed in artificial insemination laboratories, such as cell number estimation, fragmentation or symmetry.
The introduction of these imaging systems currently allows the selection of the most suitable embryos for implantation and their normal development, with the achievement of the final goal – the birth of a healthy child.
However, the final selection of the embryo, as well as the previous analysis, is carried out by a person (embryologist). But what if you entrust this task to a computer (computer program)? Mankind throughout the globe has repeatedly been convinced that a computer program is capable of demonstrating phenomenal results in the quality and speed of data analysis, exceeding human capabilities. Nowadays, society is rapidly growing interest in such a phenomenon as artificial intelligence (AI). It has not bypassed the sphere of assisted reproductive technology (ART), which is close to us.
Given the low success rate of pregnancy in IVF (35-40%) and the risk of multiple pregnancies, AI is able to make a revolution in the field of ART. Of course, the implementation of this large-scale project will require time and serious financial investments. According to our calculations, we are talking about at least one year of work (without testing), and financing in the amount of USD1000000. But we are convinced that we are able to create our own algorithm, which will allow us to save (by increasing the likelihood of pregnancy on the first attempt) childless couples from all over the world a huge amount of money without having to transplant several embryos, which means the risk of a multiple pregnancy.
Thus, from March 2, 2019 we begin work on creating our own AI algorithm, which will have a working name – Fai.
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