From hormones to embryos
What you need to know about the IVF procedure
Svetlana Kokotko, Forbes
We are looking into who is shown in vitro fertilization, whether it has contraindications and what is worth knowing about other reproductive technologies
According to WHO statistics, 48 million, or 20%, of married couples worldwide are infertile. However, thanks to modern assisted reproductive technologies (ART), infertility is no longer a sentence, but a task that has a solution. The first child conceived as a result of IVF was born in 1978 in the UK. It was the girl Louise Brown. She is now 43 years old. Since then, 5 million children have been born with the help of ART. Robert Edwards, the creator of artificial insemination technology, received the Nobel Prize in 2010. Louise Brown gave birth to two children of her own without the help of ART.
Some problems that prevent conception can be eliminated with medication or surgery. But if the treatment does not help for a year (and a woman over 35 years old — for six months), then in vitro fertilization — IVF is used. In the people, this term is not always used correctly. Traditionally, it is used in relation to any ART, but in fact it is only one of the methods in the large arsenal of reproductologists.
The main thing is not to get confused in terms.
ART methods are all scientific achievements, procedures and manipulations that can be used to help infertile people become happy parents. In addition to classical IVF, these include ICSI (targeted injection of a specially selected sperm directly into an egg), preimplantation genetic testing (PGT), assisted hatching and many more methods that make pregnancy possible.
ART programs are rather legal concepts. Sometimes a program includes several methods at once, but it bears the name of only one of them — and this creates confusion. For example, the IVF program provides at least ovulation stimulation, follicle puncture, IVF proper, embryo transfer into the uterine cavity, support of the luteal phase to preserve pregnancy.
And if, after stimulation and puncture, the eggs were frozen (without IVF), then the cryopreservation program has begun. Frozen eggs can then be used in an IVF program, or they can be used in a donation program.
Artificial insemination — the introduction of sperm from a husband or donor into the uterine cavity during ovulation — does not apply to IVF methods, because fertilization occurs inside the body, and not extracorporeal. The word "technology" does not apply to it either, since the procedure is quite simple. But it's still a method of assisted reproduction (VR).
Left: oocyte-cumulus complex. Right: sperm cells under a microscope (Photo: Maria Zhi)
In general, the topic of ART is a complex interweaving of purely medical, social and legal subjects. Let's try to figure it out.
Gentlemen, go ahead!
When a couple fails to get pregnant, often the partner is the first to see a doctor. This was the case in the era before the invention of IVF, this state of affairs persists even now. First of all, this is due to the disproportion of medical specialties: not only in Russia, but also in the USA, and all over the world, it is much easier to get to gynecologists than to urologists, and even more so to andrologists.
However, statistics show that by starting the examination and treatment with a man, you can achieve success faster. The initial assessment of infertility in a woman includes an extensive medical history, examinations, numerous laboratory tests, ultrasound and hysterosalpingography (and this is a rather unpleasant procedure). Whereas in order to confirm or exclude the "male factor", it is often enough to take a jar of sperm for analysis.
If the problem is in a man (spermatozoa are sedentary, there are few or none at all), then it is already obvious that you need to send a couple to a reproductologist to choose a program and IVF methods.
Most likely, it will require ICSI, ICSI (Intracytoplasmic sperm injection) — injection of a sperm into the cytoplasm of an egg. This technology is most often used in male infertility. An embryologist uses an electron microscope to select the best spermatozoa, and then with a super—thin needle inserts them into oocytes (one egg - one sperm).
If a man has no live sperm in his ejaculate at all or the seminal ducts are blocked, then the material is extracted surgically — a testicular biopsy is performed. This is also one of the methods of ART.
Sometimes clinics offer the PIXIE method — spermatozoa for ICSI are selected not by eye, but based on how they interact with hyaluronic acid. The technique is interesting, but studies show that it does not increase the chances of pregnancy compared to ICSI.
Who is to blame?
In 1/3 of cases, pregnancy does not occur due to the female factor (obstruction or absence of fallopian tubes, a complex form of endometriosis, polycystic ovary syndrome, etc.). In 1/3 of cases, it is the man who is infertile (varicocele, lack of testosterone, azoospermia - when there are no sperm in the ejaculate — etc.). In 1/3 of cases, both have disorders partners or it is not possible to establish the reason.
IVF as a program
For a woman, an IVF program most often begins with ovulation stimulation: you need to get several eggs, because not all embryos may be viable later.
"Usually only one follicle matures in one menstrual cycle. In order to start several at once (on average 5-15), the reproductologist uses hormonal drugs to stimulate superovulation. Drugs, their dosages, and the time of administration are selected by the attending physician strictly individually," emphasizes Yulia Fetisova, a reproductive physician at the MD GROUP Clinical Hospital of the Mother and Child Group of Companies.
There is an opinion that hormonal stimulation can lead to cancer. That's not so. "Before a woman enters the IVF protocol, she must undergo a comprehensive examination," says Nadezhda Belousova, a reproductive doctor at the European Medical Center. — The drugs used in IVF contain FSH (follicle stimulating hormone). There are receptors for it only in the ovaries, respectively, it does not affect any other organs and systems. Another thing is that under its influence, as the follicles grow in the body, the level of its own hormone estradiol increases. Therefore, if the patient has conditions in which an increase in this hormone is undesirable, the doctor selects safer analogues that do not affect the level of estradiol."
Left: hatching blastocysts. Right: two embryos of the second day of development (Photo: Maria Zhi)
A few years ago, it was widely believed that IVF can increase the risk of brain cancer. According to professionals, these concerns are completely groundless.
"Brain cancer happens not only in women, but also in men," recalls Nadezhda Belousova. — It is possible that some patients with this disease underwent in vitro fertilization. But in the same way, some patients with cancer may have once broken their arm, but no one comes up with the idea of linking these two events. An interesting article was published in the serious American magazine Fertility and Sterility. The publication examined the relationship between hormones that are used to stimulate ovulation and the risks of developing cancers of various localization. The conclusion of the authors of the article is unambiguous: the drugs used in IVF are safe from the point of view of oncology."
The maturation of the follicles is monitored by ultrasound. When they reach the desired size, a final injection is prescribed, causing ovulation.
36 hours after that, the follicles are punctured and mature eggs (oocytes) are extracted. The procedure is carried out under the supervision of ultrasound and takes only a few minutes. The woman at this time is under light intravenous anesthesia and in a couple of hours will be able to safely return home. The oocytes obtained on the same day are fertilized with the sperm of the husband or donor — this is the IVF method.
But the program continues.
Everything is under control
The fertilized egg is placed in an incubator with a special medium. In it, the embryos will develop for five to six days. At this time, it is very important to provide them with optimal conditions. "This can be achieved, for example, with the help of so-called time—lapse incubators equipped with a system of time-lapse round-the-clock photography," says Yulia Fetisova. — These are new generation incubators that monitor and record the development of embryos 24 hours a day, while the embryos themselves do not need to be taken out of ideal cultivation conditions and placed under a microscope. Each culture cup contains the embryos of one pair and is isolated from the embryos of other patients. When manipulating one cup, the cultivation of embryos of other patients in the system is not disrupted. But the most important thing is that a detailed development report and the presence of built—in artificial intelligence in the incubator help doctors choose the best embryo for transfer."
Some couples are recommended to do preimplantation genetic testing (PGT) before transferring embryos into the uterine cavity. "This helps to reduce the number of unsuccessful IVF attempts, the loss of pregnancies that have occurred, and in some cases exclude the possibility of having a sick child," explains Irina Fasel, a reproductive doctor, obstetrician—gynecologist, specialist in miscarriage at the MAMA clinic. — To conduct such a study, it is necessary to take several cells from the embryo for analysis, that is, to perform a biopsy. It is advisable to carry out it on the fourth day of embryo development, when it reaches the morula stage. Morula's biopsy is a unique development of Russian specialists. The procedure allows you to get the highest quality material for diagnosis (which means that the reliability of the study is significantly increased). The method is completely safe for the embryo: at the morula stage, it has a very high growth rate and consists of dozens of cells, so the loss of several of them is quickly replenished. The next day after the biopsy, the morula becomes blastocyst, and there are no traces of intervention."
Embryo transfer
Usually, it is this stage of the program that many married couples define for themselves as IVF. But no, fertilization has already taken place, and all further events will develop not extra-, but intracorporally — in the uterus. The transfer process itself takes several minutes and is performed without anesthesia.
Sometimes, before the transfer, an auxiliary hatching may be required (from the English hatching — "hatching"). The fact is that the embryo in the first days of development is surrounded by a dense protective shell. Then he needs to get out of it and attach to the endometrium. If the shell is too dense, the embryo cannot be released, and its development freezes at a certain stage. To avoid this, the embryologist dissects the shell.
On the left: an embryo in a catheter for transfer. On the right: Dewar vessel for storage of cryomaterial (Photo: Maria Zhi)
Usually, one, rarely two embryos are transferred into the uterine cavity. It is not recommended to plant more: multiple pregnancies create additional risks during gestation.
The remaining healthy embryos can be frozen. They can be used in the following IVF protocols, if this time the transplant does not end with pregnancy. Then the procedure will begin immediately with the transfer (ovulation stimulation, follicle puncture and fertilization will no longer be required).
If the first IVF attempt led to a successful pregnancy and childbirth, then in a few years you can return to the clinic for another baby (or maybe not for one). Children born in cryoprotocols are no different from babies conceived naturally. The technique of safe freezing is called vitrification.
Freezing programs
In 2018, in the United States, due to the negligence of the staff, two large centers of reproduction at once failed in the operation of cryophages, as a result of which several thousand oocytes and embryos were destroyed. For many people who used the services of these cryobanks, it was stress and pain. Similar incidents have occurred in Spain, Australia, Canada and the UK. It is quite possible that there were other minor "accidents", information about which was simply not leaked to the press.
It is possible to freeze not only embryos, but also oocytes and spermatozoa.
Sometimes this is done for medical reasons — for example, one of the future parents will have chemotherapy. Sometimes — for social reasons (I want to live for myself, make a career, etc.).
In the wake of the pandemic, the procedure of cryopreservation of germ cells has become especially relevant: an infection can reduce the chances of IVF success.
On the left: view of the cryopreservation from the inside. On the right: the process of defrosting (thawing) of the embryo (Photo: Maria Zhi)
"We sounded the alarm a year and a half ago," says Victoria Tabolova, a reproductive doctor at the K+31 clinic. — Even then, the first data began to appear that the SARS-CoV-2 virus, which causes COVID-19, reduces male fertility. We recommended the partners of our patients not to wait and cryopreservate the sperm. Such tactics have borne fruit. For example, one couple's wife's cells were fertilized with her husband's sperm collected a couple of months after the illness. The embryos, unfortunately, did not develop. Then we took the material of the same man, but frozen before he got sick with coronavirus — and everything turned out, the long-awaited baby was born. There is no data on the effect of the SARS-CoV-2 virus on female reproductive function yet, but it can also complicate the course of pregnancy."
In any case, Victoria Kimovna advises couples who plan to enter the IVF program to get vaccinated against COVID-19, and in two months it will be possible to plan conception.
Donor programs
Naturally, of all the donor programs, sperm donation is the easiest and most accessible. Purely technically.
Therefore, over the years of ART and donation, there has been a specific social problem associated with this. If the donor is too "active", and the donation is anonymous, then there is a risk that his grown-up biological children will accidentally meet and want to marry each other. Therefore, in some countries there is a limit on the number of children born from one donor.
Sperm and egg donation can be anonymous and non-anonymous. If you make the questionnaire open, then at the age of 18 the child will be able to find out who his biological parent is and meet with him. But for most couples who use such a service, this option is extremely undesirable — they want to keep the secret of the birth of a long-awaited child. Some people prefer to know the donor in order to get medical information if necessary (if, for example, a child has hereditary diseases). But such reinsurance is usually not justified. All donors undergo a thorough comprehensive examination — these are physically and mentally healthy men and women under 35 years of age.
Embryo donation is also possible if both partners have problems. Genetically, the child will not be yours. But if a woman herself carried him out and gave birth to him, then usually psychologically she perceives him exactly as her own.
In accordance with Russian Clinical guidelines, a couple can have IVF even in the absence of infertility:
if both future parents are carriers of some mutation and the unborn child has a high risk of inheriting the pathology (then preimplantation diagnosis of embryos grown in vitro is carried out);
if there is no sex in the couple (either spouse is not capable of it for some reason);
if one of the spouses is HIV-infected.
Surrogacy
From a purely medical point of view, this is about the same as embryo donation: a fertilized egg belongs to one woman, another carries and gives birth to a child.
Ethically and legally, this is the most difficult plot in the whole ART topic. The UN notes that the line between surrogacy and child trafficking is too thin for this issue to be regulated at the level of private contracts.
Russia is one of the few countries where both voluntary and commercial surrogacy is allowed. However, Article 51 of the Family Code states: "Persons who are married to each other and have given their written consent to the implantation of an embryo to another woman for the purpose of carrying it, can be recorded by the child's parents only with the consent of the woman who gave birth to the child (surrogate mother)." That is, the priority right to parenthood remains with the woman who gave birth to the child.
Portal "Eternal youth" http://vechnayamolodost.ru