Why does implantation not occur? Embryo implantation - symptoms and signs. How to increase the likelihood of successful embryo implantation? When is fetal implantation early or late?

Why don’t embryos take root in the uterus after transfer to IVF?

The key question after unsuccessful IVF is: “ Why does the embryo not take root after transfer? in the uterus? How can you influence? Let's consider these questions in detail.

What can prevent the embryo from attaching?

Why does the embryo not take root in a uterus with impaired decidualization?

The endometrium is transformed into high-quality decidual tissue in the second half of the cycle at. It is proportionally represented by immune cells (NK cells and Tx).

The mucous membrane is an intelligent “detector”. Until recently, it was believed that a genetically “wrong” embryo is not capable of long-term survival. In fact, such an embryo is capable of producing many biologically active substances. He thus tries to “please” the endometrium.

A fully decidualized endometrium, a hormone-dependent tissue, “recognizes” the genetically altered embryo and stops synthesizing a number of nutrients for it. As a result, the embryo stops developing. Nature saves a woman from disappointment and termination of pregnancy.

There are two options for impaired mucosal decidualization:

• (insufficient number of NK cells);
• increased local activity (lack of local immunoregulation and excessive mobilization of NK cells).

As a result of disorders, the endometrium reacts equally to a full-fledged and genetically modified embryo. The attachment of a defective embryo in this case leads to That is, after IVF, the embryo does not take root, although it lingers in the uterus for some time.

What can be done to ensure that the embryo takes root?

The treatment performed (in order to increase the chances of attachment) is selected taking into account the morphological changes in the decidual tissue.

To improve the quality of the endometrium in case of deficiency of immune activity, it is recommended:

• local irritation of the mucous membrane using pipell biopsy (collection of endometrial cells with a disposable tube with a side hole and a piston inside) or;
• moderate ovarian stimulation;
• support of the luteal phase with low doses of human chorionic gonadotropin;
• introduction of seminal fluid;
• intrauterine injection of peripheral mononuclear cells cultured with human chorionic gonadotropin.

With increased immune activity, a condition precedes inflammation occurs, and embryos do not engraft after IVF transfer.

• avoid local irritation of the uterine mucosa;
• carry out standard ovarian stimulation;
• sufficient support for the luteal phase;
• use corticosteroids, intralipids, intravenous immunoglobulins;
• sexual rest after embryo transfer;
• intrauterine injection of follicular fluid.

Effect of stimulation on implantation

A significant reason why embryos do not implant after IVF is controlled ovarian stimulation (COS). But it should immediately be noted that the exact cause and mechanism of changes in the uterus that occur under the influence of CBS have been little studied. There is no possibility to histologically examine the endometrium on the eve of transfer, since if the integrity of the mucous membrane is damaged, embryo transfer cannot be performed (it will be ineffective). That is, obtaining material to study the issue is problematic.

Studies show that in stimulated cycles, a premature release of progesterone can be observed (even before follicle puncture), which negatively affects the implantation properties of the endometrium.

The level of preimplantation losses after stimulation of ovulation, compared with natural pregnancy, is significantly higher - this confirms the unfavorable effect of CBS on implantation.

Which embryos take root better: fresh or “cryo”

Analysis of fresh and “cryo” cycles (transfer is carried out in a natural cycle) showed a pattern that the pregnancy rate in cryoprotocols is higher than in fresh protocols. And the frequency of miscarriages in fresh protocols is higher than in “cryocycles”.

Cryo embryos take root better in the uterus. In addition, Italian scientists have confirmed that the frequency of clinical and progressive pregnancies in “cryo” cycles is higher, and the frequency of miscarriages is lower.

Therefore, it was concluded that freezing embryos and transferring them in a natural cycle (without stimulation) is a fairly effective technique and allows one to overcome unfavorable endometrial transformations that occur during stimulation.

Implantation window offset

Within one menstrual cycle a woman has several days when the blastocyst is able to take root in the uterine cavity. This period is called the implantation window. The search for methods for determining the implantation window is still ongoing. A method for determining the expression of more than 200 genes in the endometrium has become widespread. By studying these genes, scientists can determine the period during which an embryo can take root in the uterus.

In women with repeated unsuccessful attempts at in vitro fertilization, a shift in the implantation window (earlier or later than expected) was detected in 25% of cases. Taking into account and using this information in practice, in 50% of cases the fact of pregnancy in women with repeated unsuccessful cycles is obtained.

Diseases that prevent embryos from implanting after IVF

There are a number of pathologies and conditions that can interfere:

• (level increases);
• . From excess weight negatively affects egg maturation and implantation.
• Age. It has long been believed that age does not have the best effect on oocyte quality. But it turns out that age may prevent the implantation of embryos obtained from donor eggs. Studies have shown that after 45 years, the implantation properties of the inner lining of the uterus significantly decrease.
• Immunological disorders.

The influence of morphological changes in the structure of the endometrium

Implantation is negatively affected by: thin endometrium. New technique gives more positive results regarding endometrial growth compared to standard treatment methods.

If the embryo does not take root, what happens to it next? The fertilized egg stops developing and leaves the uterine cavity along with menstrual flow.

The same happens in natural conditions, more often than women realize. In a natural cycle, the chance of conceiving is 30%. A significant number of embryos conceived in conditions of absolute health are genetically defective.

“Healthy” endometrium prevents them from attaching in 30% of cases at the pre-implantation stage. In 30% of cases, a defective embryo is attached, but within a few days the endometrium (at the post-implantation stage) stops its development. In 10% of cases, implanted embryos in the uterus lead to spontaneous miscarriages, a sign of which is bloody discharge.

Embryo implantation after IVF transfer. What is late implantation

Will the transferred egg fall out after replantation? When does embryo implantation occur after transfer? What are these? These questions are the most common among future IVF mothers.

Let's consider what is necessary for full implantation of a blastocyst, what to do to make it happen, and the differences between embryo implantation during IVF.

Conditions for implantation during IVF

The mechanism of embryo implantation after transfer (during IVF) is theoretically no different. The process is little studied even in natural cycles. It is known that it can extend over time and consists of two main phases: adhesion and adhesion (or penetration).

Necessary conditions for success:

• Active. Provided with the preparedness of the cells of the uterine mucosa.

• Produced on time.

Reproductologists have such a concept as an implantation window. This is the period during which the uterus is able to interact with the embryo. The implantation window is limited in time, so the effectiveness of IVF largely depends on the timeliness of transfer to the uterus.

The peak of receptivity - the ability of endometrial cells to interact with the embryo - occurs on days 20–21 of the cycle, but can shift depending on the drugs used for stimulation, the body’s sensitivity to them and the duration of the menstrual cycle. Most often, the implantation window opens at 20-21 days in the natural cycle, with controlled stimulation of ovulation - at 19-20, with hormone replacement therapy - at 21-22 days.

IVF is characterized by a lengthening of the interval during which implantation occurs - it lasts up to 3 days. Normally the process lasts 40 hours.

Late implantation does not affect pregnancy outcome. But defective embryo implantation after transfer - common reason spontaneous abortion.

When does implantation of the embryo occur after the transfer?

It is reliably known that embryo implantation occurs after transfer, when hatching is completed. After transferring three-day-old embryos at the morula stage, the initiation of implantation occurs 2–3 days after transfer (these are 2 and 3 DPP). After - on the same day or the next day.

The immune system

The role of the immune system in the implantation process has not been thoroughly studied. It is certain that it has an impact. Pregnancies after IVF are associated with the presence of antithyroid, antiphospholipid antibodies, activated natural killer cells - NK in the blood serum of women.

For a long time it was believed that the immune system is suppressed so that there is no conflict between the mother’s body and the protein molecules of the embryo. Scientists have proven that cellular interactions actually occur and become more complex. The appearance of atypical reactions leads to implantation disorders at the stage of adhesion and invasion.

Reasons for the absence or failure of implantation

There are several reasons why embryo implantation after transfer becomes unsuccessful:

• . The reason is a poor-quality genome formed during fertilization.
• Endometrial receptivity is impaired. Causes – consequences of infectious inflammatory processes, hormonal regulation disorders.
• The embryo cannot get rid of the thickened protein membrane on its own. This often occurs in older patients and is associated with. Other reasons are embryo transfer after ovulation, prolonged hormonal induction of ovulation, disruption of endocrine organs, smoking, embryo cultivation in an artificial environment.

Medication support

To increase the likelihood of successful implantation after embryo transfer, progesterone support is prescribed, starting from the day of the puncture (or no later than 3 days after the puncture). Under the influence of drugs, the transformation (preparation) of the endometrium for the expected implantation is initiated.

Support regimens contain blood thinning drugs: heparin and its analogues, aspirin. Under their influence, blood flow in the uterus increases, conditions for implantation improve.

Signs of embryo implantation after transfer and symptoms

Individual sensations - dizziness, metallic taste in the mouth, weakness, malaise, increased basal and general body temperature, and others are difficult to attribute to symptoms of embryo implantation after transfer. They may be associated with previously performed progesterone, prescribed to support implantation, or the result of “soul-searching” - looking for signs of an upcoming pregnancy.

A significant sign of embryo implantation after transfer is implantation bleeding, which is rare. It can easily be confused with bloody discharge, occurring due to insufficient support of the luteal phase. Therefore, only you can judge the nature of their origin.

Can embryos fall out?

Nature is wise, embryos do not fall out either after artificial transfer to, or to.

Inside the uterus - on the mucous membrane - there are many villi. As soon as the embryo comes into contact with them, they envelop and hold it. In addition, the uterus is a hollow organ, but its walls are adjacent to each other. Once hatching has occurred, the exposed embryo adheres. The outer cell mass surrounding the embryo is very sticky - the embryo cannot fall out.

What happens if implantation never occurs? In the process of constant cell division, a moment comes when the energy reserves to maintain them become insufficient, and there has been no contact with the mother’s body, and there is nowhere to receive nutrition from. The embryo dies and leaves the uterus along with menstrual flow.

In conclusion, watch the video - the opinion of a specialist obstetrician-gynecologist-reproductologist, Ph.D. Kamenetsky Boris Aleksandrovich about whether embryos can fall out of the uterine cavity.

The process of in vitro fertilization is quite labor-intensive, both for future parents and doctors. The protocol begins with preparation and medical examination, while patients must follow all the specialist’s recommendations.

The actions of doctors also play an important role in the IVF process. If something goes wrong, the procedure will most likely end in failure. If implantation does not occur during embryo transfer, the protocol is considered unsuccessful. In this case, it is necessary to identify the cause and get rid of it in order to increase the chances of repeated IVF.

Why implantation does not occur during IVF, and how to detect a violation, worries many expectant mothers. As soon as the embryos are transferred, the woman begins to think about whether the long-awaited pregnancy will occur or not. You can find out the answer to this question 10-14 days after cell replantation using an hCG test or a pregnancy test.

If IVF does not take root, the signs will be as follows. The main sign of lack of implantation is a very low level of hCG. This hormone begins to be secreted by the fetus as soon as it attaches to the wall of the uterus. Accordingly, if implantation has not occurred, hCG will not begin to be produced, and a blood test will show this.

The level of hCG in a woman’s body can also be determined by a pregnancy test for home use. It is a kind of indicator that is colored if the hormone is present in the urine. But it is worth noting that on early stages tests may show negative result, this is due to their low sensitivity.

Another sign of lack of implantation is heavy bleeding or menstruation. If a woman gets her period, we can conclude that the fetus has not implanted and pregnancy has not occurred.

Many patients are concerned about the question, what symptoms may appear during fetal implantation? As a rule, this process is not accompanied by any symptoms. Pain in the chest and lower abdomen, nausea and drowsiness are the consequences of taking hormonal drugs in preparation for IVF.

But some women may experience implantation bleeding due to damage to small capillaries during the process of embryo attachment. Such discharge is scanty and light, and it appears 5-7 days after replanting. If the blood is dark and profuse, then there is a threat of miscarriage.

Causes

Why the embryo does not take root after transfer is a question that worries approximately 50% of all women who have undergone IVF. It is with this probability that pregnancy may not occur.

As a rule, the woman has already undergone examination and cured all pathologies that may affect implantation. The procedure was completed according to all the rules, but ended in failure. Let's look at the main reasons why fetal implantation does not occur after IVF:

• poor endometrium;
• inflammation of the fallopian tubes and adhesions;
• hormonal problems;
• low-quality embryos;
• patient age over 40 years;
• genetic disorders;
• incompatibility of partners;
• bleeding disorders;
• obesity in women;
• medical error or incorrect fulfillment of doctor’s instructions during the preparation process.

State reproductive organs women plays a very important role in the process of pregnancy. If the patient has been diagnosed with endometriosis, hydrosalpinx, or polyps in the uterus, then the likelihood of successful IVF is significantly reduced. Problems with the uterus prevent the fetus from attaching, and hydrosalpinx (adhesions with the formation of fluid in the tubes) has a toxic effect on the embryo and prevents it from developing.

If the reason for the lack of implantation during IVF is poor endometrium, then special attention is paid to eliminating this problem, otherwise the attempt will again be unsuccessful. In case of hydrosalpinx, it is recommended to remove the fallopian tubes before IVF if conservative treatment in the previous protocol did not bring results.

If there is no implantation after IVF, the doctor may suspect incompatibility between the partners. In this case, the mother’s body perceives the embryo as an enemy and destroys it. To identify the disorder, a special HLA typing test is prescribed. Also, the cause of miscarriage may be a chromosomal abnormality of the embryo, for the detection of which PGD (preimplantation genetic diagnosis) is prescribed.

In the event that a mother is found to have disturbances in the hematopoietic system, she is prescribed treatment. Too thick blood disrupts placental blood flow and leads to fetal death. Therefore, during repeated IVF, blood-thinning drugs will be prescribed as prophylaxis.

The reason for the lack of implantation during IVF can be endocrine disorders, often a lack of progesterone. In this case, the woman passes additional examination see an endocrinologist and, if necessary, treatment. If there is a lack of progesterone, drugs will be prescribed to support pregnancy, for example, Utrozhestan or Duphaston.

Often the reason for the lack of implantation is bad embryos. They are not viable enough and therefore do not take root in the uterus. This can occur due to poor quality of eggs and sperm, as well as due to improper actions of the embryologist.

To improve the quality of the embryos, treatment may be prescribed to both the man and woman. Additional ART methods are also used, for example, PIXI, which make it possible to study the quality of cells and select the most viable ones for fertilization. It is also very important to choose the most favorable day of the cycle for replanting.

Future parents should remember that the older they are, the worse the quality of the reproductive cells. Accordingly, the likelihood of unsuccessful implantation after IVF greatly increases. Therefore, if a man and woman want to undergo IVF, it is better to do this before the age of 35.

Treatment

Many patients wonder what to do after unsuccessful IVF? The first thing you need to do is stop being upset; there is no need for depression here. Then it is recommended to consult a doctor and consult; a specialist should assess the situation and voice possible reasons failures.

During the period of preparation for the next protocol, a woman should lead a moderately active lifestyle, play sports, such as yoga, and eat right. If you are overweight, you must definitely fight it, since obesity negatively affects the implantation process.

It is worth noting that lack of weight also has a bad effect on a woman’s reproductive function. If the patient wants to become pregnant using IVF and carry healthy baby, she must bring her weight back to normal.

Reasons for failure in IVF (Video)

After fertilization of the embryo, it is implanted into the uterus. From this moment on, he begins to fully develop into female body. Embryo implantation during IVF must occur in the natural environment of the uterus. Typically, a woman expects her period to be missed, and when the IVF procedure is successful, she becomes pregnant.

It is known that implantation after IVF is carried out after the replantation of a fertilized oocyte. The time at which implantation occurs after transfer depends on what stage of development the cell was transplanted at - a three-day morula or a five-day blastocyst. Optimal timing transplants to the uterine mucosa take from 2 to 4 days.

Point zero is the day of egg retrieval and IVF ICSI procedure. The sequence of processes from the moment the egg leaves the ovary until it is implanted through the meatus fallopian tube into the uterine cavity is divided into the following stages:

• the initial stage of development (during this period the result of natural fertilization is assessed);
• the beginning of cell fragmentation;
• then the egg shell divides, the embryo gradually reaches the development of a morula;
• development of the blastocyst, when a cavity appears in the embryo (at this time the fertilized oocyte is transplanted);
• fixation in the uterus;
• formation of the embryo genome.

During the transfer of a three-day-old embryo, attachment occurs after 3 or 4 days. When replanting a five-day period is practiced, this process is carried out the next day.

On what day after transfer is implantation of the embryo carried out during IVF?

Patients who are preparing for the process of in vitro fertilization should know when, after transfer, attachment of the fertilized oocyte to the endometrium occurs.

Between fertilization and attachment of the oocyte, no less than 7 and no more than 10 days pass. This period is counted from the day of ovulation. A cell that has not penetrated the mucosa has a protective shell. Successful attachment occurs when the membrane is shed and trophoblast is formed.

An embryo that has developed correctly and has no defects is correctly assessed by the woman’s immune system. Then it is considered that implantation during IVF occurred correctly and the patient develops pregnancy. If the fetus has genetic abnormalities, then it cannot grow in the uterus because its mucous membrane rejects such material.

The implantation process takes approximately 1.5 days after transfer. Next, the natural development of the embryo occurs. Unsuccessful episodes of artificial insemination occur if the egg has a high shell density. This phenomenon often occurs in patients after overcoming the 40-year mark. The implantation process will be successful if there is a sufficient amount of progesterone in the mother’s blood, the hormone responsible for the process of endometrial growth.

IN medical practice Attachment of the embryo earlier than a week later is rare. The most common is late implantation, when 10 days occur from ovulation to the attachment of the fertilized oocyte. If there are no symptoms of the onset of pregnancy after this period, then the woman is prescribed an ultrasound examination.

When is fetal implantation early or late?

Early implantation of the embryo after IVF is said to occur if it is completely in the uterine cavity until a week after the oocyte leaves the follicle. Late implantation of the embryo is diagnosed if it is immersed in the mucous membrane after ten or more days, if counted from the day of ovulation.

There are such reasons for deviations from the normal timing of fetal implantation.

1. Some individual structural features of a woman’s body.
2. Abnormal structure of the fallopian tube. If a woman has a partial obstruction, the egg may linger in the tube for some time, causing implantation to occur somewhat later.
3. Abnormal development of the embryo itself. Sometimes the process of cell division occurs too slowly in the formed zygote. In this case, it will be in the uterus later than usual. Too active division of the zygote provokes early attachment - it will occur earlier than on the 7th day.

Signs of embryo implantation after IVF

Some signs of embryo implantation after transfer are dizziness, the presence of a metallic taste in the mouth, weakness, and general malaise. They are not considered an important sign of a successful procedure, because they may appear as a response to ovulation induction. Due to the implantation of embryos, women experience another important symptom - an increase in basal temperature.

Women rarely experience implantation bleeding, which develops immediately after implantation and indicates that pregnancy has begun. This phenomenon can be easily confused with discharge that develops due to insufficiency of the luteal phase.

The most significant signs of successful IVF are the results of examinations for human chorionic gonadotropin and estradiol. The patient must periodically donate blood for these tests so that it is possible to accurately determine the onset of pregnancy.

Factors influencing the success of the procedure

Successful implantation of an embryo into the uterine cavity occurs when the organ is completely ready to accept it. If the surface of the endometrial mucosa is normal and the body produces the required amount of progesterone, then the woman begins to bear a child. The successful development of pregnancy will depend on subsequent hormone levels.

Most reproductive specialists advise transferring five-day-old fertilized oocytes. Then they will definitely develop in the uterine cavity. In addition, implantation of a five-day pregnancy will help to avoid dangerous complications - ectopic or stillbirth.

The choice of the day on which embryo implantation occurs is important for the successful onset and subsequent development of pregnancy. There is a statement that to create necessary conditions To engraft a fertilized oocyte, you need to have coitus on the day of replantation. It will improve blood circulation in the pelvic area, making it easier for the embryo to take root.

How do pinopodia affect implantation?

Pinopodia are formations on the endometrium that facilitate the attachment of the embryo. Throughout almost everything monthly cycle They are not here. They appear in the implantation window: the mucosa is then most prepared for the implantation of a fertilized embryo.

The appearance of pinopodia depends on the presence of estrogens in the blood. They contribute to the fact that the mucous membrane begins to thicken, and a significant number of glandular formations develop in it. After ovulation, increased production of progesterone occurs. It is under the influence of this important hormone that the process of formation of pinopodia occurs.

Medical studies have shown that pinopodia take approximately 20 to 23 days to form. At the same time, attachment of the oocyte into the cavity occurs.

Why is implantation not carried out during IVF?

Failures during in vitro fertilization are caused by certain pathologies, a violation of the technology that facilitates the attachment and implantation of the embryo.

The reasons for failure with IVF are as follows.

1. Hormonal imbalance disorder. Possible implantation is indicated by increased amounts of sex hormones. If a woman's progesterone levels decrease, implantation may not be possible.
2. Pathologies of the immune system.
3. Failure to comply with transfer times.
4. Abnormal structure of the embryo.
5. Violation of the structure of the endometrium.
6. Benign tumors.

Signals of unsuccessful embryo implantation

The later the embryos are implanted, the greater the likelihood of their death. Due to the lack of implantation under unfavorable conditions, the eggs die approximately two weeks after ovulation.

Signs of failed implantation are:

• no signs of pregnancy two weeks from the day of ovulation;
• negative pregnancy test results;
• severe bleeding after the oocyte leaves the follicle;
• separation of the embryo with bleeding;
• the occurrence of vaginal bleeding 14 days from the day of ovulation;
• absence visible changes uterine cervix;
• unchanged basal temperature.

FAQ

Duration of embryo viability without implantation

The lifespan of an embryo outside the uterine cavity is limited to two weeks.

What is the thickness of the endometrium that is considered normal?

For implantation to occur successfully, it is necessary that the thickness of the endometrium is not below 7 mm and not more than 13 mm.

What is the difference between replanting when transferring three-day and five-day embryos?

Implantation of five-day-olds into the uterus is preferable because they have better viability. Younger embryos do not yet have the necessary genetic material, so when implanted at three days old, the risk of their death increases. When transferring five-day-old embryos, the probability of failure decreases significantly.

Implantation after cryotransfer in a normal cycle

This option will be successful, since it does not require repeated stimulation. In this case, it is possible to achieve successful preparation of the endometrium and achieve the most favorable conditions for the development of pregnancy.

Is it possible to engraft two embryos on different days?

This is possible provided that the implantation of another fetus occurs when the mucous membrane is ready to accept it. If another embryo is implanted a day or two later, it will develop normally.

Can colds and coughs interfere with embryo implantation?

A slight cold will not interfere with the process. But a severe cough can interfere with it, because it provokes the expulsion of the embryo.

Is sex allowed during embryo implantation?

When conducting IVF sessions, it is prohibited to have sexual intercourse after the transfer, because any impact can adversely affect their development.

Can embryos be implanted on the day of menstruation?

This is not possible on the day of menstrual bleeding. Before implantation, the endometrial structure must be well developed. The onset of menstruation prevents the normal attachment of the embryo.

The value of basal temperature during and after implantation

A core body temperature of up to 37 degrees is considered normal. During fertilization and subsequent implantation, it should increase - to approximately 37 and a half degrees. A decrease in this indicator is an unfavorable sign.

Is it possible for blood or discharge to appear after the fetus is implanted into the uterus?

After the fertilized egg attaches, a small discharge mixed with blood may appear. If vaginal discharge is not observed, this is also a natural sign of implantation.

Does ultrasound help see engraftment?

A routine ultrasound helps identify signs of fetal development at 5 weeks. Transvaginal ultrasound can detect pregnancy as early as 21 days.

Does D dimer increase during implantation?

During pregnancy, the concentration of these substances in the blood increases slightly. This is explained by the peculiarities of changes in blood composition.

anonymously

Good afternoon, Ara Leonidovich! I've heard a lot of good reviews about you. We are looking for a specialist who could help us prepare for the next, hopefully victorious, IVF protocol. We live in another city and for this reason I would like to come to you for the first consultation with as many ready-made tests as possible. My husband and I have been planning a pregnancy for 3 years, we had a laparoscopy - the tubes are passable, we had an ovarian resection, as a result of which one ovary stopped functioning. 2 IVF - no implantation, hysteroscopy - nothing was found except for isolated endometriosis tracts, the culture tank is clean, 1 cryo transfer - no implantation. We want to undergo a complete examination to find the reason for the lack of implantation. Since there is one ovary, and during stimulation only 5 eggs were taken ( good quality, all were fertilized and grew up to day 5), I would like to minimize further eco protocols. My husband is fine. I am 29 years old, my husband is 26. What other tests need to be taken? How can I get to you for a consultation with all the ready-made tests? Help us find the cause of failure and make IVF successful! Thanks in advance for your answer!

The range of studies to identify the cause of an unsuccessful attempt and PE can be determined after a face-to-face consultation. Rough plan examination includes: exclusion of chronic endometritis - I recommend performing an aspiration biopsy of the endometrium followed by morphological and immunohistochemical studies to determine the receptivity of the endometrium, i.e. endometrial sensitivity to implantation Determination of the hormonal profile - FSH (follicle-stimulating hormone), LH (luteinizing hormone), Prolactin, Estradiol, 17-OH-progesterone, Androstenedione, Androstenediol glucuronide, DHEA sulfate (dehydroepiandrosterone sulfate), Total testosterone, Free testosterone, Dihydrotestosterone , SHBG (sex hormone binding globulin) Determination of thyroid hormone levels - TSH (thyroid-stimulating hormone), T4 (thyroxine), T3 (triiodothyronine), Anti-TG (antibodies to thyroglobulin), Anti-TPO (antibodies to microsomal thyroid peroxidase), Thyroglobulin Study on the biocenosis of the vagina and culture of the flora of discharge from the genital organs with determination of sensitivity to the main spectrum of antibiotics and bacteriophage Sexually transmitted infections (chlamydia, mycoplasmosis, ureaplasmosis, trichomoniasis, gonorrhea, herpes, HPV, etc.) Hemostasis indicators Fibrinogen, Prothrombin , Thrombin time, APTT, Antithrombin III, Lupus, D-dimer, Protein-C Study of the TORCH complex Determination of the genetic risk of disorders of the blood coagulation system (FGB, F2, F5, SERPINE1, ITGA2, ITGB3) Identification of antiphospholipid syndrome - APS- (definition IgM and IgG class antibodies to phospholipids: cardiolipin, phosphatidylserine, phosphatidylinositol, phosphatidylic acid). Determination of a genetic defect in folate cycle enzymes (MTHFR, MTR, MTRR) Genotyping of a married couple, HLA class II (DRB1, DQA1, DQB1 loci) Violation of most of these parameters can contribute to impaired sensitivity of the uterine mucosa to embryo implantation and, accordingly, lead to miscarriage at extremely early stages.