Habitual miscarriage: causes

Genetic, anatomical, endocrine, immunological and infectious factors are distinguished in the structure of habitual pregnancy losses. If you exclude all of the above reasons, a group of patients remains, the origin of a habitual miscarriage in which it seems unclear (idiopathic miscarriages). According to C. Coulam et al. (1996), 80% of idiopathic miscarriages are caused by unrecognized immune disorders.

There is no convincing evidence pointing to endometriosis as the cause of a habitual miscarriage, and that medical or surgical treatment of endometriosis reduces the frequency of habitual miscarriage.

According to the current ideas, in addition to the genetic and partly infectious causes leading to the laying of the abnormal embryo, the implementation of the damaging effect of other factors (anatomical, endocrine, immunological) consists in creating an unfavorable background for the development of a genetically valuable fetal egg, which leads to the depletion of reserve capabilities chorion and stopping development (embryogenesis). Critical terms in the first trimester of pregnancy are 6-8 weeks (death of the embryo) and 10-12 weeks (expulsion of the fetal egg).

[1]

Genetic causes of habitual miscarriage

Genetic factors in the structure of the causes of habitual miscarriage are 3-6%. In sporadic interruption of pregnancy in the first trimester, about 50% of abortus have chromosomal abnormalities. Most of them (95%) are changes in the number of chromosomes - monosomy (loss of one chromosome), trisomy (the presence of an additional chromosome) resulting from errors in meiosis, as well as polyploidy (an increase in the chromosome composition for a full haploid set) that occurs when the ovum is fertilized with two and more sperm. In sporadic miscarriages, trisomy is most common, 60% of all mutations (most often on chromosome 16, and also 13, 18, 21, 22), followed by Shereshevsky-Turner syndrome (chromosome 45 X0) - 20% 15% fall on the share of polyploidy (especially triploidy).

In the case of abortion in the number of chromosomes in the study of karyotypes of parents, most pathologies are not detected and the probability of chromosomal disease of the fetus during subsequent pregnancy is 1%. In contrast, in the study of abortus in couples with a habitual miscarriage, structural changes in chromosomes (intra- and interchromosomal) are observed in 3-6% of cases. In the study of karyotype of parents, in 7% of cases, balanced chromosome rearrangements are found. Most often these are reciprocal translocations in which the segment of one chromosome is located on the site of another segment of the non-homologous chromosome, as well as the mosaicism of the sex chromosomes, inversion and detection of chromosomes in the form of a ring. In the case of such rearrangements, in one of the spouses the process of pairing and separation of chromosomes is complicated during meiosis, resulting in the loss (deletion) or doubling (duplication) of chromosome regions in gametes. As a result, there are so-called unbalanced chromosomal rearrangements, in which the embryo is either not viable, or serves as a carrier of severe chromosomal pathology. The probability of a child with unbalanced chromosomal abnormalities in the presence of one of the parents in a karyotype of balanced chromosome rearrangements is 1-15%. Differences in data are related to the nature of the restructuring, the size of the segments involved, the sex of the carrier, the family history.

Diagnostics

Anamnesis

• Hereditary diseases among family members.
• The presence of congenital anomalies in the family.
• The birth of children with mental retardation.
• Presence in a married couple and relatives of infertility and / or miscarriage of an unknown origin.
• The presence of unclear cases of perinatal mortality.

Special research methods

• The study of karyotype of parents is especially shown to married couples at the birth of a newborn with malformations in addition to the history of miscarriage, as well as with the habitual miscarriage of pregnancy in the early stages.
• Cytogenetic analysis of abortus in cases of stillbirth or neonatal mortality.

Indications for consultation of other specialists

If the parents determine the changes in the karyotype, a consultation of a geneticist is needed to assess the risk of the birth of a child with a pathology or, if necessary, to resolve the issue of donation of an oocyte or sperm.

Further management of the patient

In the presence of a pathological karyotype in a married couple, even one parent is recommended to perform prenatal diagnosis during pregnancy - a chorionic biopsy or amniocentesis - in view of the high risk of developmental disorders in the fetus.

Anatomical causes of habitual miscarriage

To the anatomical reasons of habitual miscarriage are:

• congenital malformations of the uterus (complete doubling of the uterus, bicorne, saddle, single-horned uterus, partial or full intrauterine partition);
• acquired anatomical defects;
• intrauterine synechia (Asherman's syndrome);
• submucous myoma of the uterus;
• isthmic-cervical insufficiency.

The incidence of anatomical abnormalities in patients with a habitual miscarriage varies between 10-16%. The frequency of occurrence of uterine malformations, in which miscarriage is possible (and not infertility), in relation to all malformations of the uterus is as follows: bicorne uterus 37%, saddle uterus 15%, intrauterine partition 22%, full uterine duplication 11% , unicorn uterus - 4,4%.

Diagnosis of habitual miscarriage

Anamnesis

In the anatomical pathology of the uterus, late pregnancy interruptions and premature births are more often noted, but early termination of pregnancy is possible with implantation on the intrauterine partition or near the myomatous node.

For ischemic-cervical insufficiency pathognomonic sign is the spontaneous termination of pregnancy in the second trimester or early premature birth occurring relatively quickly and painlessly.

With malformations of the uterus, it is necessary to pay attention to anamnestic indications of the pathology of the urinary tract (often associated with congenital abnormalities of the uterus) and the nature of the formation of menstrual function (indicating the hematometer with a functioning rudimentary horn of the uterus).

Special survey methods

• At present, hysterosalpingography is carried out for the diagnosis, which allows studying the shape of the uterine cavity, revealing the presence of submucous nodes of myoma, synechia, septum, and also determining the patency of the fallopian tubes. With the purpose of diagnostics of uterine pathology it is rational to conduct hysterosalpingography during intermenstruation and ovulation, i.e. In the first phase of the menstrual cycle after the termination of bloody discharge (7-9th day of the cycle). For the diagnosis of ischemic-cervical insufficiency, the study is conducted in the second phase of the menstrual cycle (18-20 days) to determine the state of the internal throat of the cervix. Before conducting hysterosalpingography, inflammatory diseases of the pelvic organs should be excluded or treated.
• Hysteroscopy in recent years has become widespread and has become the gold standard for diagnosis of intrauterine pathology. However, due to the higher cost compared to hysterosalpingography, the method is used in women with an indication of the presence of an intrauterine pathology according to preliminary data of ultrasound (ultrasound). With hysteroscopy, you can examine the uterine cavity, determine the nature of the intrauterine pathology and, with the necessary equipment (resectoscope), carry out low-traumatic surgical treatment - removal of synechia, submucous myoma, endometrial polyp. When removing the intrauterine partition, preference is given to hysteroresectoscopy with laparoscopic control, which prevents the possibility of perforation of the uterine wall.
• Ultrasound is performed in the first phase of the menstrual cycle, which allows presumably to diagnose a submucous uterine myoma, intrauterine synechia, and in the second phase of the cycle - to reveal an intrauterine partition and a bicornic uterus. This method is especially important in the early stages of pregnancy, when its sensitivity in the diagnosis of these conditions is 100%, and specificity - 80%. Out of pregnancy, diagnosis requires additional confirmation by other methods.
• Foreign authors point out the advantage of sonohysterography (ultrasound using a transvaginal transducer with a pre-introduction of 0.9% sodium chloride solution into the uterine cavity) before hysterosalpingography, as it allows differential diagnostics between the intrauterine partition and the two-legged uterus. Sonogetherography can not only study the shape of the uterine cavity, but also determine the configuration of the bottom of the uterus body. In our country this method has not been widely used.
• In some complex cases, MRT of pelvic organs is used to verify the diagnosis. The method provides valuable information for abnormalities of the development of the uterus, accompanied by an atypical arrangement of organs in the small pelvis. MRI is important in the presence of rudimentary horn of the uterus to decide whether it should be removed. The need to remove the rudimentary horn of the uterus arises in the case of its communication with the tube and ovary to prevent the formation and development of a fetal egg in it. Termination of pregnancy in anatomical abnormalities of the uterus may be due to unsuccessful implantation of the fetal egg (on the intrauterine partition, near the submucous myoma), insufficiently developed vascularization and reception of the endometrium, close spatial relationships in the uterine cavity (for example, when the cavity is deformed by the myoma node), often concomitant ICN, and hormonal disorders.

Treatment of habitual miscarriage of pregnancy

Surgery

In the presence of an intrauterine septum, submucous nodes of myoma and synechia, surgical treatment by hysteroresectoscopy is most effective. The frequency of subsequent miscarriages in this group of women after treatment is 10% compared with 90% before surgery. When comparing the results of metaplasty, performed by laparotomy and transcervical hysteroresectoscopy, R. Heinonen (1997) received results indicating a less traumatic and more effective hysteroresectoscopy; The percentage of pregnancies that resulted in the birth of viable children was 68% and 86%, respectively.

Surgical removal of the intrauterine partition, synechia, as well as submucous nodes of myoma leads to the elimination of miscarriages in 70-80% of cases. However, it does not have an effect in women with a developmental disorder of the uterus who have a history of normal labor with subsequent repeated miscarriages. Probably, in such cases the anatomical factor is not the leading cause and it is necessary to look for other reasons for miscarriage.

It is proved that abdominal metaplasty is associated with a significant risk of postoperative infertility and does not improve the prognosis of subsequent pregnancy. Therefore, preference is given to hysteroscopy and laparoscopic operations.

Medication

The effectiveness of the introduction of the spiral, high doses of estrogen preparations, the introduction of the Foley catheter into the uterine cavity after the removal of the synechia, the intrauterine partition has not been proven. It is recommended to plan pregnancy not earlier than 3 months after the operation. To improve the growth of the endometrium, cyclic hormone therapy is performed for 3 menstrual cycles [14]. Within 3 months in the first 14 days of the cycle, it is advisable to take a preparation containing 2 mg of 17-beta-estradiol for the next 14 days - 2 mg of 17-beta-estradiol and 20 mg of dydrogesterone (10 mg of dydrogesterone in the combination plus 10 mg of dydrogesterone in a separate tableted form).

Further management of the patient

Features of the course of pregnancy with a double-horned uterus or doubling of the uterus (when there are 2 cavities of the uterus):

• In the early stages of pregnancy, bleeding often occurs from an "empty" horn or uterine cavity due to a pronounced decidual reaction; tactics should be conservative at the same time and consist in the use of spasmolytic and haemostatic agents;
• threat of termination of pregnancy at various times;
• development of isthmico-cervical insufficiency;
• retardation of intrauterine development of the fetus due to placental insufficiency.

In the early stages of pregnancy bleeding is appropriate for bed and half-bed regimes, the appointment of hemostatic, spasmolytic and sedative drugs, therapy with gestagens (dydrogesterone in a daily dose of 20 to 40 mg) to 16-18 weeks gestation.

[2], [3], [4], [5]

Endocrine causes of habitual miscarriage

According to different authors, the endocrine causes of miscarriage are from 8 to 20%. The most significant of these are the inadequacy of the luteal phase (NLF), hypersecretion of LH, dysfunction of the thyroid gland, diabetes mellitus.

Severe thyroid disease or diabetes can lead to repeated abortions of pregnancy. However, with compensated diabetes mellitus, the risk of habitual miscarriages does not differ from that in the population.

At the same time, the high incidence of hypothyroidism in the population requires screening with a measurement of the level of TSH. In patients with a habitual miscarriage, luteal phase insufficiency is observed in 20-60% of cases, and ultrasound signs of polycystic ovaries - in 44-56%. According to the literature, the effect of individual hormonal disorders on the formation of the symptom complex of a habitual miscarriage remains controversial. Studies M. Ogasawara et al. (1997) did not reveal significant differences in the incidence of abortion in the presence of NLF and without it in patients with two or more previous miscarriages in the history with the exclusion of autoimmune, anatomical and infectious causes.

Insufficiency of the function of the yellow body can be the result of a number of unfavorable factors:

• disorders of secretion of FSH and LH in the first phase of the menstrual cycle;
• early or, conversely, too late peak of LH surge;
• hypoestrogenia as a consequence of inferior folliculogenesis. All these conditions are not subject to correction by progestational therapy with gestagens in the post-vivo period. Prospective studies conducted by L. Regan et al. Showed a significant increase in the incidence of miscarriages in patients with hypersecretion of LH on the 8th day of the menstrual cycle compared to women with normal LH levels in the blood (65% and 12% miscarriages, respectively). The damaging effect of untimely release of LH is associated with the premature resumption of the second meiotic division and the ovulation of the immature oocyte, as well as with the induction of production of androgens by teki cells along with the violation of the reception of the endometrium under the effect of gestagenic insufficiency. However, a preliminary decrease in the predovulatory level of LH by gonadoliberin agonists without additional measures aimed at prolonging the subsequent pregnancy does not give the expected decrease in the frequency of miscarriages.

The gold standard for the diagnosis of NLP is the histological examination of the material obtained from endometrial biopsy in the second phase of the cycle during 2 menstrual cycles.

Diagnosis of other causes of ovulatory dysfunction, such as hyperprolactinaemia, hypothyroidism, functional excess of androgens (ovarian or adrenal), should be accompanied by the appointment of appropriate treatment.

Diagnostics

Anamnesis and physical examination

• Anamnesis. Factors that need attention: later menarche, irregular menstrual cycle (oligomenorrhoea, amenorrhea, a sharp increase in body weight, loss of body weight, infertility, habitual miscarriages in the early stages).
• Examination: physique features, height, body weight, hirsutism, severity of secondary sexual characteristics, presence of striae, examination of the mammary glands for a galactorrhea.
• Tests of functional diagnostics: measurement of rectal temperature during 3 menstrual cycles.

Special research methods

• Hormonal research:
  • in the 1st phase of the menstrual cycle (7-8th day) - determination of the content of FSH, LH, prolactin, TSH, testosterone, 17-hydroxyprogesterone (17-OP), DHEAS;
  • in the 2nd phase of the menstrual cycle (21-22 days) - determination of the content of progesterone (normative indicators of the level of progesterone are very variable, the method can not be applied without taking into account other factors).
• Ultrasound:
  • in the first phase of the menstrual cycle (5-7th day) - diagnosis of the pathology of the endometrium, polycystic ovaries;
  • in the 2nd phase of the menstrual cycle (20-21 days) - measurement of the thickness of the endometrium (10-11 mm, correlates with the content of progesterone).
• Endometrial biopsy for NLF verification is performed 2 days before the expected menstruation (on the 26th day with a 28-day cycle). A similar method is used in cases where the diagnosis is not clear. To study changes in the endometrium in the so-called "implantation window" period, a biopsy is performed on the 6th day after ovulation.

Treatment

In the diagnosis of NLF (according to the rectal temperature charts, the duration of the second phase is less than 11 days, there is a gradual increase in temperature, insufficient secretory transformation of the endometrium from endometrial biopsy, low serum progesterone), it is necessary to identify the cause of such disorders.

If NLP accompanies hyperprolactinemia, an MRI of the brain is performed. An alternative method is the radiography of the skull (the area of the Turkish saddle).

The first stage in hyperprolactinaemia is the elimination of pituitary adenoma requiring surgical treatment. In the absence of pronounced changes, hyperprolactinaemia is regarded as functional, and bromocriptine is prescribed to normalize the level of prolactin. The initial dose of bromocriptine is 1.25 mg / day for 2 weeks, after controlling the level of prolactin in the absence of normalization, the dose is increased to 2.5 mg / day. With a marked increase in the level of prolactin, the initial dose is 2.5 mg / day. When pregnancy occurs, bromocriptine should be withdrawn.

When hypothyroidism is detected, the character of the pathology of the thyroid gland is established together with the endocrinologist. In any case, therapy with levothyroxine sodium is shown daily, the dose is selected individually before the normalization of the TSH level. At the onset of pregnancy, treatment with levothyroxine sodium should be continued. The question of the expediency of increasing the dose in the first trimester of pregnancy is decided together with the endocrinologist after receiving the results of hormonal examination (level of TSH, free thyroxine).

NLF correction is performed in one of two ways. The first way is stimulation of ovulation, the second way - substitution therapy with progesterone preparations.

The first treatment option: stimulation of clomiphene ovulation with citrate. This method of treatment is based on the fact that most of the disorders of the luteal phase are laid in the follicular phase of the cycle. The constantly lowered level of progesterone in the 2 nd phase is a consequence of disturbed folliculogenesis in the 1 st phase of the cycle. This disorder will be successfully corrected by low doses of clomiphene citrate in the early follicular phase with greater success than the progesterone in the 2 nd phase of the cycle.

In the 1st cycle, the dose of clomiphene citrate is 50 mg / day from the 5th to the 9th day of the menstrual cycle. Efficacy is monitored by rectal temperature graphs, progesterone level measurement in the 2nd phase of the cycle, or with dynamic ultrasound. In the absence of sufficient effect in the 2nd cycle of ovulation stimulation, the dose of clomiphene citrate should be increased to 100 mg / day from the 5th to the 9th day of the cycle. The maximum possible dose in the 3rd cycle of ovulation stimulation is 150 mg / day. Such an increase in the dose is possible only with the normal tolerability of the drug (the absence of intense pain in the lower abdomen and lower back and other signs of ovarian hyperstimulation).

The second variant of treatment: substitution therapy with progesterone preparations, which contribute to the full secretion transformation of the endometrium, which gives the necessary effect in patients with habitual miscarriage of pregnancy with safe ovulation. In addition, in recent years, it has been established that the administration of progesterone preparations has not only a hormonal but also an immunomodulatory effect, suppressing the rejection reactions of immunocompetent cells in the endometrium. In particular, a similar effect is described for dihydrogesterone at a dose of 20 mg / day. For the purpose of replacement therapy, dydrogesterone is used at a dose of 20 mg / day or micronized progesterone vaginally at a dose of 200 mg / day. Treatment is carried out on the 2nd day after ovulation (the day after the rectal temperature increase) and lasts 10 days. At the onset of pregnancy treatment with progesterone drugs should be continued.

Modern studies have not confirmed the effectiveness of human chorionic gonadotropin in the treatment of habitual miscarriage.

When hyperandrogenism (ovarian or adrenal origin) in patients with habitual miscarriage of pregnancy is shown drug treatment due to the effect of androgens on the usefulness of ovulation and the state of the endometrium. If the biosynthesis of adrenal androgens is disturbed, their virilizing effect on the female fetus is possible, so steroid therapy is carried out in the interests of the fetus.

[6], [7], [8]

Hyperandrogenia of ovarian genesis (polycystic ovaries)

Anamnesis, results of physical and special examination

• Anamnesis: later menarche, disorder of the menstrual cycle according to the type of oligomenorrhoea (more often primary, less often secondary). Pregnancy rarely occurs, as a rule, spontaneously interrupt in the first trimester, between pregnancies, long periods of infertility.
• Inspection: hirsutism, acne, striae, high body mass index (not necessarily).
• Graphs of rectal temperature: anovulatory cycles alternate with cycles with ovulation and NLF.
• Hormonal examination: high testosterone level, FSH and LH levels may increase, the ratio of LH / FSH is greater than 3. AU: polycystic ovaries.

Treatment

Non-drug treatment

Decreased body weight - diet therapy, exercise.

Medication

• Orlistat in a dose of 120 mg with each main meal. The duration of the course is determined by taking into account the effect and tolerability.
• Preliminary decrease in testosterone level with drugs containing cyproterone acetate (2 mg) and EE (35 μg), during 3 menstrual cycles.
• Cancellation of the contraceptive, hormonal support of the second phase of the cycle (gestagen therapy) - dydrogesterone at a dose of 20 mg / day from the 16th to the 25th day of the menstrual cycle. In the absence of self-ovulation, the next step is taken.
• Stimulation of ovulation clomiphene citrate at the initial dose of 50 mg / day from the 5th to the 9th day of the menstrual cycle with simultaneous therapy with gestagens (dydrogesterone at a dose of 20 mg / day from the 16th to the 25th day of the cycle) and dexamethasone (0, 5 mg).
• In the absence of pregnancy, the dose of clomiphene citrate is increased to 100-150 mg / day with the administration of gestagens in the second phase of the cycle and dexamethasone (0.5 mg). It was found that, although dexamethasone only lowers the level of adrenal androgens, ovulation and conception occur significantly more often with clomiphene citrate and dexamethasone than with clomiphene citrate alone [12].
• 3 cycles of stimulation of ovulation are carried out, after which a break is recommended during 3 menstrual cycles with gestagenic support and decision of the question of operative treatment with laparoscopic access (wedge resection of ovaries, laser vaporization).

Further management of the patient

Conducting pregnancy should be accompanied by gestational support up to 16 weeks gestation (dydrogesterone at a dose of 20 mg / day or micronized progesterone at a dose of 200 mg / day), dexamethasone is prescribed only in the I trimester of pregnancy. Monitoring is necessary for the timely diagnosis of ischemic-cervical insufficiency and, if necessary, its surgical correction.

Adrenal hyperandrogenism (pubertal and post-pubertal adrenogenital syndrome)

Adrenogenital syndrome (ACS) is a hereditary disease associated with a violation of the synthesis of adrenal cortex hormones due to the defeat of genes responsible for the synthesis of a number of enzyme systems. The disease is inherited autosomally-recessively with the transfer of mutant genes from both parents who are healthy carriers.

In 90% of cases adrenogenital syndrome is caused by mutations in the gene CYP21B, leading to a violation of the synthesis of 21-hydroxylase.

Anamnesis, results of physical and special examination

• Anamnesis: later menarche, the menstrual cycle is somewhat elongated, oligomenorrhoea is possible, spontaneous interruptions of pregnancies in the first trimester, there may be infertility.
• Inspection: acne, hirsutism, android type of build (broad shoulders, narrow pelvis), clitoral hypertrophy.
• Graphs of rectal temperature: anovulatory cycles alternate with cycles with ovulation and NLF.
• Hormonal research: high level of 17-OP, DHEAS.
• Ultrasound: the ovaries are not changed.

The pathognomonic sign outside of pregnancy is an increase in the concentration in the blood plasma of 17-OP.

At present, a test with ACTH is performed to diagnose the latent, non-classical form of adrenal hyperandrogenism. For this sample synaktene is used - a synthetic polypeptide with the properties of endogenous ACTH, i.e. Stimulating in the adrenal glands the initial phases of the synthesis of steroid hormones from cholesterol.

Sinakten assay (ACTH analogue): subcutaneously injected into the shoulder 1 ml (0.5 mg) of synapture, preliminary determine the initial content of 17-OP and cortisol in the morning 9-hour blood plasma sample. Blood sampling is performed 9 hours after the injection to determine the level of 17-OP and cortisol. Further, the determination index ( D ) is calculated by the formula:

D = 0.052 × 17-OP + 0.005 × Cortisol / 17-OP-0.018 × Cortisol / 17-OP

If the coefficient D is less than or equal to 0.069, this indicates that there is no adrenal hyperandrogenism. With a coefficient D of more than 0.069, it should be assumed that hyperandrogenism is caused by a disorder in the adrenal function.

Medication

The basis for the treatment of hyperandrogenism due to deficiency of 21-hydroxylase is glucocorticoids, which are used to suppress excessive secretion of androgens.

Further management of the patient

In connection with the virilizing effect of the mother's androgen on the fetus with the established diagnosis of adrenal hyperandrogenism, dexamethasone treatment at an initial dose of 0.25 mg is prescribed before the onset of pregnancy and is continued at an individually selected dose (0.5 to 1 mg) throughout the pregnancy. In a woman with a habitual miscarriage of pregnancy, suffering from adrenal hyperandrogenism, it is inadvisable to cancel treatment, as the incidence of miscarriages in the absence of treatment reaches 14%, with the continuation - 9%.

Considering the fact that patients with adrenogenital syndrome can transmit this gene to the fetus, prenatal diagnosis is necessary: in 17-18 weeks of pregnancy, a mother's blood test is prescribed to determine the content of 17-OP. With an elevated level of the hormone in the blood determine its concentration in the amniotic fluid. If the content of 17-OP in the amniotic fluid is increased, adrenogenital syndrome in the fetus is diagnosed. Unfortunately, in terms of the level of 17-OP in the amniotic fluid it is impossible to determine the degree of severity of adrenogenital syndrome (mild or solitary heavy form). The issue of maintaining a pregnancy in this situation is decided by the parents.

If the father of the child is the carrier of the adrenogenital syndrome gene and there were cases of the birth of children with this syndrome in the family, the patient even without adrenal hyperandrogenism receives dexamethasone in the interest of the fetus (to prevent virilization of the female fetus) at a dose of 20 μg / mg / day in 2-3 receptions after a meal. At 17-18 weeks after the decision on the sex of the fetus and the expression of the gene adrenogenital syndrome (according to the results of amniocentesis) treatment continues until the end of pregnancy, if the fetus is a girl with adrenogenital syndrome. If the fetus is a boy or a girl who is not a carrier of the adrenogenital syndrome gene, dexamethasone can be withdrawn.

If a woman with a habitual miscarriage of pregnancy suffers adrenal hyperandrogenism, then treatment with dexamethasone is carried out throughout the pregnancy and is only revoked after childbirth. On the 3rd day after birth, the dose of dexamethasone is gradually reduced (by 0.125 mg every 3 days) until complete withdrawal in the postpartum period.

[9], [10], [11]

Hyperandrogenism of mixed genesis (ovarian and adrenal)

Anamnesis, results of physical and special examination

• Anamnesis: later menarche, menstrual irregularity in the type of oligomenorrhoea (more often primary, less often secondary), amenorrhea, traumas, concussions of the brain are possible. Pregnancy rarely occurs, as a rule, spontaneously interrupt in the first trimester, between pregnancies, long periods of infertility.
• Physical examination: hirsutism, acne, striae, acanthosis nigricans, high body mass index, arterial hypertension.
• Graphs of rectal temperature: anovulatory cycles alternate with cycles with ovulation and NLF.
• Hormonal examination: high testosterone, FSH and LH levels may be increased, the ratio of LH / FSH greater than 3, high level of DHEAS, 17-OP, may be hyperprolactinaemia.
• Ultrasound: polycystic ovaries.
• Electroencephalography: changes in brain bioelectrical activity.
• Hyperinsulinemia, lipid metabolism disorder (high cholesterol, low and very low density lipoproteins), decreased glucose tolerance or elevated blood glucose levels.

Treatment

Non-drug treatment

Decreased body weight (low-calorie diet, physical activity).

Medication

The first stage - in the presence of insulin resistance, recommend the appointment of metformin in a daily dose of 1000-1500 mg to increase the sensitivity to insulin.

The second stage - with pronounced violations of the menstrual cycle and high testosterone level shows the appointment of drugs with antiandrogenic effect, containing cyproterone acetate (2 mg) and ethinylestradiol (35 μg), for 3 months.

The third stage is the stimulation of ovulation with subsequent gestagen support (the scheme is described above) and the use of dexamethasone in a daily dose of 0.25-0.5 mg.

With hyperprolactinaemia and hypothyroidism, appropriate medication correction should be performed in cycles of ovulation stimulation. At the onset of pregnancy, bromocriptine should be canceled, taking levothyroxine is continued.

With ineffective stimulation of ovulation, the question of the appointment of direct inducers of ovulation, the desirability of surgical treatment of polycystic ovaries or in vitro fertilization should be resolved.

Further management of the patient

In patients with metabolic syndrome, pregnancy often complicates arterial hypertension, nephropathy, hypercoagulation, in connection with which blood pressure control, hemostasiograms from early pregnancy and correction of emergent disorders (if necessary) with antihypertensive drugs, antiaggregants and anticoagulants are mandatory. The gestagenic drugs are prescribed up to 16 weeks gestation - didrogesterone at a dose of 20 mg / day or micronized progesterone at a dose of 200 mg / day in 2 divided doses.

All women with hyperandrogenia represent a risk group for development of ischemic-cervical insufficiency. Monitoring of the cervical status should be performed from the 16th week of pregnancy, if necessary, surgical correction of ischemic-cervical insufficiency.

Immunological causes of habitual miscarriage

It is now known that about 80% of all previously unexplained cases of repeated loss of pregnancy (after the exclusion of genetic, anatomical, hormonal causes) is associated with immune disorders. Isolate autoimmune and alloimmune disorders, leading to a habitual miscarriage of pregnancy.

In autoimmune processes, the subject of aggression of the immune system is the tissues of the mother's body, i.e. There is a directionality of the immune response against its own antigens. In this situation, the fetus suffers again as a result of damage to the maternal tissues.

In alloimmune disorders, the immune response of a woman is directed against the embryo / fetal antigens obtained from the father and potentially foreign to the mother's body.

The autoimmune disorders most often encountered in patients with a habitual miscarriage include the presence of anti-typhospholipid, antithyroid, antinuclear autoantibodies in the serum. Thus, it is established that 31% of women with habitual miscarriage outside pregnancy have autoantibodies to thyroglobulin, thyroid peroxidase (thyroid microsomal [thyroid peroxidase] autoantibodies); in these cases, the risk of spontaneous miscarriage in the first trimester of pregnancy increases to 20%. With habitual miscarriages of pregnancy, the presence of antinuclear and anti-thyroid antibodies indicates the need for further examination to identify the autoimmune process and verify the diagnosis.

A generally recognized autoimmune condition leading to the death of the embryo / fetus is currently the antiphospholipid syndrome (APS).

Alloimmune disorders

Currently, alloimmune processes leading to rejection of the fetus include the presence in spouses of an increased (more than 3) amount of common antigens of the system of the main histocompatibility complex (often observed in related marriages); low level of blocking factors in the mother's serum; increased content of natural killer cells (NK cells CD56, CD16) in the endometrium and peripheral blood of the mother both outside and during pregnancy; high concentration levels of a number of cytokines in the endometrium and serum, in particular, y-interferon, tumor necrosis factor a, interleukins-1 and 2.

Currently, alloimmune factors leading to early pregnancy loss, and ways to correct the above conditions, are under study. There is no consensus on the methods of therapy. According to some researchers, active immunization with donor lymphocytes does not have a significant effect, other authors describe a significant positive effect with such immunization and treatment with immunoglobulins.

Currently, one of the immunomodulating agents in the early stages of pregnancy is progesterone. In particular, studies have demonstrated the role of dydrogesterone in a daily dose of 20 mg in women with a habitual miscarriage in the first trimester of pregnancy with an increased level of CD56 cells in the endometrium.

[12], [13], [14], [15], [16], [17]

Genetically determined thrombophilia

Thrombophilic conditions during pregnancy leading to habitual miscarriage include the following forms of genetically determined thrombophilia.

• Deficiency of antithrombin III.
• Mutation factor V (Leiden's mutation).
• Deficiency of Protein C.
• Deficiency of Protein S.
• Mutation of the prothrombin gene G20210A.
• Hyperhomocysteinemia.

A survey to identify rare causes of thrombophilia is necessary in cases that have been:

• in a family history - thromboembolism at the age of 40 years from relatives;
• reliable episodes of venous and / or arterial thrombosis at the age of up to 40 years;
• recurrent thromboses in the patient and the next of kin;
• thromboembolic complications during pregnancy and after childbirth when using hormonal contraception;
• repeated loss of pregnancy, stillbirth, intrauterine growth retardation, placental abruption;
• early onset of pre-eclampsia, HELLP-syndrome.

Infectious causes of habitual miscarriage

The role of the infectious factor as a cause of habitual miscarriage is now widely debated. It is known that with primary infection in early pregnancy, incompatible life with embryo damage is possible, which leads to sporadic spontaneous miscarriage. However, the probability of reactivation of the infection in the same period with the outcome in repeated loss of pregnancy is negligible. In addition, microorganisms that provoke a habitual miscarriage are not found at present. Recent studies have shown that in most women with a habitual miscarriage and the presence of chronic endometritis, the prevalence in the endometrium of 2-3 or more species of obligate anaerobic microorganisms and viruses is noted.

According to V.M. Sidelnikova et al., In women with habitual miscarriage, out of pregnancy, the diagnosis of chronic endometritis was histologically verified in 73.1% of cases and in 86.7% the persistence of opportunistic microorganisms in the endometrium was observed, which certainly can trigger the activation of immunopathological processes . Mixed persistent viral infection (herpes simplex virus, Coxsackie A, Coxsackie B, enteroviruses 68-71, cytomegalovirus) is significantly more common in patients with a habitual miscarriage than in women with normal obstetric anamnesis. K. Kohut et al. (1997) showed that the percentage of inflammatory changes in the endometrium and decidual tissue in patients with primary habitual miscarriage is significantly higher than in women after a miscarriage with at least one timely delivery in the anamnesis.

Bacterial viral colonization of the endometrium becomes, as a rule, a consequence of the inability of the immune system and the nonspecific protective forces of the body (complement system, phagocytosis) to completely eliminate the infectious agent, and at the same time there is a restriction of its spread due to the activation of T-lymphocytes (T- natural killers) and macrophages. In all the cases listed above, a persistence of microorganisms arises, characterized by the involvement of mononuclear phagocytes, natural killers, T-helpers synthesizing various cytokines into the focus of chronic inflammation. Apparently, this state of the endometrium prevents the creation of local immunosuppression in the preimplantation period, which is necessary to form a protective barrier and prevent the rejection of a half-foreign fetus.

In this connection, pregnancy in women with habitual miscarriage should be excluded from the diagnosis of chronic endometritis. To establish or exclude this diagnosis, endometrial biopsy is used on the 7-8th day of the menstrual cycle with histological examination, PCR, and bacteriological examination of the material from the uterine cavity. When verifying the diagnosis, chronic endometritis is treated according to the standards for the treatment of pelvic inflammatory disease.