RU2465589C1 - Method for prediction of missed miscarriage - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention may be used for prediction of missed miscarriage; blood of pregnant women is examined for the concentrations of tumour necrosis factor alpha (TNFα), interleukin 1 beta (IL 1β), interleukin 6 (IL6). It is added with determining the lymphocyte CD95+(L CD95+) count, the level of fertility alpha-2-microglobulin (FAMB), the concentration of placenta growth factor (PGF) and total IgE. If the values are appeared to be as follows: the concentration of TNFα (pkg/ml) - 294±39.5; the concentration of IL 1β (pkg/ml) -588+46.; the concentration of IL6 (pkg/ml) - 85.2+13.1; the L CD95+ count (%) -14.1±5.2; the level of FAMB (ng/ml) - 215+42; the level of PGF (pkg/ml) - 21±6.2; the content of total IgE (pkg/ml) - 68±24, missed miscarriage is predicted.

EFFECT: method is non-invasive, safe for woman and foetus health, accessible; it ensures higher prediction accuracy for missed miscarriage.

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Description

Currently, there is an increase in the frequency of an undeveloped pregnancy. The risk of developing an undeveloped pregnancy (failed abortion) increases significantly with the activation of the infectious process in a pregnant woman, the presence of immunodeficiency states, genetically determined thrombophilia, the development of auto- and alloimmune processes, impaired immunobiological gestational tolerance [Dobrokhotova Yu.E., Ozerova RI, Mandrykina Zh.A., Rora L.S. Some aspects of the etiology and pathogenesis of embryonic loss in the first trimester of gestation. Russian Bulletin of the Obstetrician-Gynecologist. - 2008. - No. 5. - S.15-18].

The current level of obstetrics currently excludes the possibility of reliable prediction of an undeveloped pregnancy due to the similarity of risk factors for the development of this pathological condition and other complications of gestation (threatened abortion, spontaneous miscarriage, chronic placental insufficiency) [Sidorova IS, Makarov I.O. The course and management of pregnancy in the trimesters. M .: MIA, 2007. - P.85-86].

The diagnosis of an undeveloped pregnancy is made only in the presence of a fait accompli of the death of the embryo [Kulavsky V.A., Syrtlanov I.R., Frolov A.L. Features of the course of pregnancy in women who had a history of undeveloped pregnancies and fetal death at different gestational periods. Journal of Obstetrics and Women's Diseases. - 2007. - No. 3. - S. 107-112].

In recent years, the immunological aspects of the development of an undeveloped pregnancy have become particularly relevant. Much attention is paid to the study of the cytokine profile at the systemic and local level [Dobrokhotova Yu.E., Jobava EM, Ozerova RI Non-developing pregnancy. M .: Geotar-Media, 2010. - S. 37-44].

It is believed that one of the mechanisms that prevent unwanted immune reactions at the interface between the mother and the fetus is trophoblast-induced lymphocyte apoptosis [Talayev V.Yu., Babaykina ON, Lomunova MA et al. The effect of cyto- and syncytiotrophoblast of human placenta on apoptosis of lymphocytes. Immunology. - 2005. - No. 3. - S.132-138].

The early mechanisms of regulation of reactions caused by the action of a damaging agent on the fetoplacental complex are associated with a change in the functions of immunocompetent cells that are realized through the action of pro-inflammatory and anti-inflammatory cytokines. Subsequently, with an increase in the alternative-exudative processes, a significant change in the ratio of immune factors occurs with an increase in the pro-inflammatory link with an imbalance of anti-inflammatory interleukins. To reduce the functional aggression of activated lymphocytes by trophoblast, apoptosis of immunocompetent cells is induced [Makatsaria AD, Bitsadze V.O., Aniskina S.V. Syndrome of a systemic inflammatory response in obstetrics. M .: MIA, 2006. - S.305-346].

A known method for predicting the threat of miscarriage by analyzing risk factors with determining a threshold coefficient [Mozheiko LF, Tikhonenko IV Scale of the threat of miscarriage. Ministry of Health of the Republic of Belarus. Minsk, 2009].

In the known forecasting method, the assessment of the identified risk factors is carried out with the calculation of the threshold coefficient, which is used to judge the degree of risk of miscarriage in the first trimester of gestation.

The disadvantage of this method is the inability to isolate in the general group of women at risk of miscarriage of pregnant women who are threatened by an undeveloped pregnancy, which reduces the prognostic accuracy of this method.

A known method for predicting an undeveloped pregnancy by using ultrasound of the fetal egg and extraembryonic formations [Volkov A.E. Ultrasound diagnostics in obstetrics and gynecology (practical guide). Rostov-on-Don: Phoenix, 2009. - P.26-31].

In the known method for predicting an undeveloped pregnancy by ultrasound examination of the fetal egg, embryo, yolk sac, amnion and chorion cavity, cyst of the corpus luteum of the ovary, ultrasound criteria for impaired development of the fetal egg are revealed in the form of: no image of the embryo with an average internal diameter of the fetal egg of 14 mm or more, the absence of the yolk sac with sizes of an average inner diameter of the ovum of more than 10 mm, abnormal vascularization of the yolk sac, consisting in the register ation only venous blood flow, premature disappearance of the yolk sac to 10 weeks of gestation, hypoplasia amnionalnoy cavity, absence of corpus luteum cysts in the ovaries. If available, they judge the possible development of an undeveloped pregnancy in the first trimester of gestation.

The disadvantage of this method is the low accuracy of prediction of an undeveloped pregnancy due to the lack of informativeness of ultrasound criteria, the lack of their specificity, the possibility of their registration in other pregnancy complications (threatened abortion, spontaneous miscarriage) and developmental anomalies of the ovum.

A known method for predicting a non-developing pregnancy by evaluating embryotropic autoantibodies [Radzinsky V.E., Dimitrova V.I., Mayskova I.Yu. Non-developing pregnancy. M .: Geotar-Media, 2009. - P.75-78].

In the known method for predicting an undeveloped pregnancy using the ELI-P test (ELISA-detected Probability of pathology in Pregnancy, 1998), the serum content of natural regulatory autoantibodies is determined. The level of detected embryonic autoantibodies assess the state of immunoreactivity of the examined pregnant woman. Three types of immunoreactivity are distinguished: hyporeactivity (less than 15% of embryonic autoantibodies), normoreactivity (15-20%), hyperreactivity (more than 20%). With an undeveloped pregnancy, hyporeactivity was observed in 47.9% of pregnant women, and in 33.8% normoreactivity was determined.

The disadvantage of this method is the low accuracy of prediction of an undeveloped pregnancy due to the fact that with an undeveloped pregnancy all three types of immunoreactivity can occur. Thus, personified decision-making on assigning a woman to a high-risk group for developing an undeveloped pregnancy is significantly difficult.

Closest to the claimed is a method for predicting an undeveloped pregnancy by registering in the blood of women at early stages of gestation levels of pro-inflammatory cytokines by the enzyme immunoassay [Tirskaya Yu.I., Rudakova EB, Shakina IA, Pilinenko MA, Poltorak E .A., Lyubavina A.E. Fetal Loss Syndrome. Therapist. - 2009. - No. 11. - S.19-23].

In this method for predicting an undeveloped pregnancy, the concentration of cytokines, tumor necrosis factor alpha, interleukin 1 betta, interleukin 6, is determined in pregnant women’s blood serum, and a possible development of an undeveloped pregnancy is judged by deviations from the norm.

The disadvantage of this closest to the claimed method is the low accuracy of prediction of an undeveloped pregnancy due to the unidirectional changes in the proposed indicators for various clinical variants of miscarriage, that is, both with spontaneous miscarriage and with an undeveloped pregnancy, which makes it difficult to predict a non-developing pregnancy. This method does not take into account an integrated approach to assessing various pathogenetic links of an undeveloped pregnancy, namely, the general biological property of the choroid of the fetal egg (chorion - the fetal part of the placenta) as the induction of apoptosis of immunocompetent cells, the state of the endometrium of the uterine cavity (decidual membrane - the maternal part of the placenta) and an additional assessment of the degree of vascular endothelial disorders to the assessment of the level of interleukins.

The problem solved by the invention is a method for predicting an undeveloped pregnancy.

The technical result is to increase the accuracy of forecasting. The specified technical result is achieved by the fact that in the method for predicting an undeveloped pregnancy by determining in pregnant women serum levels of tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL 1β), interleukin 6 (IL 6), an additional determination is made of the content of the apoptosis marker - lymphocytes with phenotype CD95 + (L CD95 +), a marker of the functional activity of the decidual membrane - alpha-2-microglobulin fertility (AMHF), markers of vascular endothelial dysfunction - placental growth factor (FRF), total immunoglobin Uline E (IgE). When these indicators change compared with the norm, a non-developing pregnancy is predicted.

A method for predicting an undeveloped pregnancy is as follows.

A pregnant woman is examined taking into account the revealed significant differences in the studied parameters during a physiologically ongoing pregnancy, with the development of a spontaneous miscarriage and with an undeveloped pregnancy. All laboratory parameters are determined in the venous blood of a pregnant woman taken on an empty stomach.

The survey is carried out by determining:

- concentration of tumor necrosis factor alpha (TNFα);

- concentrations of interleukin 1 betta (IL 1β);

- concentrations of interleukin 6 (IL 6);

- lymphocyte counts CD95 + (L CD95 +);

- concentrations of alpha-2-microglobulin fertility (AMHF);

- the level of placental growth factor (FRP);

- concentrations of total IgE.

The above data were obtained when determining the concentration of TNFα, IL 1β, IL 6, FRP, total IgE in the blood serum by enzyme-linked immunosorbent assay using the reagent kit LLC Protein circuit (St. Petersburg, Russia); identification of the lymphocyte phenotype (CD95 +) was carried out by the standard method of immunofluorescence analysis using monoclonal antibodies to the surface antigen CD 95 of human lymphocytes and FITS-labeled Fab fragments of anti-mouse immunoglobulins produced by NPF MedBioSpektor (Russia); alpha-2-microglobulin fertility was determined in blood serum by enzyme-linked immunosorbent assay using diagnostic kits "AMGF-Fertitest" developed at the Research Institute of Human Morphology RAMS.

Laboratory parameters are presented according to different variants of the course of pregnancy.

In the first trimester of physiological pregnancy, the above parameters had the following quantitative characteristics:

- tumor necrosis factor alpha (PCG / ml) - 42.4 ± 10.1;

- interleukin 1 betta (PCG / ml) - 328 ± 27.2;

- interleukin 6 (PCG / ml) - 9.8 ± 3.4;

- the content of lymphocytes CD95 + (%) - 30.2 ± 4.3;

- alpha-2-microglobulin fertility (ng / ml) - 926 ± 127;

- placental growth factor (PCG / ml) - 105 ± 8.6;

- total IgE (PCG / ml) - 232 ± 22.

For the first trimester of pregnancy, ending in spontaneous miscarriage, the following indicators are characteristic:

- tumor necrosis factor alpha (PCG / ml) - 182 ± 26.3;

- interleukin 1 betta (PCG / ml) - 405 ± 32.6;

- interleukin 6 (PCG / ml) - 54.1 ± 10.3;

- the content of lymphocytes CD95 + (%) - 46.5 ± 6.9;

- alpha-2-microglobulin fertility (ng / ml) - 463 ± 89;

- placental growth factor (PCG / ml) - 63 ± 7.1;

- total IgE (PCG / ml) - 408 ± 49.

For the first trimester of pregnancy ending in a non-developing pregnancy, the following indicators are characteristic:

- tumor necrosis factor alpha (PCG / ml) - 294 ± 39.5;

- interleukin 1 betta (PCG / ml) - 588 ± 46.3;

- interleukin 6 (PCG / ml) - 85.2 ± 13.1;

- the content of lymphocytes CD95 + (%) - 14.1 ± 5.2;

- alpha-2-microglobulin fertility (ng / ml) - 215 ± 42;

- placental growth factor (PCG / ml) - 21 ± 6.2;

- total IgE (PCG / ml) - 68 ± 24.

Example 1. Pregnant K., 24 years old, registered at the place of residence in the antenatal clinic of the city clinic with a diagnosis of:

Pregnancy II, 4-5 weeks. Chronic salpingo-oophoritis in remission. Ectopia of the cervix. A burdened obstetric and gynecological history.

Among the diseases noted chickenpox and measles rubella in childhood, SARS 2 times a year. Extragenital diseases are absent. Tuberculosis, syphilis, viral hepatitis denies. Denies bad habits. Gynecological diseases: ectopia of the cervix from 19 years; acute salpingo-oophoritis at the age of 20, outpatient treatment with a positive effect. Parity: the first pregnancy ended in a non-developing pregnancy in the period of 8 weeks at 22 years old, instrumental curettage of the uterus was performed. Surveys to identify the causes of non-developing pregnancy have not been conducted. Contraception - a condom, interrupted sexual intercourse. The husband is healthy. At the local obstetrician-gynecologist was observed irregularly. No pre-test preparation was carried out. Pregnancy occurred spontaneously for 3 months without contraception. A complete clinical and laboratory examination was carried out upon registration - the indicators corresponded to the "pregnancy rate". Laboratory examination for predicting the development of a non-developing pregnancy: serum TNFα level - 48.3 pcg / ml; IL 1β - 321.8 pg / ml; IL 6 - 10.5 PCG / ml; the content of lymphocytes CD95 + - 32.7%; AMHF - 829 ng / ml; FRP - 99.3 pg / ml; total IgE - 219 pg / ml. The indicators corresponded to the physiological norm. She took the Vitrum Prenatal forte vitamin and mineral complex.

In the dynamics of observation after 2 weeks (with a gestational age of 6-7 weeks), a survey was conducted to predict the development of an undeveloped pregnancy: TNFα level - 265.1 pcg / ml; IL 1β - 602.5 pg / ml; IL 6 - 79.4 pg / ml; the content of lymphocytes CD95 + - 10.3%; AMHF - 237.6 ng / ml; FRP - 19.8 pg / ml; total IgE - 76 pg / ml. According to the ultrasound examination, deviations during pregnancy were not noted. Given the results of the examination - a high risk of developing an undeveloped pregnancy in the absence of clinical and ultrasound signs of complications of gestation, it was decided to conduct a pregnant woman on an outpatient basis. Prescribed antioxidant (vitamin E), metabolic (folic acid), sedative (valerian) hormone therapy (duphaston).

An ultrasound scan of the pelvic organs was performed during the gestational age of 9-10 weeks. A non-developing pregnancy was diagnosed. A woman has been hospitalized in the gynecological department for abortion. Abortion was performed by curettage of the uterine cavity, without complications. Histological examination of abortive material confirmed the diagnosis of “non-developing pregnancy”.

Clinical example: in this clinical example, a pregnant woman, in the absence of clinical signs of gestational complications, developed an undeveloped pregnancy. Moreover, the estimated indicators 3 weeks before the clinical implementation of the pathological process corresponded to: TNFα level - 265.1 pcg / ml; IL 1β - 602.5 pg / ml; IL 6 - 79.4 pg / ml; the content of lymphocytes CD95 + - 10.3%; AMHF - 237.6 ng / ml; FRP - 19.8 pg / ml; total IgE - 76 PCG / ml and, according to the proposed method for predicting an undeveloped pregnancy, indicated a high risk of developing failed abortion.

Example 2. Pregnant P., 27 years old, registered at the place of residence in the women's consultation of the city clinic with a diagnosis of

Pregnancy III, 5-6 weeks. Chronic genital herpetic infection. A burdened obstetric and gynecological history.

Of the past illnesses, SARS, mumps in childhood. Tuberculosis, syphilis, viral hepatitis denies. An allergic history without features. No bad habits have been identified. Extragenital diseases are absent. Gynecological diseases: chronic salpingo-oophoritis, last exacerbation a year and a half ago, outpatient treatment in a day hospital. Parity: the first pregnancy at age 21 ended in medical abortion for a period of 7-8 weeks, without complications; the second - at 25 years of an undeveloped pregnancy of 11 weeks against the background of the first clinical episode of primary genital herpes (vesicle grouped rashes in the genital area, accompanied by burning and itching, low-grade fever), confirmed by positive PCR for scraping the cervical canal epithelium and IgM 1 antibody titer: 400 in the absence of IgG. In the post-abortion period, additional examination (control of antibody titers of IgM and IgG classes) and treatment (antiviral, immunomodulating, metabolic therapy) were performed. In the control analyzes conducted after 6 months, positive dynamics were noted: IgM titer 1: 200, IgG 1: 800, PCR scraping of the cervical canal epithelium negative; after 9 months, only IgG class titers of 1: 400 remained elevated.

Before the onset of true pregnancy, there were no clinical manifestations of herpes infection. When taking pregnancy records for a period of 5-6 weeks in a complex of generally accepted clinical and laboratory examinations, a study was made of the estimated parameters for predicting an undeveloped pregnancy. The level of TNFα was 163.5 PCG / ml; IL 1β - 381.6 pg / ml; IL 6 - 47.6 pg / ml; L CD95 + - 41.2%; AMHF - 509 ng / ml; FRP - 68.5 pcg / ml; total IgE - 376 pg / ml, which corresponded, according to the recommended forecasting method, to a high risk of spontaneous miscarriage. Preventive treatment was prescribed, including antispasmodics, Magne-B6, human recombinant interferon alpha-2.

In the gestational age of 7-8 weeks, a second study was conducted: the level of TNFα was 204.1 PCG / ml IL 1β - 431.2 pg / ml; IL 6 - 62.9 pkg / ml; L CD95 + - 50.8%; AMHF - 425 ng / ml; FRP - 59.4 pg / ml; total IgE - 437 pg / ml. The survey results showed a negative dynamics of prognostic indicators, the absence of the effect of preventive treatment and an increased risk of spontaneous miscarriage. Given the absence of clinical and ultrasonic manifestations of the threat of abortion, the preventive treatment consisted of antioxidants, small doses of acetylsalicylic acid and magnesium-B6. Despite the ongoing therapy, after 3 weeks in a period of 10-11 weeks, spontaneous abortion occurred. The postabortion period was uneventful. Histological examination confirmed the diagnosis of “spontaneous miscarriage”.

Clinical example: in this clinical example, a pregnant woman has a miscarriage. Estimated prognostic indicators for 5 and 3 weeks before a spontaneous miscarriage corresponded: the level of TNFα (PCG / ml) was 163.5 and 204.1; IL 1 (3 (PCG / ml) - 381.6 and 431.2; IL 6 (PCG / ml) - 47.6 and 62.9; L CD95 + (%) - 41.2 and 50.8; AMGF ( ng / ml) - 509 and 425; FRP (PCG / ml) - 68.5 and 59.4; total IgE (PCG / ml) - 376 and 437 (5-6 weeks and 7-8 weeks of gestation, respectively), which , according to the recommended forecasting method, despite the preventive treatment being carried out, indicated a high risk of spontaneous miscarriage.

Example 3. Pregnant L., 32 years old, got registered on pregnancy at the antenatal clinic with a diagnosis of

Pregnancy IV, 3-4 weeks. Mixed neurocirculatory dystonia. Varicose disease of the lower extremities. A burdened obstetric and gynecological history.

From the anamnesis: annually ARVI, does not remember childhood infections; tuberculosis, syphilis, viral hepatitis denies. An allergic history without features. Bad habits are smoking (up to 10 cigarettes per day). Mixed type NDC since 20 years. Varicose disease of the lower extremities for 5 years, drug and surgical treatment was not carried out. Gynecological diseases - cervical ectopia (cryodestruction with a positive effect in 28 years). The husband is healthy. Contraception is a condom. Parity: the first pregnancy at age 23 ended in medical abortion; the second pregnancy at age 25 ended in spontaneous miscarriage in the period of 6-7 weeks; the third pregnancy at 29 years ended in a non-developing pregnancy in the period of 7-8 weeks. After an undeveloped pregnancy, an examination was conducted to identify its causes. Antiphospholipid antibodies were detected in the blood. For the treatment of antiphospholipid syndrome, small doses of glucocorticoids, small doses of aspirin, normal human immunoglobulin, and fraksiparin were prescribed. After 1 year, a control examination showed no antiphospholipid antibodies in the blood. Real pregnancy planned. Three months before pregnancy, a complete clinical and laboratory examination was performed. Deviations of laboratory parameters were not detected. It was recommended to quit smoking, a complex of vitamins and minerals. I registered for pregnancy in the early stages of gestation (3-4 weeks). The results of the examination for predicting an undeveloped pregnancy: the level of TNFα was 278.3 PCG / ml; IL 1β - 563.4 pg / ml; IL 6 - 79.6 PCG / ml; L CD95 + - 19.1%; AMHF - 250 ng / ml; FRP - 26.8 pg / ml; total IgE - 79.5 pg / ml. The reaction to lupus anticoagulant is weakly positive (+). The data obtained indicate a high risk of developing an undeveloped pregnancy.

For the prevention of non-developing pregnancy and treatment of antiphospholipid syndrome, fraxiparin, wobenzym, chimes, magne-B6 were prescribed.

Examination data after 3 weeks in the gestational age of 6-7 weeks: the level of TNFα was 310.2 PCG / ml; IL 1β - 595.7 pg / ml; IL 6 - 91.5 PCG / ml; L CD95 + - 18.9%; AMHF - 233 ng / ml; FRP - 25.4 pg / ml; total IgE - 71.6 pcg / ml, which indicates a continuing high risk of developing an undeveloped pregnancy. The reaction to lupus anticoagulant is moderately severe (++). Clinically, pregnancy was uneventful. The treatment was continued, in addition, given the negative dynamics of laboratory parameters, small doses of glucocorticoids were prescribed.

After 3 weeks in the gestational age of 9-10 weeks, the next examination was conducted: the level of TNFα was 49.5 pcg / ml; IL 1β - 341.2 pg / ml; IL 6 - 11.3 PCG / ml; L CD95 + - 27.4%; AMHF - 819 ng / ml; FRP - 98.8 PCG / ml; total IgE - 216 pg / ml, which indicates the compliance of prognostic parameters with the physiological norm of pregnancy. The reaction to lupus anticoagulant is negative. Clinically, pregnancy was uneventful. After 3 weeks during the clinical and laboratory examination, deviations from the physiological course of pregnancy were not detected. Given the high risk of developing chronic placental insufficiency in a pregnant woman with varicose veins with a preventive goal, diosmin 600 mg 2 times a day was prescribed from 14-15 weeks - 2 courses of 4 weeks with an interval of 8 weeks. The pregnant woman regularly visited the antenatal clinic, carried out all the medical recommendations for examination and treatment. It was delivered at 39 weeks of gestation by cesarean section according to the totality of indications: an obstetric history burdened by the fetal loss syndrome, a primipara of an older age. A lively mature girl was born with a body weight of 3000 g and a length of 50 cm. The postoperative period in the mother and the period of early adaptation in the newborn baby proceeded without features. The result of histological examination of the placenta: the degree of maturity of the placenta corresponds to gestational age, involutive-dystrophic changes.

Clinical example conclusion: in this clinical example, a pregnant woman against the background of antiphospholipid syndrome from early terms showed prognostic indicators characteristic of a high risk of developing an undeveloped pregnancy, respectively 3-4 weeks and 6-7 weeks of pregnancy: the level of TNFα (PCG / ml) was 278.3 and 310.2; IL 1β (PCG / ml) - 563.4 and 595.7; IL 6 (PCG / ml) - 79.6 and 91.5; L CD95 + (%) - 19.1 and 18.9; AMHF (ng / ml) - 250 and 233; FRP (PCG / ml) - 26.8 and 25.4; total IgE (PCG / ml) - 79.5 and 71.6. After 6-7 weeks (in the period of 9-10 weeks of pregnancy) after the start of treatment with antiphospholipid syndrome as a probable cause of an undeveloped pregnancy, normalization of the estimated parameters was noted, which indicates, according to the proposed forecasting method, that there is no risk of developing an undeveloped pregnancy. A clinical example demonstrates the possibilities of preventive treatment of an undeveloped pregnancy in pregnant women at high risk for this complication of gestation in identifying a possible cause and timely prediction of the pathological process.

Thus, the use of markers of apoptosis (L CD95 +), vascular endothelial dysfunction and cell proliferation (AMGF, FRP, total IgE) to predict non-developing pregnancy, along with pro-inflammatory cytokines (TNFα, IL 1β, IL 6), significantly expands the prognostic capabilities of the method , allows you to timely record changes in the early stages of the pathological process and conduct preventive treatment.

The reduced accuracy of prediction of an undeveloped pregnancy only by the presence of pro-inflammatory cytokines is due to the fact that both in an undeveloped pregnancy and in spontaneous miscarriage, their changes are unidirectional.

Changes in the indicators proposed for predicting an undeveloped pregnancy (lymphocytes with the CD95 + phenotype, AMHF, FRP, total IgE) provide a timely opportunity to judge deep damage to the ovum and its choroid; can be used to monitor the effectiveness of preventive measures and the effectiveness of periconceptional preparation in women at high risk for the implementation of an undeveloped pregnancy.

Based on the verification of the diagnosis of “non-developing pregnancy” (confirmed by histological examination of the removed fetal egg), the sensitivity, specificity, accuracy, and prognostic value of the positive and negative results of this method for predicting an undeveloped pregnancy from early gestational periods, which are equal to 91%, 87, are determined from evidence-based medicine. %, 90%, 89%, 92%, which indicates a high information content and reliability of the proposed forecasting method.

The positive effect of the proposed method for predicting an undeveloped pregnancy gives new opportunities to predict the development of an undeveloped pregnancy with high efficiency due to the assessment of previously unused parameters. The method is non-invasive, safe for the health of the pregnant woman and the fetus, widely available for modern obstetric institutions.

At the filing date, the applicants did not find a forecasting method with the claimed combination of features, as a result of which we conclude that the claimed technical solution meets the criteria of the invention of “novelty”.

According to the results of a comparative analysis, the totality of the features of the proposed forecasting method provides it with new properties in the form of increasing the accuracy of forecasting, that is, according to the applicants, ensures the compliance of the proposed method with the criterion of "inventive step".

The criteria of the invention "industrial applicability" is confirmed by the fact that the claimed method for predicting can be successfully applied in mass examinations of pregnant women with the identification of accurate and early signs of an undeveloped pregnancy.

Claims (1)

A method for predicting an undeveloped pregnancy, including determining the concentration of tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL 1β), interleukin 6 (IL 6) in the blood of pregnant women, followed by analysis of the data, characterized in that they additionally determine the content of CD95 + lymphocytes ( L CD95 +), the level of alpha-2-microglobulin fertility (AMHF), the concentration of placental growth factor (FRF) and total IgE, and with the value of these indicators: the concentration of TNFα (PCG / ml) - 294 ± 39.5; the concentration of IL 1β (PCG / ml) - 588 ± 46.3; the concentration of IL 6 (PCG / ml) - 85.2 ± 13.1; L content of CD95 + (%) - 14.1 ± 5.2; AMHF level (ng / ml) - 215 ± 42; the level of FRP (PCG / ml) - 21 ± 6.2; the content of total IgE (PCG / ml) - 68 ± 24 predict non-developing pregnancy.