Bacterial causes of miscarriage

In addition to viral infection, bacterial infection and bacterial-viral associations play an important role in the interruption of pregnancy.

In recent years, work has appeared that shows the role of disturbances in the normal microflora of the genital tract in the premature termination of pregnancy. With sporadic interruption, infection is the leading cause of loss, especially in the second and third trimesters of pregnancy. Chorioamnionitis is usually the result of an ascending infection, which is more typical of the second trimester of pregnancy. Infection can directly affect the fetus, and possibly through the activation of pro-inflammatory cytokines that have a cytotoxic effect. Loss of pregnancy can be associated with hyperthermia, an increased level of prostaglandins, premature rupture of the bladder due to microbial proteases.

As for the habitual miscarriage, the role of infection raises many debatable questions and many believe that the infection in the habitual miscarriage of such a role as in sporadic does not play. Nevertheless, in recent years, many studies have shown the important role of infection in the habitual abortion of pregnancy.

Bacterial vaginosis is found in almost half of women with habitual miscarriage of infectious genesis.

Chlamydia infection was reported by many researchers, was found in 57.1% and 51.6%, respectively, in women with miscarriage. A screening examination of women planning pregnancy is suggested for the presence of chlamydia. According to some authors, the effect of chlamydia is through inflammatory cytokines. However, most researchers believe that chlamydial infection is more common in patients with infertility, and not with miscarriage.

Streptococcus group B, according to many authors, is often associated with a delay in fetal development, is periodically determined in cervical cultures in 15-40% of pregnant women. When infection is possible premature discharge of water, premature birth, chorioamnionitis, bacterial postpartum endometritis. Diseases of newborns occur in 1-2% of infected mothers. In the newborn, especially prematurely, there are diseases caused by streptococcus corpses B - pneumonia, meningitis, sepsis, proceeding very hard.

According to most researchers, miscarriage is characterized not by a monoinfection, but by a combined urogenital infection, which often occurs in subclinical form, which makes it difficult to identify it.

To clarify the role of conditionally pathogenic microorganisms in the genesis of miscarriage, we, together with the laboratory of microbiology, carried out a wide range of species identification of microorganisms (representatives of opportunistic saprophytes, pathogens) of the vaginal microcenosis, cervix and endometrium outside of pregnancy in three groups of women: miscarriage of an obviously infectious genesis (chorioamnionitis, endometritis, infected fetus), with an undeveloped pregnancy without obvious signs of infection and in healthy fertile women.

Microbiological examinations of ribbon scrapings of endometrium in women of three groups showed that asymptomatic persistence of microorganisms in the endometrium was found in 67.7% of women with an infectious genesis of miscarriage, in 20% of women with a nondecreasing pregnancy in the anamnesis and was not found in the control. More than 20 kinds of microorganisms of the conditionally pathogenic group were found in the endometrium. A total of 129 strains were identified, including obligate anaerobes of 61.4% (bacteroids, eubacteria, peptostreptococci, etc.), microaerophils - 31.8% (predominantly genital mycoplasma and diphtheria), facultative anaerobes - 6.8% (group streptococci D, B, epidermal staphylococcus). Only 7 women have monocultures isolated, others have associations of 2-6 species of microorganisms. In a quantitative assessment of the growth of microorganisms, it was shown that massive seeding (10 ³ -10 ⁵ cfu / ml) of endometrium occurred in only 6 of 50 women with positive endometrial seeding results. All these women were sown with aerobic-anaerobic associations and mycoplasma with a predominance of coliform bacteria or streptococcus group D. These patients had the most burdened anamnesis in terms of the number of spontaneous miscarriages. In other women, the amount of microflora in the endometrium was in the range of 10 ² -5x10 ⁵ cfu / ml endometrial homogenate.

A clear connection was established between the presence of microorganisms in the endometrium and the morphological changes in the structure of the endometrium. Histological verification of the diagnosis of "chronic endometritis" was carried out when infiltrates consisting mainly of lymphocytes, plasma cells, as well as histocytes and neutrophils were detected in the stroma of the endometrium obtained in the first phase of the menstrual cycle, which agrees with the literature data. Histological signs of a chronic inflammatory process were found in 73.1% of the surveyed women in the main group and in 30.8% of the women in the comparative group and were not detected in the control group.

When comparing the results of a parallel histological and microbiological study of the endometrium obtained in the first phase of the menstrual cycle, it was established that histological signs of inflammation were found in 86.7% of cases in cases of microorganism isolation from the endometrium. At the same time, with a histological diagnosis of chronic endometritis, sterile endometrial cultures were present in 31.6% of women. These results indicate, on the one hand, the leading role of opportunistic microorganisms in the persistence of the inflammatory process in the endometrium, and on the other - the incomplete detection of the causative agents of chronic endometritis, primarily, apparently due to viral and chlamydial etiology, both as approximately 1/3 of the verified histological diagnoses of chronic endometritis were not confirmed by excretion of the pathogen.

In addition, it was found that with the persistence of microorganisms in the endometrium, 70% of women showed dysbiosis as part of the microcenosis of the vagina. At the same time, in the group of women with sterile endometrial crops, the composition of the vaginal microcenosis in the overwhelming majority of patients (73.3%) met the criteria of the norm.

Dysbiotic manifestations in the microcenosis of the vagina consist in a sharp decrease in the amount of lactoflora, the predominance of microorganisms such as gardnerella, bactereroids, fusobacteria, vibrios, ie, in this group of women in the microflora of the vagina the obligate anaerobic component predominated, whereas in the group of women with sterile endometrial crops The leading component in the composition of the vaginal microcenosis was lactobacilli.

With regard to the microflora of the cervical canal, sterile sowing of the discharge was relatively rare in both groups (in 8% and 37.8% of the women in the main and comparative groups, but statistically significantly less in the main group of women). In those cases where the growth of microorganisms in cervical mucus is detected, the association of several bacterial species is much more common in women of the main group. Such leading pathogens of purulent inflammatory processes as escherichia, enterococci, genital mycoplasmas and obligate anaerobes (bacteroides, peptostreptococci) occur 4 times more often in the cervical channel of women with persistence of microorganisms in the endometrium. Gardnerelli, mobilnuncus, clostridia were found in the cervical canal only in patients with persistence of microorganisms in the endometrium.

The development of dysbiotic processes in the microcenosis of the lower part of the genital tract is the leading pathogenetic link in the mechanism of ascending infection of the endometrium, especially in patients with ischemic-cervical insufficiency. Given that the composition of the vaginal microcenosis is a hormonal dependent state, a decrease in the level of vaginal colonization resistance may be due to hormonal deficiency that has occurred in most of our patients.

Studies of recent years have shown that the background of chronic endometritis is changing local immunity. If in the endometrium of healthy women outside pregnancy B-, T-, NK-cells, macrophages are represented in a small amount, then with chronic endometritis, there is a sharp activation of cellular and humoral inflammation reactions at the local level. This is manifested in an increase in leukocyte infiltration of the endometrium, the number of T-lymphocytes, NK cells, macrophages, in a sharp increase in titers IgM, IgA, IgG. Activation of local immune reactions can lead to disruption of placentation, invasion and development of the chorion and, ultimately, to termination of pregnancy in the event of its onset against the background of chronic endometritis.

Persistent for a long time, a virus-bacterial infection can lead to a change in the antigenic structure of infected cells due to the actual infected antigens included in the structure of surface membranes, and the formation of new cell antigens determined by the cellular genome. At the same time, an immune response develops to heterogenized autoantigens that leads to the appearance of autoantibodies, which, on the one hand, has a destructive effect on the cells of one's own organism, but, on the other hand, is a protective reaction aimed at preserving homeostasis. Autoimmune reactions, viral-bacterial colonization of the endometrium are among the most common etiologic factors that cause the development of the chronic form of DIC syndrome.

In the event of pregnancy, autoimmune reactions and activation of the infection can lead to the development of disseminated intravascular coagulation, the emergence of local microthrombosis in the placentation with the formation of infarctions followed by detachment of the placenta.

Thus, chronic mixed viral-bacterial infection in patients with habitual miscarriage, persisting for a long time in the body and remaining asymptomatic, leads to activation of the hemostatic system and immunity at the local level, which directly participate in the processes of fetal death and rejection.

In conditions of chronic endometritis during the gestational process, the immune system, evolutionarily determined to recognize and eliminate foreign antigens, can cause an inadequate response of the mother's body to the development of pregnancy.

Recent studies have shown that more than 60% of women with habitual miscarriage of blood cells (lymphokines and monocytes) after incubation with trophoblastic cells in vitro produce soluble factors that exert toxic effects on the development processes of the embryo and trophoblast. In women with undisturbed reproductive function and in whom miscarriages were due to genetic or anatomical reasons, this phenomenon is not detected. In a biochemical study, it was found that embryotoxic properties belong to cytokines produced by type 1 CD4 + cells and, in particular, to interferon.

The system of interferon was formed in phylogeny simultaneously with the immune, but it differs from the latter. If the immune system is aimed at maintaining the constancy of the body's protein environment, its function of recognizing and destroying foreign substrates, including viruses and bacteria, interferon protects the body from the spread of foreign genetic information and its own genetic material from destructive influences. Unlike the immune system, the interferon system does not have specialized organs and cells. It exists in every cell, as each cell can be infected and must have a system for recognizing and eliminating foreign genetic information, including viral nucleic acids.

Depending on the source of production, interferons are divided into

• I type - non-immune (here carry a-IFN and beta-IFN). This type of interferon is produced by all nuclear cells including non-immunocompetent ones;
• II type - immune-y-IFN - its production is a function of immunocompetent cells and is realized in the process of immune response.

There is a gene for each type of interferon. Interferon genes are located on the 21st and 5th chromosomes. Normally, they are in the severed state and for their activation, induction is necessary. Secreted as a result of induction, IFN is secreted by cells into the blood or surrounding intercellular fluid. Initially, it was thought that the basic biological role of interferon is reduced to its ability to create a state of immunity to viral infection. By now, it has been established that the action of interferons is much broader. They activate cellular immunity by enhancing the cytotoxicity of natural killers, phagocytosis, antigen presentation and expression of histocompatibility antigens, activation of monocytes and macrophages, etc. The antiviral effect of interferon is associated with the induction of protein kinase and 2-5 'oligoadenylate synthetase inside the cell of the synthesis. These two enzymes are responsible for inducing and maintaining a state of immunity to viral infection.

The interferon system, although it does not prevent the penetration of the virus particle into the body, but sharply limits its spread. At the same time, antiproliferative and immunomodulatory actions of interferon can make a significant contribution to the implementation of the antiviral effect of interferon. The interferon system can block the proliferation of virus-infected cells and simultaneously adjust almost all links of immunity to eliminate the pathogen. This is the link between the interaction of the immunity system and the interferon system. In this case, interferon is the first line of defense "against the virus, a little later connected immunity. Depending on the dose, interferon affects the production of antibodies by B-cells. The process of antibody formation is regulated by T-helpers. T-helpers, depending on the main histocompatibility complex antigens expressed on them, are divided into two subtypes Th1 and Th2. Cytokines, where u-IFN belongs, suppresses antibody formation. The forms of interferons stimulate almost all functions of macrophages and promote the functional activity of NK cells, which carry out the nonspecific and antigen-dependent lysis of virus-infected cells.

In the process of physiological pregnancy, there is a complex reorganization of the interferon system, depending on the period of pregnancy. In the first trimester a number of authors note the activation of interferon- enenesis and its subsequent decrease in the II and III trimesters. During pregnancy, interferon is produced not only by the blood cells of the mother, but also by cells and tissues of fruit origin. According to its physical and biological properties, trophoblastic interferon refers to IFN-a and is determined in the blood of the mother and fetus. In the trimester, the trophoblast produces 5-6 times more interferon than in the third trimester, and under the influence of viruses the trophoblast secretes a mixture of interferons.

One of the functions of interferon during pregnancy is to prevent the transplacental spread of the viral infection. With a viral infection, the content of interferon increases both in the mother's blood and in the blood of the fetus.

Another pathogenetic mechanism of antiviral activity of interferon trophoblast is associated with its ability to induce the expression on the trophoblast of class I antigens of the main histocompatibility complex. This leads to an increase in the activity of cells involved in the interaction with viruses: cytotoxic T cells, macrophages, NK and thereby, to the activation of local inflammatory changes by which the spread of the viral infection from the mother to the fetus is prevented. However, excessive activation of inflammatory cytokines, including interferons, with a large dose of infection can lead to the development of immune reactions aimed at eliminating the pathogen with simultaneous disruption of the normal development and function of the trophoblast, placenta.

Recently, interferon-y is considered as a cytotoxic factor in women with habitual miscarriage. It is known that normally interferon status is characterized by a low serum content (> 4 U / ml) and a pronounced ability of leukocytes and lymphocytes to produce these proteins in response to inducers. Under normal conditions, all types of interferon are synthesized in a certain proportional relationship. The disproportion of production of various types of interferon can lead to the development of a pathological process. Acute viral infections lead to a sharp increase in the level of serum interferon at the same time activation of interferon-dependent intracellular antiviral mechanisms occurs. In the initial episode of genital herpes, the rate of inclusion of the interferon system in antiviral protection is not high enough to slow the spread of the virus. This, apparently, can be one of the reasons for the chronization and this disease.

In case of recurrent viral infections, interferonogenesis is suppressed, this is expressed in baseline serum interferon indices combined with a sharply suppressed ability of lymphocytes and leukocytes to produce a-, beta-and y-interferon. Such a state of the interferon system is called interferon deficient.

With a mixed chronic viral infection, the IFN-status is characterized by an almost complete lack of the leukocyte-producing IFN-γ.

In autoimmune disorders, the state of the immunity system and interferon is most often characterized by the presence of inverse correlation links: at normal or even elevated levels, the functioning of the immune system, oppression of interferonogenesis is noted.

Thus, both for autoimmune pathologies and for chronic diseases of the viral nature, a deep suppression of interferon-enease-interferon deficiency is characteristic. The difference between them is only in the opposite dynamics from the side of the serum interferon: in autoimmune states the latter is elevated, with chronic mixed viral infections - remains within the background values.

The degree of inhibition of interferon production indicates the severity of the chronic process, and the need for adequate therapy, taking into account the detected changes in the parameters of the IFN-status.

As already mentioned above, T-helpers are divided into two types depending on the expressed antigens of the main histocompatibility complex, and also on the type of secreted cytokines: Th1 and Th2. TM cells secrete IL-2, TNF-beta, IFN-y, which stimulate cellular immunity processes. Th2 cells isolate il-4, il-5, il-10, which inhibit cellular immunity reactions and promote the induction of antibody synthesis. With a normally developing pregnancy, starting from early terms, cytokines Th2 - regulatory ones prevail in the blood from cytokines. They are distinguished by the fetoplacental complex during all three trimesters and are determined simultaneously in decidual tissue and in placenta cells. Th1 cytokines (IFN-y and il-2) are synthesized in small amounts compared to the amount of cytokines in the first trimester and are hardly defined in the II and III trimesters. The Th1 and Th2 cytokines are in antagonistic relationships. This explains the presence of a high level of Th2 in normal pregnancy. It is believed that Th2 cytokines block the reactions of cellular immunity, promote the development and invasion of trophoblast, and also stimulate stoiogenesis (progesterone, hCG). Simultaneous presence of small amounts of IFN-y is necessary to limit trophoblast invasion.

With a clinical threat of interruption of pregnancy, the cytokine profile changes toward the predominance of y-IFN and il-2, with a minimum content of H-4 and il-10. Most T-helpers in the endometrium of women with habitual miscarriage are of the Th1 type. This variant of the cytokine response is accompanied by the production of il-2, y-IFN, and this answer does not depend on the age, the number of previous pregnancies.

Proinflammatory cytokines activate the cytotoxic properties of NK cells and the phagocytic activity of macrophages that are in increased amounts in the endometrium and decidual tissue in patients with chronic endometritis and can have a direct damaging effect on the trophoblast. It is known that Th1 cytokines inhibit the synthesis of chorionic gonadotropin. In sum, the processes that induce pro-inflammatory cytokines inhibit and, ultimately, can stop the development of pregnancy in its early stages, thereby participating in the pathogenesis of habitual miscarriage.

[1], [2], [3], [4], [5], [6], [7]