Tactics of preparation with non-pregnancy of infectious genesis

Habitual miscarriage is characterized by the presence of persistent forms of bacterial and viral infections in the mother’s body.

History of pregnancy termination with various manifestations of infection: high temperature, premature rupture of membranes, endometritis after miscarriage or childbirth; acute and/or chronic inflammatory processes of the genitals. If infectious genesis of miscarriage is suspected, examination includes the following parameters:

• bacteriological examination of the cervical canal;
• Gram smear microscopy;
• viruria - determination of viral antigens in urine sediment cells using the indirect immunofluorescence method;
• determination of herpes simplex virus, cytomegalovirus, chlamydia, mycoplasma, ureaplasma in cervical canal mucus using the PCR method;
• determination of antibodies to the herpes simplex virus (IgG) and cytomegalovirus (IgG) in the blood.

To select immunomodulatory therapy and determine the order of treatment, the following is carried out:

• assessment of immune status: determination of subpopulations of T-cell immunity; level of immunoglobulins IgG, IgM, IgA classes;
• assessment of interferon status: IFN levels in serum, interferon response of lymphocytes (spontaneous, virus-induced (IFNa), mitogen-induced (IFNu) and sensitivity of lymphocytes to IFN inducers;
• histochemistry of immunocompetent cells for the selection of a metabolic therapy complex.

Manifestations of acute infection, or exacerbation of chronic, are always accompanied by changes in the hemostasis system, therefore hemostasis control and normalization of all parameters are extremely important for the treatment of infection. Treatment and preventive measures for infection of the patient, or more correctly, the married couple, depend on the severity of the infectious process, the characteristics of the immune and interferon status and the financial capabilities of the patients.

Unfortunately, this has to be taken into account. It is not worth reducing the cost of treatment at the expense of its quality, but it is also not advisable to exaggerate the role of certain very expensive means.

When assessing the vaginal biocenosis in a group of women with suspected infectious genesis of miscarriage, it was found that normocenosis was present in 38.7% of women, vaginosis was detected in 20.9%, vaginitis in 22.1%, and candidiasis in 18.2%. In the control group of women with intact reproductive function, normocenosis was present in 85%, candidiasis in 10%, and vaginosis in 5%.

When identifying an infection in the cervical canal, it was found that in the group of women with suspected infectious genesis of miscarriage, PCR diagnostics revealed persistence of ureaplasma in 36.6% of patients, mycoplasma in 15.2%, and chlamydia in 20.9%. Bacteriological examination of the cervical canal mucus revealed opportunistic microorganisms in 77.1% of women, mainly: Escherichia coli, enterococci, mycoplasma, obligate anaerobes (bacteroides, peptostreptococci), group B, D streptococci, etc.

The conducted microbiological studies of tape scrapings of the endometrium in the first phase of the menstrual cycle showed that asymptomatic persistence of microorganisms in the endometrium was detected in 67.7% and was not detected in the control group. Obligate anaerobes accounted for 61.4% (bacteroides, eubacteria, peptostreptococci, etc.), microaerophiles - 31.8% (genital mycoplasmas, diphtheroids), facultative anaerobes - 6.8% (group B streptococci, epidermal staphylococcus).

Only 10.8% of women were found to have monocultures, while the rest had associations of 2-6 types of microorganisms. When quantitatively assessing the growth of microorganisms, it was found that massive seeding (10 ³ -10 ⁵ CFU/ml) occurred only in 10.2% of women with an extremely burdened anamnesis, while in the remaining women the amount of microflora in the endometrium was within the range of 10 ² -5x10 ² CFU/ml of endometrial homogenate.

When detecting viruses by PCR in the mucus of the cervical canal and specific antibodies in the blood, carriage of the herpes simplex virus was found in 45.9% of women and a recurrent form of genital herpes in 19.6% of women, carriage of cytomegalovirus in 43.1%, and recurrent infection in 5.7% of the examined women. In these conditions, termination of pregnancy is apparently caused not so much by the persistence of infectious agents (opportunistic microorganisms and viruses) as by the characteristics of the patient's immune system. The following algorithm for therapy outside pregnancy is suggested.

• Stage 1 - individually selected antibiotics, trichoyol, antimycotics in therapeutic doses from day 1 to day 7-9 of the cycle.

Most researchers, when detecting chlamydia, mycoplasmosis, ureaplasmosis, conduct treatment with a combination of doxycycline 100 mg 2 times a day, trichopolum (metronidazole) 0.25 3 times a day, nystatin - 0.5 g 4 times a day. From the 1st to the 7-9th day of the cycle. If it is possible to determine sensitivity to antibiotics, then an individual approach will be preferable.

In case of chlamydia, treatment with antibiotics such as rulid 0.15 - 3 times a day for 7 days; or sumamed (azithromycin) 0.5 - 2 times a day; erythromycin 0.5 - 4 times a day for 9 days may be more successful. Recently, the drug vilprafen (josamycin) 0.5 - 3 times a day for 9 days has been recommended, especially for mycoplasma and ureaplasma.

Proteolytic enzymes are involved in virtually all immune processes:

• affect individual components of the immune system, immunocompetent cells, antibodies, complement, etc.;
• have an immunomodulatory effect to normalize all parameters of the immune system;
• have a direct stimulating effect on the processes of phagocytosis, the secretory activity of macrophages, and natural killers.

The immunomodulatory effect of enzymes is manifested in achieving optimal activity of various cells participating in immunological reactions. Enzymes, even in small concentrations, promote the breakdown and removal of circulating immune complexes (CIC), this is especially important in the case of a combination of infection and autoimmune disorders.

An important property of enzymes is their effect on the hemostasis system and, first of all, their ability to dissolve fibrin deposits in vessels, thereby restoring blood flow, facilitating the process of thrombus destruction. This feature of enzymes is extremely useful, since chronic inflammatory processes are accompanied by depletion of the body's own fibrinolytic potential.

Enzymes, by destroying immune complexes, make microorganisms more accessible to the action of antibiotics.

According to our data, combined therapy with the inclusion of systemic enzyme therapy (at a dose of 5 pills 3 times a day 40-45 minutes before meals, washed down with 1 glass of water) is more successful and allows achieving better results, in a shorter time to prepare 92% of women for pregnancy. In the comparative group, completely randomized with the use of the same drugs, but without systemic enzyme therapy, successful preparation for pregnancy was only in 73% of patients.

Infection with group B streptococcus during pregnancy may result in premature rupture of membranes, premature birth, chorioamnionitis, and bacterial postpartum endometritis. Diseases of the newborn (pneumonia, sepsis, meningitis) occur in 1-2% of infected mothers.

For group B streptococcus infection, the drug of choice is ampicillin. For urinary tract infection, ampicillin at a dose of 1-2 g every 6 hours for 3-7 days.

In case of asymptomatic course of chronic carriage of group B streptococcus, ampicillin is prescribed 0.25 4 times a day, 3-7 days. Along with antibiotics, it is necessary to take antimycotics, since repeated treatment often leads to the development of dysbiosis not only vaginal, but most often intestinal. Therefore, after treatment with antibiotics and antimycotics, it is necessary to make smears to assess the effect of systemic treatment on vaginal processes. Of the modern antimycotics, fluconazole derivatives (diflucan) are now recommended. Other drugs that are no less effective, but not so expensive can be recommended: nystatin, nizoral, tioconazole, etc.

If there was vaginal pathology simultaneously with the detected infection in the endometrium and cervix, then after the course of therapy it is necessary to make smears to make sure that additional local treatment is not required. With favorable smears, it is possible to recommend the use of eubiotics vaginally (atsilakt, lactobacterin) and orally in the form of biokefir or lactobacterin, primadophilis, etc.

If bacterial vaginosis is detected:

• leucorrhoea with an unpleasant odor, a feeling of discomfort, itching;
• in a Gram smear, lactobacilli are practically absent, “key cells” are detected, there are practically no or few leukocytes, pH> 4.5;
• Bacteriological examination reveals a huge number of microorganisms >10 ³ CFU/ml, with gram-negative bacteria predominating: gardnerella, bacteroides, mobiluncus, etc.

To treat vaginosis, a set of measures is needed, including general impact on the body and local treatment. We use metabolic complexes or vitamins, sedatives, normalization of the hormonal profile (cyclic hormonal therapy with the drug Femoston).

Vaginal treatment: vaginal cream dalacin (clindamycin) 2% application to the vagina, at night, 7-day course of treatment. In the absence of a history of candidiasis or if antimycotics were prescribed at the same time, after a course of dalacin - acylact or lactobacterin in vaginal suppositories for 10 days.

Alternative treatment: metronidazole 0.5 - vaginal tablets for 7 days, ginalgin - vaginal tablets.

Ginalgin is a combination drug (chlorquinaldol 100 mg and metronizasol 250 mg) in the form of vaginal tablets, 1 tablet at night for 10 days. When using ginalgin, there may be a local reaction in the form of itching, which goes away after the end of therapy.

Some authors recommend the use of vaginal suppositories "betadine" (200 mg polyvinylpyrrolidone; 100 mg iodine) 2 times a day for 14 days; terzhinan - a combination drug (ternidazole 200 mg, neomycin sulfate 100 mg, nystatin 100 thousand IU, prednisolone 3 mg) 1 suppository at night for 10 days; macmiror complex (nifuratel and nystatin) 1 suppository or 2-3 g of cream at night for 10 days.

If vaginal candidiasis is detected, we prescribe clotrimazole - vaginal tablets (suppositories) 100 mg once a day for 6 days, vaginal tablets at a dose of 500 mg once at night for 1-3 days. At the same time, especially in case of recurrent candidiasis, we recommend taking diflucan 150 mg once or taking other antimycotics (nizoral, nystatin, fluconazole, etc.). Clotrimazole is effective not only against fungi, but also against gram (+) cocci, bacteroids, trichomonads.

An alternative method of treatment is pimafucin, in the form of vaginal suppositories and tablets for oral administration; Klion-Dpo 1 vaginal tablet for 10 days; betadine; macmiror complex, terzhinan.

In case of recurrent candidiasis, when traditional treatment does not help or helps for a short period of time, it is advisable to do a culture to identify the species of fungi and their sensitivity to various antifungal drugs. Thus, when detecting fungi of the genus Glabrata, treatment with Ginopevarill in the form of vaginal suppositories at night for 10 days is more effective.

Recently, due to the insensitivity of some types of fungi to antimycotics, a very old method is recommended in a new version: boric acid 600 mg in gelatin capsules vaginally for 2 to 6 weeks. In case of recurrent candidiasis, treatment of the sexual partner is necessary.

If before treatment the immune parameters were within normal limits, then the treatment can be supplemented with the use of metabolic complexes or vitamins, general tonics and completed at this stage by resolving the pregnancy.

After completion of general and local antimicrobial treatment, with a decrease in all parameters of T-cell immunity, it is advisable to conduct immunomodulatory therapy. T-activin is used at 2.0 ml intramuscularly every other day for 5 injections, then 2.0 ml once every 5 days for another 5 injections.

In case of imbalance of T-cell link of immunity, the drug Immunofan is used, which is both an immunomodulator and an interferon inducer. The distinctive feature of this drug is that it activates the reduced parameters and reduces the increased ones.

Immunofan is prescribed in a dose of 1.0 ml intramuscularly every 2 days for a total of 10 injections.

At the 2nd stage of treatment, it is necessary to evaluate the interferon status and, if reduced parameters of a- and y-IFN production are detected, recommend a course of treatment with an interferon inducer, taking into account the sensitivity of immunocompetent cells. We have experience in using ridostin, lorifan, imunofan, cycloferon, derinat, tamerit.

Lorifan is a high-molecular interferon inducer of natural origin, belongs to early interferon inducers, is effective in respiratory viral infections, various forms of herpes. The drug has an immunomodulatory effect, stimulates specific and non-specific links of immunity, T-cell and humoral immunity, has an antibacterial and antitumor effect. It is prescribed as intramuscular injections once a day with an interval of 3-4 days, the course of treatment is no more than 2 weeks. Side effects include a short-term increase in temperature. Contraindicated during pregnancy.

Ridostin is a high-molecular interferon inducer of natural origin. Stimulates the production of early interferon (alpha and beta) and has antiviral, antibacterial, and antitumor effects. It is effective against herpesvirus infections and chlamydia. Ridostin is prescribed as intramuscular injections of 2 ml on days 1, 3, 6, 8, and 10 of the cycle. Contraindicated in pregnancy.

Cycloferon is a synthetic analogue of a natural alkaloid - a low-molecular inducer of interferon-alpha has antiviral, immunomodulatory, anti-inflammatory and antitumor activity. Cycloferon is highly effective in rheumatic and systemic diseases of connective tissue, suppressing autoimmune reactions and providing an anti-inflammatory effect. Cycloferon penetrates cells and accumulates in the nucleus and cytoplasm of the cell, which is associated with the mechanism of action. The main producers of interferon under the influence of cycloferon are T-lymphocytes, natural killer cells. Normalizes the balance between T-cell subpopulations. Cycloferon is effective against hepatitis, herpes, cytomegalovirus, including autoimmune diseases. It has a pronounced antichlamydial effect. It is prescribed intramuscularly at 1 ml (0.25) on the 1st, 2nd, 4th, 6th, 8th, 11th, 14th day of the cycle. If necessary, a repeated course is carried out after 6-12 months. In chronic forms of viral infection, it can be used in maintenance doses of 0.25 intramuscularly once every 5 days for up to 3 months. Contraindicated during pregnancy.

Neovir is a low-molecular synthetic IFN superinducer. When administered parenterally, Neovir causes rapid formation of high titers of early interferon-alpha, beta and y in the body. The drug has antiviral and antitumor effects. Neovir is effective in acute infections, including acute herpesvirus infection and hepatitis. It is less effective in chronic viral infections than in acute ones. The course of treatment is 3 injections of 250-500 mg at intervals of 16-24 hours. The course of treatment can be repeated after 48 hours. Contraindicated during pregnancy.

Polyoxidonium is a synthetic drug with an immunostimulating effect, increases the body's immune resistance to local and generalized infections. Its action is based on the activation of phagocytosis and antibody formation. It is prescribed intramuscularly in doses of 12 mg once a day, 5-10 injections per course of treatment. Before injection, the drug is dissolved in 1 ml of physiological solution or in 0.25 ml of 0.5% novocaine solution. Contraindicated during pregnancy.

Immunofan is a hexopeptide with a molecular weight of 836 D. Immunofan is immediately destroyed to its constituent amino acids after administration. The drug has an immunomodulatory, detoxifying, hepatoprotective effect and causes inactivation of free radical and peroxide compounds. A distinction is made between the rapid phase of imunofan action in the first 2-3 hours and lasting 2-3 days after administration, the middle and slow phases. In the first hours, a detoxifying effect is manifested, antioxidant protection is enhanced, lipid peroxidation is normalized, the breakdown of phospholipids of the cell membrane and the synthesis of arachidonic acid are inhibited. During the middle phase (from the 3rd to the 10th day), the phagocytosis reaction and death of intracellular bacteria and viruses are enhanced. As a result of the activation of phagocytosis, a slight exacerbation of foci of chronic inflammation, supported by the persistence of viral or bacterial antigens, is possible. During the slow phase (from 10 days to 4 months), the immunoregulatory effects of the drug are manifested - restoration of impaired indices of cellular and humoral immunity. The effect of the drug on the production of specific antiviral antibodies is equivalent to the effect of some vaccines. The drug stimulates the production of IgA when it is insufficient, does not affect the production of IgE and, thus, does not increase allergic reactions - immediate hypersensitivity. The effect of Immunofan does not depend on the production of PgE2 and can be used together with anti-inflammatory drugs of steroid and non-steroid series.

Immunofan is administered intramuscularly or subcutaneously at 1.0 ml of 0.005% solution once a day every 2 days, for a total of 10-15 injections.

The drug is not contraindicated during pregnancy, except for Rh-conflict pregnancy (possibly increase in antibody titer). During pregnancy, we use Immunofan in the II and III trimesters in courses of 1.0 ml intramuscularly daily No. 5-10 depending on the clinical situation: in case of exacerbation of viral-bacterial infection complicated by prolapse of the fetal bladder, isthmic-cervical insufficiency, suspected chorioamnionitis, increased levels of proinflammatory cytokines in the peripheral blood and/or cervical mucus, acute respiratory viral infections in patients with habitual miscarriage.

Tamerit is a combination of synthetic drugs, has anti-inflammatory, immunomodulatory and antioxidant effects. It is based on the effect of tamerit on the functional and metabolic activity of macrophages and neutrophils. It is used as intramuscular injections in a dose of 1 ampoule (100 mg), diluted with 2-3 ml of water for injections, a course of 5-10 injections every other day. It is used to treat chronic inflammatory processes, including those with an autoimmune component in pathogenesis.

Derinat is a biologically active substance obtained from sturgeon milt, 1.5% sodium deoxyribonucleate solution. It has an immunomodulatory effect at the cellular and humoral levels; stimulates reparative processes, hematopoiesis, has an anti-inflammatory effect, has a weak anticoagulant effect. It can be used in the treatment of chronic adnexitis, vaginitis, prostatitis.

It works very well in chronic viral carriage, chronic fatigue syndrome. Patients note an improvement in their well-being and performance.

The drug is used 5.0 ml intramuscularly every 2 days, a total of 5 injections. The drug is painful, it must be administered slowly.

Unfortunately, there are no clinical trials on the use of Derinat during pregnancy. Judging by the composition, it is a natural product that cannot have a pathogenic effect. However, it is not yet approved for use during pregnancy in the form of intramuscular injections.

Derinat drops are used to prevent acute respiratory infections and acute respiratory viral infections, 2-3 drops 2-3 times a day. The drops have an immunomodulatory effect and protect against acute and exacerbation of chronic infections transmitted by airborne droplets. The drops can also be used during pregnancy.

The selection of interferon inducers is carried out individually based on the sensitivity of blood cells to different drugs.

According to research data, ridostin, lorifan, imunofandikloferon, tameryt are more effective and sensitivity to them is almost the same in 85% of patients. Neovir and polyoxidonium, according to research data, were ineffective in our patients, these are drugs of the acute phase of inflammation, and patients with habitual miscarriage have a chronic, low-symptom infection.

Along with interferon inducers, antiviral therapy is carried out using the drug Viferon-2 in the form of rectal suppositories, 1 suppository 3 times a day for 10 days.

Viferon is a complex drug that includes interferon and antioxidant components - ascorbic acid and alpha-tocopherol. In addition, Viferon combines the qualities of both interferon and an interferon inducer.

Treatment at the 2nd stage is also carried out against the background of metabolic therapy of systemic enzyme therapy. After completion of the second stage of treatment, a control assessment of the effectiveness of the treatment is carried out:

• bacteriological examination of the cervix;
• Gram smears;
• PCR diagnostics from the cervix: herpes simplex viruses, cytomegaloviruses, chlamydia, mycoplasma, ureaplasma;
• assessment of immune and interferon status.

When all parameters are normalized, pregnancy can be permitted.

If the therapy is not effective enough, endovascular laser blood irradiation and plasmapheresis may be suggested.

ELOK - endovascular laser irradiation of blood is performed using the ULF-01 unit, generating helium-neon radiation with a wavelength of 0.65 nm and an output power of 1 mW. For intravascular irradiation of blood, a monofiber quartz light guide is used, inserted through a puncture needle into the cubital vein. The duration of the procedure is on average 5 minutes. Treatment is carried out once a day in a course of 7 sessions.

After completion of the course of therapy, normalization of hemostatic parameters is noted, since low-power laser light leads to an increase in fibrinolytic activity.

During all stages of therapy, metabolic therapy complexes are prescribed, which are selected individually based on the study of lymphocyte histochemistry. It is known that the enzymatic status of human peripheral blood lymphocytes is its phenotypic feature and characterizes its somatic state not only at the time of the study, but also with a high degree of reliability in the near future. In addition, it has a reliable correlation with the clinical symptoms of many diseases and can be used for their early diagnosis and prognosis. Intracellular metabolism in leukocytes is subject to changes depending on the phase of the menstrual cycle: an increase in enzyme activity during ovulation is regarded as an intensification of energy metabolism in the whole body. When studying enzyme activity in women with habitual miscarriage, it was found that in the dynamics of the menstrual cycle, a reliable depression of oxidation-reduction enzymes is noted, especially alpha-glycerol phosphate dehydrogenase (GPDH). The absence of a peak in enzyme activity in the ovulation phase was revealed; a decrease in the activity of succinate dehydrogenase (SDH) was noted in the second phase of the cycle.

In contrast to the normative parameters, the activity of acid phosphatase (AP) in women with miscarriage and chronic viral-bacterial infection is significantly increased in all phases of the cycle.

Pregnancy is accompanied by an increase in tissue metabolism processes, as well as the conjugation of enzymatic activity of lymphocytes in the ovulation phase and the first weeks of pregnancy. Depression of enzymes is an unfavorable factor in the prognosis of a planned pregnancy. In terms of preparation for pregnancy, normalization of cytochemical indicators is one of the criteria for readiness for conception. Metabolic therapy courses are recommended for both the expectant mother and the father. If it is impossible to individually select metabolic therapy, you can use the average type of therapy, which is most acceptable for our patients.

Metabolic therapy course:

Complex I - 5-6 days from day 8-9 of the cycle to day 13-14:

• cocarboxylase 100 mg 1 time intramuscularly or benfotiamine 0.01 - 3 times;
• riboflavin mononucleotide 1.0 i/m once a day;
• calcium pantetanate 0.1-3 times;
• Lipoic acid 0.25 - 3 times;
• Vitamin E 1 capsule (0.1) - 3 times.

II complex - from the 15th to the 22nd day of the cycle:

• riboxin 0.2 - 3 times a day;
• pyridoxal phosphate (pyridoxine) 0.005 - 3 times;
• folic acid 0.001 - 3 times;
• phytin 0.25 - 3 times;
• potassium orate 0.5 - 3 times before meals;
• vitamin E 1 drop (0.1) - 3 times.

Despite the fact that the metabolic therapy complex includes many vitamins, it is not clear to replace these complexes with multivitamins, since the complexes are designed to restore the Krebs cycle, and then normalize the oxidation-reduction processes in cells. There is no such sequence when taking multivitamins. But we recommend taking vitamins between metabolic therapy complexes. If NLF is detected in patients with infectious genesis of miscarriage, the therapy complex can be supplemented by prescribing cyclic hormonal therapy (Femoston) or Duphaston, Utrozhestan - in the second phase of the cycle.

Thus, antibacterial therapy, immunomodulatory therapy and metabolic therapy complexes allow normalizing immune parameters and preparing a woman for pregnancy.

Pregnancy can be allowed if: hemostasis parameters are within normal limits, there are no pathogenic microorganisms in the cervix during bacteriological examination and by the PCR method, there are no IgM antibodies to HSV and CMV, viruria parameters are quite satisfactory, viral activity is no more than “+”, normal immunity and interferon status indicators, normocenosis of the vagina and the husband’s spermogram indicators are within normal limits.