RU2348399C2 - Method of treatment of chronic placental insufficiency - Google Patents

Abstract

FIELD: medicine; obstetrics.

SUBSTANCE: treatment of chronic placental insufficiency is ensured by intravenous drop-by-drop introduction of Cytoflavine dosed 10 ml in 5% glucose solution 200 ml, 1-2 times a day throughout 5-10 days. Herewith twice every 3-5 days, Perftorane infusions are combined with inhalation of humidified 40% oxygen-air mixture through nasal catheter. Perftorane is dosed 0.75 ml/kg of body weight, infusion velocity is 15 drops/min.

EFFECT: normalised amount of amniotic fluid, lipid peroxidation in fetoplacental system, prolonged pregnancy to optimal delivery term.

15 tbl, 2 ex

Description

The present invention relates to medicine, namely to drug therapy, and can be used in obstetrics and gynecology for the treatment of chronic placental insufficiency.

The frequency of placental insufficiency (PN) currently has no tendency to decrease and, according to various authors, ranges from 33% to 77% [Radzinsky V.E., Orazmuradov A.A., Sobolev V.A. et al. Experience with the use of perftoran in the complex treatment of placental insufficiency in severe gestosis // Anest. and rean. - 2001. - No. 6. - S.25-29]. It is known that concomitant pregnancy-related functional inferiority of the placenta determines the intrauterine suffering of the fetus, leads to a delay in its development, and in the structure of causes of perinatal mortality is more than 20% [Cesarean section / Ed. V.I.Krasnopolsky. 2nd ed. - M .: TOO Tehlit, Medicine, 1997. - P.41]. A consequence of this complication of pregnancy is also a high incidence of newborn children, a decrease in their physical, intellectual, mental and social adaptation at subsequent stages of development [Strizhakov AN, Davydov AI, Belotserkovtseva LD Decompensated form of placental insufficiency // Selected lectures on obstetrics and gynecology. - Rostov-on-Don: Phoenix, 2000. - P.62-76]. Particularly difficult are subcompensated and decompensated forms of ST, which are increasingly found in modern obstetric practice. The use of traditional complex therapy in such situations is rarely effective, forcing early termination of pregnancy in the interests of the fetus, which in the future requires long-term nursing and rehabilitation of newborns [Sidorova IS, Makarov I.O. Clinical and diagnostic aspects of placental insufficiency. - M .: MIA, 2005. - S.196-201].

Given the above, the search for new methods of treatment of chronic placental insufficiency (CRF) is an extremely urgent task.

For the prototype of the invention, a well-known method for the treatment of chronic renal failure was selected, including complex drug therapy, including rheologically active agents (reopoliglyukin, antiplatelet agents), in combination with metabolic preparations, among which actovegin is mainly used [Serov V.N., Strizhakov A. N., Markin S.A. Guide to Practical Obstetrics. - M .: MIA, 1997. - S.204-211]. A mandatory component is the treatment of the underlying pathology, which has become the leading cause of the formation of PN.

The known method is as follows: infusion of reopoliglyukin 200-400 ml in combination with trental 5 ml, starting from 8-10 drops / min, gradually increasing the rate of administration to 20-25 drops / min depending on the well-being of the woman, 5 -7 infusions per course and actovegin as a metabolic component of 160-200 mg in 200 ml of 5% glucose solution for 5-10 days.

The known method improves uterine-placental blood flow, normalizes the rheological and coagulation properties of blood, and also provides correction of metabolic and metabolic disorders.

However, in the case of damage to the compensatory-adaptive mechanisms of the fetoplacental complex (FPK) - with subcompensated and decompensated forms of PN, such treatment is not effective enough, forcing the question of early termination of pregnancy in the interests of the fetus to be raised. Such obstetric tactics are justified in order to reduce perinatal mortality, but are not able to significantly affect the indicators of perinatal morbidity, since the full rehabilitation of a premature baby, who also suffered severely in utero, unfortunately, often turns out to be impossible. It is known that in these children a high frequency of central nervous system damage is subsequently recorded, as a result of which a lag in physical and psychomotor development is formed, first of all, the formation of speech function, which subsequently significantly disrupts their social adaptation.

An extremely unfavorable factor, often concomitant with chronic renal failure, is oligohydramnios, which significantly worsens the condition of the fetus and increases the risk of perinatal mortality. As suggested by V.E. Radzinsky and A.P. Milovanov [Extraembryonic and amniotic structures in normal and complicated pregnancy / Ed. V.E. Radzinsky and A.P. Milovanov. - M .: MIA, 2004. - 393 p.], The main mechanism leading to chronic oligohydramnios is inflammatory lesion and necrosis of decidual cells, as well as the nearby layer of extravillous cytotrophoblast, which carry out local, paracrine regulation of transport through the membranous membranes of urea and other nitrogenous metabolic products. A similar conclusion is based on the fact that, according to the results of morphological studies of the membranes, in case of oligohydramnios, both secretory and resorption functions are violated, which leads to a change in the biochemical, hormonal and immunological composition, i.e. “insufficiency” of the membranes develops, the severity of which correlates with changes in the volume of amniotic fluid. The authors of this monograph emphasize that to date there is no method for the pathogenetic correction of oligohydramnios and indicate the great importance of paraplacental exchange for normalizing the disturbed volume of amniotic fluid and the effect through it on the homeostasis of the fetoplacental system.

The objective of the invention is:

- normalization of the processes of amniotic fluid production with concomitant chronic renal failure, by restoring an adequate morphofunctional state of the membranes by optimizing paraplacental exchange and correcting the main pathogenetic mechanisms of this pathology;

- prolongation of pregnancy to the optimal term of delivery, which avoids the extremely unfavorable combination of intrauterine growth retardation (SVR) of the fetus and its prematurity;

- reduction in perinatal mortality, improving the health status of newborns and children of the first year of life.

The problem is solved in that in the known method for the treatment of chronic renal failure, including complex drug therapy, cytoflavin is prescribed in a dose of 10.0 ml intravenously in 200.0 ml of a 5% glucose solution 1-2 times a day for 5-10 days and infusions of perftoran in a dose of 0.75 ml / kg of weight twice during the course of cytoflavin, with an interval of 3-5 days, at a rate of 15 drops / min, against the background of inhalation of a moistened 40% oxygen-air mixture through a nasal catheter.

The present invention meets the criteria of the invention of "novelty", since in the process of conducting patent information research, no sources of scientific, technical and patent information have been identified that would discredit the novelty of the proposed solution.

The present invention meets the criterion of "inventive step", since no technical solutions with essential features of the proposed method have been identified.

In recent years, a large number of works have appeared devoted to the study of the specifics of the action of a plasma-replacing drug with a gas transport function - perfluorane [Ivanitsky GR, Vorobyov SI Blood substitute "Perftoran" // Vestn. RAS. - 1997. - T.67, No. 11. - S.998-1013] and substrate antihypoxant - cytoflavin [Afanasyev V.V. Cytoflavin in intensive care: A manual for doctors. - SPb .: VMedA, 2005. - 36 p.]. It was found that perfluorane is able to significantly improve tissue gas exchange and metabolism, rheological properties of blood and peripheral microcirculation, has a pronounced membrane-stabilizing and dose-independent immunoprotective action [Baryshev B.A. Perftoran. Blood substitute with gas transport function // Instruction for doctors of clinics of St. Petersburg State Medical University named after Acad. I.P. Pavlova. - St. Petersburg: Publishing House of St. Petersburg State Medical University. - 2001. - 25 p.].

A known method for the treatment of preeclampsia is that for the treatment of preeclampsia, perftoran is administered intravenously through an infusomat at a rate of 50 ml / h at a dose of 3.5 ml per kg of body weight not more than 3-4 times. The method allows to improve utero-placental blood flow, increase oxygen saturation of the intervillous space, which in turn enhances the activity of extravillous cytotrophoblast. The selected doses and regimens make it possible to exclude side effects caused by perfluorane in pregnant women.

Cytoflavin belongs to the group of metabolic agents and has pronounced antihypoxic, antioxidant and neurotropic effects, normalizing the processes of oxygen utilization by tissues that have already survived hypoxia, and also improves hemorheology and increases the immunobiological resistance of the body [Afanasyev V.V. Cytoflavin in intensive care: A manual for doctors. - SPb .: VMedA, 2005. - 36 p.]. Among the special indications in the instructions for medical use of the drug, cytoflavin emphasizes the possibility of using the drug during pregnancy in the absence of allergic manifestations on its components, while regarding perfluorane, it is indicated that during pregnancy the drug can be used only for health reasons.

The use of cytoflavin in the treatment of cerebral palsy is also known [Sprakh V.V., Lavrik S.Yu., Alimova EB et al. Clinical and neurophysiological evaluation of the effectiveness of cytoflavin in spastic forms of cerebral palsy // West. SPbGMA them. I.I. Mechnikova. - 2005. No. 3. - S.23].

The inventors did not find any literature sources that indicated the use of cytoflavin and perftoran for the treatment of chronic renal failure, the technical effect of which is to normalize the amount of amniotic fluid with concomitant oligohydramnios, prolong pregnancy, reduce perinatal mortality and reduce perinatal morbidity.

The proposed dose of perftoran for the treatment of chronic renal failure was substantiated experimentally. In the course of our own in vitro experiment, 3 series of studies were carried out - with test systems of isolated blood of women with uncomplicated pregnancy (I series - normative indicators, n = 10), with serums of patients with subcompensated (II series, n = 20) and decompensated PN (III series, n = 20). The effect of perftoran was studied in doses of 0.05 ml, 0.1 ml and 0.2 ml, corresponding to the standard volume of produced bottles. A study of the effect of the studied doses of perfluoran on lipid peroxidation (LPO) and antioxidant defense systems (AODC) showed its distinct antioxidant effect regardless of the dose used, and more pronounced (p <0.01) with respect to activation of antioxidant factors than suppression of prooxidant (p <0.05). Since the described effect of the drug turned out to be dose-independent, we considered it appropriate for obstetric practice to focus on the lowest dosage studied - 0.05 ml (bottle size 0.05 l), which, in terms of the average weight of a woman (70.0 kg), is 0 75 ml / kg.

To confirm the safety of perftoran administration under the conditions of the Central Scientific Research Institute of Higher Professional Education NizhGMA Roszdrava, in vivo experiments were performed on laboratory animals (pregnant female white rats of the Wistar strain), in which, based on the study of fetal somatometry, placenta organometry, morphological examination of the placenta, and assessment of indicators of pre- and post-implantation embryonic mortality, total embryonic death and fetal survival according to generally accepted morphological tests [Manual on experimental (report Inic) the study of new pharmacological substances / Ed. R.U. Khabrieva. - M .: Medicine, 2005. - P.89-92] it was confirmed [Ivanitsky G.R., Vorobyov S.I. Blood substitute "Perftoran" // Vestn. RAS. - 1997. - T.67, No. 11. - S.998-1013] the absence of the toxic effect of the drug perftoran at a dose of 1.5 ml / kg of weight during fetogenesis, and its effectiveness has been proved with a single dose of 0.75 ml / kg of weight for the treatment of induced secondary chronic renal failure hypoxic and infectious-hypoxic genesis, modeled in laboratory animals by prolonged exposure to altitude hypoxia and additional infection. The positive effect of small doses of perftoran in the conditions of simulated CRF manifested itself in an increase to the standard values of somatometric parameters of the fetus, weight and volume (p <0.05) of the placenta, a significant decrease in hemodynamic disturbances both at the organ (p <0.001) and tissue levels ( p <0.001), a significant increase in the number of functionally active elements of the placenta (p <0.001), a statistically significant decrease in inflammatory changes (p <0.001).

Among the results of this experiment, it should be noted that in the case of infectious-hypoxic genesis of induced CRF, visual inspection of the membranes in 100% of cases revealed their green staining, which we regarded as hypoxic changes. Perftoran therapy reduced the frequency of similar coloration of the membranes in the afterbirths of animals under similar conditions to 1.9% (p <0.001). Microscopic examination deserves special attention the fact of a significant increase in the frequency of registration of proliferative changes (p <0.01) and severe inflammatory infiltration (p <0.001) - with focal and diffuse manifestations - in the membranes of the placenta from animals with simulated chronic renal failure hypoxic and infectious-hypoxic genesis. Under the influence of perfluorane therapy, proliferative (p <0.001) and inflammatory processes (p <0.001) in the membranes were detected much less frequently and practically corresponded to the frequency of occurrence of such disorders in the aftermath of intact animals.

In our opinion, a similar effect of the drug is due to its ability to improve the processes of oxygen transport, including in paraplacental structures, as well as its dose-dependent immunoprotective effect, which significantly reduces the frequency of inflammatory changes in the membranes. In view of the foregoing, in clinical studies we justifiably hoped for an improvement in the morphofunctional state of the membranes and, accordingly, the restoration of the normal amount of amniotic fluid under the influence of perfluorane, and suggested the ability of the drug to effectively affect paraplacental metabolism and provide pathogenetic correction of oligohydramnios.

The proposed method is as follows. The complex drug therapy for pregnant women with subcompensated and decompensated PN, carried out in preparation for the upcoming delivery, is prescribed cytoflavin in a dose of 10.0 ml intravenously in 200.0 ml of a 5% glucose solution 1-2 times a day for 5-10 days and infusion of perftoran in a dose of 0.75 ml / kg of weight twice during the course of cytoflavin, with an interval of 3-5 days, at a rate of 15 drops / min against the background of inhalation of a moistened 40% oxygen-air mixture through a nasal catheter.

Before use, perfluoran should be thawed in accordance with the attached instructions, 15 minutes before the start of the infusion, preliminary sedation should be carried out by i / m administration of 10 mg of relanium and 20 mg of suprastin [Radzinsky V.E., Orazmuradov A.A., Sobolev V.A. et al. Experience with the use of perftoran in the complex treatment of placental insufficiency in severe gestosis // Anest. and rean. - 2001. - No. 6. - S.25-29], perform a standard biological test with a mandatory mark in the history of childbirth and, in the absence of a reaction, infusion at a rate of 15 drops / min against the background of inhalation of a moistened 40% oxygen-air mixture through a nasal catheter. Given the incompatibility of perftoran with reopoliglyukin in the same system, drug infusions should be carried out on different days during the course of cytoflavin administration.

The proposed method allows to obtain the following positive effect. With subcompensated PN, it decreases by 2.6 times the frequency of detecting oligohydramnios, due to the improvement of the functional state of the fetus, it provides the possibility of prolonging pregnancy until the term is full-term in the overwhelming majority of cases, by 1.8 times reduces the frequency of registration of hypotrophy in newborns, and by 4 times reduces the risk of postanoxic encephalopathy with a dubious and unfavorable prognosis (stages II and III), significantly improves the indicators of physical and psychomotor development of children of the first year take it. With decompensated PN, in the case of initial oligohydramnios, it helps to restore the amount of amniotic fluid to normal 2.2 times more often, due to the distinct stabilization of the functional state of the fetus, it allows prolongation of pregnancy up to 34 weeks, i.e. terms corresponding to the maturation of the surfactant system of the fetal lungs, significantly reduces the manifestations of malnutrition, 5 times reduces the need for prolonged mechanical ventilation in newborns, significantly improves the indicators of physical and psychomotor development of children in the first year of life.

The method allows to increase the oxygen supply to the amniotic structures and improve its utilization by tissues that have already survived hypoxia, as well as to increase their immunobiological resistance, which, in turn, enhances the functional activity of villous, extravillous cytotrophoblast and decidual cells, reduces inflammatory and necrotic changes in them, contributing to the normalization of the processes of production of amniotic fluid, paraplacental exchange and the maintenance of the compensatory capabilities of the placenta and the fetus at the proper level out.

A similar conclusion is based on the results of a clinical study conducted on the basis of 2 maternity hospitals in the city of N. Novgorod (Municipal Unitary Hospital "Maternity Hospital No. 4" and Maternity Hospital No. 7 of the Municipal Unitary Hospital "City Clinical Hospital No. 40").

A total of 88 pregnant women with diagnosed chronic renal failure in the period from 28 to 36 weeks were examined. Depending on the degree of violation of the compensatory capabilities of the placenta and the fetus, all patients were divided into two groups. The first group included 44 women with subcompensated PN, the second group included 44 pregnant women with manifestations of the decompensated form of this pathology. Verification of the diagnosis was carried out on a scale for assessing the state of FPK and the severity of chronic renal failure according to the results of an echographic study proposed by I.S. Sidorova and I.O. Makarov (1997).

Depending on the method of therapy, 2 subgroups were allocated within each group - control (20 and 18 women, respectively) and the main (24 and 26 patients). In the control subgroup, the treatment of placental insufficiency was carried out in accordance with generally accepted methods: rheologically active agents were used - intravenous infusions of reopoliglyukin - 200-400 ml in combination with 5 ml trental; Metabolic therapy with Actovegin was prescribed in a dose of 160-200 mg intravenously in 200 ml of a 5% glucose solution for 5-10 days.

The main subgroup as a metabolic component of the above complex therapy received cytoflavin - 10.0 ml of the drug in 200 ml of 5% glucose solution daily 1-2 times a day for 5-10 days. Perfluorane infusions were additionally prescribed: twice 0.75 ml / kg of weight with an interval of 3-5 days - before and in the middle of the course administration of cytoflavin, while inhaling a moistened 40% oxygen-air mixture through a nasal catheter. Before use, in accordance with the attached instructions for use, the drug was subjected to gradual thawing at room temperature and was administered intravenously dropwise at a rate of 15 drops / min after setting a standard biological sample. 15 minutes before the start of the infusion, in order to prevent the characteristic side effects caused by the activation of the compliment system, premedication was carried out by introducing 10 mg of Relanium and 20 mg of suprastin intramuscularly. Given the incompatibility of perftoran with reopoliglukin in the same system, drug infusions were carried out during the course of cytoflavin administration on different days.

An obligatory component of the therapy in all subgroups was the treatment of the main pathology, which turned out to be the leading cause of PN formation.

In order to assess the effectiveness of the therapy, a general clinical examination of patients with a detailed study of the condition of newborns of the 1st year of life was used [Methods of a comprehensive assessment of the health status of young children: a training manual. 2nd ed. / Ed. E.F. Lukushkina. - N. Novgorod: Publishing house of the Novosibirsk State Medical Academy, 1999. - 42 p.].

The condition of the fetoplacental system was studied using ultrasound scanning on devices Aloka SSD 650, Aloka SSD 1700, Aloka SSD 5500. Advanced fetometry, echographic assessment of the placenta and amniotic fluid were carried out according to generally accepted standards [Demidov VN, Bychkov PA, Logvinenko A .V., Voevodin S.M. Ultrasound biometry. Reference tables and equations // Clinical lectures on ultrasound diagnostics in perinatology / Ed. M.V. Medvedeva and B.I. Zykina. - M .: Medicine, 1990. - P.83-92]. The Dopplerometric study of the uteroplacental-fetal blood flow (MPPC) was performed in color Doppler mapping. The curves of blood flow velocities in both uterine and umbilical arteries were studied, followed by the calculation of the resistance index according to the generally accepted method [Medvedev MV, Kuryak AF, Yudina EV Dopplerography in obstetrics. 1st ed. - M.: Real time, 1999. - 160 p.].

The intrauterine condition of the fetus was evaluated using a cardiotocographic (CTG) study on a Sonicard Oxford 8002 fetal monitor with computer analysis according to the Dawes / Redman criteria.

The intensity of lipid peroxidation was studied by the method of chemiluminescence (CL) of blood serum induced by hydrogen peroxide [Kuzmina EM The use of induced chemiluminescence for assessing free radical reactions in biological substrates // Biochemistry and Biophysics of Macroorganisms. - Gorky, 1983. - P.41-48], the results were expressed in terms of maximum induced CL (I max). The total antioxidant activity (AOA) of blood serum was calculated as the ratio of I max / S - by changing the luminosity of the luminescence induced by CL (I max) for 30 seconds, taking into account the indicator S (area under the curve). Evaluation of the results was carried out in comparison with the average indicators obtained during the examination of 10 patients with uncomplicated pregnancy in the III gestational trimester.

Evaluation of the immune status included the study of the expression of surface markers of peripheral blood lymphocytes (CD3 +, CD4 +, CD8 +, CD16 +, CD20 +, CD25 +) by the indirect immunofluorescence method using a set of monoclonal antibodies, the quantification of Ig A, M, G in blood serum using immunodiffusion plates and circulating immune complexes (CEC) by the turbodiametric method. The data obtained were analyzed in comparison with the average values obtained during the examination of 20 women with uncomplicated pregnancy in the III trimester of the gestational process.

The study of the state of the blood coagulation system was carried out by examining the coagulogram and the platelet activation index. Solutions of adrenaline, ADP and a suspension of ristomycin were used as aggregation inducers.

The hormone-producing function of FPK was evaluated by the content of α-fetoprotein (AFP), estriol (E ₃ ), placental lactogen (PL), chorionic gonadotropin (CGT) and trophoblastic β-glycoprotein (TBG) in the peripheral blood of the mother using the enzyme-linked immunosorbent assay “DRG-international” (Germany), “Vector-Best” (Novosibirsk), “Alkor Bio” (St. Petersburg). The results were expressed as a component of the median corresponding to the average statistical value of the indicator for a given gestational age. Threshold levels of deviations of 0.5 and 2 MoM were considered [Shmagel K.V., Chereshnev V.A. Immunity of a pregnant woman. - M .: Honey. book, N. Novgorod: Publishing house of the Novosibirsk State Medical Academy, 2003. - P.86].

Pathomorphological examination included visual assessment and placenta organometry. Histological techniques were carried out according to the formulas set out in the classical manuals [G. Avtandilov Fundamentals of pathological practice. - M .: Medicine, 1994. - 510 p.].

Statistical processing of the results was carried out using the Microsoft Excel 2000 software, intergroup differences were evaluated by Student t-test, the critical level of reliability of the null statistical hypothesis was taken to be 0.05.

The age of the examined women ranged from 18 to 40 years, and in both groups, every third patient was older than 30 years. It was noted that among pregnant women with a decompensated course of PN, patients with higher education (p <0.01) prevailed, who were 2 times more likely (p <0.05) to work in their specialty and had occupational hazards. In the anamnesis, every second nulliparous in both groups had from 1 to 10 medical abortions. A study of the nature of the course of previous pregnancies in multiparous revealed in the group of patients with decompensated PN a distinct tendency to increase the frequency of the syndrome of fetal loss, hyperandrogenism, gestosis, as well as a significant increase in SVRP - 5 times (p <0.05), in comparison with women of group I . An analysis of the somatic health of the women examined showed that hypertension in women of group II occurred 5 times (p <0.001), and chronic renal pathology in the form of pyelo- and glomerulonephritis was almost 2 times more likely (p <0.05) than with subcompensated PN. Among pregnancy complications, gestosis prevailed in both groups, mainly of moderate severity, as well as inflammatory diseases of various etiologies and localization, among which, in the II group, exacerbated or manifested for the first time infections of the TORCH complex (p <0.01), mainly of viral origin ( p <0.05), as well as gestational pyelonephritis (p <0.05), while in the subcompensated form of PN, inflammatory diseases of the genital tract of conditionally pathogenic etiology were most often recorded (p <0.05).

Thus, according to all the considered signs, the most unfavorable situation was revealed in the group of patients with decompensated PN, which resulted in a noticeable 3.2-fold increase in the number of premature deliveries (p <0.001) performed exclusively by surgery (p < 0.001).

Gestosis complicated the course of pregnancy in 68.1% of patients of group I and in 81.8% of group II, and a severe course of this complication was 3 times more likely to occur with decompensated PN (p <0.01). By the time of admission to the hospital, edematous syndrome was recorded in the considered groups with a frequency of 90.9% and 72.7%, respectively, proteinuria - 43.2% and 75.1%, and the average blood pressure values were 143.4 ± 4 with subcompensated PN. 2 / 93.6 ± 2.4 mm Hg, while in the decompensated form they were within 159.6 ± 3.9 / 105.3 ± 2.2 mm Hg. The comparative effect of the therapy on gestosis revealed a clear positive effect in the main subgroups of patients. So, the edematous symptom complex and proteinuria with subcompensated PN in the subgroup using the proposed method were stopped, respectively, 2 and 4 times more often than in the control (p <0.05). In the decompensated course of PN, a similar composition of infusion therapy contributed to a more noticeable decrease in the levels of systolic (p <0.05) and diastolic (p <0.01) blood pressure in comparison with the control, and therefore the frequency of detection of manifestations of retinal angiopathy characteristic of gestosis decreased in compared with the control 2.5 times (p <0.05).

The lag of the standing height of the uterine fundus (VDM) from the gestational age for subcompensated PN was initially within 3.6 ± 0.43 cm, and for decompensated 4.9 ± 0.59 cm. When applying the proposed treatment method (main subgroup) with In the subcompensated form of ST, the existing lag decreased by 45.9%, which significantly differed from the control subgroup (p <0.05). In a decompensated course, differences with the control, where these changes clearly progressed (p <0.05), after completion of therapy in the main subgroup turned out to be significant due to the stabilization of this indicator (p <0.001).

The effectiveness of the therapy becomes especially evident when comparing the periods of inpatient treatment of patients and the time of delivery. Thus, with subcompensated PN, the duration of observation of patients of the main group in an obstetric hospital was on average 22 (22.3 ± 1.7) days, while in the control it was limited to 13 (12.8 ± 1.5) days (p <0, 05), which led to a significant decrease in the number of early deliveries in the main subgroup (p <0.05). In case of decompensated PN, the time of admission of pregnant women to the hospital was within 30.2 ± 0.7 weeks, and the implementation of the proposed therapy extended the observation time of patients until delivery on average up to 25 days (25.6 ± 2.2), whereas traditional treatment forced to be limited to 14 (14.2 ± 2.2) days (p <0.01). Delivery periods in the main subgroup were 34.4 ± 0.6 weeks, and in the control 32.6 ± 0.4 weeks. (p <0.05).

With subcompensated PN, 30% of the control women and 45.8% of the main subgroups were admitted to independent births, and in the main group, the frequency of untimely discharge of amniotic fluid in childbirth decreased by 2 times (p <0.05). With decompensated PN, all patients were delivered promptly, however, in the main subgroup, planned delivery was performed 2 times more often than in the control (p <0.01). Intraoperative blood loss with the proposed method of treatment was significantly reduced in both groups of patients (p <0.05).

In the group of patients with subcompensated PN, there were no cases of perinatal mortality. In the case of a decompensated course of ST in the control subgroup, 3 children died antenatally, while when using the proposed method such outcomes were not observed.

A study of the effect of the therapy on the indicators of the physical development of newborns showed the following (Table 1).

Table 1 Indicators of physical development and condition of newborns Indicators Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup Body weight g 2361 ± 110.6 2743 ± 98.1 * 1379 ± 81.4 1594 ± 83.1 Height, cm 46.2 ± 0.64 48.1 ± 0.51 * 39.7 ± 0.58 41.4 ± 0.56 * Ponderal Index 51.1 ± 1.84 57.1 ± 1.56 * 35.0 ± 1.59 38.3 ± 1.58 Head circumference, cm 31.7 ± 0.29 32.9 ± 0.28 ** 28.2 ± 0.47 30.3 ± 0.41 * Chest circumference, cm 29.6 ± 0.39 31.5 ± 0.31 *** 25.0 ± 0.61 25.7 ± 0.52 Apgar score of 1 ′, points 7.2 ± 0.15 7.7 ± 0.19 * 6.3 ± 0.25 7.3 ± 0.13 ** 5-point Apgar score 7.9 ± 0.10 8.3 ± 0.10 ** 7.4 ± 0.18 7.6 ± 0.10

* - significance of differences relative to the control subgroup: * - p <0.05; ** - p <0.01; *** - p <0.001.

The frequency of deviations in the physical and neuropsychiatric development of children under the age of one year decreased (Table 2). So, hypotrophy at birth was recorded in the main subgroups, compared with the control, significantly less frequently (p <0.05). With subcompensated PN in the main group, the incidence of hypoxic-ischemic encephalopathy of the II and III stages in children decreased by 4 times (p <0.05). With a decompensated form, newborns from mothers who received the proposed method of treatment needed a prolonged mechanical ventilation 5 times less often (p <0.05). Under the age of one year, children from mothers of the main subgroups, in comparison with the control, significantly decreased the frequency of lag in physical and psychomotor development (p <0.05), and the level of formation of fine motor skills, comprehensible and active speech skills corresponded to age.

An analysis of the initial ultrasound data showed that in the group of patients with subcompensated PN, ZVRP was initially detected in 75.0% of cases, with the asymmetric form prevailing - 63.7%, whereas with decompensated PN, this pathology occurred in all the women examined, with symmetrical the lag of the main dimensions of the fetus in 72.7% of cases. The lag of the photometric parameters by 1-2 weeks (VIRS I degree) occurred, respectively, in 54.5% and 31.8%, II degree in 40.9% and 36.4% and III degree in 4.6 % and 31.8% of cases. Under the influence of the proposed therapy, a sufficient increase in fetometric indicators was revealed in comparison with the control in both groups of the examined women 3.5 times more often (p <0.05). It should be noted, however, that in group I there was a significant (p <0.05) increase in all the main sizes of the fetus - abdominal circumference (coolant), biparietal head size (BDP) and hip length (DB), while in II such improvement it was possible to achieve only with respect to bone size - BDP and DB (see tables. 3 and 4).

Table 3 The average increase in the main photometric indicators under the influence of ongoing therapy Indicators Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup The growth of BDP, mm 4.9 ± 0.46 6.6 ± 0.47 * 3.6 ± 0.70 6.3 ± 0.77 * Coolant growth, mm 18.0 ± 2.78 26.2 ± 2.56 * 20.3 ± 2.97 24.7 ± 3.04 DB gain, mm 4,5 ± 0,62 6.9 ± 0.64 * 3,5 ± 0,60 6.0 ± 0.59 ** DB / coolant before treatment,% 23.8 ± 0.19 23.9 ± 0.22 23.1 ± 0.28 22.9 ± 0.22 DB / coolant after treatment,% 24.3 ± 0.24 23.1 ± 0.26 ** 23.0 ± 0.25 23.7 ± 0.23 *

* - significance of differences relative to the control subgroup: * - p <0.05; ** p <0.01.

Table 4 The effect of ongoing therapy on the dynamics of echographic parameters Estimated
Ultrasound parameter Subcompensated Mon Decompensated Mon Control Main Control Main subgroup, subgroup, subgroup, subgroup, n = 20 n = 24 n = 18 n = 26 Pre-treatment vvrp 75% 75.0% one hundred% one hundred% Sufficient growth fetometric 20.0% 70.8% ** 10.5% 38.5% * indicators Violation placenta maturation: - before treatment 60.0% 66.7% 55.5% 61.5% - after treatment 50.0% 25.0% ⁺⁺ 77.7% 50.0% * Low water: - before treatment 35.0% 33.3% 44.4% 42.3% - after treatment 45.0% 12.5% * 55.6% 19.2% *

* - significance of differences relative to the control subgroup: * - p <0.05; ** - p <0.01;

- the significance of differences in the subgroup before and after treatment, ⁺ - p <0.05; ⁺⁺ - p <0.01.

Violation of the maturation of the placenta according to ultrasound was initially found in 63.4% of patients of group I and in 58.5% - II. Under the influence of therapy in the main subgroups, the frequency of recording such changes in comparison with the control decreased by 2 times with subcompensated PN, and 1.6 times with decompensated PN (p <0.05).

In addition, it was possible to identify a clear positive effect of the combined use of cytoflavin and perftoran on the processes of amniotic fluid production. Thus, oligohydramnios, as the most prognostically unfavorable symptom of chronic renal failure, was initially detected in 34.2% of women of group I and 43.4% of women in group II. Under the influence of the proposed therapy, the frequency of registration of this symptom decreased in both groups of examined patients, respectively, 2.6 and 2.2 times (p <0.05), while in the control of violations of amniotic fluid production progressed.

Table 5 Changes in IR in the vessels of the uteroplacental-fetal bed under the influence of ongoing therapy Indicators Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup MA before treatment 0.66 ± 0.03 0.66 ± 0.01 0.69 ± 0.02 0.70 ± 0.01 MA after treatment 0.68 ± 0.02 0.61 ± 0.01 ** ⁺⁺ 0.71 ± 0.02 0.69 ± 0.03 A. umbilical cord before treatment 0.73 ± 0.05 0.73 ± 0.04 0.78 ± 0.02 0.79 ± 0.01 A. umbilical cord after treatment 0.77 ± 0.01 0.72 ± 0.02 * 0.79 ± 0.01 0.77 ± 0.01

* - significance of differences compared with the control subgroup: * - p <0.05; ** - p <0.01;

⁺⁺ - significance of differences within the subgroup before and after treatment, p <0.01.

The results of the dopplerometric study revealed serious baseline disorders of MPPK in both groups of patients. So, at the time of initiation of therapy in pregnant women with subcompensated PN, isolated violation of the uteroplacental blood flow (I A degree) occurred in 45.9% of patients, and placental-fetal (I B degree) - in 13.8% of women. Combined disorders of MPPK (II degree) were observed in 40.3% of pregnant women of group I and 64.1% - in II, where critical changes in the parameters of the placental-fetal blood flow were detected in 35.9% of cases. With subcompensated PN, the proposed method of treatment had a corrective effect on vascular resistance in the uterine (p <0.01) and umbilical (p <0.05) arteries (Table 5), improving the state of MPPK in 29.1% of cases (p < 0.05), and in the rest, ensuring its adequate stabilization in comparison with the control due to the complete absence of negative dynamics (p <0.01). With decompensated PN, the proposed therapy caused a similar trend.

Table 6 Change in the basic indicators of basal rhythm variability under the influence of ongoing therapy Change is variable. Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup The episodes are high. var. min - before treatment 10.4 ± 0.99 7.2 ± 1.11 * 7.0 ± 0.32 7.2 ± 0.28 - after treatment 8.9 ± 1.02 10.7 ± 0.9 ⁺ 5.0 ± 0.61 ⁺⁺ 10.3 ± 0.89 *** ⁺⁺ Episodes of low var., Min - before treatment 0.6 ± 0.39 1.2 ± 0.46 4.2 ± 1.18 4.0 ± 1.03 - after treatment 7.8 ± 0.58 ⁺⁺⁺ 1.6 ± 0.35 *** 10.3 ± 1.20 ⁺⁺⁺ 4.6 ± 0.98 *** STV, ms - before treatment 8.5 ± 0.56 8.5 ± 0.54 6.2 ± 0.52 6.5 ± 0.45 - after treatment 7.6 ± 0.63 10.3 ± 0.61 ** ⁺ 6.4 ± 0.54 9.2 ± 0.60 ** ⁺⁺⁺

* - significance of differences compared with the control subgroup: * - p <0.05; ** - p <0.01; *** - p <0.001;

⁺ - significance of differences within the subgroup before and after treatment: ⁺ - p <0.05; ⁺⁺ - p <0.01;

⁺⁺⁺ - p <0.001.

The functional state of the fetus, evaluated according to CTG, initially suffered severely in both groups. Thus, reactive HCT was detected in patients with subcompensated PN in 50.0%, and in decompensated ones in 100% of cases, accompanied by decelerations, respectively, in 25.0% and 50.0% of cases. It should be noted a clear positive effect of therapy in the main subgroups on the condition of the fetus. So, the frequency of detection of an active non-stress test (HCT) in the case of the combined use of the proposed method with subcompensated PN decreased by 4 times (p <0.01), and no deceleration was recorded at all (p <0.01). In the decompensated form, the number of observations with reactive HCT and decelerations decreased in the main subgroup by 6.5 times (p <0.001), whereas after traditional treatment, such violations according to CTG data continued to be recorded with a frequency of 81.3% and 42.3% of cases, respectively . The change in the basic indicators of basal rhythm variability clearly confirms the positive effect of the proposed therapy (see table 6).

According to the results of our own studies, the initial disturbances in the lipid peroxidation system were expressed in a significant activation of lipid peroxidation processes with subcompensated PN (p <0.001), while in the decompensation phase, the intensity of free radical reactions practically corresponded to the level characteristic of uncomplicated pregnancy, which is apparently associated with the depletion of bioenergetic body capabilities and the lack of the necessary substrate for oxidation. AOSZ turned out to be suppressed in proportion to the severity of compensatory violations - with a subcompensated PN of 2, and with a decompensated 3 times in comparison with the standard value (p <0.001). Normalization of the parameters of lipid peroxidation and AOA of blood serum with subcompensated PN was promoted only by the therapy of the proposed method, the conduct of which even in the decompensated form caused significant positive changes (tables 7 and 8).

Table 7 The effect of therapy on the level I max. The investigated parameter Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup I max before treatment, rel. lum. units 0.426 ± 0.048 ⁿⁿⁿ 0.431 ± 0.047 ⁿⁿⁿ 0.225 ± 0.036 0.227 ± 0.053 I max after treatment, rel. lum. units 0.357 ± 0.061 ⁿ 0.244 ± 0.056 ⁺ 0,304 ± 0,044 0.214 ± 0.060 I max normal in healthy pregnant 0.215 ± 0.025

ⁿ - significance of differences compared with the standard value: ⁿ - p <0.05; ⁿⁿⁿ - p <0.001;

⁺ - significance of differences within the subgroup before and after treatment, p <0.05.

Table 8 The effect of therapy on the level of AOA The investigated parameter Subcompensated Mon Decompensated Mon Control subgroup Main subgroup Control subgroup Main subgroup OJSCA before treatment, rel. 0.062 ± 0.012 ⁿⁿⁿ 0.057 ± 0.016 ⁿⁿⁿ 0.039 ± 0.013 ⁿⁿⁿ 0.037 ± 0.009 ⁿⁿⁿ AOA after treatment, rel. 0.061 ± 0.014 ⁿⁿⁿ 0.102 ± 0.009 * ⁺ 0.037 ± 0.010 ⁿⁿⁿ 0.077 ± 0.016 * ^{+ n} AOA is normal in healthy pregnant women 0.123 ± 0.009

* - significance of differences relative to the control subgroup, p <0.05;

⁺ - significance of differences within the subgroup before and after treatment, p <0.05;

ⁿ - significance of the difference compared with the standard value: ⁿ - p <0.05; ⁿⁿⁿ - p <0.001.

An analysis of the initial state of coagulograms with subcompensated PN showed that changes in the state of the blood coagulation system in patients of this group affected both the vascular-platelet and its coagulant units, while decompensation also affected the fibrinolysis system, almost corresponding to the manifestations of the chronic respiratory syndrome syndrome. It should be noted that in both groups it was possible to identify a sufficient corrective effect of the proposed therapy on the hemostatic system and rheological parameters of the blood, while in the control a similar effect was not observed (Table 9).

The proposed method has improved the parameters of cellular and humoral immunity (table 10).

The initial changes in the functional activity of FPC with subcompensated PN were expressed in a marked decrease in the concentrations of AFP, estriol, and TBH, with a simultaneous increase in the content of CGT. At the same time, the level of PL corresponded to average values, which confirmed the absence of critical disturbances in the condition of the fetus. A different situation occurred with decompensated PN, when the content of hormones and peptides of fruit origin was already outside the threshold values, the concentration of PL decreased significantly, indicating severe suffering of the fetus, while the deviation of the levels of CGT and TBH from the median was not so significant. The proposed method of treatment had a distinct positive effect in both groups of women examined, while conventional treatment with subcompensated PN contributed to the restoration of the functional activity of FPK to a much lesser extent, and with decompensation did not prevent the progressive deterioration of its condition (see table 11).

The obtained results found convincing evidence when analyzing the data of morphological studies of the placenta. Thus, the mass and volume of placentas from women of the main subgroup with subcompensated PN were significantly higher (p <0.001) compared with the control, the area of pathological macrocenters was 2 times less (p <0.001), the blood supply to the placental tissue was more uniform (p <0 , 05), the structure of the villous tree was much more likely to correspond to a gestational period (p <0.05), and the pathological immaturity variant in the form of a deficit of terminal specialized villi was detected 2.5 times less often. Compensatory-adaptive reactions occurred 2 times more often (p <0.001), and involutive-dystrophic changes in the placenta (p <0.05) - significantly less. With decompensated PN, there were no significant differences in the compared subgroups in terms of the area of pathological macro-foci, which, apparently, is associated with initially severe destructive processes and severe vascular disorders, which have become a morphological basis for damage to the main compensatory mechanisms of FPK. However, it should be noted that the proposed method of treatment contributed to an increase in the mass and volume of the placenta in comparison with the control (p <0.01), provided more uniform blood supply to the placental tissue (p <0.01), activated 2.1 times the compensatory adaptive reactions (p <0.05) and reduced the frequency of involutive-dystrophic disorders in the placenta.

It should be emphasized that hypoxic changes (green staining) of the membranes during visual examination of the placenta from women who received treatment by the proposed method were significantly less likely to be detected in comparison with the control, both with subcompensated (p <0.01) and decompensated PN (p <0.05), with a simultaneous decrease in the frequency of registration of involutive-dystrophic disorders according to the results of a morphological study (p <0.001), which ensured a clear normalization of the processes of amniotic fluid production.

Thus, our results open up the possibility of using the proposed method of treatment to effectively correct the state of the fast-acting system of amnion-cytotrophoblast-decidual tissue, which performs paraplacental exchange and neuroimmunoendocrine regulation in the mother-placenta-fetus system, to carry out pathogenetically substantiated therapy of oligohydramnios, as well as repair damaged compensatory Adaptive mechanisms of FPK.

So, we were able to identify a clear positive effect of the proposed method of treatment on the functional state of the fetus, placenta and membranes, which helps to strengthen and stabilize the adaptive capabilities of FPK and can reduce the frequency of oligohydramnios, normalize the processes of amniotic fluid production, prolong pregnancy for a long time and significantly improve perinatal outcomes with subcompensated and decompensated forms of PN.

Example 1

Extract from the history of pregnancy and childbirth No. 1180 for 2006 (maternity hospital No. 4) of patient B., 19 years old. Diagnosis: pregnancy 34-35 weeks. Gestosis I (5 points on the scale of G.M.Savelyeva). Subcompensated PN (3 points on the ISSidorova scale): violation of MPPK II, ZVRP I - symmetrical form, premature maturation of the placenta, oligohydramnios.

For the treatment of chronic renal failure, the patient was given cytoflavin 10.0 ml intravenously in 200 ml of 5% glucose solution once a day for 10 days as a part of complex therapy, supplementing it with infusions of perftoran at a dose of 0.75 ml / kg of weight twice with an interval in 4 days.

The following data confirm the effectiveness of the treatment (table 12).

According to the results of the analyzes, there was an improvement in biochemical and immunological and hemocoagulation parameters, the functional state of the placenta and indicators of the uteroplacental blood flow. By the time of completion of therapy, the degree of maturity of the placenta corresponded to the gestational age, the amount of amniotic fluid returned to normal. The pregnancy was prolonged for 18 days - up to 37 weeks. A woman is delivered by cesarean section. A live full-term girl weighing 2730, height 46 cm, with an Apgar score of 8/8 points was extracted, applied to the chest on the 3rd day, on the 8th day in a satisfactory condition she was discharged under the supervision of a local pediatrician.

Example 2

Extract from the history of childbirth No. 881 for 2006 (maternity hospital No. 4) of patient Ts., 21 years old. Diagnosis: pregnancy 31-32 weeks. Decompensated PN (2 points): violation of MPPK II, ZVRP II - symmetrical form, accelerated maturation and hyperplasia of the placenta, oligohydramnios. Combined gestosis II (8 points) against a background of gestational pyelonephritis in the acute stage. Mycosis of smooth skin. Condylomatosis Bacterial vaginosis.

For the treatment of chronic renal failure, the pregnant woman received 10.0 ml of cytoflavin 2 times a day for 10 days as part of complex therapy, in combination with infusions of perftoran 0.75 ml / kg of weight twice with an interval of 4 days.

The following data confirm the effectiveness of the treatment (see table 13).

According to the results of the analyzes, there was an improvement in biochemical, immunological and hemocoagulation parameters, the functional state of the placenta and indicators of the uteroplacental blood flow. The pregnancy was prolonged for 32 days - up to 36 weeks. By the time of delivery, the degree of maturity of the placenta corresponded to the gestational age, the amount of amniotic fluid returned to normal. The patient is delivered by cesarean section. A live girl with signs of prematurity I, weighing 1760, height 44 cm, with an Apgar score of 8/8 points was removed. Attached to the chest on the 8th day, on the 10th day in a satisfactory condition, was discharged under the supervision of a local pediatrician. Some lag in the physical and neuropsychic development of the child was leveled by the age of 3 months (see Tables 14 and 15).

Table 14 Indicators of the physical development of the child in the first 6 months of life Age months one 2 3 four 5 6 Weight g 2500 3800 4200 4800 5300 5700 Height, cm 46 49 52 54 56 60

Claims (1)

A method for the treatment of chronic placental insufficiency, including complex drug therapy, characterized in that they are prescribed intravenous drip of cytoflavin at a dose of 10 ml in 200 ml of 5% glucose solution 1-2 times a day for 5-10 days and twice, with an interval of 3 -5 days, carry out infusions of perftoran in a dose of 0.75 ml / kg of body weight at a rate of 15 drops / min against the background of inhalation of a moistened 40% oxygen-air mixture through a nasal catheter.