RU2393841C1 - Method of treating threatened miscarriage in early pregnancy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to obstetrics. The method involves preliminary preferred position of placenta aspect. The pregnant women on their 1-2 trimester of pregnancy suffering disordered uteroplacental hemodynamics are prescribed with transdermal exposure to deponite-10. The exposure involves an acupuncture point BM-147 of the leg corresponding to the placenta side and lasts for 12-24 hours. The therapeutic course is 1-2 sessions. The therapeutic course is 1-2 sessions.

EFFECT: method reduces medicament load on a body of the pregnant woman.

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Description

The invention relates to medicine, specifically to obstetrics and gynecology, and relates to means and methods of treating pregnant women with chronic placental insufficiency (FPF).

The invention relates to medicine, namely to obstetrics, and will find wide application for the treatment of threatening pregnancy in the I-II trimester.

In recent years, the sphere of scientific interests in the perinatal protection of the fetus has shifted to early pregnancy - to the first trimester, since it is during this period that the fetoplacental system forms, the laying of fetal organs and tissues, extraembryonic structures and provisional organs, which in most cases determines the further course pregnancy (G.M.Savelieva, 2000; A.N. Strizhakov, 2004). In addition, in the later stages of pregnancy, complications and the presence of extragenital pathology in a woman complicate the diagnosis of the fetoplacental system and fetus and obstetric tactics.

(FPF) in the structure of causes of perinatal mortality is more than 20%. Long-term observations of many authors on the development of children born to mothers with diagnosed FPI have led to the conclusion that this pathology causes not only a sharp increase in perinatal mortality, but also numerous changes in the child’s body, which during the first years of life cause disturbances in his physical and mental development, as well as increased somatic and infectious morbidity (N.L. Garmasheva, N.N. Konstantinova, 1978; E.M. Vikhlyaeva, 1983; I.P. Ivanov, 1983; V.E. Radzinsky, 1992) .

The treatment of FPF includes the treatment of the underlying disease, as well as a set of measures aimed at improving the uteroplacental circulation and metabolic processes in the fetoplacental complex. Having carefully studied the literature on the earliest stages of the development of the embryo and fetus, the formation of obstetric complications, it was concluded that to date, no schemes have been developed for effective therapy for miscarriage. Over the past 15 years, many studies have been devoted to studying the pathophysiological role of nitric oxide in obstetrics, the use of nitric oxide donors as new pharmacological agents.

Existing data on a decrease in the expression of NOS in the fetoplacental complex during pregnancy complications, in particular during gestosis, confirm its possible deficiency and dictate the need to study the effectiveness of vasodilators as exogenous nitric oxide donors (G. Lutt et al., 1999). These drugs belong to the group of peripheral nitrovasodilators and in their action mimic the endothelial relaxation factor, which is identified as NO, in fact being NO-therapy. As a prophylaxis of pregnancy complications in women with hypertension and chronic glomerulonephritis occurring with hypertension, O.V. Zozulya et al. For the first time, a transdermal nitroglycerin patch (Nitroderm TTS) was used, which releases nitric oxide and thereby stimulates the endothelial relaxing factor.

S. Kohler et al. (1999), studying the features of utero-placental and fetoplacental hemodynamics after transdermal use of glycerol trinitrate with the threat of premature birth, found that the maximum effect of the drug was observed after 24 hours. Glycerol trinitrate reduces the resistance of blood vessels in the pool of uteroplacental hemodynamics, while its effect on fetal blood flow is minimal. However, the main feature was noted: the effect of nitroglycerin was noted on the side of that uterine artery, where the disorders were more pronounced.

It is known that the main method of treating miscarriage remains the appointment of pharmacological drugs, such as indomethocin (RF patent No. 20088003), antioxidant nutrients (abstract of Cand. Diss. T.P. Kiyazeva, 1997), B-adrenergic agonists (A.A. Agadzhanova , 1996), calcium channel blockers (Kupferminc M. et al., 1993) and others.

However, these methods do not take into account the individual characteristics of pregnant women, which increases the drug load on the mother and fetus and can lead to undesirable complications.

Also known are methods of treating miscarriage using discrete plasmapheresis (RF patent No. 2031663) and abdominal decompression (RF patent No. 2051630). However, due to their specificity, they have not received much practical application.

A method for treating threatening abortion of late pregnancy is described (T.I. Vosheva). Features of central hemodynamics with the threat of late termination of pregnancy, taking into account the type of blood circulation and treatment method. St. Petersburg, abstract of Cand. Diss. 1997, p. 8). The essence of the method lies in the fact that women with the threat of abortion in the period of 14-26 weeks on the background of etiopathogenetic therapy with tocolytic drugs (B-adrenergic agonists (brikanil and others) in combination with isoptin or panangin 3 times a day), are treated with electric sleep with using LENAR. The course of treatment is 10 sessions.

The disadvantages of these methods include the possibility of complications of drug therapy, as well as the appointment of medications without taking into account the preferred location of the placenta in a pregnant woman, which significantly affects the effectiveness of treatment.

There is a method of treating miscarriage (RF patent No. 2086242, 1997.08.10) by correcting metabolism, characterized in that the use of ozonized saline solution obtained by passing through saline solution for 20-30 min ozone-oxygen mixture with an ozone concentration of 500-700 μg / l / min, which is administered in a volume of 400 ml intravenously at a rate of 8-10 ml / min daily for 3-5 days.

The disadvantage is that when using ozonized compounds, a large concentration of reactive oxygen species occurs.

A known method for the prevention and treatment of placental insufficiency in pregnant women (RF patent No. 2149592, 2000.05.27), including drug correction, characterized in that they additionally introduce sodium or calcium alginate 2 g of pure substance per day in the form of an aqueous solution or gel at once in the morning on an empty stomach 30-40 minutes before meals for 21 days, in two courses, the first - up to 12-14 weeks of pregnancy, the second - 4-6 weeks after the end of the first.

The disadvantage - the difficulty lies in the need for highly qualified medical staff to perform manipulations and monitor pregnant women.

A known method of treating fetoplacental insufficiency (RF patent No. 2195289, 2002.12.27), including the use of reopoliglyukin, characterized in that first, intravenous administration of ozonized physiological solution with a concentration of dissolved ozone of 1.5-2 mg / l in an amount of 400 ml followed by intravenous dropwise administration of 400 ml of reopoliglukin 1 time per day every other day with a course of 3 infusions.

The disadvantage is that when using ozonized compounds, a large concentration of reactive oxygen species occurs.

It is effective to use nitroglycerin preparations (transdermal form) as donors of nitric oxide with the threat of premature birth (B. Gorzelanak et al., 1999). The authors used the drug in the second trimester of pregnancy. During therapy with nitroglycerin, the indicators of fetoplacental hemodynamics were studied before and after treatment, the indicators of maternal hemodynamics with normal blood pressure values. After analyzing the results, the researchers came to the conclusion: nitroglycerin during transdermal use does not adversely affect the hemodynamics of the mother and fetus. The tocolytic effect of the drug was pronounced, which confirms the significant role of NO in the regulation of vascular and uterine tone.

These results were reflected in the work of F. Facchinetti et al. (2005). They proved that nitric oxide donors have a pronounced tocolytic effect on the myometrium. However, it was noted that NO, together with prostaglandins, promotes the maturation of the cervix to childbirth. In vivo in rats, a decrease in the content of nitric oxide before childbirth in myocytes and an increase in concentration in the cervix were proved (E. Ekerhovd, B. Brannstorm et al., 2002).

A known method of treating threatening termination of pregnancy (RF patent No. 2176920, 2001.12.20) by prescribing tocolytic drugs, characterized in that the side of the preferential location of the placenta is preliminarily determined by ultrasound and, with right-sided localization of the placenta, a 3-fold administration of tocolytic drugs is prescribed at 8, 15, 23 hours, with a left-sided location of the placenta - 5-fold administration of tocolytics - 7, 11, 15, 19, 23 hours, and with ambilateral localization of the placenta, systolodiast parameters are additionally measured the right and left uterine arteries and at a Vs / Vd index lower than normal on the right, therapy is carried out at the same hours as with right-sided placenta localization, and with a decrease in Vs / Vd on the left - at the same hours as with left-sided placenta localization .

A known method of treating fetoplacental insufficiency in pregnant women (RF patent No. 23234486, 2008.05.20), which consists in the appointment of traditional therapy and simultaneous therapeutic inhalations using a gaseous agent, characterized in that therapeutic inhalation is carried out using xenon, for which, first, in a half-open respiratory the circuit is supplied with 100% oxygen for 5-10 minutes, then the respiratory circuit is transferred to the closed one and a mixture of xenon and oxygen is supplied - in case of compensated chronic placental insufficiency accuracy at a ratio of 60:40, with a subcompensated 70:30, and for repeated procedures in the absence of a significant effect of the therapy 80:20, for 2-10 minutes, then the xenon supply is stopped, the respiratory circuit is transferred to half-open and for 5 -8 min increase the oxygen concentration in the inhaled mixture to 100%, only perform 2-3 inhalations with an interval of 5-10 days.

The disadvantage of this method is that therapeutic inhalations are carried out 1) with xenon, which dramatically increases the cost of the treatment process. The production of inert gases, in particular xenon, requires expensive equipment and complex production schemes;

2) to all pregnant women, without taking into account the state of free radical activity in the body;

The prototype of the claimed invention selected a method of treating threatening termination of pregnancy according to the patent No. 2176920, 2001.12.20, according to which the placenta is determined for the pregnant woman and with right-sided localization, tocolytics are prescribed three times a day: 8, 15, 23 hours, and with left-sided localization - five times the administration of tocolytics during the day: 7, 11, 15, 19, 23 hours.

The disadvantage of the prototype method is the complexity and significant drug load on the body.

A new technical task of the claimed invention is to increase the effectiveness of treatment by reducing side effects as a result of the use of new drugs that can reduce the drug load in the treatment of the threatening condition of pregnancy.

To accomplish this task, a method of two-dimensional ultrasound scanning reveals a violation of the uteroplacental hemodynamics and determines the side of the preferential location of the placenta, and those pregnant women who have a violation of the uteroplacental hemodynamics carry out a transdermal effect with deposit 10 on the acupuncture point BM-147 on the side of the dominant uterine arteries, treatment 1-2 sessions. With a right-handed and with an ambilateral location of the placenta - on the right side, with a left-side location - on the left side. The duration of one session is 24 hours, which is determined by the time of release of nitric oxide from the patch. The need to determine the location of the placenta by the ultrasound method before treatment is due to the fact that deposit-10 has a pronounced antispasmodic effect and the dominant uterine artery undergoes the greatest dilatation.

The solution to this problem made it possible to develop etiotropic pathogenetically substantiated prophylaxis and therapy of placental insufficiency in pregnant women in early pregnancy and achieve the following positive results:

- simplify the method of treatment,

- eliminate excessive drug effects on the body,

- high efficiency.

Modern ideas about the essence of the main pathogenetic links of obstetric pathology are somehow connected with a change in the functional state of the endothelium (E.A. Malakhovskaya, M.S. Zainulina, 2004). The complex of changes in the state of cell endothelium in obstetric pathology is defined as endothelial dysfunction and is inadequate, i.e. reduced or excessive formation in the endothelium of various biologically active substances (N.N. Petrishcheva, 2003). Given the main functions of the endothelium, these changes represent an imbalance between the production of vasodilating and angioprotective factors, on the one hand, and vasoconstrictor and prothrombotic factors, on the other.

Violation of biosynthesis in the endothelium of factors that regulate vascular tone and thrombosis of the vascular wall leads to the development of typical clinical manifestations of obstetric pathology, such as miscarriage, placental insufficiency, gestosis (Martinez-Abundis, 2000).

The existing data on the decrease in the expression of eNOS in the fetoplacental complex during the complicated course of pregnancy dictate the need to study the effectiveness of nitrovasodilators as exogenous donors of nitric oxide in obstetrics. These drugs belong to the group of peripheral nitrovasodilators and in their action mimic the endothelial relaxation factor, which is identified as NO, actually being a replacement for NO-therapy.

Among the abundance of biologically active ones produced by endothelium, nitric oxide is the most important, which, being produced continuously by endothelium using endothelial NO (eNOs) from L-arginine, supports the normal basal vascular tone (V.I. Buvaltsev, 2006).

An important role, according to J.M. Joyce et al. (2002), NO and NO synthase play during pregnancy, providing increased uterine blood flow due to the vasodilating effect and an increase in their content in the bloodstream.

A number of authors believe that, during pregnancy, NO synthesis increases (S.V. Khlybova et al., 2007), which inhibits uterine contractility (L. Lau et al., 2001), reduces peripheral vascular resistance and maintains adequate blood flow in the mother and the fetus (F. Medaglia et al., 2001). It is believed that low levels of NO cause gestosis (E.S. Severin, 2003).

The results of the study of vasoactive peptides after treatment with nitric oxide donors (deponite-10) showed that in group I the level of NO increased by 1.2 times and amounted to 28.50 pg / ml (23.95-42.45). In the group of pregnant women with an alternative treatment regimen, the concentration of NO increased by 1.2 times and amounted to 31.1 pg / ml (27.0-42.5). The revealed changes in the NO concentration after therapy in the study groups are obviously due to the needs of a developing pregnancy, when the formation of the vascular system of the uterus, placenta and fetus occurs (B.P. Kopnin, 2001). In our study, in groups with complicated pregnancy there is an imbalance between the components of the endothelial system, which explains the reduced concentration of NO in the blood serum.

When studying the concentration of NOs in the blood serum of the pregnant study groups, the following changes were revealed. In patients of group I after treatment with nitric oxide donors (deponit-10), the NOs level was 38.32 pg / ml (30.55-47.03), which was 1.4 times higher than the data before treatment. The most significant increase in NOs in dynamics was observed in the blood serum of group II patients and amounted to 46.8 pg / ml (37.6-55.9). In this group, the level of Nos increased by 1.7 times compared with the data before treatment and exceeded the result of group I by 1.2 times.

Our data on the content of nitric oxide metabolites in peripheral venous blood testified to an early onset of systemic endothelial dysfunction, however, timely treatment with nitric oxide donors reduced the expression of VEGF and endothelin-1 while increasing the level of NO and NOs, thereby reducing placental ischemia. We found that during therapy with deponite-10, the concentration of vasoactive compounds, physiological vasodilators, increases, which once again proves the validity of ion therapy with nitric oxide donors. Deponit-10, releasing dosed nitric oxide into the mother’s peripheral bloodstream, reduces endothelial dysfunction, hypoxemia and stops the pathological expression of growth factors at the site of placenta invasion.

Compared with traditional therapy, complex therapy using deponit-10 had a positive effect on the clinical course of pregnancy, which manifested itself in an improvement in the general condition of patients, quick relief of symptoms of early vomiting of pregnant women, reduction of pain, normalization of myometrial tone, decrease in the number of medications taken, increase total body reactivity.

In contrast to generally accepted methods, the use of this method avoids undesirable complications of drug therapy for the mother and fetus, since it takes into account the individual (physiological) characteristics of the body of each pregnant woman.

To complete the assessment of the effectiveness of monotherapy with nitric oxide donors for hemodynamic disturbances in the first half of pregnancy, during our study, we studied the indicators of blood flow intensity in the AP and SMA pools. Before and after treatment, the systolic diastolic ratio did not undergo significant changes.

This allowed us to conclude that nitric oxide donors do not adversely affect fetal blood flow and the fetus and require further study in this direction.

And finally, the most important thing in this fragment of research is the proven absolute safety for the fetus with Deponit-10 therapy. Treatment with deponite-10 leads to an increase in the level of NO and NOs, stops the expression of VEGF and endothelin-1 and contributes to an increase in the intensity of uteroplacental blood flow.

The results obtained in the treatment with deponit-10 can reduce the drug load on the fetus in early pregnancy, reduce the economic costs of treatment.

A detailed description of the method and examples of its specific implementation.

To select a treatment strategy for threatening termination of pregnancy in the I-II trimesters after a general clinical examination (complaints, medical history, vaginal examination, etc.), which allows to determine the severity of clinical manifestations, an ultrasound examination is performed to detect violations of uteroplacental hemodynamics and determine the preferred location of the placenta .

All studies were performed on a Simens Sonoline G50 ultrasound device (registry No. 93/68) operating in a pulsed Doppler mode using color Doppler imaging. A convex electronic sensor with a frequency of 3.5 MHz is used.

If the placental location is ambilateral, an additional Dopplerometric study of blood flow in the right and left uterine arteries is performed. The study of blood flow velocity curves in the uterine arteries is carried out by longitudinal scanning in the region of the lateral walls of the uterus.

Pregnant women in whom these disorders are identified are treated with deponite-10. The treatment regimen is a transdermal form in the form of a band-aid on the acupuncture point BM-147 on the side of the dominant uterine artery, 1-2 sessions under the control of a Doppler study of uteroplacental hemodynamics.

For all pregnant women with a threat of termination of pregnancy at a gestational age of 9-24 weeks of pregnancy, the drug Deponit-10 (DEPONIT 10) was prescribed as monotherapy. The drug was approved by the Head of the Department of State Control of Medicines and Medical Equipment of the Ministry of Health of the Russian Federation on September 17, 2003. It was approved by the Pharmacological Committee of the Ministry of Health of the Russian Federation on July 10, 2003, protocol No. 5b, registration number: No. P-8-242 N008886. Deponit-10, venodilator from the group of nitrates. Nitrates release nitric oxide from their molecule, which is a natural endothelial relaxing factor. It has an antispasmodic effect on the smooth muscles of the vascular wall, promotes the redistribution of blood flow. The therapeutic system is transdermal, which, after attaching the patch to the skin, provides continuous release of nitroglycerin from the drug reservoir, which ensures its circulation in the circulatory system at relatively constant concentrations for the recommended time for replication.

The appropriateness of choosing an acupuncture point VM-147 for exposure is determined by a pronounced increase in uteroplacental hemodynamics, which is confirmed by our experimental and clinical data.

At the time of the study, all pregnant women revealed violations of the uteroplacental blood flow of grade IA-IIB. The study of blood flow in uteroplacental hemodynamics was carried out after 5-6 and 24-48 hours and 3-5 days after the end of treatment. A therapeutic patch is applied on the skin, on the lower leg, depending on the location of the placenta. Since the dominant artery undergoes the greatest dilatation during deponitis-10 therapy due to the pronounced antispasmodic effect, when the placenta is located on the right, the patch is attached on the right, on the left - on the left, and on an ambilateral location - on the right. The duration of the patch is 12-24 hours, the number of sessions is 1-2. The frequency of use is determined by the Dopplerometry indicators - until they are normalized. If after the first session the utero-placental blood flow indicators have not returned to normal, a second session is performed - the old adhesive plaster is removed and a new one is attached.

It should be noted that the use of deponite-10 in pregnant women did not affect the performance of central hemodynamics. The duration of therapy was determined by the results of a Doppler study. If, against the background of therapy, after 4-6 hours, an increase in blood flow intensity in the uteroplacental pool is noted, then therapy is continued until the blood flow intensity in the uterine vessels is completely restored.

We present clinical examples that explain the practical implementation of the method.

Example 1

Pregnant I-va Yu.B., 30 years old. Medical history N2844 / 396. Examination May 11, 2007 D.S .: 9-10 weeks of pregnancy. ART (IVF SM). Threatening s / abortion.

By ultrasound, the left-lateral location of the placenta. Dopplerometric examination revealed abnormalities of uteroplacental hemodynamics of the IA degree: in the right uterine artery, Vs / Vd is 3.7 - normal; in the left uterine artery, Vs / Vd is 5.5, which indicates spasm. Conducted 1 session with deposit-10 by the claimed method. Then, after 4-6 hours, a Dopplerometric study was performed. The results of the dopplerometric study revealed the restoration of uteroplacental hemodynamics and amounted to: in the right uterine artery, Vs / Vd is 2.25, which is normal, in the left uterine artery, Vs / Vd is 2.57 - normal. In relation to the PDM indicators, the left uterine artery was dilated prior to the course with Deponit-10, where violations were determined. This testified to the normalization of blood flow and, thus, the effectiveness of treatment with this method.

Example 2

Pregnant T-va L.I., 35 years old. Medical history N2485 / 340. Examination April 23, 2007 D.S .: 16-17 weeks of pregnancy. Threatening late c / abortion. Violation of uteroplacental hemodynamics.

By ultrasound, the left-sided location of the placenta. A dopplerometric study revealed a violation of the uteroplacental hemodynamics in the pool of both uterine vessels: in the right uterine artery, Vs / Vd is 2.5 - more than normal; in the left uterine artery, Vs / Vd is 2.6, i.e. more than normal; blood flow in the umbilical artery is not violated. Vs / Vd-3.0 - normal. Conducted 1 session with deposit-10 by the claimed method. Then, after 4-6 hours, a Dopplerometric study was performed. Dopplerometry revealed a complete restoration of uteroplacental hemodynamics, which indicated the greatest effectiveness of deponite-10 therapy in this pregnant woman. In terms of Dopplerometry, hemodynamics normalized, in relation to the PDM indicators, before the course of the NBO course, the uterine arteries were dilated both on the right and on the left. This testified to the normalization of blood flow and, thus, the effectiveness of treatment with this method.

In the course of the study, all pregnant women were divided into two clinical groups: the main group consisted of 75 patients with a pathological pregnancy in the I-II trimesters who underwent inpatient treatment in the conditions of the department of pregnancy pathology with a diagnosis of “threatened abortion” (UPB). The second was 50 pregnant women with a diagnosis of “threatened abortion,” with an alternative treatment regimen, observed in the Obstetric Monitoring system of the Federal State Institution RNIIAP.

The threat of abortion was established when the patient complained of spotting from the genital tract, pain in the lower abdomen, and dopplerometric examination revealed violations of the uteroplacental hemodynamics or disturbances in the umbilical artery. During the examination of patients of all groups, we used generally accepted methods: medical history, complaints, laboratory tests.

NO synthase activity was measured by increasing NO production from 1-arginine in the presence of NADPH. The formed NO was quantified by EPR spectrometry of mononitrosyl complexes with ferrous iron and diethyl dithiocarbomatum, which possess characteristic paramagnetic properties. EPR signals were recorded on a Zeiss EP-9 radio spectrometer. The endogenous level of nitric oxide in the form of a nitrite anion (NO ₂ ) was determined using the Griss reagent.

Pregnant women in the control group (with a physiological course) underwent standard complex therapy. It included antispasmodic (mainly no-shpa - 2.0 intramuscularly or by mouth, suppositories with papaverine - into the rectum), metabolic (actovegin - intravenously, folic acid - 1 t × 3 times a day), antibacterial ( ampicillin - 1.0 intramuscularly 4 times a day) preparations. Patients were also prescribed progesterone preparations, chorionic gonadotropin. The duration of alternative therapy was 3-5 days, and the intensity of the infusion therapy with vasoactive drugs was also determined by violations of the uteroplacental hemodynamics, depending on the clinical situation.

To compare the samples (main group), the paired Wilcoxon test was used before and after treatment.

The advantage of the claimed methodology.

1. Ease of use - available to nursing staff

2. Economic feasibility - low cost of the procedure

3. The absence, in contrast to pressure chambers, of excessive pressure on the body

4. High efficiency

5. The lack of emotional factor in the confined space of the pressure chamber

6. The ability to monitor the status of the pregnant woman in real time

7. Control of peroxidation and free radical mechanism.

Thus, treatment according to the specified method can be recommended in case of a threatened abortion in the early stages of pregnancy. The proposed treatment method for threatening abortion will reduce the number of preterm births and reduce perinatal morbidity and mortality.

The proposed method for the treatment of threatening abortion in the I-II trimester, taking into account the physiological functions of the body, can be used in all pregnant women with this pathology, since it is simple and available for use in obstetric hospitals of any level.

Claims (1)

A method for treating a threatening state of pregnancy, including a preliminary determination of the side of the preferential location of the placenta and the appointment of drug therapy depending on the lateralization of the placenta, characterized in that in 1-2 trimesters of pregnancy, pregnant women with a revealed violation of the uteroplacental hemodynamics carry out a transdermal effect of 10-deposit on the acupuncture point BM-147 lower leg, located on the side of the placenta, for 12-24 hours, the course of treatment is 1-2 sessions.