Clinical and Pharmacological Justification for the Use of Metabolically Active Agents in Preparing Pregnant Women for Labor

The dissertation is devoted to the clinical and pharmacological justification for the use of the metabolically active agent actovegin in the preparation of pregnant women for labor. The research was conducted in the context of perinatal medicine and is aimed at addressing the problem of improving the effectiveness of prenatal preparation among women in the high-risk group for the development of labor abnormalities. The work examines the biochemical mechanisms of myometrial contractile activity, energy metabolism in the muscle cells of the uterus, and the role of impaired mitochondrial function in the pathogenesis of dysfunction of labor activity.

The relevance of the research is conditioned by the increase in morbidity among pregnant women, the rise in the number of labor abnormalities, and the necessity of searching for new approaches to preparation for labor. A system for the use of metabolically active agents has been proposed in the work, taking into account the concept of cellular energy deficit of the myometrium. The research combines experimental and clinical methods: the study of the influence of actovegin on the contractile activity of the myometrium in experiments on pregnant rats, assessment of fetal condition based on data from cardiotocography, ultrasonic examination, and Dopplerometry, as well as the development of a methodology for preparation for labor for pregnant women at high risk.

Relevance of the Research Topic.

Preparation of pregnant women for labor in contemporary conditions acquires even greater significance than before, since, in the opinion of V.I. Kulakov /2002/, in the context of low birth rates in Russia, the favorable outcome of each pregnancy constitutes a paramount task for both obstetricians-gynecologists and neonatologists, that is, obstetrics increasingly acquires a perinatal character. The most relevant tasks in this direction are the preparation of women for pregnancy and childbirth and rational delivery management. N.I. Kulakov /2002/ notes that the necessity of preparing women for pregnancy is conditioned by a number of factors. First and foremost, the fact that morbidity among adolescent girls is increasing /the level of which is 10–15% higher than among young men/. Inflammatory diseases, including chronic ones, endometriosis, and menstrual cycle disturbances are predominant at this age. At the same time, gynecological morbidity among adolescents is increasing against the background of rising somatic pathology and socially significant diseases.

Negative trends in the health status of pregnant women and newborns have taken a steady character. The number of anemias among pregnant women is increasing /43.9%/, gestoses /21.4%/, and pathology of the cardiovascular and renal systems /by 1.5 times/. Physiological labor accounts for 31.1%. More than half of newborns are discharged as patients from obstetric hospitals. All of the above dictates the necessity of examination and corresponding preparation of women for pregnancy, as well as for labor /V.I. Kulakov, 2002, 2004/.

One of the problems of perinatal obstetrics is intensive monitoring during pregnancy and labor, with a special place being occupied by preparation for pregnancy /periconceptional prevention/.

The readiness of a woman's organism for labor is determined by the appearance of structural and functional changes occurring in the uterus before labor. The clearest picture of the degree of readiness for labor is provided by careful palpatory assessment of cervical maturity /G.G. Chechinashvili et al., 1982; E.A. Chernuha, 2003/. When making a decision on the completion of pregnancy, the most important indicator determining the course of subsequent events is the degree of uterine maturity. "An immature cervix /not ready for labor/ is incapable of adequate dilation in response to uterine contractions. The determination of the degree of cervical maturity is highly subjective, and even experienced specialists may reach different conclusions regarding its maturity. For a more objective conclusion on the degree of cervical maturity, several scoring systems have been developed /prof. G.G. Chechinashvili, Bishop score, etc./. It is considered that the degree of cervical dilation has far greater significance compared with the number of points for all other parameters /cervical length, external os opening, consistency of the cervix, position of the cervix in relation to the pelvic axis, and the location of the presenting part of the fetus./ M. Enkin et al., 2003/.

An attempt at labor induction with an immature cervix leads to a high rate of labor induction failure, prolonged labor, a high rate of operative delivery, and other complications, including infectious complications, chorioamnionitis, as well as the development of uterine hypertonus and other side effects associated with the use of oxytocin /M. Enkin et al. 2003/.

This acquires particular significance in pregnant women at high risk for the development of labor abnormalities or in cases of premature termination of pregnancy. Therefore, the optimal variant is the creation of conditions for the development of spontaneous labor activity. /E.T. Mikhaillenko, M.Ya. Chernuha,/ 1988.

Despite the fact that in recent years new methods of pharmacological and non-pharmacological influence have been developed with the aim of accelerated formation of the organism's readiness for labor /application of prostaglandin gels, antigestagens, acupuncture-reflexotherapy, etc./, the problem of effective preparation for labor remains far from resolved. For this reason, questions of prenatal preparation, which play a large role in reducing perinatal and maternal morbidity, remain highly relevant /Yu.L. Volkov, 1989; N.D. Gasparyan, 2002; Novikova S.B., Petrukhin V.A., Titchenko L.I., Levashova I.I., 2002, et al./.

In the pathogenesis of disturbances of uterine contractile activity, the leading role, especially in the development of uterine inertia, is attributed to biochemical processes in the uterus itself, the necessary level of which is ensured by neural and humoral factors /E.T. Mikhaillenko, M.D. Kursky, V.V. Chub, 1980/.

Many factors influence the development of regular labor activity, namely: biological readiness of the organism on the eve of labor, hormonal homeostasis, fetal condition, concentration of endogenous prostaglandins and uterotonics in the blood, and sensitivity of the myometrium to them.

It is also important to consider energy metabolism in the myometrium during pregnancy and labor. Energy for muscle contraction and relaxation is mainly provided by ATP. Regulation of smooth muscle tone has its own regularities and is accomplished through the interaction of signals from conducting systems /calcium ions, which regulate reactions in smooth muscle cells according to the principle of synergism and antagonism /V.V. Abramchenko, 1991; A.B. Mikhailov, 1999; I.S. Sidorova, 2000; G.A. Savitsky, A.G. Savitsky, 2003, et al././

Activation of myometrial cells through a sequential chain of processes causes an increase in intravascular calcium concentration and the formation of actomyosin, which leads to the contraction of smooth muscle fibers. Relaxation of the myometrium is also accomplished through a complex biochemical process, one aspect of which is the removal of excess Ca2+ from the cell through sodium-calcium exchange /G. Reis et al., 1999; Covacs, Kronenberg, 1997/.

In the mechanism of smooth muscle contraction, smooth muscle cells contract using the same mechanism as skeletal muscles — the sliding of actin and myosin filaments. However, these cells differ significantly in their structure and functions. Unlike cardiac and skeletal muscle, smooth muscle: lacks striations; is responsible for the contraction of blood vessels, the digestive tract, the uterus, and the respiratory passages; consists of elongated, spindle-shaped cells containing actin and myosin-P.

In smooth muscle cells, filaments are loosely arranged along the long axis of the cell. In addition, smooth muscle cells are connected to the plasma membrane in special discoid contacts called dense bodies /Faller D.M., Shields D., 2003/. It is assumed that intermediate filaments and dense bodies of smooth muscle cells, containing α-actinin, perform the same function as the H-discs of striated muscles. Bundles of actin and myosin filaments are attached at one end to the dense bodies of the plasma membrane and at the other end to intermediate filaments. Unlike striated muscles, smooth muscles contract without the participation of the troponin-tropomyosin complex, although contraction is also initiated by Ca2+ ions. The increase in Ca2+ concentration in smooth muscle cells is mediated by the calcium-binding protein calmodulin, which activates myosin light chain kinase, which in turn phosphorylates one of the two light chains of myosin. Upon phosphorylation, the head domain of myosin binds to actin, initiating contraction /Faller D.R., Shields D., 2003/.

Taking into account the concepts of energy deficit and impaired mitochondrial function in the pathogenesis of labor abnormalities /B.B. Abramchenko, 2000/, contemporary obstetrics possesses a number of methods of influence on cellular energy deficit with the aim of preventing labor abnormalities and preparing pregnant women for labor. One of the promising agents in this direction appears to be actovegin, which influences processes of intracellular metabolism, thereby increasing the energetic potential of the cell. Under the action of actovegin, the exchange of high-energy phosphates /ATP/ is increased within the cell; enzymes of oxidative phosphorylation are activated; the activity of acid phosphatase and lysosomal activity of the cell is increased; the activity of alkaline phosphatase is increased, the synthesis of carbohydrates and proteins is accelerated; the influx of potassium ions into the cell is increased, and potassium-dependent enzymes are activated: catalase, sucrase, glucosidase; the breakdown products of anaerobic glycolysis — lactate and β-hydroxybutyrate — are accelerated /B. Nordvik, 1997; I.E. Gridchik et al., 1997; G.L. Gromyko, 1997/.

The above premises are, evidently, the basis for the use of metabolically active agents in the preparation of pregnant women for labor who are at high risk for the development of labor abnormalities, taking into account the concept of cellular energy deficit and impaired mitochondrial function in the pathogenesis of labor abnormalities.

----------Objective of the Present Study~

To study the effectiveness of the preparation of pregnant women for labor using metabolically active agents in the absence of biological readiness for labor in pregnant women at high risk for the development of labor abnormalities.

Tasks of the Study

1. Experimentally, in animal experiments /on pregnant rats/, to study the influence of actovegin on the contractile activity of the myometrium.

2. To study the clinical course of pregnancy and labor in pregnant women prepared with actovegin in the absence of biological readiness for labor.

3. To evaluate the influence of actovegin on the contractile activity of the myometrium and the condition of the fetus, including data from cardiotocography, ultrasonic examination, and Dopplerometry.

4. To develop a methodology for the preparation of pregnant women threatened with the development of labor abnormalities using actovegin.

Scientific Novelty and Significance of the Work

For the first time, a system for the use of metabolically active agents in the preparation of pregnant women for labor has been developed, taking into account the concept of cellular energy deficit of the myometrium in this category of pregnant women.

Practical Significance of the Work

Methods for the preparation of pregnant women for labor using metabolically active agents have been developed in the group of pregnant women at high risk for the development of labor abnormalities.

Main Provisions of the Dissertation Presented for Defense

1. Two methodologies for the preparation of pregnant women for labor using metabolically active agents in the group at high risk for the development of labor abnormalities have been developed and implemented.

2. A clinical-experimental justification for the use of metabolically active agents in the preparation of high-risk pregnant women has been presented. In animal experiments, it was established that actovegin in a total dose of 100 mg per animal significantly increases the amplitude and frequency of myometrial contractions in pregnant rats before labor.

3. The use of the metabolically active compound actovegin for the preparation of pregnant women for labor contributes to the achievement of biological readiness for labor, serves as a means of preventing uterine inertia, and reduces the frequency of operative delivery and complications in labor.

Verification of the Work, Implementation of Results in Practice, and Personal Contribution of the Author.

The materials of the dissertation were presented at the republican scientific-practical conference with international participation "Perinatal Psychology" /St. Petersburg, 2003/; at the 4th All-Russian Congress on Perinatal Psychology, Psychotherapy, and Perinatology with international participation "Through the Integration of Sciences — to the Preservation of Reproductive Health of the Family" /Moscow, 2003/; Materials of the All-Russian Scientific-Practical Conference "Medical Technologies in the Protection of Reproductive Health of Women" /Yekaterinburg, 2003/; 5th All-Russian Scientific-Practical Conference /St. Petersburg, 2003/; Materials of the 6th Russian Forum "Mother and Child" /M., 2003/; at the republican scientific-practical conference with international participation "Perinatal Cardiology" /Yekaterinburg, 2003/; at the Russian National Congress "Man and Medicine" /Moscow, 2004, 2005/; at the II and III All-Russian Interdisciplinary Scientific-Practical Conferences /Petrozavodsk, 2004, 2005/, Materials of the 6th Russian Forum "Mother and Child" /M, 2004/; Materials of the All-Russian Scientific-Practical Conference of Obstetricians-Gynecologists, Saransk, 2004.

On the topic of the dissertation, 21 printed works have been published, including: a monograph and a patent for an invention.

The results of the work have been implemented in the clinical practice of obstetric departments and departments of pregnancy pathology of the women's consultation and maternity hospital of Khimki /Moscow Region/.

The research was conducted at the base of the obstetric department, women's consultation, and maternity hospital of Khimki /Moscow Region/.

Data processing and analysis were carried out by the author independently. In the analysis of the material, co-authors provided consultative assistance.

Structure and Volume of the Dissertation

The dissertation is presented on 164 pages of typed text and consists of an introduction, five chapters, conclusions, practical recommendations, and a list of references containing 316 sources, of which 286 are domestic and 27 are foreign. The text is accompanied by 46 tables.