Gestosis: causes and pathogenesis

Cause

Causes of gestosis

The causes of gestosis development depend on many factors, are complex and have not been fully studied. Despite numerous studies, there is still no consensus in the world about the causes of gestosis. Undoubtedly, the disease is directly related to pregnancy, since the termination of the disease before the development of severe complications always contributes to recovery.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Pathogenesis

Pathogenesis of gestosis

Many factors are involved in the genesis of gestosis, but the triggering mechanism of this disease is still unknown.

Gestosis is a disease associated with implantation of the fetal egg, and it is proved that the bases of the disease are laid in the early stages of gestation.

Due to immunological and genetic peculiarities in pregnant women at the moment of implantation, inhibition of trophoblast migration and the absence of transformation of the muscle layer in spiral arteries preserving the morphology of nonpregnant ones, which predisposes them to spasm, decrease of intervillar blood flow and hypoxia, are observed.

Hypoxia, which develops in the tissues of the utero-placental complex, causes damage to the endothelium with a violation of its thrombose-resistant and vasoactive properties, the release of mediators (endothelin, serotonin, thromboxane) that play a key role in the regulation of hemostasis and vascular tone. One of the reasons that can cause endothelial dysfunction may be an inadequate release of the endothelial relaxing factor, identified with nitric oxide, the most potent dilator synthesized by endothelial cells, whose level in gestosis is sharply reduced. In parallel with these changes, there is a disruption in the synthesis and imbalance of prostanoids of maternal and fetal origin (prostaglandins of classes E and F, prostacyclin, thromboxane, etc.) that provide dynamic equilibrium in the homeostasis system, and cause the necessary changes in the woman's body during pregnancy.

Insufficient production of prostacyclin and prostaglandin E or hyperproduction of prostaglandin F and thromboxane leads to generalized vascular spasm and an increase in total peripheral vascular resistance (OPSS), a decrease in cardiac output, reduced blood flow and glomerular filtration of the kidneys, and impaired microcirculation in the placenta.

Thrombophilic disorders occur due to the presence of genetic changes in a number of blood clotting factors in women: resistance to protein C, congenital deficiency of protein S and antithrombin, as well as other genetic disorders in the blood clotting system.

In addition, one of the main pathogenetic links in the development of gestosis is the deposition of circulating immune complexes in vital organs and their damage. In 93% of pregnant women who underwent gestosis, even in the absence of pathological changes in the kidneys, deposits of immunoglobulins of classes G, M and A.

The main links in the pathogenesis of gestosis:

• generalized vasospasm;
• hypovolemia;
• violation of rheological and coagulation properties of blood;
• endotoxemia;
• hypoperfusion of tissues;
• violation of the structural and functional properties of cell membranes with changes in the vital activity of cells;
• ischemic and necrotic changes in the tissues of vital organs with a violation of their function.

The classic triad of gestosis symptoms (edema, proteinuria, hypertension), described in 1913 by the German obstetrician Tsangemeister, is caused by a number of pathogenetic factors closely related to each other.

1. Generalized vascular spasm (mainly in the arterial blood circulation) leads to an increase in intravascular pressure, a stasis of blood in the capillaries, an increase in the permeability of small vessels. As a result of these processes, there is an increase in OPSS, which leads to the development of arterial hypertension and impaired blood circulation in vital organs. The degree of increase in OPSS is directly dependent on the severity of gestosis.
2. Long-term vasospasm leads to disruption of myocardial activity, which leads to the development of ischemic myocardiopathy. Echocardiographic study of central hemodynamics in pregnant women with gestosis revealed the following features: as the degree of severity of gestosis increases, the shock and heart rate indices decrease reliably. Most often with gestosis, hypokinetic and eukinetic types of central maternal hemodynamics are revealed. There is a directly proportional relationship between the type of central maternal hemodynamics and the severity of gestosis. Thus, in the hyperkinetic type of central maternal hemodynamics, a mild gestosis severity was revealed in 85.3% of the observations and in none severe. At the same time, in the hypokinetic type of central hemodynamics, mild gestosis severity was revealed only in 21.2% of cases.
3. Disturbances of hemodynamics in the renal vessels lead to ischemia of the cortical layer of the kidneys. The severity of disorders of renal and intrarenal blood flow is directly dependent on the type of central maternal hemodynamics and severity of gestosis. With mild severity of gestosis, violations of renal and intrarenal blood flow are detected only in 30%, at an average of 60%, and at severe - in 92%. Clinically, renal circulatory disorders are manifested by the development of renal failure, a decrease in glomerular filtration and a decrease in diuresis, proteinuria, water and sodium retention. Spasm of kidney vessels and kidney ischemia provide excessive release of renin and angiotensin, which contributes to an even greater angiospasm and increased blood pressure.
4. Spasm of cerebral vessels causes a reduction in cerebral circulation, which is confirmed by the results of a Doppler study of blood flow in the carotid artery system. However, violations of cerebral hemodynamics do not depend on the initial type of central maternal hemodynamics. According to our data, pronounced blood flow disorders in the system of carotid and supra-lateral arteries are observed only in gestoses with a rapid increase in clinical symptoms. These changes create conditions for the development of cerebral edema and its membranes, which is clinically manifested by cerebral syptomatics, and in especially severe cases by the onset of convulsive seizures (eclampsia).
5. Spasm of the uterine and spiral arteries leads to a violation of the uteroplacental blood circulation, which, in turn, causes disturbances in the fruit and placenta blood flow. Violation of utero-placental-fetal hemodynamics leads to chronic hypoxia and NWFP. The severity of disorders of utero-placental-fetal hemodynamics is also directly dependent on the type of CMG and is clearly correlated with the severity and duration of gestosis. Special attention should be paid to the analysis of observations with bilateral violation of blood flow in the uterine arteries. At this type of hemodynamic disturbances, middle-severe patients were detected in 30% of cases, and severe forms of gestosis in 70%. It should be noted that violations of utero-placental circulation and intraplacental circulation are revealed in the Doppler study at the beginning of the second trimester of pregnancy.
6. When analyzing the dynamics of OPSS changes and indices of vascular resistance in the carotid, renal, uterine, spiral arteries, the umbilical artery and its terminal branches, it is established that in uncomplicated pregnancy, the maximum decrease in peripheral vascular resistance is noted in the uterine and spiral arteries, the cord of the umbilical cord and its terminal branches. These changes are compensatory-adaptive in nature and are aimed at creating optimal conditions for the normal development of the fetus. At the same time, with gestosis, OPSS increases most, and the smallest increase in vascular resistance was noted in the utero-placental-fruiting link of the circulation. The data obtained by us can be considered as evidence that, despite gestosis, in spite of the decrease in volume indices of central hemodynamics and systemic vascular spasm, compensatory-adaptive mechanisms are formed, primarily aimed at the normal functioning of the mother-placenta-fetus system, and only with their depletion develops fetoplacental insufficiency and retardation of intrauterine development of the fetus.
7. In a number of cases, pronounced changes in the vessels contribute to the deposition of fibrin in their lumen, aggregation of erythrocytes and platelets. At the same time, perfusion of vital organs worsens even more and a syndrome of disseminated intravascular coagulation is formed.
8. Circulatory disorders cause a decrease in detoxification activity and protein-forming function of the liver. Developing in this hypo- and disproteinemia lead to a decrease in osmotic and oncotic pressure, which in turn contributes to the appearance of hypovolemia, hemoconcentration, water and sodium retention in the interstitial space.
9. The irritation of angioreceptors leads to the formation of hypovolemia. The latter is the cause of the pathological reaction of the central nervous system and hypothalamic-pituitary-adrenal system, increasing the production of antidiuretic hormone, 17-oxycorticosteroids, aldosterone, which also contributes to the retention of sodium and water in the body.

As a result of a comprehensive study of central hemodynamics and renal, cerebral and utero-placental-fetal and intraplacental blood flow, as well as analysis of the outcomes of pregnancies and births, four pathogenetic variants of systemic maternal hemodynamics were revealed in gestosis:

1. Hyperkinetic type of CMG irrespective of OPSS values and eukinetic type of CMG with normal OPSS numerical values. With this type, moderate violations of cerebral, renal, utero-placental and intraplacental blood circulation are recorded.
2. Eukinetic type of CMG with increased OPSS values (more than 1500) and hypokinetic type of CMG with normal OPSS values. At this type, blood flow disorders predominantly of I and II degree are registered in the renal artery system, utero-placental-fetal and intraplacental blood flow.
3. Hypokinetic type of CMG with elevated OPSS. In this type of severe violations of the renal, utero-placental-fetal and intraplacental blood flow are detected in 100% of observations.
4. Severe disorders of cerebral hemodynamics (increased PI in the ICA more than 2.0 and - or retrograde blood flow in the supraclavicular arteries). For this type of gestosis characterized by the rapid occurrence and growth of the clinical picture (within 2-3 days) and the development of pre-eclampsia, the maximum period from the registration of pathological values of blood flow in the internal carotid arteries to the development of the clinical picture of preeclampsia does not exceed 48 hours.

Forms

Classification of gestosis

(010-016) Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the puerperium

• 010 Pre-existing hypertension complicating pregnancy, childbirth and the post-natal period
  • 010.0 Existing essential hypertension complicating pregnancy, childbirth and the puerperium
  • 010.1 Pre-vascular hypertension, which complicates pregnancy, childbirth and the puerperium
  • 010.2 Existing renal hypertension complicating pregnancy, childbirth and the puerperium
  • 010.3 Previous cardiovascular and renal hypertension complicating pregnancy, childbirth and the puerperium
  • 010.4 Pre-existing secondary hypertension complicating pregnancy, childbirth and the puerperium
  • O10.9 Pre-existing hypertension complicating pregnancy, childbirth and the puerperium, unspecified
• 011 Existing hypertension with joined proteinuria
• 012.2. Pregnancy-induced edema with proteinuria
• 013 Pregnancy-induced hypertension without significant proteinuria
• 014.0 Preeclampsia (nephropathy) of moderate severity
  • 014.1 Severe preeclampsia
  • Pre-eclampsia (nephropathy), unspecified
• 015 Eclampsia
  • Included are convulsions caused by conditions classified under 010-014 and 016
  • 015.0 Eclampsia during pregnancy
  • 015.1 Eclampsia in childbirth
  • 015.2 Eclampsia in the puerperium
  • 015.3 Eclampsia, unspecified by timing
• 016 Hypertension in mother, unspecified. Transient hypertension during pregnancy

Gestosis is called a disease of theories, since various factors were used to explain it. There are several mutually complementary theories of gestosis, including neurogenic, renal, placental, immunological, and genetic. Currently, the role of endothelial dysfunction in the genesis of gestosis is considered to be the highest priority. Disadaptation of the endothelial cell function acts as a trigger for intravascular hypercoagulable platelets inherent in all forms of gestosis.

Each individual theory can not explain the variety of clinical manifestations, but many elements of objectively recorded abnormalities are confirmed in the pathogenesis of changes occurring during gestosis.

Among the risk factors for the appearance of gestosis, extragenital pathology (64%) is leading. The most important are:

• hypertension outside pregnancy (25%);
• pathology of the kidneys (80% of the first-born with gestosis suffer kidney disease, confirmed by kidney biopsy);
• cardiovascular diseases (50%), including 10% chronic venous insufficiency;
• endocrine pathology (diabetes - 22%, dyslipidemia - 17%, obesity - 17%);
• autoimmune diseases (67%).

Other risk factors for gestosis include:

• age of pregnant women under 17 and over 30;
• frequent infections of the upper respiratory tract;
• multiple fertility;
• genetic factor (increased frequency of the mutant form of methylenetetrahydrofolate reductase, replacement of 677 C-T);
• occupational hazards;
• adverse social and living conditions;
• presence of preeclampsia, perinatal morbidity and mortality during the previous pregnancy.

[10], [11], [12], [13]