Hestosis - Causes and Pathogenesis

Cause

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 on the causes of gestosis throughout the world. There is no doubt that the disease is directly related to pregnancy, since stopping the latter before severe complications develop always promotes recovery.

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Pathogenesis

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

Gestosis is a disease associated with the implantation of the fertilized egg, and it has been proven that the foundations of the disease are laid in the early stages of gestation.

Due to immunological and genetic characteristics, pregnant women at the time of implantation experience inhibition of trophoblast migration and absence of transformation of the muscular layer in spiral arteries, which retain the morphology of non-pregnant women, which predisposes them to spasm, decreased intervillous blood flow and hypoxia.

Hypoxia developing in the tissues of the uteroplacental complex causes damage to the endothelium with a violation of its thromboresistant and vasoactive properties, the release of mediators (endothelin, serotonin, thromboxane), which play a key role in the regulation of hemostasis and vascular tone. One of the reasons capable of causing endothelial dysfunction may be insufficient release of the endothelial relaxing factor, identified with nitric oxide, the most powerful dilator synthesized by endothelial cells, the level of which is sharply reduced in gestosis. In parallel with these changes, there is a violation of the synthesis and imbalance of prostanoids of maternal and fetal origin (prostaglandins of classes E and F, prostacyclin, thromboxane, etc.), which ensure a dynamic balance in the homeostasis system, and also 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 (TPVR), a decrease in cardiac output, a decrease in 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 have suffered from gestosis, even in the absence of pathomorphological changes in the kidneys, deposits of immunoglobulins of classes G, M and A were found.

The main links in the pathogenesis of gestosis:

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

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

1. Generalized vascular spasm (mainly in the arterial circulatory link) leads to increased intravascular pressure, blood stasis in the capillaries, and increased permeability of small vessels. As a result of these processes, OPSS increases, which leads to the development of arterial hypertension and circulatory disorders in vital organs. The degree of OPSS increase is directly dependent on the severity of gestosis.
2. Long-term vascular spasm leads to myocardial dysfunction, which leads to the development of ischemic cardiomyopathy. Echocardiographic examination of central hemodynamic parameters in pregnant women with gestosis revealed the following features: as the severity of gestosis increases, there is a reliable decrease in stroke and cardiac indices. Hypokinetic and eukinetic types of central maternal hemodynamics are most often detected in gestosis. At the same time, there is a directly proportional relationship between the type of central maternal hemodynamics and the severity of gestosis. Thus, with the hyperkinetic type of central maternal hemodynamics, mild gestosis was detected in 85.3% of cases and severe gestosis was detected in none. At the same time, with the hypokinetic type of central hemodynamics, mild gestosis was detected only in 21.2% of cases.
3. Hemodynamic disturbances in the renal vessels lead to ischemia of the renal cortex. The severity of renal and intrarenal blood flow disturbances directly depends on the type of central maternal hemodynamics and the severity of gestosis. With a mild degree of gestosis, renal and intrarenal blood flow disturbances are detected only in 30%, with an average degree - in 60%, and with a severe degree - in 92%. Clinically, renal blood circulation disturbances 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 the renal vessels and renal ischemia provide an excessive release of renin and angiotensin, which contributes to even greater angiospasm and an increase in arterial pressure.
4. Cerebral vascular spasm causes a decrease in cerebral blood flow, which is confirmed by the results of Doppler study of blood flow in the carotid artery system. However, cerebral hemodynamic disorders do not depend on the initial type of central maternal hemodynamics. According to our data, pronounced blood flow disorders in the carotid and supratrochlear artery system are observed only in gestosis with a rapid increase in clinical symptoms. These changes create conditions for the development of edema of the brain and its membranes, which is clinically manifested by cerebral symptoms, and in especially severe cases, the onset of seizures (eclampsia).
5. Spasm of the uterine and spiral arteries leads to disruption of the uteroplacental circulation, which in turn causes disruption of the fetal and fetal-placental blood flow. Disruption of the uteroplacental-fetal hemodynamics leads to chronic hypoxia and IUGR. The severity of the uteroplacental-fetal hemodynamic disorders also directly depends on the type of CMG and clearly correlates with the severity and duration of gestosis. The analysis of observations with bilateral disruption of blood flow in the uterine arteries deserves special attention. With this type of hemodynamic disorders, moderate forms of gestosis were detected in 30% of observations, and severe forms in 70%. It should be noted that disorders of the uteroplacental circulation and intraplacental circulation are detected by Doppler examination already at the beginning of the second trimester of pregnancy.
6. When analyzing the dynamics of changes in OPSS and vascular resistance indices in the carotid, renal, uterine, spiral arteries, umbilical artery and its terminal branches, it was found that in uncomplicated pregnancy, the maximum decrease in peripheral vascular resistance is observed in the uterine and spiral arteries, umbilical artery and its terminal branches. These changes are compensatory and adaptive in nature and are aimed at creating optimal conditions for normal fetal development. At the same time, in gestosis, OPSS increases to the greatest extent, and the smallest increase in vascular resistance was noted in the uteroplacental-fetal blood circulation link. The data we obtained can be considered as evidence that in gestosis, despite the decrease in volumetric indicators of central hemodynamics and systemic vascular spasm, compensatory-adaptive mechanisms are formed, aimed primarily at the normal functioning of the mother-placenta-fetus system, and only when they are depleted does fetoplacental insufficiency and intrauterine growth retardation of the fetus develop.
7. In a number of observations, pronounced changes in the vessels contribute to the deposition of fibrin into their lumen, aggregation of erythrocytes and thrombocytes. In this case, perfusion of vital organs worsens even more and disseminated intravascular coagulation syndrome is formed.
8. Circulatory disorders cause a decrease in the detoxification activity and protein-forming function of the liver. The hypo- and dysproteinemia that develops in this case lead to a decrease in osmotic and oncotic pressure, which in turn contributes to the appearance of hypovolemia, hemoconcentration, and water and sodium retention in the interstitial space.
9. Irritation of angioreceptors leads to the formation of hypovolemia. The latter is the cause of a pathological reaction of the central nervous system and the 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, uteroplacental-fetal and intraplacental blood flow, as well as an analysis of pregnancy and childbirth outcomes, 4 pathogenetic variants of systemic maternal hemodynamics in gestosis were identified:

1. Hyperkinetic type of CMG regardless of the values of OPSS and eukinetic type of CMG with normal numerical values of OPSS. With this type, moderate disorders of cerebral, renal, uteroplacental and intraplacental blood circulation are recorded.
2. Eukinetic type of CMG with increased values of OPSS (more than 1500) and hypokinetic type of CMG with normal values of OPSS. With this type, blood flow disorders are recorded mainly of I and II degrees in the system of renal arteries, uteroplacental-fetal and intraplacental blood flow.
3. Hypokinetic type of CMG with increased OPSS. With this type, severe disturbances of renal, uteroplacental-fetal and intraplacental blood flow are detected in 100% of observations.
4. Severe disturbances of cerebral hemodynamics (increase in PI in the internal carotid arteries over 2.0 and - or retrograde blood flow in the suprablock arteries). This type is characterized by forms of gestosis with rapid onset and increase in clinical picture (within 2-3 days) and development of preeclampsia, and the maximum period from recording pathological values of blood flow in the internal carotid arteries to the development of clinical picture of preeclampsia does not exceed 48 hours.

Forms

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

• 010 Pre-existing hypertension complicating pregnancy, childbirth and the postpartum period
  • 010.0 Pre-existing essential hypertension complicating pregnancy, childbirth and the postpartum period
  • 010.1 Pre-existing perivascular hypertension complicating pregnancy, childbirth and the puerperium
  • 010.2 Pre-existing renal hypertension complicating pregnancy, childbirth and the puerperium
  • 010.3 Pre-existing cardiovascular and renal hypertension complicating pregnancy, childbirth and the postpartum period
  • 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 Pre-existing hypertension with associated 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
  • 014.9 Preeclampsia (nephropathy), unspecified
• 015 Eclampsia
  • Includes: convulsions due to conditions classified to categories 010–014 and 016
  • 015.0 Eclampsia in pregnancy
  • 015.1 Eclampsia in childbirth
  • 015.2 Eclampsia in the postpartum period
  • 015.3 Eclampsia, unspecified by timing
• 016 Maternal hypertension, unspecified. Transient hypertension during pregnancy

Gestosis is called a disease of theories, since various factors have been used to explain it. There are several 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 most important. Disadaptation of endothelial cell function acts as a trigger for intravascular hypercoagulation of platelets, which is inherent in all forms of gestosis.

Each individual theory cannot explain the diversity of clinical manifestations, but many elements of objectively recorded deviations are confirmed in the pathogenesis of changes occurring during gestosis.

Among the risk factors for the development of gestosis, the leading place belongs to extragenital pathology (64%). The most important ones are:

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

Other risk factors for the development of gestosis include:

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

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