Gestosis during pregnancy

Gestosis is a complication of physiologically occurring pregnancy, characterized by profound dysfunction of vital organs and systems, occurring after 20 weeks of pregnancy and up to 48 hours after birth.

Clinically manifested by arterial hypertension, proteinuria, edema, symptoms of acute renal failure. In trophoblastic disease, gestosis can occur before the 20th week of pregnancy. HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) is a variant of severe gestosis, which is characterized by hemolysis, increased activity of liver enzymes, and thrombocytopenia. The diagnosis of eclampsia is established in the presence of seizures.

In Russia, gestosis is diagnosed in 12-21% of pregnant women, severe form - in 8-10%. Severe gestosis as a cause of maternal mortality is registered in 21% of cases. Perinatal mortality is 18-30%. HELLP syndrome is found in 4-20% of pregnant women with preeclampsia. Maternal mortality with it reaches 24%, perinatal - from 8 to 60%.

Synonyms of gestosis

Gestosis, OPG-gestosis, late gestosis, toxemia of pregnancy, nephropathy, preeclampsia, preeclampsia/eclampsia.

ICD-10 code

A comparison of disease names according to ICD-10 with the domestic classification of the Russian Association of Obstetricians and Gynecologists is presented in the table.

Compliance with ICD-10 classification of gestosis of the Russian Association of Obstetricians and Gynecologists

ICD-10 code	ICD-10	RF
O11	Pre-existing hypertension with associated proteinuria	Gestosis*
O12.2	Pregnancy-induced edema with proteinuria	Gestosis*
O13	Pregnancy-induced hypertension without significant proteinuria
O14.0	Preeclampsia (nephropathy) of moderate severity	Moderate gestosis*
O14.1	Severe preeclampsia	Severe gestosis*
O14.9	Preeclampsia (nephropathy) unspecified	Preeclampsia

* To assess the severity of gestosis, the Goke scale modified by G. M. Savelyeva is used.

Goke scale modified by G. M. Savelyeva

Symptoms	Points
	1	2	3	4
Edema	No	On the shins or pathological weight gain	On the shins, anterior abdominal wall	Generalized
Proteinuria, g/l	No	0.033-0.132	0.133-1.0	>1.0
Systolic blood pressure, mm Hg	<130	130-150	150-170	>170
Diastolic blood pressure, mm Hg	<85	85-90	90-110	>110
The period of pregnancy at which gestosis was first diagnosed	No	36-40	30-35	24-30
Chronic hypoxia, intrauterine growth retardation of the fetus	No		1-2 weeks delay	Delay of 3 weeks or more
Background diseases	No	Appeared before pregnancy	During pregnancy	Outside and during pregnancy

The severity of gestosis corresponds to the obtained sum of points:

• 7 or less - mild gestosis.
• 8-11 - moderate gestosis.
• 12 or more - severe gestosis.

Epidemiology

In recent years, the incidence of gestosis has increased and fluctuates between 7 and 22%. Gestosis remains one of the three main causes of maternal mortality in developed and developing countries. [ 1 ] In the United States, gestosis ranks second among causes of maternal mortality after various extragenital diseases and, in terms of the number of deaths, exceeds mortality from obstetric hemorrhage, infections, and other pregnancy complications. In the structure of causes of maternal mortality, gestosis consistently ranks third and accounts for 11.8 to 14.8%. [ 2 ] It remains the main cause of morbidity in newborns (640–780‰) and mortality (18–30‰). According to the WHO, every fifth child born to a mother with gestosis has some degree of impaired physical and psychoemotional development, and the incidence rate in infancy and early childhood is significantly higher. The toll, both socially and financially, is very high. [ 3 ], [ 4 ]

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Causes gestosis

Causes of gestosis

The causes of gestosis have not been established. The connection with the fetus and placenta has been proven. Gestosis could not be modeled in animals. The factors and risk levels of gestosis are listed in the table.

Risk factors for gestosis

Factor	Risk level
Chronic kidney disease	20:1
Homozygosity for the T235 gene (angiotensinogen)	20:1
Heterozygosity for the T235 gene	4:1
Chronic hypertension	10:1
Antiphospholipid syndrome	10:1
Family history of preeclampsia	5:1
Primipara	3:1
Multiple pregnancy	4:1
Violation of fat metabolism	3:1
Age >35	3:1
Diabetes	2:1
African American descent	1.5:1

Low socioeconomic level and young age as risk factors for the development of gestosis are not recognized by everyone.

[ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ]

Pathogenesis

Currently, there are various theories of gestosis pathogenesis. Recent studies have allowed to put forward the theory of SIRS with the formation of PON and the development of endothelial dysfunction, generalized vasospasm, hypovolemia, disturbance of rheological and coagulation properties of blood, microcirculation, water-salt metabolism.

The most significant role in the development of SIRS is played by a typical pathophysiological process - ischemia-reperfusion, developing initially in the placenta, and then in vital organs. Many researchers note the predominantly immune genesis of placental ischemia, associated with factors of immunological aggression from the fetus and impaired immunological tolerance in the mother. The vascular system of the placenta is the primary link for immunological aggression. At the same time, activation of the complement system, production of cytokines, in particular, TNF, release of endotoxin, activation of platelets are recorded, which leads to generalized damage to the vascular endothelium, their spasm and ischemia of vital organs. Dysfunction of the endothelium causes an increase in the permeability of histohematic barriers, a decrease in tissue perfusion and the development of the MODS syndrome. [ 14 ]

Pathogenetic disorders in the central nervous system

In the CNS, ischemia due to vasospasm of the cerebral arteries or cerebral edema is observed, which causes visual disturbances in the form of photophobia, diplopia, scotoma, amaurosis or "blind spots". When performing an EEG, extended, slow rhythms (in the form of θ- or σ-waves) are usually visible, or sometimes including slowly changing focal activity or paroxysmal spikes.

Headache may occur in 40% of patients with preeclampsia and in 80% of patients with subsequent development of eclampsia. It may be accompanied by nausea, irritability, a feeling of fear and visual impairment.

Pathogenetic disorders in the cardiovascular system

Hypertension, which may be a consequence of vascular spasm, is an early precursor to preeclampsia. At the first stage of the disease, blood pressure is not stable at rest, and the circadian biological rhythm changes depending on blood pressure fluctuations. Initially, no decrease in blood pressure is observed at night, and subsequently an inverse relationship is observed when the pressure begins to rise during sleep. The sensitivity of blood vessels to adrenaline and noradrenaline circulating in the blood, and angiotensin II increases.

In patients with severe gestosis, there is a decrease in plasma volume and protein levels in it due to its excretion in the urine and losses through the porous wall of the capillaries. A decrease in oncotic pressure is noted - indicators at the level of 20 and 15 mm Hg in moderate and severe forms of the disease, respectively.

Pathogenetic disorders in the respiratory system

The most severe complication, often of an iatrogenic nature, is OL. The reasons for its development are:

• low oncotic pressure with a simultaneous increase in intravascular hydrostatic pressure,
• increased capillary permeability.

Pathogenetic disorders in the excretory system

Most pregnant women with gestosis have decreased renal perfusion and CF along with a corresponding increase in serum creatinine concentration. The cause of the CF decrease is glomerular swelling, narrowing of the glomerular capillary lumen, and fibrin deposition in endothelial cells (glomerular-capillary endotheliosis). Increased permeability promotes a proportional increase in the concentration of high-molecular-weight proteins in the urine, such as transferrin and globulins. Despite the prevalence of oliguria (ie, diuresis less than 20-30 ml/h for 2 h), the development of renal failure is relatively rare. Acute tubular necrosis is often the cause of reversible renal failure, which has a very favorable prognosis. As a rule, premature placental abruption, DIC, and hypovolemia precede the development of renal failure.

Pathogenetic disorders in the blood coagulation system

Thrombocytopenia less than 100x109/l is observed in 15% of patients with severe gestosis. This occurs due to increased platelet consumption, which is caused by an imbalance between prostacyclin and thromboxane. Increased fibrinopeptide concentration, von Willebrand factor level, high Ville factor activity and decreased antithrombin III content indicate activation of the blood coagulation cascade. Hemolysis can be observed in liver dysfunction, with HELLP syndrome. Formation of chronic DIC syndrome occurs in 7% of patients with severe gestosis.

Pathogenetic disorders in the liver

The cause of liver dysfunction is unclear. Changes may occur due to periportal liver necrosis, subcapsular hemorrhages, or fibrin deposition in the liver sinusoids. Liver dysfunction in severe gestosis may have a negative effect on the elimination of drugs from the body that are metabolized by the liver. Spontaneous liver rupture is very rare and results in death in 60% of cases.

Read also: Gestosis - Causes and pathogenesis

Forms

The complexity of the problem of gestosis is demonstrated by the lack of a unified classification throughout the world. There are many different recommendations regarding the terminology for designating hypertensive conditions detected during pregnancy. Along with the term "gestosis", the following are used abroad: preeclampsia and eclampsia, pregnancy-induced hypertension, and OPG-gestosis (O - edema, P - proteinuria, H - hypertension).

Currently, the following classifications are accepted in the world:

• International Society for the Study of Hypertension in Pregnancy;
• Organization of gestosis;
• American Association of Obstetricians and Gynecologists;
• Japanese Society for the Study of Toxemia of Pregnancy.

A clinical classification of gestosis is used.

1. Edema.
2. Gestosis:
   1. mild degree;
   2. average degree;
   3. severe degree.
3. Preeclampsia.
4. Eclampsia.

Gestosis is also divided into pure and combined, i.e. arising against the background of chronic diseases existing before pregnancy. The frequency of combined gestosis, the course of which depends on previous diseases, is about 70%. Combined gestosis is characterized by early clinical manifestation and a more severe course, usually with a predominance of symptoms of the disease against which gestosis developed.

Currently, the diagnosis of gestosis in Russia is verified on the basis of the International Statistical Classification of Diseases and Related Health Problems, 10th revision (1998), adopted by the 43rd World Health Assembly. Block II of the obstetrics section is called "Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the postpartum period."

The use of statistical and clinical classifications of gestosis to assess morbidity leads to different interpretations of statistical indicators and assessment of the severity of this disease.

[ 15 ], [ 16 ], [ 17 ], [ 18 ]

Diagnostics gestosis

Criteria for severe gestosis

• Systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 110 mm Hg in two measurements for 6 hours.
• Proteinuria more than 5 g/day.
• Oliguria.
• Interstitial or alveolar OL (usually of iatrogenic origin).
• Hepatocellular dysfunction (increased ALT and AST activity).
• Thrombocytopenia, hemolysis, DIC syndrome.
• Intrauterine growth restriction of the fetus. Criteria for preeclampsia.
• Cerebral disorders: headache, hyperreflexia, clonus, visual impairment.
• Pain in the epigastrium or right hypochondrium, nausea, vomiting (HELLP syndrome).

[ 19 ], [ 20 ], [ 21 ], [ 22 ]

Diagnosis of gestosis is not difficult and is based on the clinical picture and laboratory and instrumental examination data. The gestational age at which hypertension or proteinuria was first documented helps in making the correct diagnosis. The onset of hypertension or proteinuria before conception or before 20 weeks of pregnancy is characteristic of chronic hypertension (essential or secondary) or renal pathology. High blood pressure established in the middle of pregnancy (20-28 weeks) may be associated with either early onset of gestosis or unrecognized chronic hypertension. In the latter case, blood pressure usually decreases in the first trimesters, and this “physiological” decrease may be even more pronounced in patients with essential hypertension, masking the diagnosis during pregnancy.

[ 23 ], [ 24 ], [ 25 ], [ 26 ]

Laboratory research

Laboratory tests recommended for the diagnosis and treatment of hypertension in pregnancy serve primarily to differentiate gestosis from chronic or transient hypertension and kidney disease. They also help to assess the severity of gestosis. Attempts to find an ideal screening test have not been successful to date. It has been shown that such parameters as blood pressure measurement in mid-pregnancy, ambulatory blood pressure monitoring, serum β-hCG, sensitivity to angiotensin II, urinary calcium excretion, urine kallikrein, uterine artery Doppler, plasma fibronectin, and platelet activation may be statistically significant as early markers of this pathology. However, their practical value for individual patients has not been proven.

Studies suggested for screening gestosis

Test	Justification
Hematocrit	Hemoconcentration confirms the diagnosis of gestosis (hematocrit over 37%) and acts as an indicator of the severity of the pathology. Values may be low if gestosis is accompanied by hemolysis.
Platelet count	Thrombocytopenia less than 100 thousand per ml confirms severe gestosis
Protein content in urine	Hypertension combined with proteinuria >300 mg/day indicates severe gestosis
Serum creatinine concentration	An increase in creatinine concentration, especially in combination with oliguria, suggests severe gestosis.
Serum uric acid concentration	An increase in serum uric acid concentration suggests
Serum transaminase activity	Increased serum transaminase activity suggests severe gestosis with liver involvement
Serum albumin concentration	A decrease in albumin concentration indicates the degree of damage (permeability) of the endothelium

Diagnostic criteria for HELLP syndrome

• Pain in the epigastrium or right hypochondrium.
• Icterus of the sclera and skin.
• Hemolysis hemolyzed blood, hyperbilirubinemia, LDH >600 U.
• Increased activity of liver enzymes AST >70 U.
• Thrombocytopenia: platelet count less than 100x10 ⁹ /l.

Read also: Gestosis - Diagnostics

Treatment gestosis

Indications for delivery are severe gestosis and preeclampsia. Pregnancy is prolonged as long as the intrauterine environment is adequate to support the growth and development of the fetus without posing a risk to the mother's health. Treatment should be carried out with the simultaneous involvement of an obstetrician-gynecologist and an anesthesiologist-resuscitator, preferably in a specialized intensive care unit.

Treatment of severe gestosis includes prevention of convulsive syndrome, antihypertensive and infusion-transfusion therapy (ITT).

Read also: Gestosis - Treatment

Prevention of convulsive syndrome

Magnesium sulfate

In pregnant women with severe gestosis and preeclampsia, magnesium sulfate is used to prevent eclamptic seizures. The initial dose of 4 g is administered over 10-15 minutes, followed by a maintenance infusion at a rate of 1-2 g/h. After this, a therapeutic concentration of magnesium sulfate equal to 4-6 mmol/l is achieved in the blood and maintained for 4 hours. During the administration of magnesium sulfate, the knee reflex and diuresis should be monitored. Disappearance of the knee reflex is a sign of hypermagnesemia. In this case, the infusion of magnesium sulfate should be stopped before the knee reflex appears. Magnesium ions circulate in the blood in free and plasma protein-bound form. They are excreted by the kidneys. The half-life in healthy individuals is about 4 hours. Impaired renal function (diuresis less than 35 ml/h) can cause hypermagnesemia, and therefore the dose of magnesium sulfate should be reduced.

In therapeutic concentrations, magnesium sulfate inhibits neuromuscular transmission and the central nervous system by influencing glutamic acid receptors. In high doses, it can cause cardiac conduction disturbances and bradycardia. The most dangerous, life-threatening effect of magnesium sulfate is respiratory depression due to slowing of neuromuscular transmission. In case of overdose, 1 g of calcium gluconate or 300 mg of calcium chloride is administered intravenously.

Effects of magnesium sulfate

Effects	Concentration of magnesium ions in blood plasma, mmol/l
Normal plasma level	1.5-2.0
Therapeutic range	4.0-8.0
Electrocardiographic changes (prolongation of the PQ interval, widening of the QRS complex)	5.0-10.0
Loss of deep tendon reflexes	10.0
Respiratory depression	12.0-15.0
Respiratory arrest, sinoatrial and AV block	15.0
Heart failure	20.0-25.0

Anticonvulsant therapy is administered for 24 hours after delivery.

Antihypertensive therapy

Antihypertensive treatment is recommended if blood pressure exceeds 140/90 mm Hg. Arterial diastolic pressure should not be reduced sharply, since its decrease can cause a decrease in the blood supply to the placenta. To select drugs and monitor the adequacy of therapy, it is advisable to determine the parameters of central hemodynamics (echoCG, rheovasography), daily monitoring of blood pressure. Diuretics are indicated only for the treatment of OL.

Antihypertensive therapy

Preparation	Class	Therapy for preeclampsia	Therapy for severe gestosis	Side effects
Clonidine	Α-Adrenergic agonist	100-300 mcg IV	Up to 300 mcg/day intramuscularly or enterally	Sedative withdrawal syndrome
Hydralazine	Peripheral vasodilator	5-10 mg IV, can be repeated after 15-30 minutes	20-40 mg	Reflex tachycardia
Nifedipine	Calcium channel blocker	10 mg per os every 15-20 minutes until the effect is achieved Parenterally slowly 6-10 mcg/kg and then using an infusion pump 6-14.2 mcg/kg per minute	10-30 mg orally	Headache Reflex tachycardia
Labetalol	α-, β-Adrenergic blocker	5-10 mg IV, can be repeated with a double dose after 15 minutes up to a maximum dose of 300 mg	100-400 mg orally every 8 hours	Bradycardia in the fetus and mother
Propranolol	Non-selective β-blocker	10-20 mg orally	10-20 mg orally	Maternal bradycardia

First-line drugs include nifedipine, clonidine, and anaprilin. The use of nitroglycerin and sodium nitroprusside has serious complications and is not recommended. The use of atenolol is associated with intrauterine growth retardation. The results of several randomized studies show that antihypertensive therapy in women with gestosis or preeclampsia does not improve perinatal outcomes.

[ 27 ], [ 28 ], [ 29 ], [ 30 ]

Infusion-transfusion therapy

Due to vasospasm, patients with preeclampsia have reduced vascular volume and are sensitive to fluid loading. It is necessary to refrain from administering large volumes of fluid, as hyperhydration and OL are possible. At the same time, it is impossible to completely avoid administering infusion solutions.

Moderate dehydration is better than hyperhydration. The volume of ITT is approximately 1-1.2 l/day. Crystalloids are preferred. The infusion rate is no more than 40-45 ml/h (maximum - 80) or 1 ml/(kg x h). In the first 2-3 days, diuresis should be positive (negative fluid balance). The optimal CVP is 3-4 cm H2O. Diuretics are used only in OL. Albumin transfusion is possible only in case of hypoalbuminemia (less than 25 g/l), preferably after delivery.

Infusion loading is necessary with epidural anesthesia, parenteral antihypertensive therapy, intravenous administration of magnesium sulfate, with oliguria or signs of central dehydration (with low CVP). [ 31 ]

Therapy for HELLP syndrome

• The priority is to exclude liver rupture and bleeding.
• Hemolysis and thrombocytopenia are indications for plasmapheresis in plasma exchange mode with additional administration of FFP.
• Platelet transfusions should be avoided unless there is active bleeding.
• Administration of glucocorticoids (according to various sources, from 10 mg dexamethasone intravenously every 12 hours). [ 32 ]

Anesthetic manual

During cesarean section, epidural anesthesia is preferable to general anesthesia (except for eclampsia). Recent studies have shown that spinal and combined spinal-epidural anesthesia are as safe as epidural. The advantages of regional anesthesia are blood pressure control, increased renal and uteroplacental blood flow, and prevention of convulsive syndrome. The dangers of general anesthesia are hemodynamic instability during induction, intubation, and extubation of the trachea. Hypertension and tachycardia can cause increased intracranial pressure (ICP). The risk of regional anesthesia is usually associated with the development of epi- and subdural hematoma.

During vaginal delivery, epidural anesthesia is administered. Despite thrombocytopenia, epidural and subdural hematomas are extremely rare in obstetrics. However, a level of prohibition of regional anesthesia is usually distinguished (platelet count 70-80x103 ^/ mm3 ⁾.

[ 33 ], [ 34 ], [ 35 ]