Preeclampsia. Eclampsia. Edema, proteinuria, and hypertensive disorders during pregnancy, childbirth, and the postpartum period: clinical guidelines

List of Abbreviations

Terms and Definitions

Arterial hypertension (AH) is a condition characterized by an increase in systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg, determined as the average of at least 2 measurements taken on the same arm with a 15-minute interval [1–3].

White-coat hypertension is diagnosed when office SBP is ≥140 mmHg and/or DBP is ≥90 mmHg on a single occasion [1].

Gestational (pregnancy-induced) hypertension (GH) is an increase in blood pressure first recorded after 20 weeks of gestation and not accompanied by significant proteinuria (<0.3 g/L) [1, 4].

Preeclampsia (PE) is a complication of pregnancy, childbirth, and the postpartum period characterized by an increase in SBP ≥140 mmHg and/or DBP ≥90 mmHg after 20 weeks of gestation, regardless of previous blood pressure levels, combined with proteinuria or at least one other parameter indicating the onset of multi-organ dysfunction.

Proteinuria is defined as protein loss >0.3 g/day or >0.3 g/L in two urine samples collected at a 6-hour interval.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic hypertension (CHTN) is defined as an increase in blood pressure (BP) ≥140/90 mm Hg before pregnancy or within the first 20 weeks of gestation, which typically persists for more than 42 days postpartum [1, 4].

Gestational (pregnancy-induced) hypertension (GH) is defined as an increase in BP first documented after 20 weeks of gestation and not accompanied by significant proteinuria (<0.3 g/L) [1, 4]. In 25% of cases, GH developing before 34 weeks of gestation is accompanied by preeclampsia (PE) [1, 4, 5].

Essential hypertension is a chronic condition manifested by hypertension in the absence of other diseases or pathological processes that are also characterized by elevated BP [1, 4].

Moderate preeclampsia (PE) is a complication of pregnancy, childbirth, and the postpartum period characterized by an increase after 20 weeks of gestation in SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, regardless of baseline BP, combined with proteinuria ≥0.3 g per day or ≥0.3 g/L in two urine samples collected at a 6-hour interval.

Severe PE is a complication of pregnancy, childbirth, and the postpartum period characterized by an increase after 20 weeks of gestation in SBP ≥160 mm Hg and/or DBP ≥110 mm Hg, regardless of baseline BP, combined with proteinuria ≥5 g per day or ≥3 g/L in two urine samples collected at a 6-hour interval, or at least one other parameter indicating the development of multiorgan failure [4].

Eclampsia is a series of seizures, initially tonic and subsequently clonic, which may occur against the background of PE of any severity in the absence of other causes.

HELLP syndrome—hemolysis, elevated liver enzymes, and low platelet count—is a serious, potentially fatal manifestation of PE (due to severe coagulopathy, hepatic necrosis and rupture, and cerebral hemorrhage) and is not a separate disorder [5, 3]. Previously, HELLP syndrome was considered a complication of PE or gestational hypertension [8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The pathogenesis of PE remains incompletely understood; the current theory of PE development during pregnancy involves a two-stage process: stage 1 involves superficial trophoblast invasion, leading to inadequate remodeling of the spiral arteries [6, 7]. This is hypothesized to trigger stage 2, which involves a maternal endothelial dysfunction response and an imbalance between angiogenic and antiangiogenic factors, leading to the clinical manifestations of the disease [6, 7]. In late-onset disease (with onset after 34⁰ weeks of gestation), placentation is generally normal, but the demands of the fetoplacental unit exceed the capacity of the blood supply. Although the placenta undoubtedly plays a major role in the development of PE, accumulating evidence indicates that this complication after 34 weeks of gestation develops with the involvement of the maternal cardiovascular system and hemodynamic features that affect placental function [8, 173-174].

1.3 Epidemiology of the Disease or Condition

Hypertensive disorders during pregnancy occur in 5–10% of cases, represent a leading cause of maternal mortality, and account for 20–25% of perinatal mortality cases. A special place among them is held by PE, a variant of hypertensive disorders, the frequency of which during pregnancy ranges from 2% to 8%. 10–15% of all maternal mortality cases are associated with PE or eclampsia, accounting for at least 70,000 deaths worldwide annually [9, 10]. Early-onset PE (with onset before 34⁰ weeks of gestation) is the primary factor leading to maternal and perinatal mortality [6, 11]. The prevalence of hypertensive disorders (including edema and proteinuria) among pregnant women in 2022 was 7.9%; edema, proteinuria, and hypertensive disorders complicated 85.2 cases per 1000 births in 2022 [12]. According to the Russian Ministry of Health, hypertensive pregnancy complications have ranked 4th among the causes of maternal mortality over the past decade [13]. Furthermore, they cause severe morbidity and disability in mothers and their children. At the same time, with proper multidisciplinary management, the majority of adverse outcomes are preventable. Because the consequences of severe hypertensive disorders reduce a woman's subsequent quality of life (high rates of atherosclerosis, diabetes mellitus, cardiovascular disease), and the incidence of impaired physical and psychosomatic development in offspring is quite high, as is their future risk of somatic diseases, this problem is of significant social and medical importance.

1.4 Features of Coding the Disease or Condition

O10 – Pre-existing hypertension complicating pregnancy, childbirth and the puerperium.

O10.0 – Pre-existing essential hypertension complicating pregnancy, childbirth and the puerperium.

O10.1 – Pre-existing hypertensive heart disease complicating pregnancy, childbirth and the puerperium.

O10.2 – Pre-existing hypertensive renal disease complicating pregnancy, childbirth and the puerperium.

O10.3 – Pre-existing hypertensive heart and renal disease complicating pregnancy, childbirth and the puerperium.

O10.4 – Pre-existing secondary hypertension complicating pregnancy, childbirth and the puerperium.

O10.9 – Pre-existing hypertension complicating pregnancy, childbirth and the puerperium, unspecified.

O11 – Pre-existing hypertension with superimposed preeclampsia.

O12 – Gestational edema and proteinuria without hypertension.

O12.0 – Gestational edema.

O12.1 – Gestational proteinuria.

O12.2 – Gestational edema with proteinuria.

O13 – Gestational [pregnancy-induced] hypertension.

O14 – Preeclampsia.

O14.0 – Mild to moderate preeclampsia.

O14.1 – Severe preeclampsia.

O14.2 – HELLP syndrome (currently not included in ICD-10).

O14.9 – Preeclampsia [nephropathy], unspecified.

O15 – Eclampsia.

O15.0 – Eclampsia in pregnancy.

O15.1 – Eclampsia in labor.

O15.2 – Eclampsia in the puerperium.

O15.9 – Eclampsia, unspecified as to time.

O16 – Unspecified maternal hypertension.

1.5 Classification of the disease or condition

Classification of blood pressure elevation severity in pregnant women [1].

Classification of hypertensive disorders during pregnancy [4]:

• Essential hypertension;

• Chronic hypertension;

• Gestational hypertension;

• Preeclampsia and eclampsia;

• Preeclampsia and eclampsia on the background of chronic hypertension.

From a clinical perspective regarding pregnancy outcomes and the impact on a woman's subsequent quality of life, it is advisable to distinguish between early-onset and late-onset PE:

• Early-onset PE (before 34⁰ weeks of gestation).

• Late-onset PE (after 34⁰ weeks of gestation).

Early-onset PE is associated with a higher risk of maternal and neonatal morbidity and mortality [11, 14–16].

Classification of PE by severity:

• Moderate PE.

• Severe PE.

Despite the prevailing opinion that dividing PE by severity is impractical [4], distinguishing between two degrees of PE—moderate and severe—during pregnancy is fundamentally important for prognosis assessment, management strategy selection, treatment, and delivery care [1]. An SBP level ≥160 mm Hg and/or DBP ≥110 mm Hg in severe PE is associated with a high risk of stroke [17–19].

Classification of eclampsia by time of onset:

• Eclampsia during pregnancy and labor.

• Postpartum eclampsia:

  - early postpartum eclampsia (first 48 hours postpartum);

  - late postpartum eclampsia (after 48 hours up to 28 days postpartum).

1.6 Clinical presentation of the disease or condition

The classic presentation of the disease is characterized by a triad of symptoms: hypertension, proteinuria, and edema, whether overt or occult [20-22]. However, edema is not a mandatory diagnostic criterion for PE. Severe PE is also characterized by additional parameters indicating the development of multiorgan failure. A diagnosis of severe PE is established in the presence of hypertension combined with at least one of the indicated symptoms (Table 1).

Table 1. Criteria for PE severity

Symptoms warning of eclampsia. Eclampsia.

The threat of eclampsia in a pregnant woman with PE is indicated by the appearance of neurological symptoms, increasing headache, visual disturbances, epigastric and right upper quadrant pain, periodic facial cyanosis, lower extremity paresthesias, abdominal and lower extremity pain without clear localization, shortness of breath, agitation or, conversely, drowsiness, difficulty breathing through the nose, coughing, dry cough, salivation, retrosternal pain. However, 25% of women do not have any preceding symptoms [23-24].

Seizures can occur during pregnancy, labor, and the postpartum period [17–19, 23, 25, 26]. Eclamptic seizures have their own characteristics: initially, isolated subtle facial muscle contractions appear (15–30 seconds), which are replaced by tonic seizures – skeletal muscle spasm (15–20 seconds), and then by generalized clonic seizures (convulsions) involving the muscles of the trunk and limbs. Eclampsia may present as a single seizure or a series of attacks. A seizure is accompanied by brief apnea, cyanosis, mydriasis, tongue biting, and frothing at the mouth. The duration of a seizure is usually no more than 1.5–2 minutes. After the cessation of seizures, the pregnant woman falls into a coma. However, non-convulsive, most severe forms of eclampsia are also possible (rarely).

More than 1/5 of all cases of eclampsia during pregnancy occur before the 31st week of gestation. Up to 44% of eclampsia cases occur in the postpartum period, especially at term. At term pregnancy, 75% of eclampsia cases occur during labor or within 6 hours postpartum. In 16% of cases, eclampsia occurs between 48 hours and 4 weeks postpartum [25]. In this regard, women with symptoms and signs indicative of PE require special monitoring [17, 23]. According to a systematic review of 59 publications (21,149 cases of eclampsia), the proportion of antepartum, intrapartum, and postpartum eclampsia was 59%, 20%, and 21%, respectively; 25% of women were normotensive, 20% had moderate hypertension, 32% had severe hypertension, and 21% had unclassified hypertension [27].

Differential diagnosis of PE/eclampsia with other diseases and conditions.

All patients who develop a seizure during pregnancy must undergo a differential diagnosis for the following conditions [28]:

• vascular diseases of the central nervous system;

• ischemic/hemorrhagic stroke;

• intracerebral hemorrhage/aneurysms;

• cerebral venous sinus thrombosis;

• brain tumors;

• brain abscess;

• arteriovenous malformations;

• infections (encephalitis, meningitis);

• epilepsy;

• drug effects (amphetamine, cocaine, theophylline, clozapine);

• hyponatremia, hypokalemia;

• hyperglycemia;

• thrombotic thrombocytopenic purpura (TTP);

• post-dural puncture headache.

Thrombotic microangiopathy (TMA) (ICD-10 M31.1) is a syndrome characteristic of a number of disparate diseases manifested by thrombocytopenia, microangiopathic hemolytic anemia, microvascular thrombosis of terminal arterioles and capillaries, and multiple organ dysfunction [29, 30]. This group includes both pregnancy-related diseases (HELLP syndrome, atypical hemolytic-uremic syndrome (aHUS)) and non-pregnancy-related ones (TTP, typical hemolytic-uremic syndrome (HUS)).

Massive intravascular hemolysis, determined visually in blood serum and by the characteristic brown color of urine, occurs in only 10% of patients. To clarify the diagnosis of intravascular hemolysis, additional laboratory data must be obtained:

1. presence of fragmented erythrocytes (schistocytes) (normal 0–0.27%);

2. lactate dehydrogenase (LDH) level >600 IU/L;

3. indirect bilirubin level >12 g/L;

4. decreased haptoglobin level <0.3 g/L.

Treatment of massive intravascular hemolysis is presented in Appendix A3.6.

HELLP syndrome is diagnosed based on the following signs: free hemoglobin in serum and urine (Hemolysis), elevated AST, ALT (Elevated Liver Enzimes), and thrombocytopenia (Low Platelets). HELLP syndrome is a potentially fatal complication of PE (severe coagulopathy, liver necrosis and rupture, intracerebral hematoma). Depending on the combination of clinical and laboratory signs, complete HELLP syndrome and ELLP syndrome in the absence of hemolytic anemia are distinguished. Thrombocytopenia is a mandatory condition for the diagnosis of HELLP syndrome, whereas hypertension in HELLP syndrome occurs in more than half of cases and is not a mandatory component

Currently, HELLP syndrome is considered one of the specific cases of pregnancy-related TMA. The clinical picture of HELLP syndrome is variable and includes the following symptoms:

• epigastric or right upper quadrant abdominal pain (86–90%);

• nausea or vomiting (45–84%);

• headache (50%);

• tenderness upon palpation in the right upper quadrant of the abdomen (86%);

• DBP ≥110 mmHg (67%);

• massive proteinuria (> 5 g/day) (85–96%);

• edema (55–67%);

• HTN (80%).

In one in three women with HELLP syndrome, the first clinical symptoms appear in the first hours after delivery.

Differential diagnosis of HELLP syndrome:

• gestational thrombocytopenia;

• acute fatty liver of pregnancy;

• viral hepatitis;

• cholangitis;

• cholecystitis;

• urinary tract infection;

• gastritis;

• gastric ulcer;

• acute pancreatitis;

• immune thrombocytopenia;

• folate deficiency;

• systemic lupus erythematosus;

• antiphospholipid syndrome;

• Budd-Chiari syndrome;

• TTP;

• HUS;

• sepsis.

Unfortunately, there are no clinical or morphological criteria that allow for a rapid diagnosis. The primary objective is to perform differential diagnosis between the more common PE/HELLP syndrome and other rare variants of TMA [29–33].

If the clinical manifestations of PE/HELLP syndrome do not regress within 48–72 hours after delivery, other variants of TMA should be diagnosed [34,35]. Distinguishing "pure obstetric" TMAs—those variants where pregnancy itself triggers the onset of TMA (PE/HELLP syndrome)—from other variants of TMA (TTP, aHUS) is possible only after delivery. This is because a patient with signs of TMA during pregnancy meets the criteria for severe PE and requires delivery, and also because only the elimination of the placenta-secreted antiangiogenic factor, soluble fms-like tyrosine kinase-1 (sFlt-1), relieves the symptoms of PE [36]. Only an ADAMTS13 level <10% allows for the diagnosis of TTP; other clinical and laboratory algorithms only allow for a suspected diagnosis. It is recommended to rule out infectious causes when TMA develops in a patient with pre-existing signs of infection before delivery or in the presence of risk factors (diabetes mellitus, obesity, operative delivery, chronic arterial hypertension) [37–40].

The diagnosis of aHUS should be considered a diagnosis of exclusion, established based on the presence of TMA symptoms persisting after delivery, and must be confirmed by laboratory data ruling out other TMAs, primarily TTP and septic secondary TMAs [41].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

Chronic arterial hypertension is diagnosed when blood pressure is ≥140/90 mm Hg prior to pregnancy or within the first 20 weeks of pregnancy, which typically persists for more than 42 days postpartum.

Gestational hypertension is diagnosed when blood pressure is ≥140/90 mm Hg after 20 weeks of pregnancy de novo without significant (<0.3 g/L) proteinuria.

Moderate PE is diagnosed when SBP is ≥140 mm Hg and/or DBP is ≥90 mm Hg after 20 weeks of pregnancy de novo or against the background of chronic arterial hypertension in combination with proteinuria.

Severe PE is diagnosed when SBP is ≥160 mm Hg and/or DBP is ≥110 mm Hg after 20 weeks of pregnancy de novo or against the background of chronic arterial hypertension in combination with proteinuria or at least one other parameter indicating the development of multiorgan failure (see Section 1.1.).

Eclampsia is diagnosed when seizures occur in the absence of other causes.

HELLP syndrome is diagnosed when hemolysis, elevated liver transaminases, and thrombocytopenia occur against the background of severe PE.

2.1 Complaints and Anamnesis

See Section 1.6.

Anamnesis collection is carried out in accordance with the clinical guidelines "Normal Pregnancy" [42].

2.2 Physical Examination

Physical examination is carried out in accordance with the clinical guidelines "Normal Pregnancy" [42]. Additionally, the following examinations are performed.

• Patients with moderate PE are recommended to visit a medical organization weekly if hypertension is medically controlled (at the pre-hospital stage) [17, 19, 43].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: With medically controlled stable blood pressure, absence of significant proteinuria (<0.3 g/L), normal platelet and liver transaminase levels, and absence of signs of fetal growth restriction and impaired blood flow according to ultrasound Doppler study, outpatient monitoring is possible with regular visits to the antenatal clinic and monitoring of the condition of the pregnant woman and the fetus.

Comment: When measuring blood pressure, the following rules must be observed: sitting position in a comfortable posture, the arm is on the table at heart level, the lower edge of the cuff (width 12–13 cm, length 35 cm) should be 2 cm above the elbow bend, the cuff size should match the arm size. Blood pressure is measured in a resting state (after a 5-minute rest) 2 times with an interval of at least one minute; if the difference is ≥5 mm Hg, one additional measurement is taken, and the last two values are averaged. Blood pressure is measured on both arms; if they differ, the higher values are used. In patients suffering from diabetes mellitus, blood pressure must be measured in both sitting and lying positions, and the higher blood pressure should be taken into account. Indicators must be recorded to the nearest 2 mm Hg.

Comment: The moment the first sounds appear corresponds to phase I of Korotkoff sounds and indicates SBP, while DBP is registered at K5 (cessation). This method of blood pressure measurement is the classical gold standard in the general population. It is used to diagnose arterial hypertension.

Comment: For the purpose of timely diagnosis and clarification of the nature of arterial hypertension, as well as ruling out white-coat hypertension, self-measurement of blood pressure at home is recommended. Daily monitoring can be performed by the patient independently 3 times a day with the maintenance of a diary.

• When conducting antihypertensive therapy, the patient is recommended to independently count fetal movements daily [17, 19, 43].

GCR CLEL 5Level of recommendation reliability – C (level of evidence – 5).

Comment: Antihypertensive therapy can affect the state of placental blood flow and, accordingly, the condition of the fetus; therefore, it is very important to independently count fetal movements, and if their character changes, it is necessary to immediately contact a medical institution.

Comment: Massive, rapidly increasing edema (weight gain ≥1 kg/week in the 3rd trimester), facial edema are considered as one of the unfavorable prognostic criteria for severe PE. However, PE occurring without generalized edema is recognized as more dangerous for the mother and fetus than PE with edema [48, 49].

2.3 Laboratory Diagnostics

Laboratory testing is carried out in accordance with the clinical guidelines "Normal Pregnancy" [42]. Additionally, the following examinations are performed.

• If PE is suspected, it is recommended to prescribe the determination of protein in the urine and the study of the level of creatinine in the urine with the calculation of the albumin/creatinine ratio [50–52].

GCP BLeE 1Grade of recommendation B (Level of evidence – 1).

Comment: The use of a catheter for urine collection is not required [53]. Proteinuria up to 20⁰ weeks of pregnancy is a sign of pre-existing kidney disease [54]. In the presence of symptoms such as severe hypertension, thrombocytopenia, cerebral, renal, or hepatic insufficiency, pulmonary edema, the presence of pronounced proteinuria is not mandatory for the diagnosis of severe PE [4, 18]. At the same time, proteinuria that arises de novo and progresses is an important diagnostic marker of PE. When protein ≥1 "+" is detected according to the results of urine test strips, quantitative protein determination is necessary. The urine albumin/creatinine ratio ≥30 mg/g indicates significant proteinuria and correlates with protein loss ≥0.3 g/day [17–19, 55].

• If PE is suspected, it is recommended to prescribe a study of the total hemoglobin level in the blood and an assessment of hematocrit [17–19, 55]

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: A decrease in hematocrit is a possible indicator of hemolysis.

• If PE is suspected, it is recommended to prescribe a study of the platelet count in the blood [17–19, 55]

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: A decrease in the platelet count (<50,000/µL) indicates the development of severe PE. A progressive decrease in the platelet count, even within normal values, should be monitored at 6-hour intervals. Before delivery, it is recommended to test the platelet count if it has not been done previously [4, 17, 18]. In recent years, several large studies have been conducted regarding the platelet-to-lymphocyte ratio as a prognostic factor and degree of severity of preeclampsia. A 2023 systematic analysis proved the low prognostic value of this method [56].

• If PE is suspected, it is recommended to prescribe a study of blood fibrinogen levels, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, and determination of the international normalized ratio/prothrombin index [1, 18, 23].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Hemostasiogram changes are non-specific and do not reflect the severity of PE, but changes in the hemostasiogram serve as an indication for prescribing thromboprophylaxis or bleeding prophylaxis.

• In case of suspected PE, it is recommended to order a blood smear examination to analyze erythrocyte morphology anomalies (as part of a blood smear examination for erythrocyte, platelet, and leukocyte morphology anomalies) [17–19, 23, 55].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The presence of erythrocyte fragments (schizocytosis, spherocytosis) indicates the development of hemolysis in severe PE.

• In case of suspected PE, it is recommended to order a general clinical biochemical blood test [17–19, 55, 57-60].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The general clinical biochemical blood test includes determination of total protein, urea, uric acid, creatinine, total bilirubin, free (unconjugated) bilirubin, ALT, AST, and blood glucose levels. Severe PE is indicated by: decreased albumin concentration associated with increased vascular endothelial permeability; elevated creatinine levels above 90 µmol/L, especially in combination with oliguria (less than 500 mL/day); elevated bilirubin concentration associated with hemolysis or liver damage; decreased uric acid concentration; elevated liver transaminases (ALT, AST).

2.4 Instrumental Diagnostics

Instrumental diagnostic examinations are performed in accordance with the clinical guidelines «Normal Pregnancy» [42]. The following additional examinations are performed.

• In case of suspected PE, it is recommended to perform fetal ultrasound (US) for fetometry, assessment of the placenta and amniotic fluid [60-61].

GCR CLEL 5Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade C (Level of Evidence – 5).

• In moderate PE, it is recommended to perform fetal US every 3–4 weeks to monitor fetal growth dynamics [61].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• During antihypertensive therapy, it is recommended to perform fetal US and Doppler ultrasound of uteroplacental blood flow every 7–10 days to clarify the fetal condition (growth rate of estimated fetal weight, assessment of paraphytal structures – amount of amniotic fluid, placental characteristics) [17, 19, 43, 35].

GCR BLEL 2Grade of recommendation B (level of evidence – 2).

Comment: in recent years, opportunities have emerged for the comprehensive assessment of fetal condition using computerized CTG with determination of short-term heart rate variability. The method can be used from 26 weeks of pregnancy, as confirmed by large-scale multicenter studies [67,67]. Since early-onset PE is frequently accompanied by fetal compromise, this method is justified when used from 26 weeks of pregnancy.

• During antihypertensive therapy, fetal CTG is recommended every 7–10 days for the timely detection of fetal compromise [17, 19, 43].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• During magnesium therapy, dynamic fetal CTG monitoring is recommended to assess fetal condition [62].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

• In the event of a seizure recorded before the 20th week of pregnancy or in the first two days postpartum; eclampsia resistant to magnesium sulfate** therapy; severe focal neurological symptoms; hemiparesis; or coma persisting for 24 hours after discontinuation of sedative therapy, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is recommended if CT results are normal but neurological symptoms and visual impairment persist [21, 22].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Brain CT examination in patients with eclampsia presenting with focal neurological symptoms or altered consciousness is performed to rule out intracranial hemorrhage.

• In PE, routine measurement of central venous pressure (CVP) is not recommended [63–65].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

2.5 Other Procedures

Other diagnostic examinations are performed in accordance with the clinical guidelines «Normal Pregnancy» [42].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Non-pharmacological therapy

3.2. Antihypertensive therapy

• Antihypertensive therapy (ATX group C; drug groups: C02 – Antihypertensives, C07 – Beta-blocking agents, C08 – Calcium channel blockers) is recommended for BP ≥140/90 mm Hg at any gestational age, measured in a clinic or office, or BP ≥135/85 mm Hg, measured at home, to reduce the likelihood of severe maternal hypertension and other complications, primarily severe PE and HELLP syndrome [5].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: In pregnant women with initially low BP, it is possible to prescribe antihypertensive therapy at BP ≥130/85 mm Hg. A 2023 meta-analysis convincingly showed that even in «mild» hypertension during pregnancy, the administration of antihypertensive therapy improves pregnancy outcomes [70]. Antihypertensive drugs should be reduced in dose or discontinued if DBP drops to <80 mm Hg [4,5, 69].

• When administering antihypertensive therapy in pregnant women with severe chronic hypertension (CH), it is recommended to target (safe for mother and fetus) SBP levels of 130–150 mm Hg and DBP levels of 80–95 mm Hg [71–73].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• When administering antihypertensive therapy in pregnant women with gestational hypertension (GH) or chronic hypertension (CH), it is recommended to target (safe for mother and fetus) BP levels of ≤135/85 mm Hg [222].

GCR CLEL 1Grade of recommendation C (level of evidence – 1).

Comment: according to the results of a network meta-analysis and systematic review, diltiazem demonstrated maximum efficacy in lowering BP in severe PE [1]. Since the drug belongs to FDA pregnancy category C, its targeted use is justified.

• In severe hypertension (SBP ≥160 and/or DBP ≥110 mm Hg), methyldopa** (oral) or #nifedipine** (oral) (Appendix A3.1) are recommended [17, 19, 71, 74, 80, 208, 214, 217, 221].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

• In chronic hypertension with SBP ≥160 mm Hg and/or DBP ≥110 mm Hg, dual or triple antihypertensive therapy is recommended [70, 72].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: In resistant hypertension, additional prescription of sustained-release #nifedipine**, oral metoprolol**, or clonidine** [1, 206, 207] after 20 weeks of pregnancy is possible. #Nifedipine** can cause a marked decrease in BP, a dramatic reduction in placental blood flow, and, accordingly, a critical fetal condition. Therefore, treatment with #nifedipine** requires BP monitoring 3 times a day to avoid maternal hypotension, and sublingual administration of the drug is contraindicated. The main drugs for routine management of hypertension in pregnant women and dosing regimens are listed in Appendix A3.1.

• In resistant hypertension, the alpha-blocker urapidil** (ATX group C02CA06) is recommended. The drug belongs to FDA category C, which allows its cautious use in pregnancy during urgent situations. At the same time, the use of the drug is contraindicated in the postpartum period during breastfeeding [81].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Special attention should be paid to preventing a sharp drop in BP, which may cause maternal or fetal complications as a result of falling below critical perfusion thresholds. Elevated BP should be reduced to a target SBP of 130–140 mm Hg and DBP of 80–90 mm Hg at a rate of 10–20 mm Hg every 10–20 min.

3.3. Anticonvulsant therapy

• In severe PE and eclampsia, intravenous administration of magnesium sulfate** is recommended as the first-line drug for the prevention and treatment of seizures [18, 81–87].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment: Magnesium sulfate** is superior to benzodiazepine derivatives, phenytoin**, and nimodipine** in preventing eclampsia, and its use does not increase the rate of Cesarean section (CS), hemorrhage, infectious diseases, or neonatal depression [25, 59]. In patients with pre-existing hypertension or gestational hypertension, magnesium sulfate** may be administered for fetal neuroprotection at a gestational age of ≥33⁶ weeks if delivery is anticipated within the next 24 hours [19, 61, 85–87]. However, in emergency maternal and/or fetal indications, delivery should not be delayed in order to administer magnesium sulfate for fetal neuroprotection [19, 84–87]. Magnesium sulfate** is administered at an initial dose of 4 g of dry substance (16 ml of a 25% solution) over 10–15 minutes, followed by 1 g/hour (4 ml/hour of a 25% solution) [17–19] (Appendix A3.3). These doses of magnesium sulfate** are less toxic to the mother while providing the same clinical effect compared to the previously recommended doses (6 g bolus and 2 g/hour) [17, 43]. It is not recommended to discontinue the administration of magnesium sulfate** solely based on a decrease in blood pressure, as it exerts an anticonvulsant rather than a hypotensive effect [84, 90, 91]. Evidence indicates that the maintenance dose of magnesium sulfate depends on the creatinine level: 2 g/hour if the creatinine level is < 97 µmol/L (1.1 mg/dL) and 1 g/hour if the creatinine level is > 97 µmol/L (1.1 mg/dL) [214].

• Magnesium sulfate** is not recommended for prolonged use (>5–7 days) during pregnancy due to the risk of fetal/neonatal osteopathy [19, 86].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• Magnesium sulfate** is not recommended in moderate preeclampsia [17, 25, 92].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Administration of magnesium sulfate** as routine therapy for moderate preeclampsia during pregnancy does not prevent the progression of preeclampsia. At the same time, given that eclampsia can occur against the background of preeclampsia of any severity, anticonvulsant therapy with magnesium sulfate is paramount in the management of preeclampsia. Furthermore, the latest meta-analysis shows a lack of clear understanding regarding more effective doses and routes of administration of magnesium sulfate in the first place [93].

Comment: Administration of bolus doses of diazepam** has a negative effect on the fetus [18, 19, 20, 25, 59]. The use of #sodium thiopental** (it crosses the placental barrier and is excreted in breast milk, and is therefore used only if the expected benefit to the mother outweighs the potential risk to the fetus) should be considered solely for sedation and anticonvulsant therapy when magnesium sulfate** is ineffective, and as induction for general anesthesia and mechanical ventilation [94–96]. Administration regimen: The solution should be injected intravenously slowly, at a rate of no more than 1 ml/min. Initially, 1–2 ml is usually injected, and after 20–30 seconds, the remaining amount. The maximum single and daily intravenous doses are 1.0 g (50 ml of a 2% solution) [20]. The anticonvulsant effect of #phenytoin** is less pronounced compared to magnesium sulfate, but it may also be considered in cases of moderate preeclampsia. Administration regimen: slow intravenous injection of 20 mg/kg of body weight (maximum 1000 mg) in 100 ml of saline over 20 minutes. Then, a maintenance dose of 500 mg is given orally after 10 hours [215].

3.4. First aid for a patient with PE

See Appendix A3.5

3.5. Management of a patient with PE in the emergency department

See Appendix A3.2

3.6. Management of a patient with PE in the intensive care unit

See Appendices A3.5 and A3.6.

Level of evidence A ( trustworthiness category – 1).

Level of evidence C ( trustworthiness category – 5).

• In PE, it is recommended to limit intravenous and oral fluid intake to prevent pulmonary edema [87].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In preeclampsia and acute pulmonary edema, recommended is an infusion of nitroglycerin** at 5 mcg/min, increasing every 3–5 min to a maximum dose of 100 mcg/min [74].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In severe preeclampsia and eclampsia, prolonged mechanical ventilation is recommended in the following cases: impaired consciousness of any etiology (medications, cerebral edema, circulatory disorders, space-occupying lesion, hypoxia); cerebral hemorrhage; coagulopathic bleeding; shock; acute lung injury or acute respiratory distress syndrome (ARDS), alveolar pulmonary edema; hemodynamic instability (uncorrectable hypertension ≥160/100 mm Hg or hypertension requiring adrenergic and dopaminergic agents (C01CA)); progressive multiple organ failure [102–106].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Preeclampsia and HELLP syndrome are specific pregnancy-associated forms of TMA. When obstetric TMA is suspected, differential diagnosis with other forms is required: aHUS, TTP, CAPS, acute fatty liver of pregnancy. Pregnancy and the postpartum period are high-risk factors for the development of various forms of TMA [107, 108, 209–212]. Differentiating thrombotic microangiopathies manifesting during pregnancy is clinically challenging but crucial for ensuring proper management due to the direct impact on fetal and maternal outcomes.

• When HELLP syndrome is suspected, a surgical consultation is recommended to rule out acute surgical pathology [4].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: In HELLP syndrome, there is a high risk of subcapsular liver rupture and other abdominal organ pathologies that indicate emergency surgical treatment.

• In preeclampsia with clinical secondary TMA (HELLP syndrome) at any gestational age, plasmapheresis and plasma transfusions are not recommended as they delay the main treatment method—delivery [112].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The use of fresh frozen plasma is limited by current regulatory legal acts governing the use of blood components, in which thrombotic thrombocytopenic purpura is the only form of thrombotic microangiopathy mentioned [113].

• Initiation of renal replacement therapy is recommended according to KDIGO criteria in acute kidney injury (AKI) caused, among other things, by HELLP syndrome [211, 212, 222–225].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• Plasma exchange is indicated in patients with HELLP syndrome and stage 1–2 AKI [226–227].

GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).

Comment: Plasma exchange is indicated in patients with stage 1–2 AKI upon the development of conditions in which endogenous products circulate in the blood that can contribute to the further progression of AKI and are not effectively removed by renal replacement therapy (RRT) methods. These include myoglobin, hemoglobin, proteolytic enzymes, endotoxin, paraproteins, autoantibodies, protein-bound toxins, etc. Such conditions include sepsis, rhabdomyolysis, hemolytic uremic syndrome, liver failure, HELLP syndrome, acute pancreatitis, paraproteinemic hemoblastosis, vasculitis, etc.).

• In TMA during pregnancy, plasma exchange (PE) is not recommended [114].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Differential diagnosis of various TMAs in the first days of the disease is extremely difficult. PE is recommended as 1st-line therapy only for patients with TTP and aHUS with antibodies to factor H, while classifying almost all other causes of aHUS as class II (2nd-line therapy). PE removes autoantibodies and circulating complement activators, replacing missing or defective complement regulators with 'donor' molecules. Prior to delivery—that is, before the removal of the placenta, the main trigger for complement activation—PE is ineffective.

• In TMA with a verified diagnosis of TTP (ADAMTS13 <10%) in the postpartum period, plasmapheresis and plasma transfusion are recommended [115–118].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In aHUS (ADAMTS13 level >10%, catastrophic antiphospholipid syndrome (CAPS) ruled out) in the postpartum period, eculizumab** is recommended [41, 119].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The decision to prescribe eculizumab** is made after consulting a nephrologist.

• In aHUS (ADAMTS13 level >10%, Thrombotic Microangiopathy Associated with Complement System (TMACS) excluded) in the postpartum period, plasma exchange is recommended only if eculizumab** is not available [117, 120-122].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In the postpartum period with persistent clinical and laboratory manifestations of TMA, it is recommended to perform differential diagnosis between HELLP syndrome, TTP, and aHUS, and, if technically feasible, perform plasma exchange to prevent the avalanche-like progression of TMA [123].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: In case of progression or persistence of TMA symptoms in the postpartum period, early plasma exchange (within 24 hours) may be performed in medical organizations if technically feasible (by decision of an interdisciplinary board, or in urgent cases, by members of the on-duty team) [124-126,114,115]. The use of plasma exchange in complement-mediated conditions is based on its ability to effectively remove autoantibodies or mutated complement system regulators, replacing missing or defective complement regulators. The necessity of its use is justified by the rapid development of TMA in pregnant and postpartum women when it is not possible to rapidly exclude TTP and verify aHUS. "Rapid" plasma exchange has proven itself as a 1st-line therapy in children who were subsequently verified to have aHUS [127, 128]. However, there is not a single systematic review, meta-analysis, or RCT proving the efficacy of plasma exchange in aHUS compared to eculizumab**. A number of guidelines recommend plasmapheresis as the starting therapy for aHUS before clarifying the diagnosis and excluding TTP and/or if eculizumab** is not available.

• In TMA without signs of bleeding, platelet concentrate is not recommended [129].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In TMA in the postpartum period, heparin prophylaxis (ATC group BO1AB – group of heparins) is recommended if the platelet count is >50,000/μL [130, 131].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In TMA and severe anemia due to hemolysis (hemoglobin <70 g/L), transfusions of red blood cell-containing donor blood components (packed red blood cells, washed red blood cells) are recommended for replacement purposes [132-133].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The frequency of transfusions is determined by laboratory and clinical indicators (hemoglobin, red blood cell count, presence of hemolysis, pulse rate, blood pressure).

3.7. First aid for eclampsia

See Appendix A3.5

3.8. Delivery

See Appendix A3.

Comment: Regimes and doses of corticosteroids for the prevention of neonatal respiratory distress syndrome, as well as specific conditions allowing for the expansion of their application, are detailed in the Russian Ministry of Health Clinical Guidelines "Premature Birth" [137].

• In preeclampsia, emergency delivery is recommended in case of bleeding from the genital tract, suspected placental abruption, or acute fetal hypoxia [138].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In preeclampsia, urgent delivery is recommended after stabilization of the condition in the presence of persistent headache and visual disturbance; persistent epigastric pain, nausea, or vomiting; progressive deterioration of liver and/or kidney function; eclampsia; arterial hypertension refractory to medical management; platelet count <100*10⁹/L; fetal compromise according to CTG; absent or reversed end-diastolic flow in the umbilical artery; absent or reversed flow in the ductus venosus; IUGR <5th percentile combined with fetal or fetoplacental perfusion pathology (absent or reversed flow in the uterine artery); severe oligohydramnios (<5 cm) in 2 evaluations 24 hours apart at a gestational age of more than 30 weeks [139-141].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: CTG abnormalities include spontaneous or recurrent late or severe variable decelerations; variability of less than 5 bpm for 60 min, absence of Dawes-Redman criteria for 60 min, and a Fischer CTG score of less than 6 points.

• In gestational arterial hypertension and moderate preeclampsia at 24⁰ to 33⁶ weeks of gestation, expectant management is initially recommended [19, 43, 142, 143].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment: In gestational arterial hypertension or preeclampsia, expectant management is possible under strict dynamic monitoring of maternal and fetal condition until 37⁶ weeks of gestation [2, 144]. It is used when serious consequences for the mother are unlikely, but clear benefits for the fetus are expected. If a negative trend in the condition of the mother or fetus is detected, delivery is indicated [19, 43, 142]. Clinical situations precluding expectant management [4, 17, 19, 43] on the maternal side: severe preeclampsia and signs of impending eclampsia (regardless of gestational age); uncontrolled BP refractory to therapy (≥160/110 mm Hg); persistent headaches unresponsive to therapy; epigastric pain or right upper quadrant pain unresponsive to repeated analgesics (ATC group NO2); visual, motor, or sensory disturbances; cerebrovascular disorders (stroke); left ventricular failure; myocardial infarction; PRES syndrome; new or worsening renal dysfunction (serum creatinine > twice baseline); pulmonary edema; eclampsia; suspected placental abruption or vaginal bleeding in the absence of placenta previa; abnormal laboratory tests (elevation of liver transaminases ≥500 IU/L); progressive decrease in platelet count <100x10⁹/L; coagulopathy (INR >2) in the absence of alternative causes; premature rupture of membranes; HELLP syndrome [19, 43, 146]. Clinical situations precluding expectant management on the fetal side: fetal distress; antenatal fetal death; lethal congenital malformations; extreme prematurity; persistent or reversed end-diastolic flow in the umbilical artery; persistent reversed diastolic flow in the umbilical artery.

• In severe preeclampsia and IUGR <5th percentile at <33⁶ weeks of gestation, delivery is not recommended in the absence of negative dynamics in the pregnant woman's condition and a stable fetal condition [43, 142, 143, 147, 148].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment: According to the TRUFFLE study, to determine the correct delivery date at a gestational age >32⁰ weeks, a combination of computerized CTG monitoring and ultrasound Doppler assessment of the fetoplacental blood flow, specifically the evaluation of the pulsatility index in the umbilical arteries, is recommended. This approach ensures better clinical outcomes in children with neurological impairments (based on 2-year follow-up) [140].

• In gestational arterial hypertension or moderate preeclampsia, delivery at 37⁶ weeks of gestation is recommended as the preferred management strategy [19, 43].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In severe preeclampsia, the following management strategy is recommended depending on the gestational age: 22-24 weeks – termination of life-threatening pregnancy or, in the absence of a life-threatening situation, vaginal delivery; 25-33 weeks – prolongation of pregnancy in the absence of uncontrolled hypertension, progressive maternal organ dysfunction, fetal distress, prevention of fetal respiratory distress syndrome, cesarean section – according to obstetric indications; ≥ 34 weeks – treatment, preparation, delivery, cesarean section according to obstetric indications [43].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: In all clinical situations involving preterm delivery, the conclusion of an interdisciplinary board is required. Prolongation of pregnancy in severe preeclampsia is possible in level 3 medical organizations after the conclusion of an interdisciplinary board.

Comment: In severe PE at a gestational age of less than 32 weeks, cesarean section is preferred; after 32 weeks, vaginal delivery is preferred in cephalic presentation [19].

Comment: The final choice of the delivery method should be based on the analysis of the clinical situation, the condition of the mother and fetus, the facility's capabilities, the experience of the medical team, and the patient's informed consent.

• In the 3rd stage of labor, after blood pressure has normalized, to prevent hemorrhage, it is recommended to administer oxytocin** 10 IU intramuscularly or 5 IU intravenously as an infusion [148].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• To prevent early postpartum eclampsia during and at the end of delivery, it is recommended to infuse #magnesium sulfate** at a dose of 1.0 g/hour (depending on hourly diuresis) for at least 24 hours [4, 17, 19, 43, 82–86, 155].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment: In women who received an infusion of #magnesium sulfate** for 8 hours before delivery and discontinued it after delivery, the probability of developing eclampsia is the same as in women who received an infusion of magnesium sulfate** for 8 hours before delivery and 24 hours after [3, 19, 78, 105].

Comment: Heparin group drugs (LMWH - B01AB - heparin group) are recommended as the drugs of choice for postoperative thromboprophylaxis, as they are safe during breastfeeding. Enoxaparin sodium**, nadroparin calcium, dalteparin sodium, and parnaparin sodium** are used as LMWH.

• In the perioperative period, in the absence of contraindications, elastic compression of the lower extremities is recommended to reduce the risk of venous thromboembolic events [156].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

3.9. Obstetric analgesia

• In case of cesarean section, in the absence of contraindications, all anesthesia methods are recommended: epidural, spinal, combined spinal-epidural, and general anesthesia [63, 157–160].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: General anesthesia should be performed if neuroaxial anesthesia is contraindicated; readiness for airway management difficulties is required [161]. It is mandatory to use opioids in adequate doses to reduce the hypertensive response to laryngoscopy [162].

• In PE, regional anesthesia/analgesia is recommended for anesthetic management of cesarean section and labor in the absence of contraindications [63, 65, 159, 161].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

• If eclampsia develops during emergency delivery, to prevent potential complications (progression of neurological symptoms, bleeding risk), general anesthesia is recommended as the method of choice [157, 163].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In the case of vaginal delivery for pain relief in labor, in the absence of contraindications, epidural analgesia is recommended [96].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

3.10. Postpartum management

• In the postpartum period, to prevent severe hypertension, antihypertensive therapy is recommended taking into account contraindications during lactation [72, 73, 74].

Level of evidence C ( trustworthiness category – 5).

Comment: In the early postpartum period, women with PE should be considered at high risk for early preeclamptic complications for at least 3 days; their blood pressure and clinical status should be monitored at least every 4 hours when the woman is awake [5]. Antihypertensive medication should be continued; treatment of any hypertension with antihypertensive drugs should be considered up to the 6th postpartum day [5]. Thereafter, antihypertensive therapy may be slowly tapered over several days, but not stopped abruptly. Eclamptic seizures may first develop in the early postpartum period. In women with PE, anti-inflammatory and antirheumatic drugs, namely nonsteroidal anti-inflammatory drugs (NSAIDs) (ATC group M01A), should not be used for postpartum analgesia, except when other analgesics (ATC group N02) are ineffective; this is particularly important for women with kidney disease, or in cases of placental abruption, acute kidney injury (AKI), or other risk factors for AKI (e.g., sepsis, postpartum hemorrhage) [5].

To detect postpartum hypertension, blood pressure must be measured within 6 hours after delivery in every uncomplicated normotensive woman due to the risk of late-onset PE [2]. Blood pressure fluctuations are common after delivery. Transient hypertension may occur after delivery in an uncomplicated normotensive pregnancy; this may be due to pain (inadequate analgesia), the use of certain medications (NSAIDs for pain relief, etc.), hypervolemia after regional anesthesia, extracellular fluid accumulated during pregnancy shifting into the intravascular space, or the recovery of non-pregnant vascular tone [2]. Postpartum blood pressure elevation is physiological, and if "mild" hypertension develops (usually on days 3–6), it generally resolves spontaneously without the need for drug treatment [2, 164]. Since PE can also have late manifestations, it is important to regularly measure blood pressure (i.e., at least once a day) during the first 5 days after delivery [2]. It is recommended to monitor blood pressure every day after discharge from the hospital for 1 week [15]. All women who had hypertension during pregnancy should be re-examined 3 months postpartum to ensure that blood pressure, urinalysis, and any other abnormal lab tests have normalized [5]. If proteinuria or hypertension persists, appropriate further investigation and treatment must be initiated [5].

• In the postpartum period, in case of severe hypertension, antihypertensive therapy is recommended until target values of SBP <160 mm Hg and DBP <110 mm Hg are achieved [19, 43, 165].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: In severe hypertension (BP >150–160/100–110 mm Hg lasting >15 minutes or isolated DBP elevation >120 mm Hg and target organ damage), hypotensive therapy should be initiated with a preference for fast-acting drugs (nifedipine**, #nitroglycerin**) (dosing regimen – see Appendix A3.1).

The regimen for #nitroglycerin** administration: intravenous infusion, starting dose 5 mcg/min, then increasing by 5 mcg/min every 5 minutes (maximum dose 200 mcg/min) [216], [228], [229].

• During lactation, it is recommended to prescribe #nifedipine**, #enalapril**, and methyldopa as antihypertensive therapy (Appendix A3.1) [166-168, 174, 217, 221].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: All of the above medications taken by a nursing mother are excreted in breast milk; however, most antihypertensive drugs are present in breast milk in very low concentrations, with the exception of #nifedipine**, whose concentration in breast milk is similar to that in maternal plasma [62, 63]. The internationally recognized drugs and lactation database LactMed, provided by the TOXNET system, considers the oral use of a large number of antihypertensive agents acceptable during lactation [169, 170, 219]. These include ACE inhibitors (ATC group C09A) #captopril**, quinapril, #perindopril**, #enalapril; the angiotensin receptor blocker (ATC group C09CA06) #candesartan; calcium channel blockers (ATC group C08) amlodipine**, verapamil**, #diltiazem, #nifedipine**; the diuretic (ATC group C03AA03) #hydrochlorothiazide**; the aldosterone antagonist (ATC code C03DA01) #spironolactone**; beta-blockers (ATC group C07) metoprolol**; the central α2-agonist methyldopa**; and the peripheral α1-blocker doxazosin**. The doses of drugs passing through milk are much lower than the known safe doses of the same drugs used directly in newborns and infants [173]. Only a small proportion of medications are contraindicated in nursing mothers or associated with side effects in their infants [173-175].

Anticancer drugs (ATC group L), radioactive drugs (ATC group V10), lithium (ATC group N05AN), oral retinoids (ATC group D10AD), amiodarone** (ATC group C01BD), gold salts (ATC group M01CB), and drugs that inhibit milk production are strictly contraindicated during lactation [173–175].

When taking #enalapril**, renal function and blood potassium levels must be monitored [213]. It should be borne in mind that in the postpartum period, the administration of methyldopa** may provoke the development of depressive states (the postpartum period is characterized by increased vulnerability to depression) [168] (for dosing regimen, see Appendix A3.1).

• During lactation, if monotherapy for arterial hypertension is ineffective, it is recommended to consider a combination of #nifedipine** and #enalapril** [19] (for dosing regimen, see Appendix A3.1).

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: If the above regimen is ineffective, it is recommended to add #atenolol** to it, or to replace one of the drugs used with these medications (for dosing regimen, see Appendix A3.1).

Dosing schedule: 12.5–25 mg 2 times a day, maximum dosage is 75 mg 3 times a day [220].

• During lactation, the administration of diuretics (furosemide**, hydrochlorothiazide**, and spironolactone**) is not recommended, as they may reduce milk production [172].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

• Patients with severe arterial hypertension and severe preeclampsia during pregnancy are recommended to be discharged no earlier than 7 days after delivery [26].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: As a rule, the risk of disease exacerbation persists for 7 days after delivery and applies to all women with hypertensive disorders during pregnancy [87, 94]. The incidence of postpartum HELLP syndrome ranges from 7% to 30%, and postpartum eclampsia reaches 28% [26].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

• At the stage of preconception care or during the 1st visit of a pregnant patient, it is recommended to identify the preeclampsia risk group [47].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comment: Patients with a history of early and/or severe preeclampsia belong to the high-risk group for preeclampsia. Other risk factors for preeclampsia include: chronic arterial hypertension, multiple pregnancy, diabetes mellitus, obesity, antiphospholipid syndrome, pregnancy following assisted reproductive technologies [1], advanced maternal age, family history of preeclampsia, duration of sexual cohabitation before pregnancy of less than 6 months, first pregnancy, chronic kidney disease, connective tissue diseases, and Factor V Leiden mutation [5].

• A pregnant patient at high risk for preeclampsia is recommended to be prescribed daily self-monitoring of blood pressure throughout pregnancy [47].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comment: During the 1st trimester ultrasound scan, it is recommended to measure the pulsatility index (PI) in the uterine arteries to predict early preeclampsia. Optimal preeclampsia screening includes risk calculation based on the assessment of risk factors, measurement of mean blood pressure, uterine artery PI, and determination of placental growth factor (PlGF) [179–182] (e.g., the preeclampsia risk calculator created by The Fetal Medicine Foundation). If PlGF determination is not available, preeclampsia screening includes risk calculation based on the assessment of risk factors, measurement of mean blood pressure, and uterine artery PI [5]. PlGF is the best, but still relatively inaccessible biochemical marker. In high-risk preeclampsia, low values of this marker indicate a high risk of early preeclampsia, often combined with fetal growth restriction (false-positive rate is 9%) [183].

Comment: To confirm the diagnosis of preeclampsia, it is also possible to determine the ratio of angiogenic factors sFlt-1/PlGF [75, 188, 189], which is a reliable yet currently less accessible research method. An sFlt-1/PlGF ratio <38 rules out the development of preeclampsia within 7 days. At a gestational age of <34 weeks, an sFlt-1/PlGF ratio >85, and at a gestational age of >34 weeks, an sFlt-1/PlGF ratio >110 indicates a high probability of preeclampsia development. However, these values are not universal; other cut-off values for the sFlt-1/PlGF ratio developed by laboratories or provided by developer companies are also possible [190–192].

• A pregnant patient at high risk for preeclampsia is recommended to be advised to avoid work involving prolonged standing or excessive physical exertion, night shift work, and work causing fatigue [193–195].

GCR BLEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade B (Level of Evidence – 2).

• A pregnant patient at high risk for preeclampsia is recommended aerobic exercise 3–4 times a week for 45–90 minutes, which is associated with less weight gain and a reduced risk of developing arterial hypertension [196].

GCR ALEL 1Grading of Recommendations Assessment, Development and Evaluation A (Level of Evidence – 1).

• A pregnant patient at high risk for preeclampsia is not recommended to be prescribed bed rest for the prevention of preeclampsia [18, 19, 78].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• A pregnant patient at high risk for preeclampsia with low calcium intake (less than 600 mg/day) is recommended to be prescribed oral calcium supplements throughout pregnancy at a dose of 1 g/day [197–199].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: The prescription of calcium supplements throughout pregnancy in patients at high risk for preeclampsia reduces the risk of developing this condition.

• A pregnant patient at high risk for preeclampsia is recommended to be prescribed oral #acetylsalicylic acid** from 12 weeks of pregnancy to 36 weeks of pregnancy at 150 mg/day [197, 198].

GCR BLEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade B (Level of Evidence – 2).

Comment: There is robust evidence for the efficacy of #acetylsalicylic acid** administration in women at high risk for preeclampsia and associated placental disorders based on pathological placentation. An analysis of priority publications has convincingly demonstrated the benefits of evening administration (at bedtime) of low-dose #acetylsalicylic acid** (150 mg) initiated before 16 weeks and continued until 36 weeks of gestation to reduce the risk of severe and early preeclampsia identified based on the results of extended combined 1st trimester screening [197, 198]. At the same time, according to the results of a multicenter open-label randomized (phase 3) study, discontinuation of acetylsalicylic acid is possible in pregnant women with a high risk of preeclampsia according to extended combined 1st trimester screening if the sFlt-1/PlGF ratio does not exceed 38 when tested at 24–28 weeks [218].

• A pregnant patient at high risk for preeclampsia is not recommended G03DA group drugs, pregn-4-ene derivatives, for the prevention of preeclampsia [61].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• A pregnant patient at high risk for preeclampsia is not recommended magnesium sulfate** for the prevention of preeclampsia [61].

GCR CLEL 5Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade C (Level of Evidence – 5).

• A pregnant patient at high risk for preeclampsia is not recommended folic acid** for the prevention of preeclampsia [87].

GCR CLEL 5Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade C (Level of Evidence – 5).

• A pregnant patient at high risk for preeclampsia is not recommended diuretics for the prevention of preeclampsia [4, 17, 18, 200]

GCP BLeE 1Grade of recommendation B (Level of evidence – 1).

• A pregnant patient at high risk for preeclampsia is not recommended heparin group drugs for the prevention of preeclampsia [61].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• A pregnant patient at high risk for preeclampsia is not recommended tocopherol (vitamin E) and ascorbic acid (vitamin C)** for the prevention of preeclampsia [201].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• A pregnant patient at high risk for preeclampsia is not recommended cod liver oil for the prevention of preeclampsia [202].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• A pregnant patient at high risk for preeclampsia is not recommended garlic extract (dietary supplements) in tablets for the prevention of preeclampsia [203].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• A pregnant patient at high risk for preeclampsia is not recommended salt restriction for the prevention of preeclampsia [68].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comment: The optimal daily salt intake is 4 g.

6. Organization of Medical Care

• When SBP ≥160 mm Hg or DBP ≥100 mm Hg, or in severe preeclampsia/eclampsia, emergency hospitalization in the intensive care unit (ICU) of a level III obstetric and gynecological medical organization is recommended [18–20].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

The question of the admissibility of evacuation and the patient's transportability is decided individually; absolute contraindications to transportation include bleeding of any intensity. When deciding on the transfer of a patient to another hospital, placental abruption (ultrasound) must be ruled out as one of the life-threatening complications of preeclampsia (see Appendix B3).

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Khodzhaeva Zulfiya Sagdullaevna – MD, Professor, Deputy Director for Scientific Work of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

2. Shmakov Roman Georgievich – MD, Professor of the RAS, Director of the Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky, Chief freelance specialist in obstetrics of the Russian Ministry of Health (Moscow). No conflict of interest.

3. Kan Natalia Enkynovna – MD, Professor, Honored Scientist of the RF, Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

4. Baranov Igor Ivanovich – MD, Professor, Head of the Scientific and Educational Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Vice President of the Russian Society of Obstetricians and Gynecologists (Moscow). No conflict of interest.

5. Gorina Ksenia Alekseevna – PhD, Researcher at the 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

6. Dolgushina Natalia Vitalievna – MD, Professor, Deputy Director for Scientific Work, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health of the Russian Ministry of Health (Moscow). No conflict of interest.

7. Kalachin Konstantin Aleksandrovich – Anesthesiologist-Resuscitator at the Department of Anesthesiology and Intensive Care, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

8. Kirsanova Tatyana Valerievna – PhD, Senior Researcher at the Department of Reproductive Hematology and Clinical Hemostasiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

9. Klimenchenko Natalia Ivanovna – PhD, Senior Researcher at the Department of Obstetric and Extragenital Pathology, Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

10. Klimov Vladimir Anatolievich – PhD, Head of the Medical Care Organization and Information Service, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

11. Kamilla T. Muminova – Ph.D. (Medicine), Researcher at the 1st Department of Obstetrics and Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

12. Nikolaeva Anastasia Vladimirovna – PhD, Chief Physician, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

13. Rogachevsky Oleg Vladimirovich – MD, Head of the Department of Extracorporeal Treatment and Detoxification, Institute of Anesthesiology-Resuscitation and Transfusiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

14. Serov Vladimir Nikolaevich – Academician of the RAS, MD, Professor, Honored Scientist of the RF, President of the Russian Society of Obstetricians and Gynecologists, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

15. Silaev Borislav Vladimirovich – Candidate of Medical Sciences, Head of the Department of Anesthesiology and Intensive Care, Acting Head of the Department of Anesthesiology and Critical Care at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health. Associate Professor at the Department of Anesthesiology and Critical Care, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Moscow). No conflict of interest.

16. Fedorova Tatyana Anatolyevna – Doctor of Medical Sciences, Professor, Deputy Director of the Institute of Anesthesiology, Intensive Care and Transfusiology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). No conflict of interest.

17. Kholin Aleksey Mikhailovich – Candidate of Medical Sciences, Head of the Telemedicine Department at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow). No conflict of interest.

18. Natalia V. Artymuk – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics, Gynecology, and Women's Reproductive Health of the Russian Ministry of Health in the Siberian Federal District (Kemerovo). No conflict of interest.

19. Bezhenar Vitaly Fedorovich – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Reproductology at the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief Freelance Obstetrician-Gynecologist of the Healthcare Committee of the Government of Saint Petersburg (Saint Petersburg). No conflict of interest.

20. Belokrinitskaya Tatyana Evgenyevna – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at the Faculty of Advanced Training and Professional Retraining of Specialists, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist of the Russian Ministry of Health for Obstetrics, Gynecology and Women's Reproductive Health in the Far Eastern Federal District (Chita). No conflict of interest.

21. Gaysin Ilshat Ravilevich – Doctor of Medical Sciences, Professor at the Department of Hospital Therapy with Courses of Cardiology and Functional Diagnostics, Faculty of Advanced Training and Professional Retraining of Specialists, Izhevsk State Medical Academy (Izhevsk). No conflict of interest

22. Katkova Nadezhda Yuryevna – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Additional Postgraduate Education, Privolzhsky Research Medical University of the Russian Ministry of Health (Nizhny Novgorod). No conflict of interest

23. Kinzhalova Svetlana Vladimirovna – Ph.D. in Medicine, Head of the Department of Anesthesiology and Intensive Care, Ural Research Institute for Maternal and Infant Care of the Russian Ministry of Health. Member of the Association of Obstetric Anesthesiologists and Intensivists (Yekaterinburg). No conflict of interest.

24. Kulikov Alexander Veniaminovich – Doctor of Medical Sciences, Professor at the Department of Anesthesiology, Intensive Care and Transfusiology, Faculty of Advanced Training and Professional Retraining of Specialists, Ural State Medical University of the Russian Ministry of Health (Yekaterinburg). Member of the Federation of Anesthesiologists and Intensivists and the Association of Obstetric Anesthesiologists-Intensivists (Yekaterinburg). No conflict of interest.

25. Malyshkina Anna Ivanovna – Doctor of Medical Sciences, Professor, Director of the V.N. Gorodkov Ivanovo Research Institute of Motherhood and Childhood of the Russian Ministry of Health, Head of the Department of Obstetrics and Gynecology, Medical Genetics, Faculty of General Medicine, Ivanovo State Medical Academy of the Russian Ministry of Health, Chief Freelance Specialist of the Russian Ministry of Health for Obstetrics, Gynecology and Women's Reproductive Health in the Central Federal District (Ivanovo). No conflict of interest.

26. Ovezov Alexey Muradovich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology and Intensive Care, Faculty of Advanced Medical Training, M.F. Vladimirsky Moscow Regional Research Clinical Institute (MONIKI), Chief Anesthesiologist-Intensivist of the Ministry of Health of the Moscow Region (Moscow). Member of the Federation of Anesthesiologists and Intensivists and the Association of Obstetric Anesthesiologists-Intensivists. No conflict of interest.

27. Penzhoyan Grigory Artemovich – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Perinatology, Faculty of Advanced Training and Professional Retraining of Specialists, Kuban State University of the Russian Ministry of Health (Krasnodar). No conflict of interest.

28. Protsenko Denis Nikolaevich – Candidate of Medical Sciences, Associate Professor at the Department of Anesthesiology and Intensive Care, N.I. Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Chief Physician of Moscow City Clinical Hospital No. 1 named after S.S. Yudin, Chief Specialist in Anesthesiology and Intensive Care of Moscow (Moscow), Member of the Federation of Anesthesiologists and Intensivists and the Association of Obstetric Anesthesiologists-Intensivists (Moscow). No conflict of interest.

29. Pylaeva Natalya Yuryevna – Candidate of Medical Sciences, Associate Professor at the Department of Anesthesiology, Intensive Care and Emergency Medical Care, Faculty of Training of Higher Qualification Medical Personnel and Additional Professional Education, V.I. Vernadsky Crimean Federal University, S.I. Georgievsky Medical Academy (Simferopol). Member of the Association of Obstetric Anesthesiologists-Intensivists. No conflict of interest

30. Radzinsky Viktor Evseevich – Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Obstetrics and Gynecology with a Course of Perinatology, Peoples' Friendship University of Russia (Moscow). No conflict of interest.

31. Sidorova Iraida Stepanovna – Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Professor at the Department of Obstetrics and Gynecology No. 1, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Moscow). No conflict of interest

32. Shalina Raisa Ivanovna – Doctor of Medical Sciences, Professor, Honored Doctor of Russia, Professor at the Department of Obstetrics and Gynecology, Faculty of Pediatrics, N.I. Pirogov Russian National Research Medical University (Moscow). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. obstetrician-gynecologists

2. obstetrician-gynecologist residents

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnosis, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Appendix A3. Reference Materials

Appendix A3.1 Main drugs for elective antihypertensive therapy in patients during pregnancy, labor, and the postpartum period [1, 19-21]

Appendix A3.2 Management of a patient with PE in the emergency department

In the admission ward, the severity of preeclampsia is assessed based on the following indicators: blood pressure, level of consciousness, headache, seizures, shortness of breath, abdominal pain, uterine bleeding, fetal heart rate.

The anesthesiologist-intensivist must be called by the obstetrician-gynecologist to the admission ward and must begin providing medical care in the following conditions [1, 4, 24]:

• seizes (history of seizures);

• unconsciousness;

• high blood pressure – above 160/110 mm Hg;

• respiratory disorders;

• vomiting;

• uterine bleeding ( placental abruption), hemorrhagic shock.

Appendix A3.3. Administration regimens and monitoring of magnesium sulfate**

Appendix A3.4. Clinical and laboratory monitoring during magnesium sulfate administration**

Appendix A3.5. First aid for a patient with PE and eclampsia

• Assess the severity of preeclampsia: BP, consciousness, headache, seizures, dyspnea, abdominal pain, genital bleeding, fetal heart rate.

• Secure venous access: peripheral vein.

• Administer magnesium sulfate** 25% 16 ml IV slowly (over 10 min) and 100 ml via infusion pump at a rate of 1 g/h (infusion of magnesium sulfate** solution only, diluted with 0.9% sodium chloride** solution).

• If BP is above 140/90 mm Hg – antihypertensive therapy: methyldopa**, #nifedipine** (doses and administration regimen – see Appendix A3.1).

• In case of seizures: ensure airway patency.

• In the absence of consciousness and/or a series of seizures – transfer to mechanical ventilation with total muscle relaxation.

• When evacuating a patient with preeclampsia/eclampsia by a basic ambulance crew, the crew must notify the obstetric hospital to which the patient is being transported.

• In preeclampsia with life-threatening clinical manifestations, delivery should be addressed after maternal stabilization, if possible, after antenatal corticosteroid therapy for fetal RDS at a gestational age of less than 34 weeks and transfer of the mother to a level III obstetric hospital.

• BP monitoring,

• repeat proteinuria tests,

• blood tests at least twice a week (more frequently if necessary) (hemoglobin, platelets, ALT, AST, LDH),

• renal function tests, including uric acid (do not use first morning urine for quantitative proteinuria assessment), hourly diuresis.

The presence of hyperuricemia in pregnant women with hypertension indicates a high risk of adverse maternal and fetal outcomes [57]. In early pregnancy, all women should be tested for proteinuria to detect pre-existing kidney disease, and in the second half of pregnancy, to rule out preeclampsia. Detection of proteinuria ≥1+ is an indication for prompt determination of the albumin-creatinine ratio [4, 16, 18, 24, 40, 61].

The goal of timely referral is to provide pregnant women and the institution with sufficient time to determine individual risk and choose further management in a calm, elective setting [18, 59].

Appendix A3.6. Treatment of massive intravascular hemolysis

When a diagnosis of massive intravascular hemolysis (free hemoglobin in blood and urine) is established and immediate hemodialysis is unavailable, conservative management can help preserve renal function [128, 205–208]. Depending on the clinical picture, several treatment options are possible.

With preserved diuresis (>0.5 ml/kg/h):

• In severe metabolic acidosis with pH <7.2 – administration of 4% sodium bicarbonate** 100 ml to prevent the formation of hematin hydrochloride in the renal tubules.

• Intravenous administration of balanced crystalloids** at 60-80 ml/kg of body weight at an infusion rate of up to 1000 ml/h.

• Parallel stimulation of diuresis with furosemide** 20–40 mg IV fractionally to maintain a urine output rate of up to 150–200 ml/h.

• An indicator of the effectiveness of the therapy is a decrease in free hemoglobin levels in the blood and urine. High-volume infusion therapy may worsen the course of preeclampsia, but this tactic will help prevent the development of acute tubular necrosis and acute renal failure [128].

In case of oliguria or anuria [128, 129, 206, 209]:

It is necessary to discontinue magnesium sulfate** and restrict fluid intake (only to correct visible losses) up to complete withdrawal, and initiate renal replacement therapy (hemofiltration, hemodialysis) if renal failure is confirmed:

• urine output rate <0.5 ml/kg/h for 6 h after the initiation of infusion therapy, stabilization of blood pressure, and stimulation of diuresis with intravenous administration of 100 mg of furosemide** (ATX group C03CA01).

• a 1.5-fold increase in serum creatinine levels, or a decrease in glomerular filtration >25%, or the development of renal dysfunction and failure of stage "I" or "F" according to the RIFLE classification or stage 2–3 according to the AKIN or KDIGO classifications.

Appendix B. Physician Action Algorithms

Appendix B1. Extended combined prenatal screening with identification of risk groups for the development of PE

Appendix B2. Differential diagnosis of hypertensive disorders during pregnancy

Appendix B3. Management of PE depending on the severity of the condition [18, 40, 84, 141]

Appendix C. Patient Information

Among hypertensive disorders during pregnancy, the frequency of which varies from 2% to 30%, preeclampsia (PE) is observed in 2–5% of pregnancies and makes a significant contribution to dramatic complications during pregnancy, as well as short- and long-term negative consequences for the future quality of life of the woman and her child. Thus, PE remains to this day one of the leading causes of maternal, perinatal, and infant mortality and morbidity worldwide.

To reduce the risk of developing PE during pregnancy, the expectant mother must undergo a thorough examination by a general practitioner, and if necessary, by a cardiologist and nephrologist. If elevated blood pressure is detected, selection of antihypertensive drugs is provided, and in the conception cycle — transition to medications approved for use during pregnancy. With the onset of pregnancy, it is necessary to systematically monitor blood pressure one to two times a day and record its values in a logbook.

If you belong to the high-risk PE group (history of PE) or are identified as high-risk for PE based on 1st-trimester screening data, you are indicated to take medications for PE prevention from 16 to 36 weeks of gestation.

Careful monitoring by specialists, a mindful attitude towards your own condition and the condition of the child will help avoid many problems and successfully carry the pregnancy to term. If any pregnancy complication associated with elevated blood pressure did occur, especially if the pregnancy had to be terminated prematurely, it is necessary to consult a general practitioner after childbirth for examination and rehabilitation aimed at improving the quality of life.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.