Ovarian hyperstimulation syndrome: clinical guidelines

List of Abbreviations

Terms and Definitions

Ascites – accumulation of fluid in the abdominal cavity, associated with the development of multiple organ failure (dysfunction).

Intra-abdominal hypertension (IAH) – a sustained or intermittent pathological increase in intra-abdominal pressure (IAP) of ≥12 mm Hg.

Assisted reproductive technologies (ART) – fertility treatment methods in which some or all stages of conception and early embryo development are carried out outside the maternal organism (including the use of donor and/or cryopreserved germ cells, reproductive organ tissues, and embryos), as well as surrogate motherhood (definition in accordance with Article 55 of Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 25, 2023) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation").

Respiratory failure – a condition in which the body either fails to maintain normal arterial blood gas composition or achieves it at the cost of increased work of breathing, leading to a decrease in the functional reserves of the body.

Paracentesis – a therapeutic and diagnostic surgical procedure aimed at detecting internal organ injuries, removing ascitic fluid, and administering medications into the abdominal cavity.

Ovarian stimulation / ovarian stimulation – pharmacological therapy aimed at inducing follicular development in the ovaries.

Acute respiratory distress syndrome (ARDS) – an acute diffuse inflammatory lesion of the lung parenchyma developing as a non-specific response to various damaging factors and leading to acute respiratory failure (as a component of multiple organ failure) due to impaired lung tissue structure and a reduction in the mass of aerated lung tissue.

Multiple organ failure – a universal syndrome of critical conditions caused by excessive uncontrolled systemic inflammation in response to sepsis, hypovolemic shock, or severe trauma.

Ovarian hyperstimulation syndrome (OHSS) – an excessive systemic response to ovarian stimulation, characterized by a wide spectrum of clinical and laboratory manifestations. It can be classified as mild, moderate, or severe, depending on the degree of tense ascites, ovarian enlargement, and respiratory, hemodynamic, and metabolic complications.

Spontaneous ovarian hyperstimulation syndrome – a condition developing as a result of the activation of vasoactive mediator production by the ovaries against the background of pregnancy.

Acute kidney injury (AKI) – renal dysfunction with a reduction in filtration and reabsorption processes, leading to disorders of water, electrolyte, nitrogenous, and other types of metabolism.

Intra-abdominal hypertension syndrome (IAH) – a persistent increase in IAP ≥12 mm Hg (with or without abdominal perfusion pressure <60 mm Hg), which is associated with the manifestation of multiple organ failure (dysfunction).

Thoracentesis – a therapeutic and diagnostic surgical procedure aimed at removing pleural fluid or gas from the pleural cavity.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Ovarian hyperstimulation syndrome (OHSS) – an excessive systemic response to ovarian stimulation, characterized by a wide spectrum of clinical and laboratory manifestations. It can be classified as mild, moderate, or severe, depending on the degree of tense ascites, ovarian enlargement, and respiratory, hemodynamic, and metabolic complications (1–5). Cases of OHSS developing during spontaneous pregnancy are known (6,7).

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

The triggering factor for the development of OHSS is the administration of an ovulatory dose of chorionic gonadotrophin** (CG), which triggers a pathophysiological cascade via the vascular endothelial growth factor against the background of an imbalance of its type 1 and type 2 receptors, as well as activation of the renin-angiotensin system. OHSS may develop immediately after transvaginal oocyte retrieval (TVOR), or within the subsequent 10 days during an established pregnancy (1,4,5,8–12). In some cases, OHSS may develop after ovarian stimulation with clomifene** (13). The pathophysiological mechanisms of spontaneously occurring OHSS during pregnancy, as well as familial recurrent episodes of this syndrome in subsequent pregnancies not associated with ovarian stimulation, are due to polymorphisms of genes encoding follicle-stimulating hormone and thyroid-stimulating hormone receptors (6,7,14–17).

OHSS represents a systemic aseptic inflammatory response of the vascular endothelium to high plasma concentrations of sex steroid hormones, accompanied by generalized endothelial damage and marked vascular permeability, leading to massive leakage of protein-rich fluid into the interstitium and the formation of ascites, hydrothorax, and anasarca. Progressive ascites contributes to an increase in IAP and further elevation of the diaphragm, causing cardiac compression, an increase in pleural and intrathoracic pressure, and a decrease in inferior vena cava blood flow and venous return (18). OHSS is characterized by a hyperdynamic type of hemodynamics, manifested by arterial hypotension, increased cardiac output, decreased peripheral vascular resistance, and increased activity of the renin-angiotensin-aldosterone system and the sympathetic nervous system (5, 19).

Impairment of renal excretory function occurs as a result of a decrease in circulating blood volume and an increase in IAP with compression of the renal parenchyma, decreased renal blood flow, increased prerenal azotemia, reduced urine output down to oligo-anuria, and the development of AKI (20,21).

Respiratory disorders accompany severe OHSS and are caused by pleural effusion and limitation of diaphragmatic mobility due to elevated IAP. The effusion can be bilateral or unilateral (more often on the right) and occurs against the background of ascites. The mechanism of effusion formation is attributed to the ability of ascitic fluid to penetrate into the right pleural cavity along the thoracic lymphatic duct passing into the mediastinum through the aortic hiatus of the diaphragm (22,23).

In patients with OHSS, high concentrations of pro-inflammatory cytokines are detected in blood serum, follicular fluid, and peritoneal transudate, under the influence of which systemic activation of coagulation processes occurs, leading to a high risk of thromboembolic complications (TEC) (19,24).

1.3 Epidemiology of the Disease or Condition

Epidemiological evaluation of OHSS is difficult due to the lack of a unified classification of the syndrome. The current incidence of OHSS is low, which is associated with correct risk factor assessment and selection of the trigger for final oocyte maturation. The incidence of severe OHSS ranges from 2% (25) to 9% (26). According to recent data, severe forms of the syndrome requiring hospital admission occur in 1% of cases and are associated with the administration of CG** as a trigger for final oocyte maturation (27). According to the RAHR Register in the Russian Federation for 2021, 88,954 cycles of assisted reproductive technologies (ART) with autologous oocytes and 429 cases of OHSS requiring hospitalization were registered (2020 – 462 cases), which accounts for 0.3% of initiated cycles (in 2020 and 2021) (28).

1.4 Features of Coding the Disease or Condition

N98.1 Ovarian hyperstimulation.

1.5 Classification of the disease or condition

Classification of OHSS by severity (23, 29)

Ovarian size may not correspond to the severity of OHSS after TVP due to follicular aspiration. If there are signs of severe or critical OHSS, women must be assigned to this category regardless of ovarian size.

Classification of OHSS by time of onset (29)

• Early OHSS develops within the first 7 days after TVP (first 9 days after hCG administration as a trigger for final oocyte maturation) and is associated with an excessive ovarian response to ovarian stimulation.

• Late OHSS occurs 8 or more days after TVP (10 or more days after hCG administration as a trigger for final oocyte maturation) and is associated with endogenous hCG production in the setting of established pregnancy.

If pregnancy does not occur in the ART cycle, symptoms of OHSS of any severity resolve with the onset of menstruation. Late OHSS is more severe, lasting up to 7–10 weeks of gestation with fluctuating exacerbation and alleviation of symptoms.

1.6 Clinical presentation of the disease or condition

The severity of OHSS correlates with the degree of hemodynamic disturbances, which determine the clinical picture and reflect the severity of vascular permeability.

The onset of OHSS can be either gradual with progressive clinical symptoms or sudden ("acute"), characterized by a sharp fluid redistribution in the body within a few hours or a shorter period, leading to ascites accompanied by hemodynamic disturbances.

Typical clinical symptoms of OHSS include ascites with IAH (30–32), oligo/anuria with AKI development in severe and critical cases (20,21), respiratory disorders associated with hydrothorax (22,23), and jaundice associated with liver dysfunction (23,33).

Fever accompanies the course of OHSS in 80% of patients with the severe form of the syndrome; in 20% of cases, temperature elevation occurs due to a urinary tract infection, in 3.8% due to pneumonia, in 3.3% due to an upper respiratory tract infection, in 2.0% due to catheter-site phlebitis, in 1.0% due to subcutaneous cellulitis at the abdominal paracentesis puncture site, in 1.0% due to a surgical wound infection, and in 0.5% due to a gluteal abscess at the site of intramuscular progesterone injections. Non-infectious fever in every second patient with OHSS is associated with endogenous pyrogenic mechanisms. Isolated cases of sepsis in severe OHSS have been described (22,23,34,35).

OHSS is characterized by a high risk of VTE. Additional risk factors include: a history of venous VTE, presence of high-risk thrombophilia (antithrombin, protein C and S deficiency, homozygous Factor V Leiden mutation, homozygous prothrombin G20210A mutation, antiphospholipid syndrome), hyperestrogenemia, and restricted mobility (36–41). Clinical and laboratory symptoms indicating a high risk of VTE in OHSS include: headache, poor concentration, visual floaters, tinnitus, edema localized in the neck and upper extremities, hematocrit >55%, leukocytosis >25×10⁹/L, and thrombocytosis >350×10³/µL. In 84% of cases, thrombosis occurs against the background of pregnancy. In 75% of cases, thrombosis is diagnosed in the venous bed with predominant localization in the vessels of the upper extremities, neck, and head. Spontaneous arterial thrombosis localized in cerebral vessels may develop. Thrombi in the femoral, popliteal, carotid, subclavian, iliac, ulnar, mesenteric arteries and aorta are less common. The incidence of pulmonary embolism in patients with OHSS and deep vein thrombosis of the lower extremities is 29%, whereas in women with OHSS and arterial thrombosis, the risk of this complication ranges from 4% to 8% (36–41).

2. Diagnostics, medical indications and contraindications for diagnostic methods

*Recommendations apply to all patients with OHSS unless otherwise specified.

Diagnostic criteria: OHSS is diagnosed upon the development of ascites (and/or hydrothorax) and enlarged ovaries (>6 cm³) following ovarian stimulation.

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comments: OHSS increases the risk of exacerbations of chronic somatic diseases, such as chronic pyelonephritis, gastric or duodenal ulcer. Acute surgical pathologies, such as acute appendicitis, must also be ruled out (5,23).

Comment: Genital tract spotting or bleeding may occur in OHSS in the setting of pregnancy with a threat of miscarriage, as well as in ectopic pregnancy.

2.3 Laboratory Diagnostics

Comments: The frequency of testing is determined by the severity of OHSS: in mild and moderate OHSS – once every 7 days until recovery; in severe and critical OHSS – daily until hematocrit normalizes (<40%), then once every 7 days until recovery. Hematocrit >40% is associated with moderate OHSS, >45% with severe OHSS, and >55% with critical OHSS and a high risk of VTE. Leukocytosis >12×10⁹/L reflects the severity of the systemic inflammatory response. In some cases, it can reach 50×10⁹/L without a left shift of the leukocyte formula. A left shift of the leukocyte formula is associated with an escalating inflammatory response due to exacerbations of chronic diseases (e.g., pyelonephritis), activation of opportunistic microflora with the development of pneumonia, or the addition of complications requiring surgical intervention (adnexal torsion, acute appendicitis, pelvioperitonitis, peritonitis) (1,8,22,29). A platelet count of 500×10³/µL–600×10³/µL is associated with a high risk of VTE (23).

Comments: Frequency of testing: once every 5 days until recovery. The biochemical blood test includes the determination of total protein, albumin, free and conjugated bilirubin, glucose, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, sodium, potassium. OHSS is characterized by hypoproteinemia and hypoalbuminemia, elevated concentrations of urea and creatinine, hyponatremia and hyperkalemia, and elevated liver enzymes. If electrolyte imbalances are present, blood sodium and potassium levels should be measured daily until values normalize. In the presence of oliguria/anuria, blood urea and creatinine levels should also be measured daily until values normalize and oliguria/anuria resolves.

Comment: Frequency of testing: once every 5-7 days until recovery. The coagulogram includes the determination of activated partial thromboplastin time, fibrinogen level, prothrombin (thromboplastin) time, and international normalized ratio (INR) in the blood.

Comment: Repeat determination of serum hCG (free beta-subunit) may be performed if ectopic or non-viable pregnancy is suspected.

Comment: Frequency of testing: once every 7 days.

Comment: Frequency of testing: once every 7 days; if body temperature rises to ≥38^oC, once every 3 days.

• In severe and critical OHSS, it is recommended to test blood procalcitonin levels to assess the severity of the systemic inflammatory response (35).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Frequency of testing: once every 5 days. An elevated procalcitonin level is determined in 50% of patients with severe OHSS in the range of 0.5-2.0 ng/mL with leukocytosis >12*10⁹/L.

• In severe and critical OHSS, it is recommended to measure blood osmolality (osmolarity) to assess and timely correct its disorders (8,9,23).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: Frequency of testing: daily until parameters normalize.

• If body temperature rises to ≥38^oC, it is recommended to perform a microbiological (culture) urine test for bacterial pathogens (using automated seeding) to detect asymptomatic bacteriuria (35).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• If there are signs of purulent-inflammatory complications, it is recommended to perform microbiological (culture) testing of urine, sputum, and abscesses for aerobic and facultatively anaerobic opportunistic pathogens, as well as a microbiological (culture) blood test for sterility (23).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• If spontaneous bacterial peritonitis is suspected, it is recommended to perform a microbiological (culture) test of peritoneal fluid for aerobic and facultatively anaerobic opportunistic pathogens (23), (47).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• 24 hours after the removal of ascetic fluid, and then daily until the ascites resolves, it is recommended to measure blood total protein and albumin levels for the timely correction of hypoproteinemia (29).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: CA125 levels reach maximum values (>5000 IU/mL) by the 2nd week of OHSS development, when the ovaries reach their maximum volume. If pregnancy occurs, the elevated CA125 level persists until the second half of pregnancy and then decreases to normal values (44).

Comment: Ascetic fluid is characterized by a high protein and albumin content, a low leukocyte count, a relatively high erythrocyte count, and high concentrations of all pro-inflammatory cytokines and C-reactive protein.

2.4 Instrumental Diagnostics

Comment: The frequency of the examination is determined by the patient's condition and the severity of OHSS. If clinical signs of ascites progress, the amount of fluid in the abdominal cavity should be assessed immediately to determine indications for its removal.

Comments: The frequency of the examination is determined by the patient's condition and the severity of OHSS. In case of dyspnea or dry cough, the examination should be performed every 3 days. If clinical symptoms worsen, the amount of fluid should be assessed immediately to determine indications for its removal.

• In severe and critical OHSS, it is recommended to use an indirect method for assessing the severity of intra-abdominal hypertension (IAH) based on intra-abdominal pressure (IAP) according to Appendix G1 (32).

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

2.5 Other Procedures

• In moderate, severe, and critical OHSS, recommended is a consultation (examination) by an anesthesiologist-intensivist to determine the treatment tactics (1, 8, 9).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In severe and critical OHSS, recommended is 24-hour monitoring by an anesthesiologist-intensivist to ensure timely intensive care if needed (1, 8, 9).

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

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

*Recommendations apply to all patients with OHSS unless otherwise specified.

3.1. Non-pharmacological treatments

• In mild OHSS managed in an outpatient setting, it is recommended to inform the patient about the need for daily self-monitoring of fluid balance based on body weight, diuresis, and fluid intake to ensure timely diagnosis of oliguria (1, 8, 9).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: Patients should be informed of the need for daily fluid balance monitoring. Urine output <1000 mL per day requires reassessment of OHSS severity and consideration of hospital admission.

• In mild OHSS managed in an outpatient setting, it is recommended to inform the patient about the need to limit physical activity in order to adhere to the prescribed rest and protection regimen (52).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In mild OHSS managed in an outpatient setting, it is recommended to inform the patient about the need for a fluid intake of at least 1 L per day to normalize the water-electrolyte balance (1, 8, 9).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In mild OHSS managed in an outpatient setting, it is recommended to inform the patient about the need to consume protein-rich foods to prevent and correct hypoproteinemia (1, 8, 9).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In severe and critical OHSS, nutritional support with standard balanced formulas is recommended (54), (55), (56), (57).

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: Total caloric intake must cover protein requirements at 1.2–1.5 g/kg/day. Carbohydrate intake must completely match protein utilization. Essential components of nutritional support include minerals, water-soluble and fat-soluble vitamins, which are also recommended for daily use (57).

3.2. Pharmacotherapy

• In OHSS requiring inpatient treatment (see Appendix B), intravenous administration of 0.9% sodium chloride solution** is recommended to normalize the water-electrolyte balance (22, 23), (58), (59).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Currently, there is no compelling evidence regarding the advantages of any specific fluid affecting the water-electrolyte balance (crystalloids), not only in the treatment of OHSS but also in other critical conditions (60), (61), (62), (63). The choice of solution is determined by electrolyte imbalance. In hyponatremia (sodium <135 mmol/L), 0.9% sodium chloride solution** is preferred. The volume of infusion therapy should be directly dependent on the degree of hypovolemia and overt fluid losses (volume of ascites, hydrothorax, vomiting, diuresis) or occult losses (inability to take fluids enterally). At the same time, a large volume of administered fluid and aggressive infusion therapy provoke the progression of polyserositis and may contribute to the worsening of intra-abdominal hypertension (IAH) (29, 32, 64, 65). Following hemodynamic stabilization, normalization of plasma colloid-oncotic pressure and electrolyte disorders, and restoration of diuresis, the volume of intravenously administered fluid should be reduced as early as the first hours (day) of hospitalization, and enteral fluid intake and nutritional support should be initiated (8, 22, 23, 29, 57).

• In OHSS requiring inpatient treatment with pronounced hemoconcentration (hematocrit >45%), hypoalbuminemia (albumin <25 g/L), or severe ascites with elevated intra-abdominal pressure (IAP), intravenous administration of 20% human albumin solution** at a dose of 2–4 mL/kg as a plasma-substituting agent is recommended (66), (23).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: The dosing regimen for human albumin** depends on concomitant factors and complications (23, 24, 30, 52). Routine use of human albumin** for the correction of hypoalbuminemia is not recommended. Absolute indications for prescribing human albumin** are the presence of ascites and hypoalbuminemia (<25 g/L). The advisability of administering human albumin** to correct hypovolemia in critically ill patients remains an unresolved issue (67).

• If pain is present, prescribing paracetamol** is recommended for pain relief (8, 23, 29).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Severe pain can be a symptom of other acute conditions: ovarian torsion and rupture, ectopic pregnancy, acute appendicitis, pelvic inflammatory disease, which necessitates a surgical consultation. The use of other analgesics and antipyretics is not recommended due to contraindications for use during pregnancy (5, 8, 23, 29).

• In the presence of nausea and vomiting, prescribing metoclopramide** is recommended for their relief (68).

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: Metoclopramide** is not contraindicated for use during pregnancy according to the product instructions.

Comment: The administration of diuretics is possible in the presence of persistent oliguria only after adequate replacement of circulating blood volume, with a hematocrit level <38% and in the absence of tense ascites (8, 22, 23, 29).

• In patients at high risk for OHSS after transvaginal oocyte retrieval (TVOR) and upon the development of OHSS, it is recommended to prescribe heparin sodium**, or enoxaparin sodium**, or nadroparin calcium, or dalteparin sodium in prophylactic doses for the prevention of thromboembolic events (70), (71), (72), (73), (39).

GCR BLEL 3Recommendation Grade B (Level of Evidence — 3).

Comments: The duration of thromboprophylaxis is individual and is determined by coagulogram parameters, risk factors, and the onset of pregnancy.

• In case of risk of secondary infection, especially in critically ill patients, with unstable hemodynamics, and with a recurrent fever of ≥38^oC, antibacterial therapy is recommended (34), (44), (74).

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: The duration of antibiotic therapy is individual and is determined by pathogen susceptibility and the onset of pregnancy. Empirical antibiotics should have a broad spectrum of activity against the most common bacteria in this population, including E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, and P. vulgaris. The initial regimen includes 3rd-generation (J01DDD) or 4th-generation (J01DE) cephalosporins combined with metronidazole**. Antibacterial therapy should be adjusted 48–72 hours after the start of treatment if there is no improvement in clinical and laboratory parameters indicating a positive disease trend and/or if the pathogen is resistant to the administered therapy (23), (75).

• In spontaneous bacterial peritonitis, empirical antibacterial therapy is recommended prior to obtaining the results of microbiological (culture) testing (47).

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: Empirical antibacterial therapy should be initiated immediately after the diagnosis of spontaneous bacterial peritonitis is established. The most common pathogens are gram-negative aerobic bacteria (e.g., E. coli); first-line antibiotics include cefotaxime** 2 g intravenously every 12 hours (ceftriaxone**, ceftazidime** may be used).

3.3. Surgical treatment

Comment: For adnexal torsion, a minimally invasive surgical approach with detorsion and ovarian preservation is recommended. Adnexectomy is performed only when oophorectomy is unavoidable, such as in cases of severe ovarian necrosis. Ovariopexy may be considered in situations where the ovarian ligament is congenitally long, in patients with recurrent torsion, or when an obvious cause of adnexal torsion cannot be found (77), (78).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

• To correctly prescribe the ovarian stimulation regimen and final oocyte maturation trigger in patients undergoing ART programs, it is recommended to assess OHSS risk factors: age <35 years, presence of polycystic ovary syndrome (PCOS), anti-Müllerian hormone level >3.4 ng/mL, antral follicle count >24 in both ovaries, history of OHSS in previous ovarian stimulation cycles, and body mass index <18 kg/m² (1), (8).

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Patients with excessive ovarian reserve and/or PCOS must be informed that they are at high risk for OHSS.

Comment: An excessive ovarian response to stimulation is characterized by the presence of >18 follicles measuring ≥11 mm on the day of the final oocyte maturation trigger injection and/or >18 oocytes retrieved during transvaginal puncture (8), (83), (84), (85).

Comment: After transvaginal puncture, GnRH antagonists (ganirelix**, cetrorelix**) can be prescribed starting from the day of puncture for 5–8 days at a dose of 0.25 mg/day subcutaneously or 0.5–0.75 mg once on the day of puncture (within 2 hours after puncture) in case of an excessive ovarian response to ovarian stimulation and cycle segmentation for the purpose of preventing OHSS (87), (88), although this recommendation has controversial efficacy (89). The use of #letrozole for the prevention of OHSS has not yet received official recognition, but its administration at a dose of 7.5 mg daily for 5 days starting from the day of transvaginal puncture reduces the risk of OHSS in high-risk patients (90), (91), (92).

Comment: #Cabergoline for the prevention of OHSS can be prescribed in an ovarian stimulation protocol with an hCG trigger in case of an excessive ovarian response at a dose of 0.5 mg orally once daily for 5–8 days starting from the day of the final oocyte maturation trigger injection or the day after transvaginal puncture (93).

Comment: #Calcium gluconate** for the prevention of OHSS can be prescribed in an ovarian stimulation protocol with an hCG trigger in case of an excessive ovarian response for 3 days intravenously by drip 1 time per day at a dose of 10 ml of a 10% solution per 200 ml of sodium chloride** solution (95).

Comment: #Metformin** significantly reduces the risk of OHSS in protocols with GnRH agonists, but at the same time increases the risk of gastrointestinal side effects almost 3-fold. In protocols with GnRH antagonists, #metformin** does not reduce the risk of OHSS (8), (98).

6. Organization of Medical Care

Treatment of patients with mild OHSS is carried out in an outpatient setting with dynamic monitoring.

Treatment of patients with moderate, severe, and critical OHSS is carried out in an inpatient setting.

Due to the pronounced polymorphism of clinical symptoms of OHSS and the likelihood of rapid deterioration of the patient's condition, it is advisable to hospitalize patients in specialized departments that have experience in managing such patients, access to an interdisciplinary approach, and the necessary list of medicines.

Treatment should be administered by physicians with clinical experience in managing this category of patients, since the clinical picture of OHSS has a pronounced polymorphism of clinical and laboratory symptoms and can change very rapidly toward worsening the patient's condition. Decisions on management tactics should be made quickly with a minimal probability of errors.

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Korneeva Irina Evgenyevna – D.Sc. in Medicine, Associate Professor, Leading Researcher at the F. Paulsen Sr. Scientific and Clinical Department of Assisted Reproductive Technologies, Institute of Reproductive Medicine, 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. Dolgushina Nataliya Vitalievna – D.Sc. in Medicine, Professor, Deputy Director for Research, 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.

3. Korsak Vladislav Stanislavovich – D.Sc. in Medicine, Professor, General Director of the International Center for Reproductive Medicine JSC, President of the Russian Association of Human Reproduction (RAHR) (Saint Petersburg). No conflict of interest.

4. Nazarenko Tatyana Alekseevna – D.Sc. in Medicine, Professor, Director of the Institute of Reproductive Medicine, 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.

5. Shabanova Natalya Evgenyevna – Ph.D. in Medicine, Associate Professor, Head of the Department of Clinical Pharmacology of Antimicrobial and Immunobiological Drugs, Institute of Microbiology, Antimicrobial Therapy and Epidemiology, 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. Artymuk Natalya Vladimirovna – D.Sc. in Medicine, 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 of the Russian Ministry of Health, Chief freelance specialist in gynecology of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health in the Siberian Federal District (Kemerovo). No conflict of interest.

7. Bazina Marina Ivanovna – D.Sc. in Medicine, Associate Professor, Head of the Department of Obstetrics and Gynecology, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after V.F. Voino-Yasenetsky of the Russian Ministry of Health, Chief freelance specialist in reproductive health of the Ministry of Health of Krasnoyarsk Krai (Krasnoyarsk). No conflict of interest.

8. Bashmakova Nadezhda Vasilievna – D.Sc. in Medicine, Professor, Chief Researcher, Ural Research Institute for Maternal and Infant Welfare of the Russian Ministry of Health, Chief freelance specialist in obstetrics of the Russian Ministry of Health, Chief freelance specialist in gynecology of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health in the Ural Federal District. No conflict of interest.

9. Belokrinitskaya Tatyana Evgenyevna – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Additional Professional Education, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance specialist in obstetrics of the Russian Ministry of Health, Chief freelance specialist in gynecology of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health in the Far Eastern Federal District (Chita). No conflict of interest.

10. Kalugina Alla Stanislavovna – D.Sc. in Medicine, Professor, Professor at the Department of Obstetrics, Gynecology and Neonatology, First Saint Petersburg State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health (Saint Petersburg), Chief freelance specialist in women's reproductive health in the Northwestern Federal District. No conflict of interest.

11. Krasnopolskaya Ksenia Vladislavovna – Corresponding Member of the RAS, D.Sc. in Medicine, Professor, Head of the Department of Reproductology at MONIIAG, Chief freelance specialist in women's reproductive health of the Ministry of Health of Moscow Region (Moscow). No conflict of interest.

12. Malyshkina Anna Ivanovna – D.Sc. in Medicine, Professor, Director of the Ivanovo Research Institute of Motherhood and Childhood named after V.N. Gorodkov, Head of the Department of Obstetrics, Gynecology and Medical Genetics of the Faculty of Medicine, Ivanovo State Medical Academy of the Russian Ministry of Health, Chief freelance specialist in obstetrics of the Russian Ministry of Health, Chief freelance specialist in gynecology of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health in the Central Federal District (Ivanovo). No conflict of interest.

13. Moiseeva Irina Valerievna – D.Sc. in Medicine, Head of the Department of Assisted Reproductive Technologies, Samara Regional Medical Center "Dynasty", Chief freelance specialist in reproductive health of the Ministry of Health of Samara Region, Chief freelance specialist in women's reproductive health in the Privolzhsky Federal District (Samara). No conflict of interest.

14. Popandopulo Viktoriya Alexandrovna – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology, Maykop State Technological University, Professor at the Department of Obstetrics and Gynecology of the Faculty of Medicine, Astrakhan State Medical University of the Russian Ministry of Health, Chief Medical Officer of Kuban Medical Center LLC, Chief freelance specialist in obstetrics of the Russian Ministry of Health, Chief freelance specialist in gynecology of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health in the Southern Federal District (Krasnodar). No conflict of interest.

15. Smirnova Anna Anatolyevna – Ph.D. in Medicine, Associate Professor at the Department of Women's Diseases and Reproductive Health, Institute of Advanced Training of Doctors, National Medical and Surgical Center named after N.I. Pirogov, Chief reproductologist of the federal network "Fomin Clinics" (Moscow). No conflict of interest.

16. Kulikov Alexander Veniaminovich – D.Sc. in Medicine, Head of the Department of Anesthesiology, Intensive Care and Toxicology, Ural State Medical University of the Russian Ministry of Health (Yekaterinburg).

17. Marshalov Dmitry Vasilievich – D.Sc. in Medicine, Associate Professor at the Department of Simulation Technologies and Emergency Medicine, Saratov State Medical University named after V.I. Razumovsky of the Russian Ministry of Health, Head of the City Center for Clinical Hemostasiology and Transfusiology, Excellence in Public Health (Saratov).

15. Petrenko Alexey Petrovich – Ph.D. in Medicine, Associate Professor at the Department of Emergency, Urgent, Anesthesiology and Critical Care Medicine, Saratov State Medical University named after V.I. Razumovsky of the Russian Ministry of Health (Saratov).

16. Pyregov Alexey Viktorovich – D.Sc. in Medicine, Professor, Deputy Chief Medical Officer for Anesthesiology and Intensive Care, Moscow Regional Perinatal Center. Chairman of the Committee on Anesthesiology and Intensive Care in Obstetrics and Gynecology of the Association of Anesthesiologists-Reanimatologists (Moscow). No conflict of interest.

17. Silaev Borislav Vladimirovich – Ph.D. in Medicine, Head of the Department of Anesthesia, Intensive Care and Critical Care Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

18. Shifman Efim Munevich – D.Sc. in Medicine, Professor, Professor at the Department of Anesthesiology and Intensive Care, Faculty of Advanced Medical Training, Moscow Regional Research and Clinical Institute (MONIKI) named after M.F. Vladimirsky, President of the Association of Obstetric Anesthesiologists-Reanimatologists, Honored Doctor of the Republic of Karelia, Expert in Anesthesiology and Intensive Care of the Federal Service for Surveillance in Healthcare (Moscow).

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. obstetrician-gynecologists

2. obstetrician-gynecologist residents

3. anesthesiologists-reanimatologists

4. anesthesiology and intensive care residents

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

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

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A3. Reference Materials

Not applicable.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Ovarian hyperstimulation syndrome (OHSS) is a complication of infertility treatment during ovulation induction in assisted reproductive technology programs. OHSS occurs when too many follicles (more than 18) mature in the ovaries during stimulation, releasing large amounts of female sex hormones (estrogens) into the bloodstream. High hormone levels in the blood alter vascular wall properties, making them permeable to the liquid portion of blood, which leads to fluid accumulation in the pelvic and abdominal cavities, and in some cases, in the pleural cavity (chest cavity).

The severity of symptoms increases as fluid accumulates and blood hemoconcentration worsens. Depending on the severity of manifestations, mild, moderate, and severe ovarian hyperstimulation syndrome are distinguished. Patients are hospitalized in cases of moderate and severe OHSS. Mild OHSS occurs in approximately 30% of cases.

Main complaints:

- discomfort in the epigastric region (feeling of heaviness);

- minor deterioration in general well-being;

- nausea, vomiting;

- infrequent urination in small portions.

For the prevention and treatment of mild OHSS, it is sufficient to follow a sparing regimen, perform breathing exercises prescribed by the attending physician, maintain moderate physical activity (walking), eat a protein-rich diet (meat, fish, seafood, grains, nuts), regulate bowel movements, drink fluids, and if necessary, the physician may prescribe special outpatient treatment.

Fluid accumulation in the abdominal cavity leads to moderate OHSS. Complaints include weakness, weight gain, dyspnea on exertion, abdominal distension, infrequent urination in small portions (fluid retention), nausea, and sometimes vomiting and diarrhea. When these symptoms appear, hospitalization in a 24-hour inpatient facility is required for treatment. Typically, with infusion therapy over several days, the condition stabilizes and serious treatment is not required. However, in the event of pregnancy, a longer hospital stay may be required. If embryo implantation (attachment to the uterine wall) does not occur and pregnancy is not established, OHSS resolves with the onset of the next menstruation and rarely progresses to a severe form.

Severe OHSS occurs rarely—in only 0.2% of cases. Due to marked hemoconcentration resulting from massive fluid leakage out of the vessels, blood clotting increases, the risk of blood clots rises, and the function of many organs (kidneys, liver) is impaired.

The above complaints are accompanied by:

- dizziness, headache, floating spots before the eyes;

- severe bursting abdominal pain that worsens with movement or changes in body position;

- increased abdominal girth and tension due to fluid accumulation in the abdominal cavity;

- marked decrease in urine output;

- elevated body temperature (sometimes);

- repeated vomiting;

- decreased blood pressure;

- pronounced dyspnea even at rest;

- palpitations, cardiac arrhythmias.

If severe OHSS develops, emergency hospitalization in a specialized inpatient unit is required for treatment.

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

Appendix G1. Indirect method for assessing IAH severity.

Type: assessment tool

Purpose: assessment of IAH grade

Content: When studying various methods for indirect measurement of IAP, the maximum correlation was found between bladder pressure and inferior vena cava pressure. Bladder pressure measurement is a simple, inexpensive, and fairly accurate method proposed as the "gold standard" for measuring IAP.

Measurement of IAP is performed in the supine position. Urinary bladder catheterization is performed using a Foley catheter connected to a measuring hollow tube. Then, 20-25 ml of warm sterile isotonic sodium chloride solution** is injected into the bladder within 10-15 seconds using a syringe. After the tube is filled with the solution, the measuring tube is moved to a vertical position. The upper edge of the pubic symphysis is taken as the zero point of the scale. The IAP level corresponds to the height of the water column in the tube during the patient's exhalation.

Interpretation: The exact level of IAP (grade of IAH) is still a matter of debate. Previously, a value of 15-18 mm Hg (103) dominated the literature. Some studies described a threshold of 8 mm Hg (104). Currently, according to the recommendations of the World Society of the Abdominal Compartment Syndrome (Eng. – WSACS), the threshold value for IAP is 12 mm Hg (103). The WSACS classification of IAH is presented in Table 4.

Table 4

WSACS Classification of IAH Severity

It is inappropriate to rely solely on the IAP value as the single parameter characterizing IAH. An increase in IAP above normal values, even without any clinical manifestations, will eventually lead to organ and systemic dysfunction. In this regard, the rate of IAP increase is of great importance.

Appendix G2. Technique for performing paracentesis and thoracentesis

Type: procedure technique

Purpose: evacuation of ascitic and pleural fluid

Content: A decrease in IAP after removal of ascitic fluid by paracentesis or transvaginal puncture (TVP) leads to increased renal venous blood flow, restoration of diuresis, increased venous return and cardiac output, increased uterine perfusion, reduction of pulmonary symptoms, relief of severe respiratory failure, and a decrease in hematocrit and leukocytosis (21,105).

Indications for paracentesis:

- progressive tense ascites,

- dyspnea and respiratory failure against the background of ascites, as well as elevated IAP,

- oliguria despite adequate fluid resuscitation.

Paracentesis technique:

The patient is placed on the operating table with the head of the bed elevated. An ultrasound of the abdominal cavity is performed using a transabdominal ultrasound transducer to assess the amount of ascitic fluid, its distribution in the abdominal cavity, and to select the safest puncture site on the anterior abdominal wall. The patient's position on the table can be adjusted to ensure the safest puncture site. Under aseptic conditions, after preparing the operative field with antiseptics and disinfectants, local step-by-step infiltration anesthesia is performed, a skin incision is made with a scalpel, and the anterior abdominal wall is punctured with a small-diameter trocar, through the sleeve of which a catheter is inserted. The latter is secured to the skin of the anterior abdominal wall with a U-shaped suture around the catheter, after which an aseptic dressing is applied to the operative field. During the procedure, no more than 3 liters of ascitic fluid should be evacuated at one time, which is then sent for microbiological and biochemical analysis.

In severe OHSS, especially during pregnancy, prolonged fractional removal of ascitic fluid is advisable. For this purpose, a urological device for urinary bladder drainage with a pre-installed J-catheter is used, which is left in place for 7-20 days. The total volume of ascitic fluid evacuated during the treatment of severe OHSS can range from 30,000 to 90,000 ml. This approach has several advantages as it avoids the simultaneous evacuation of a large volume of fluid and thereby eliminates rapid fluctuations in IAP that cause hemodynamic disturbances.

TVP technique:

TVP is performed in specialized inpatient units of ART clinics under ultrasound guidance by a specialist physician skilled in this procedure, due to the high risk of ovarian injury and intra-abdominal bleeding. The vaginal wall is punctured through the lateral fornix using a special puncture needle attached via an adapter to the vaginal probe of the ultrasound machine. A similar principle for ovarian TVP allows the aspiration of ascitic fluid from the pelvic cavity using a vacuum pump and reducing IAP. The volume of aspirated fluid is determined individually, depending on the patient's condition, and as a rule, does not exceed 3000 ml due to the risk of orthostatic collapse.

Possible complications:

- Pelvic organ injury.

- Intra-abdominal hemorrhage.

- Ovarian apoplexy, torsion.

- Hemodynamic alterations.

- Purulent-inflammatory complications.

Measures for complication prevention:

- Insertion of the trocar into the abdominal cavity under ultrasound guidance.

- Removal of no more than 3000 ml of fluid at a time.

- Careful care of the drainage catheter*** (daily change of the dressing and sterile medical gauze pad, treatment of the catheter exit site with antiseptics and disinfectants).

Indications for thoracentesis:

• respiratory failure persisting after the removal of ascitic fluid from the abdominal cavity with a hematocrit level of 40%.

Thoracentesis technique:

Thoracentesis is performed with the female patient in a sitting position, leaning slightly forward and resting on her arms so that fluid from the posterodiaphragmatic region shifts to the lower parts of the pleural cavity. Under local anesthesia, the chest wall is punctured in the 7th–8th intercostal space along the posterior axillary or scapular lines. The puncture needle should be inserted strictly at the predetermined space, along the upper margin of the lower rib, as insertion beneath the lower margin carries the risk of injury to the intercostal nerve and artery. The puncture must be performed under ultrasound guidance.

Possible complications:

• Nerve injury – neuritis.

• Arterial injury – hemorrhage.

• Lung injury – pneumothorax.

• Hemodynamic changes.

• Development of pulmonary edema associated with the evacuation of exudate (transudate, blood, air) from the pleural cavity.

Measures for complication prevention:

• Insertion of the needle into the pleural cavity under ultrasound guidance.

• Gradual removal of pleural effusion using an indwelling drainage catheter.

• Since the possibility of complications (pneumothorax) cannot be completely excluded during thoracentesis, it is advisable to puncture one pleural cavity first, and on the following day, the other, after a thorough assessment of the degree of respiratory failure.