Ovarian hyperstimulation syndrome (OHSS) is one of the major complications of assisted reproductive ovulation techniques. It is a medical condition in which the body overreacts to ovulation-promoting drugs and causes a series of clinical symptoms, characterized by the development of multiple follicles in both ovaries, ovarian enlargement, increased capillary permeability, and extravasation of body fluids and proteins into the body’s third interstitial space. It is characterized by the development of multiple follicles in both ovaries, enlarged ovaries, increased capillary permeability, and extravasation of body fluids and proteins into the third interstitial space. In recent years, with the rapid development of assisted reproductive technology, the incidence of OHSS is on the rise among patients receiving ovulation treatment, with an overall incidence of about 20%. The main risk factors associated with OHSS are: 1. Age and body mass index: Young women have a higher number of ovarian Gn receptors and are more sensitive to Gn. Decrease in body mass index (BMI) is positively associated with the development of OHSS. 2. Hypersensitive ovaries: the ovaries are highly sensitive to ovulation-promoting drugs and are commonly seen in patients with polycystic ovaries and in young (<35 years old) thin individuals. 3. Basal ovarian volume, number of basal follicles and number of eggs obtained: large basal ovarian volume, high number of basal follicles and high number of eggs obtained are positively correlated with the occurrence of OHSS. 4, Ovarian response to Gn stimulation: the increase of E2 level is the result of the action of FSH on the ovary, which is also a risk factor for the occurrence of OHSS. 5. Patients with PCOS: their endocrine characteristics of high endogenous LH/FSH ratio and the structural characteristics of multiple primordial follicles in the ovary make them more sensitive to exogenous Gn stimulation. The type, dose and timing of controlled ovulation (COH) drugs: HMG or FSH have a higher incidence of OHSS when applied, and their potential to induce OHSS is in the following order: HMG>FSH>CC. 7. Application of GnRH agonists and GnRH inhibitors. 8, Application of HCG to induce ovulation: The use of HCG to induce ovulation and support luteal function after pregnancy induces an increase in the incidence of severe OHSS due to the dual source of exogenous HCG and endogenous HCG, which increases the total level of HCG. 9.People with previous history of OHSS. The pathogenesis of OHSS is not fully understood and may be related to the following factors: 1. Activation of the renin-angiotensin system. Exogenous or endogenous HCG can increase reninogen in the blood and follicular fluid, leading to increased angiotensin II production, affecting angiogenesis and increasing capillary permeability. 2. Abnormal cytokine levels. Ovulation can cause lymphocytes and macrophages to secrete more cytokines, including TNF-α and IL-1, 2, 6, 8. This is coupled with an increase in certain inflammatory mediators, such as histamine and pentoxifylline. These cytokines are capable of causing capillary damage, capillary dilation and increased permeability. VEGF is a major factor in the increase of vascular permeability in OHSS. 4.Prostaglandins. Estrogen and HCG activate the enzyme cyclooxygenase, which is needed to convert arachidonic acid into prostaglandins, and together they promote the secretion of prostaglandins and increase the production of histamine, thus increasing capillary permeability. 5, blood fibrinolytic system activation. Activation can cause arterial dilation, small venous constriction, peripheral blood stagnation, and increased vascular permeability. Pathophysiology The main pathophysiological changes of OHSS are ovarian enlargement and increased vascular permeability. Ovarian enlargement is mainly manifested by multiple follicles and luteal cysts with interstitial edema in both ovaries. The increased vascular permeability is mainly manifested by massive extravasation of body fluids and a series of secondary changes, leading to edema, pleural fluid, ascites; hematoconcentration, reduced effective blood volume; hypercoagulable blood; reduced renal perfusion, resulting in reduced urine output or even anuria; and imbalance of water, electrolytes and acid-base balance. The main clinical manifestations of OHSS are gastrointestinal discomfort, abdominal distension, dyspnea, oliguria, etc. In severe cases, the patient has reduced cardiopulmonary function, impaired liver and kidney function, pleural fluid, ascites, even pericardial effusion, adult respiratory distress syndrome, vascular embolism, and even multi-organ failure. Generally, OHSS can be divided into mild, moderate (incidence of 3%-6%) and severe (incidence of 0.1%-2%). 1. mild: symptoms and signs appear 3-7 days after HCG injection and are characterized by gastric distension, poor appetite, lower abdominal discomfort, heaviness, or mild lower abdominal pain. 2. moderate: significant lower abdominal distension, nausea, vomiting, thirst, occasional diarrhea, increased abdominal circumference, significant ascites, small amount of pleural fluid, weight gain ≥ 3 kg, and enlarged ovaries ≤ 5 cm in diameter on ultrasound. Ultrasound examination of enlarged ovaries with a diameter of 5-12 cm. 3. Severe: moderate symptoms with ascites with or without pleural fluid, dyspnea, hemoconcentration, electrolyte disturbance, hypercoagulability, impaired liver and kidney function, weight gain ≥ 4.5 kg. Laboratory tests and ancillary examinations 1. Patients with OHSS should be monitored with complete blood cell analysis, liver and kidney function tests, water and electrolyte determination, and estradiol levels. The patient should be monitored by complete blood count, liver and kidney function tests, water and electrolyte measurements, estradiol levels, etc. In severe OHSS, liver insufficiency (manifested as hepatocellular damage) and cholestasis may occur, with increased alkaline phosphatase, glutamic transaminase, glutamic oxalacetic transaminase, bilirubin and creatine kinase. 3. Ultrasonography shows enlarged ovaries and follicular flavin cysts. Also seen is peritoneal effusion, pleural effusion or pericardial effusion. 4. Liver biopsy of some patients showed hepatic steatosis and Kuffer cell hyperplasia. The ascites is an exudate and contains a high concentration of protein. Diagnosis 1, according to the patient’s medical history and clinical manifestations: weight gain, abdominal discomfort, slight swelling of the lower abdomen, nausea and vomiting, etc. 2.B ultrasound shows enlarged ovaries with multiple corpus luteum and visible abdominal pleural effusion. 3. Elevated hematocrit and white blood cell count, hyponatremia and hypoproteinemia. Severe OHSS may present with hepatic insufficiency and cholestasis. 4. Complete blood cell analysis, liver and kidney function tests, water and electrolyte measurement, weight measurement, and E2 level measurement should be performed for suspected OHSS. Treatment OHSS is a self-limiting disease with a duration of about 14 days in the absence of pregnancy; in non-pregnant patients, the disease improves with menstruation, and in pregnant patients, the disease worsens during early pregnancy. Mild OHSS is inevitable in the process of ovulation promotion. Patients usually do not feel too much discomfort, so no special treatment is needed, and most patients can recover within one week. 2. Moderate OHSS can be observed and rested in the outpatient clinic, and treatment is based on rest and rehydration, and patients are instructed to drink more water. At the same time, the weight and 24-h urine volume should be checked daily, and the urine volume should not be less than 1000 ml/d, and it is best to keep it above 2000 ml/d. Complete resolution of the disease should not be achieved until after the next menstrual period, and the patient should be hospitalized when the erythrocyte pressure volume reaches 0.45. The duration of post-pregnancy OHSS is longer and more severe, and can last for 2-3 months. 3. Severe OHSS should be treated immediately in hospital. (1) Close monitoring: record daily weight, abdominal circumference and 24-h water intake and output, and check daily or every other day blood count, red blood cell pressure, coagulation status and urine osmolality; check electrolytes and liver and kidney function weekly; monitor ovarian size and morphology and changes in thoracoabdominal fluid by ultrasound to understand the effect of treatment. (2) Supportive treatment: Give high protein diet, encourage drinking and bed rest. If crystalloid rehydration cannot maintain fluid balance, albumin (50%) or other plasma components should be used to maintain plasma colloid osmotic pressure and prevent leakage of intravascular fluid. Low-molecular dextran can be used to expand the volume and improve the microcirculation to increase the perfusion of renal blood supply. Depending on the condition, 500-1000 ml of low dextrose is administered daily. Patients with low food intake should be supplemented with 5% GS and 50-100 ml of albumin intravenously daily. A small dose of dobutamine 40 mg/d can be added to dilate the renal veins and increase renal blood flow without affecting blood pressure and heart rate in cases of oliguria. (3) Puncture and drainage of thoracoabdominal fluid: abdominal distension (ascites >5 cm under ultrasound) can be performed under ultrasound guidance to relieve abdominal distension, improve respiration, increase urine output, and reduce blood urea nitrogen level, which is significantly better than infusion therapy. A single drainage is usually 1000-2000 ml. (4) OHSS thrombosis is uncommon. When there are abnormal manifestations, the patient should be encouraged to move the lower limbs and heparin (5000 IU/bid) should be used for prevention if necessary. (5) The patient should be alerted to ovarian torsion and rupture of ovarian corpus luteum hematoma, and if there are signs of this, prompt dissection should be performed. (6) Hemodialysis is feasible in severe oliguria, anuria, hyperazotemia, acute renal failure, severe pleural fluid, ascites, and electrolyte disturbance. Diuretics should be used with caution, because oliguria in OHSS is mainly caused by insufficient renal perfusion, and if diuretics are used before the end of blood volume correction, it will aggravate hematoconcentration and lead to thrombosis. (1) Luteinizing support treatment, avoid HCG. (2) Multiple pregnancy should be promptly reduced if necessary. (3) Pregnancy aggravates the symptoms of OHSS and prolongs the course of the disease. For patients with very severe OHSS, abortion should be used to terminate the pregnancy if the above active treatment still fails to relieve the symptoms and restore the function of vital organs. Complications of OHSS 1. Vascular complications: Patients with severe OHSS especially need to be alert to thrombosis, and should be encouraged to turn over, move their limbs, massage their legs, take enteric aspirin tablets and other measures for prevention, and in severe cases, anticoagulation therapy is needed. The treatment of thrombosis includes: anticoagulation, thrombolysis, termination of pregnancy, etc. 2. Abnormal liver function: 25% to 40% of OHSS patients have abnormal liver function, which can last for more than 2 months. Patients with severe OHSS should be monitored for liver function, and once liver function abnormalities are detected, attention should be paid to liver protection therapy to prevent liver failure. 3. Respiratory complications: dyspnea and shortness of breath are the most common respiratory clinical manifestations. Arterial blood gas monitoring, puncture and drainage of pleural fluid, airway patency, assisted ventilation, continuous oxygenation, and glucocorticoids should be given to reduce capillary exudation, reduce pulmonary edema, and improve respiratory function, while antibiotics should be applied to prevent infection. 4, renal dysfunction: severe OHSS with oliguria, can be given intravenously dopamine to dilate renal blood vessels and increase renal blood flow under the premise of blood volume supplementation. If diuretics are used before the blood volume is corrected, it will aggravate the hemoconcentration and cause thrombosis, so diuretics should be used with caution or prohibited. Once renal failure occurs, hemodialysis treatment should be performed as soon as possible. 5. Ovarian torsion: torsion of normal sized ovaries is rare, but the risk of torsion increases in OHSS patients with increased ovarian size and weight. Patients with mild ovarian torsion can change position and wait for the ovary to reset naturally. Surgery is the preferred treatment for severe cases. Prevention Accurate prediction and active prevention are very important to avoid the occurrence of OHSS. Current preventive measures include timely identification of risk factors, application of individualized ovulation promotion protocols, close monitoring of ovarian responsiveness and timely adjustment of Gn dosage. Clomiphene is preferred for ovulation induction and gonadotropins are used only when clomiphene is resistant. 2. Identify high-risk groups such as younger, thinner patients with PCOS manifestations during controlled ovulation (COH). The initial dosage of Gn should be reduced in patients with high risk factors, and caution is needed in increasing the dosage during ovulation treatment. Patients with PCOS are most susceptible to OHSS due to excessive follicles, high hormone levels, and sensitive response. The average follicle diameter of 5-8 mm was scored as 1, 9-12 mm as 1.5, 13-16 mm as 2, and ≥17 mm as 3. The total score of follicles in both ovaries was accumulated, and OHSS did not occur in those with a total score <25, while OHSS occurred in those with a total score >30. 4. Strengthen monitoring: Pay attention to the patient’s complaints and signs, and closely monitor the follicular development, ovarian size and blood E2 level during ovulation promotion, and adjust the dosage of HMG according to the comprehensive judgment of the monitoring results, especially control the dosage of HCG in the luteal phase, and abandon the cycle in severe cases. 5. Use of short-acting GnRH-a to prevent OHSS: In cycles without descending regulation or with GnRH inhibitors to suppress endogenous LH, GnRH agonists can be used to produce endogenous LH by “flare up” for the purpose of ovulation promotion. Since the duration of action of LH is shorter than that of HCG, its injection can reduce the stimulation response of the ovaries during the luteal phase. 6. High-dose intramuscular progesterone injection: In case of high-risk signs of OHSS during ovulation induction, intramuscular progesterone injection of 200 mg per day without HCG to support luteal function can prevent OHSS, especially when E2>2500 pg/mL and follicle number>15. 7. In case of OHSS with GnRHa/Gn ovulation induction regimen, Gn should be stopped immediately and GnRHa should be continued to inhibit the secretion of FSH and LH by the pituitary gland to accelerate follicular atrophy. 8. If OHSS may occur, HCG injection should be abandoned and all follicles should be aspirated by puncture to cancel the cycle, which can effectively prevent the occurrence of OHSS. 9. Whole embryo freezing: In case of OHSS during the IVF-ET cycle, the embryos can be frozen and preserved without transferring until a later natural cycle. However, it should be noted that early OHSS may still occur due to the duration of HCG action for 6 days and the high level of E2 in the body. 10. Application of albumin: In patients at high risk of OHSS, intravenous injection of human albumin on the day of egg collection to improve hypoproteinemia and stop intravascular fluid leakage can prevent early severe OHSS, but its effect is still not agreed by all scholars and the application of albumin is controversial.