Ovarian Hyperstimulation Syndrome

 Ovarian hyperstimulation syndrome (OHSS)

Definition:  is an iatrogenic complication of assisted reproduction technology. OHSS usually develops several days after assisted ovulation following gonadotropin therapy. This syndrome is characterized by ovarian enlargement due to multiple ovarian cysts and an acute fluid shift into the extravascular space. Results include ascites, hemoconcentration, hypovolemia, and electrolyte imbalances. OHSS remains a lethal iatrogenic complication of the early luteal phase and/or early pregnancy after ovarian stimulation.
Classification

Mild OHSS Grade 1 - Abdominal distention and discomfort Grade 2 - Grade 1 disease plus nausea, vomiting, and/or diarrhea plus ovarian enlargement from 5-12 cm  
Moderate OHSS Grade 3 - Features of mild OHSS plus ultrasonographic evidence of ascites Severe OHSS Grade 4 - Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax and breathing difficulties Grade 5 - All of the above plus a change in the blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function.
There are two clinical forms of OHSS, both hCG related: the early-onset form (occurring in the first eight days after hCG administration) and the late-onset form (occurring nine or more days after hCG administration, related to pregnancy-induced hCG production)
Pathophysiology
The pathogenesis of ovarian hyperstimulation syndrome is unknown, but the process is related to increased vascular permeability in the region surrounding the ovaries and their vasculature. Beta-human chorionic gonadotropin (hCG) and its analogs, estrogen, estradiol, prolactin, histamine, and prostaglandins have all been implicated in the past. Vasoactive substances such as interleukins, tumor necrosis factor (TNF)-alpha, endothelin-1, and vascular endothelial growth factor (VEGF) secreted by the ovaries have been implicated in increasing vascular permeability. Withholding hCG decreases OHSS. Hence, it plays a critical role in enhancing ovarian angiogenesis and triggering the cascade of vascular permeability in ovarian vessels that leads to third spacing and OHSS. Both exogenous and endogenous gonadotropins from molar pregnancy, gonadotroph adenomas, and even pregnancy can aggravate OHSS.These changes in the ovarian vasculature are exaggerated responses to normal luteinizing hormone (LH). The function of hCG is similar to that of LH. As a result, the actions of hCG mimic these changes. Moreover, hCG exerts a follicle stimulating hormone–like action in stimulating the ovaries. In addition, it has a prolonged half-life. All of these properties of hCG lead to ovarian stimulation and changes in periovarian vasculature even after ovulation. These effects lead to poor control of the induction process, initiating and/or aggravating OHSS. Abdominal pain, nausea, and vomiting Enlargement of the ovaries causes abdominal pain, nausea, and vomiting. The enlargement is sometimes as much as 25 cm. Another consequence is discomfort resulting from increased intra-abdominal pressure due to ascites. Ascites and tense distention Ascites and tense distention occur because of the extravasation of protein-rich fluid and increasing leakage from the intravascular space due to an osmolar differential. Leakage of fluid from follicles, increased capillary permeability leading to third spacing (due to the release of vasoactive substances), or frank rupture of follicles can all cause ascites. Localized or generalized peritonitis Localized or generalized peritonitis is caused by peritoneal irritation secondary to blood from ruptured cysts, protein-rich fluid, and inflammatory mediators. Acute abdominal pain Acute abdominal pain may be due to ovarian torsion, intraperitoneal hemorrhage, or rupture of cysts secondary to enlarged ovaries with fragile walls. Hypotension and/or hypovolemia Follicular fluid and perifollicular blood containing large amounts of VEGF, which is thought to increase vascular permeability, escapes into the peritoneal cavity. The fluid is then absorbed into the general vascular bed. Blood vessels both within and outside the ovary become functionally impaired, and the result is the leakage of fluid through those vessels and a massive fluid shift from the intravascular bed to the third compartment. This process results in intravascular hypovolemia with the concomitant development of edema, ascites, hydrothorax, and/or hydropericardium. Hypotension and/or hypovolemia are also caused by compression of the inferior vena cava because of enlarged cysts or ascites. As a result, both venous return and preload decrease. Eventual outcomes are decreased cardiac output and hypotension. Dyspnea Pulmonary function may be compromised as enlarged ovaries and ascites restrict diaphragmatic movement. Other possible causes of dyspnea are the relatively rare manifestations of OHSS, such as pleural effusion, pulmonary edema, atelectasis, pulmonary embolism, acute respiratory distress syndrome (ARDS), and pericardial effusion. Hypercoagulable state A hypercoagulable state is likely due to hemoconcentration and hypovolemia resulting from third spacing and fluid shift. It is also related to increased estrogen levels. Patients have an increased risk of developing deep venous thromboses and pulmonary embolisms. Electrolyte imbalance Electrolyte imbalance occurs due to the extravasation of fluid and resultant renal dysfunction resulting from decreased perfusion. Increased reabsorption of sodium and water occurs in the proximal tubule, leading to oliguria and low urinary sodium excretion. The exchange of hydrogen and potassium for sodium in the distal tubule is reduced. As a result, hydrogen and potassium ions accumulate and cause hyperkalemia and a tendency to develop acidosis. Compensatory and electrolyte-retaining mechanisms fail. Acute renal failure The hypovolemia of OHSS leads to hemoconcentration and creates a hypercoagulable state. Microthrombi form in tubules, leading to decreased renal perfusion. Acute renal failure may result.  

Frequency
The rate of ovarian hyperstimulation syndrome depends on definitions, risk factors, stimulation protocols, and conception.  
Rates of OHSS are as follows: Mild, 8-23% Moderate, 1-7% Severe, 0.25-5% The frequency of OHSS may increase if the ovary is overstimulated, as documented by high levels of estradiol and depicted as increased number of follicles on ultrasonography. The incidence is increased when protocols combine luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropins, as compared with gonadotropins alone, to induce ovulation.

Mortality/Morbidity
Morbidity may be clinically significant in cases of severe and critical ovarian hyperstimulation syndrome, and fatalities do occur.  
Race
No racial predisposition is reported in ovarian hyperstimulation syndrome. Sex Ovarian hyperstimulation syndrome affects only women.  
Age
Only women of childbearing age are affected by ovarian hyperstimulation syndrome. The risk is increased in younger women.  
Clinical History
The patient who has ovarian hyperstimulation syndrome (OHSS) is a woman who recently had gonadotropin stimulation to induce ovulation or one who was treated with assisted reproductive technologies such as in vitro fertilization. Early OHSS is usually moderate or severe and manifests 3-7 days after the administration of hCG. Late OHSS is usually severe and occurs 12-17 days after hCG treatment.The former type is due to exogenously administered hormone, and the latter often occurs during an implanting or implanted pregnancy because pregnancy hCG exacerbates the disease. Signs of OHSS Signs of OHSS include the features listed below.(Percentages refer to all classes of OHSS.) -Ascites -Hypercoagulability (6.2%) -Thrombosis -Pleural effusion and pericardial effusion -Hemoconcentration -Leukocytosis (WBC count, >20,000/mm3) -Electrolyte abnormalities (eg, hyponatremia, hyperkalemia) -Elevated transaminase values (26%) -Acute respiratory distress syndrome (2%) -Pulmonary embolism (2%) -Acute renal failure (1%) Symptoms of OHSS Symptoms of OHSS include those listed below.(Percentages refer to cases of severe OHSS.) -Shortness of breath (92%) -Abdominal discomfort (99%) -GI disturbances - Nausea, vomiting, diarrhea (54%) -Oliguria (30%) -Peripheral edema (13%) -Lethargy -Rapid weight gain -Although OHSS usually manifests with a constellation of symptoms, atypical presentations can occur. Rare presentations such as thromboembolism, both venous and arterial, have been observed. Atypical locations of venous thromboembolism include the internal jugular vein, the subclavian vein, the inferior vena cava, the ileofemoral veins, and the intracerebral veins. Other abnormal forms of presentation include isolated hydrothorax and isolated thromboembolism. Additional situations leading to elevated hCG concentrations, such as in molar pregnancy and gonadotroph adenomas may lead to mild forms of OHSS in rare cases. Physical Physical findings of ovarian hyperstimulation syndrome include right or left lower quadrant pain below the umbilicus, as well as edema. Of note, abdominal palpation must be performed gently to avoid the possibility of rupturing a large cyst. Pelvic examination should be deferred in favor of ultrasonography of the pelvis.
Causes No single cause of ovarian hyperstimulation syndrome has been identified. The etiology appears to be multifactorial, though the cardinal events are ovarian enlargement, ascites, and hypovolemia. The hormone hCG and its analogs estrogen, estradiol, histamine, TNF-alpha, endothelin-1, and especially VEGF have all been implicated in OHSS.Increased vascular permeability in periovarian vasculature brought about by the factors described above plays an important role in OHSS.A young age, a decreased body mass index, and a history of OHSS increase the risk. Exogenous induction agents (recombinant hCG) precipitates OHSS more than endogenous agents (gonadotropin-releasing hormone [GnRH] analogs). Other precipitating factors are induction in a hyperestrogenic state and poor timing.  
Differential Diagnoses Acute Respiratory Distress Syndrome Pelvic Inflammatory Disease/Tubo-ovarian Abscess Appendicitis Pericardial Effusion Appendicitis, Acute Peritonitis and Abdominal Sepsis Cholecystitis Pleural Effusion Ectopic Pregnancy Pulmonary Embolism Ovarian Cysts Salpingitis Ovarian Torsion Hemorrhagic cyst

Pulmonary edema

Ruptured ovarian cyst
Workup Laboratory Studies
 In ovarian hyperstimulation syndrome (OHSS), the hematocrit is the most important measure in deciding if a patient should be hospitalized. If the patient's hematocrit level is greater than 60% and if she has ascites, hospitalize her immediately. Laboratory monitoring may involve the following parameters: -CBC with differential: This is helpful because decreased intravascular volume leads to hemoconcentration and an increased hematocrit. -Complete metabolic panel -Liver function: Liver function is decreased, as indicated by increased concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. -Kidney function: Renal function is reduced, BUN and creatinine values are increased, whereas albumin and protein levels are decreased. Electrolyte imbalances, hyperkalemia, and acidosis may be present. -Coagulation profile, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR): These findings aid in detecting a hypercoagulable state and in monitoring anticoagulation. -Leukocyte count: This count is related to the seriousness of OHSS and to the risk of thromboembolism. -Beta-hCG concentration: A beta-hCG measurement is especially useful at more than 12 days after an injection of hCG. A positive result at this stage indicates pregnancy, an endogenous source of hCG for OHSS. hCG upregulates vascular endothelial growth factor (VEGF) receptors, and this upregulation increases third spacing.Mild OHSS may deteriorate to severe OHSS because of the increased availability of hCG. -Estradiol levels: Values are increased. -Laboratory findings of a serum estradiol concentration greater than 2000 pg/mL and a progesterone concentration greater than 30 ng/mL in the early part of the luteal phase are warning signs of developing OHSS. Signs that may indicate a progression in severity are increases in hCG level, hematocrit, hypoproteinemia, and hypoalbuminemia (third spacing). Additional signs are decreasing renal and liver function. OHSS is critical when the signs and symptoms of severe OHSS are present with any of the following findings: renal failure, ARDS, thromboembolism, or a hematocrit level greater than 60%.

Imaging Studies :

-Ultrasonography may be needed to measure the size of the ovaries, to assess the follicles, and to evaluate ascites

-Chest radiography may be indicated if dyspnea is present.

Treatment :

Mild hyperstimulation Treatment for ovarian hyperstimulation syndrome (OHSS) is supportive, as needed. Mild ovarian hyperstimulation can develop into moderate or severe disease, especially if conception ensues. Therefore, women with mild disease should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least 2 weeks or until menstrual bleeding occurs.
Moderate hyperstimulation Treatment of moderate OHSS consists of observation, bed rest, provision of adequate fluids, and sonographic monitoring of the size of cysts. Serum electrolyte concentrations, hematocrits, and creatinine levels should also be evaluated. Some physicians have their outpatients keep track of their fluid intake and output. Intake or output less than 1000 mL/d or a discrepancy in fluid balance greater than 1000 mL/d is a cause for concern. The beginning of the resolution of OHSS is apparent when the cysts shrink, as seen on 2 consecutive ultrasonographic examinations, and when clinical symptoms recede. In contrast, early detection of progression to the severe form of the syndrome is marked by continuous weight gain (>2 lb/d), increased severity of existing symptoms, or appearance of new symptoms (eg, vomiting, diarrhea, or dyspnea).  
Severe hyperstimulation -Experience with severe OHSS is mandatory for appropriate treatment. One should transfer the patient to a different center if no one who is experienced in managing severe OHSS is available at the present location. -Severe OHSS is not common, but it is dangerous. Severe and critical forms of OHSS are potentially lethal disorders, and history taking and physical examination are paramount at the time of admission. In most clinical situations, patients require bed rest. Daily physical examination should consist of measuring the patient's weight and abdominal girth. Fluid balance must be assessed every 4 hours. -Medical treatment of severe hyperstimulation is directed at maintaining intravascular blood volume. Simultaneous goals are correcting the disturbed fluid and electrolyte balance, relieving secondary complications of ascites and hydrothorax, and preventing thromboembolic phenomena. -The main interventions are fluid management and correction of hypovolemia. These measures consists of initial fast intravenous administration of normal saline. Dextrose 5% in normal saline or normal saline is infused at a rate of 125-150 mL/h with 4-hour tabulations of urine production. If urine production is restored or improved, a maintenance protocol is started. The patient should be closely monitored for clinical signs of overhydration. If urine output is unsatisfactory, hyperosmolar intravenous therapy is indicated with an infusion of 200 mL of 25% human albumin. The use of diuretics in patients with low urine production and hypovolemia is counterproductive and dangerous. -Close surveillance of fluid management is necessary. Intravenous fluid administration is stopped when urine production, appetite, or interest in drinking increases and when an overall clinical improvement is observed. In the resolution phase of severe OHSS, the patient's fluid intake should be restricted to avoid renewed hemodilution. -To prevent thrombosis, subcutaneous heparin 5000-7500 U/d is begun on the first day of admission. It is stopped after adequate mobilization is achieved. -To manage ascites, ultrasonographic-guided vaginal paracentesis is indicated if the patient has severe discomfort or pain or if she has pulmonary or renal compromise.The procedure entails the same setup as that used for transvaginal follicular puncture. Whelan and Vlahos advise that an anesthesiologist be present. Paracentesis may be repeated if required. Critical hyperstimulation Critical OHSS may include renal failure, hepatic damage, thromboembolic phenomena, ARDS, and multiorgan failure.Its management and treatment requires intensive care in a critical care unit. Intensive care should include invasive monitoring of circulatory indicators, including venous pressure and wedge pressure. The patient may need extra oxygenation (assisted ventilation). If renal failure is present, an intravenous dopamine regimen should be started. To treat thromboembolism, therapeutic doses of anticoagulants should be administered. Thoracocentesis should be performed in the case of severe hydrothorax. Finally, if a pregnancy is maintaining a life-threatening OHSS, therapeutic abortion must be considered. Clinical Pearls What not to do Aggressive palpation of the abdomen: This can precipitate follicular rupture. Early surgical intervention: Early surgery may cause extensive bleeding from ovarian cysts. However, surgery is mandated if torsion or rupture has occurred. Neglect of deterioration in organs and systems: Remember that OHSS is a syndrome of multiorgan dysfunction. What to do Maintain a high degree of clinical suspicion and a low threshold for admission. Implement early surgical intervention in cases of ovarian torsion or hemorrhage. Perform paracentesis to address ascites. This decreases pressure on inferior vena cava and diaphragm. Place a transthoracic tube to manage pleural effusions. Resolution After several days, third-space fluid begins to re-enter the intravascular space, hemoconcentration reverses, and natural diuresis ensues. Intravenous fluids may be tapered as the patient's oral intake increases. Complete resolution typically takes 10-14 days from the onset of initial symptoms. Careful maintenance of blood volume, correction of electrolyte imbalances, and relief of secondary complications of ascites and hydrothorax are generally sufficient to support the patient during the severe phase of ovarian hyperstimulation. Anticoagulant therapy is usually unnecessary if these therapies are promptly administered. Blood coagulation may be monitored because of the danger of disseminated intravascular clotting. Surgical Care Ovarian hyperstimulation syndrome is a self-limiting disease. Therefore, treatment should be conservative and directed at symptoms. Medical therapy suffices for most patients. Women with severe symptoms often require intensive medical care. Surgery is necessary only in extreme cases, such as in the case of a ruptured cyst, ovarian torsion, or internal hemorrhage. Surgical management further aggravates electrolyte imbalances and increases morbidity. Ascites can be tapped by means of paracentesis. Harvesting of eggs in women with OHSS can lead to hemorrhage and peritonitis. However, tapping follicles when they are of moderate size may prevent OHSS. Laparotomy during torsion and intraperitoneal hemorrhage is life saving and recommended. Consultations In severe cases of OHSS, consultation with a physician specializing in fluid and electrolyte imbalances is warranted. For some cases, aggressive treatment in the surgical intensive care unit may be required. Diet Ensure that patient receives plenty of hydration. Activity Activity should be minimal. Physical examination should be performed gently because of the tendency of follicles to rupture.

Medication :

Medical therapy is aimed at the correction of fluid and electrolyte balance. Thrombosis can occur in the arteries (25%) and veins (75%). Therefore, use of heparin, low molecular weight heparin (enoxaparin sodium [Lovenox]), antiembolism stockings, and sequential compression devices (boots) are all recommended as prophylaxis against thrombosis. Heparin prophylaxis is usually started in patients with a history of thrombosis, factor V Leiden deficiency, or other thrombophilic states before the induction of ovulation. Anticoagulant These agents inhibit key factors involved in thrombogenesis.

Heparin Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but can inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Dosing Adult 5000-7500 U SC qd Interactions Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity Contraindications Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Electrolyte supplement, parenteral Used to replenish intravascular and extravascular volume.

Normal saline Used to restore interstitial and intravascular volume. Dosing Adult 1-2 L IV initially, given as fast bolus; assess hemodynamic response, then 125-150 mL/h until urine production improves; followed by maintenance dose Interactions May decrease lithium levels when administered concurrently Contraindications Edema in brain or lungs (pulmonary edema may contribute to ARDS); hypernatremia Precautions Pregnancy A - Fetal risk not revealed in controlled studies in humans Precautions Exercise caution to prevent fluid overload; monitor cardiovascular and pulmonary function; stop fluids when desired hemodynamic response observed or pulmonary edema develops; interstitial edema may occur; caution in congestive heart failure, hypertension, edema, liver cirrhosis, or renal insufficiency Blood product derivatives These agents are used to expand plasma volume. Albumin (Albuminar, Albumisol, Albunex, Albutein, Buminate) Major plasma protein responsible for colloid oncotic pressure of blood. Pooled from blood, serum, plasma, or placenta from healthy donors. Given in certain types of shock or impending shock. Use 5% solution to expand plasma volume and maintain cardiac output. Use 25% solution to raise oncotic pressure. Dosing Adult 200 mL of 25% solution IV over 20-30 min, then assess hemodynamic and renal response Interactions None reported Contraindications Documented hypersensitivity; pulmonary edema; severe congestive heart failure or anemia; protein load of 5% albumin (tends to exacerbate renal insufficiency, a potential complication of septic shock) Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in renal or hepatic failure, may cause protein overload; rapid infusion may cause vascular overload or hypotension; monitor for volume overload; caution in sodium-restricted patients; common adverse effects include congestive heart failure, hypotension, tachycardia, fever, chills, and pulmonary edema; do not dilute albumin 25% with sterile water for injection (produces hypotonic solution and, if administered, may result in life-threatening hemolysis and acute renal failure) Adrenergic agonist agent These agents increase blood pressure. Dopamine (Intropin) Naturally occurring endogenous catecholamine that stimulates beta1-adrenergic, alpha1-adrenergic, and dopaminergic receptors in dose-dependent fashion; stimulates release of norepinephrine.At low dosages (2-5 mcg/kg/min), acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilation-selective dilation of renal vasculature, enhancing renal perfusion. Also reduces sodium absorption, decreasing energy requirement of damaged tubules. This enhances urine flow, which, in turn, helps prevent tubular cast obstruction. Most clinical studies have failed to establish this beneficial role of renal-dose dopamine infusion.At midrange dosages (5-15 mcg/kg/min), acts on beta-adrenergic receptors to increase heart rate and contractility.At high dosages (15-20 mcg/kg/min), acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise blood pressure. Dosing Adult 1-5 mcg/kg/min IV Interactions Monoamine oxidase inhibitors (MAOIs) may prolong effects; beta-blockers may antagonize peripheral vasoconstriction caused by high doses; butyrophenones (eg, haloperidol) and phenothiazines can suppress dopaminergic renal and mesenteric vasodilation induced with low-dose infusion; low doses concurrently administered with diuretics may produce additive effects on urine flow; hypotension and bradycardia may occur with phenytoin; may decrease effects of phenytoin Contraindications Documented hypersensitivity; pheochromocytoma or ventricular fibrillation Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Closely monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during infusion; before infusion, correct hypovolemia with whole blood or plasma, as indicated; monitoring of central venous pressure or left ventricular filling pressure may help in detecting and treating hypovolemia; in patients who have received MAOIs the last 2-3 weeks, doses should not exceed 1/10th the initial dose of dopamine; ventricular arrhythmias and hypertension may occur in patients receiving cyclopropane or halogenated hydrocarbon anesthetics

Deterrence/Prevention -Ovarian hyperstimulation syndrome (OHSS) is a self-limiting disease of the luteal phase. Without luteinizing hormone (LH) or its imitator hCG, ovulation or the luteal phase does not occur. Avoidance of hCG during ovarian stimulation offers an opportunity to prevent OHSS in high-risk patients. However, those patients do not conceive. Other options are delaying hCG (coasting) for 1-3 days until estradiol levels plateau or decline.
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The prognosis is excellent if ovarian hyperstimulation syndrome is mild or moderate. In severe OHSS, the prognosis is optimistic if good treatment is given. Hypercoagulability may endanger the patient. Death from OHSS is largely due to hypovolemic shock and electrolyte imbalance, hemorrhage, and thromboemboli. Estimated fatality rates are 1 per 400,000-500,000 stimulated cycles.  
Patient Education
Patients are instructed to record their weight on a daily basis, to avoid exercise and intercourse, and to maintain adequate hydration after in vitro fertilization. They should measure their abdominal girth, intake, and output, and they should report urinary output of less than 1000 mL in any 24-hour period. Patients are educated to report progressive bloating, abdominal discomfort, decreases or increases in urination, cramping, dizziness, shortness of breath, and weight gain of more than 5 lb/wk.
Women should notify their doctor when they have: 

• Difficulty breathing
• Continued vomiting or nausea
• Difficulty tolerating fluids
• Abdominal swelling
• Decreased urination
• Weight gain of over 3 pounds in 2 days
• Sudden onset of abdominal pain
• Other symptoms such as facial numbness, weakness, lower extremity swelling, or redness