INTRODUCTION — Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian hyperstimulation (COH) for assisted reproduction technologies (ART). It occurs when the ovaries are hyperstimulated and enlarged due to fertility treatments (or rarely, mutations in the follicle-stimulating hormone [FSH] receptor), resulting in the shift of serum from the intravascular space to the third space, mainly to the abdominal cavity. In its severe form, OHSS is a life-threatening condition because it can cause venous or arterial thromboembolic events, including stroke and loss of perfusion of an extremity.
The pathogenesis, clinical manifestations, and diagnosis of OHSS are reviewed here. The prevention and management of OHSS are discussed separately. (See "Prevention of ovarian hyperstimulation syndrome" and "Management of ovarian hyperstimulation syndrome".)
EPIDEMIOLOGY — The frequency of OHSS depends upon the clinical setting (eg, ovulation induction/ovarian stimulation followed by timed intercourse or intrauterine insemination versus in vitro fertilization [IVF]) and the classification criteria used for OHSS (table 1) (see 'Classification' below). Although the most severe form of OHSS is rare, it represents an iatrogenic complication with a potentially fatal outcome in young women undergoing fertility treatment.
●When ovulation is induced with clomiphene citrate or aromatase inhibitors, either for timed intercourse or intrauterine insemination, ovarian enlargement consistent with mild OHSS may occur, but moderate to severe OHSS is rarely seen .
●In the setting of IVF, the overall incidence of moderate and severe OHSS in some series was 3 to 6 percent and 0.1 to 2 percent, respectively [2-4].
●In an early cohort of IVF cases, an increased incidence of severe OHSS cases was observed over time: from 0.06 percent in 1987 to 0.24 percent in 1996 [2,5].
An increase of severe OHSS requiring hospitalization from 0.9 to 1.8 percent over one year was observed in a second series, following a worldwide increase in the number of IVF cycles . Since the 2000s when gonadotropin-releasing hormone (GnRH) agonists were introduced for oocyte final maturation in patients at risk, a decrease of moderate/severe OHSS cases has been observed. Data from the Japanese registry analyzing 1,435,108 ART cycles found 11,378 cases of moderate/severe OHSS (0.79 percent) .
In a retrospective analysis of 4894 consecutive ART cycles conducted in Portugal, 51 cases (1 percent) of OHSS were reported (all OHSS patients received human chorionic gonadotropin [hCG] for final oocyte maturation). In another 71 cases considered high risk for OHSS (1.5 percent), patients received GnRH agonists for final oocyte maturation and did not develop OHSS .
PATHOGENESIS — In the spontaneous ovulatory cycle, hypothalamic-pituitary-ovarian feedback mechanisms limit follicle recruitment to a small number of early antral follicles, followed by selection of a single dominant follicle that ovulates in response to the midcycle luteinizing hormone (LH) surge (see "Normal menstrual cycle"). OHSS occurs when the equilibrium established by feedback mechanisms seen in the normal menstrual cycle is disrupted by the administration of exogenous gonadotropins followed by human chorionic gonadotropin (hCG).
OHSS can be viewed as an exaggeration of a physiologic process. The successive stages of OHSS are (algorithm 1):
●Recruitment of a large number of small antral follicles into a functional cohort
●Sustained development of numerous large antral follicles until ovulation (or luteinization)
●Excessive production of vascular endothelial growth factor (VEGF) by the developing corpora lutea, after hCG administration
●Exaggerated perifollicular neovascularization with some of the new blood vessels exhibiting increased permeability
●Escape of follicular fluid and perifollicular blood containing large amounts of VEGF into the peritoneal cavity
●Functional impairment of blood vessels (not only within the ovary)
●Massive fluid shift from the intravascular to the third compartment, also known as "third spacing," resulting in intravascular hypovolemia concomitant with the development of edema, ascites, hydrothorax, diminished renal blood flow, and/or pericardial effusion
●Impairment of cardiac, renal, pulmonary, and liver function
OHSS typically occurs in the setting of (table 2):
●Ovarian stimulation with gonadotropins with an exuberant ovarian response, evidenced by multiple follicular development, high serum estradiol concentrations, and ovarian enlargement by the end of stimulation 
●Use of exogenous hCG to trigger the final steps of oocyte maturation 
●Production and release of vasoactive substances by granulosa/luteal cells
●Binding of the vasoactive substances to their receptors and activation of downstream signalling, leading to increased vascular permeability 
●Pregnancy following ovarian stimulation, where rising hCG secretion from the placenta can stimulate increased VEGF secretion from the ovary
Ovulatory hCG injection — Exogenous human chorionic gonadotropin (hCG) administration plays a key role in the pathogenesis of OHSS. Regardless of the degree of ovarian response to gonadotropin stimulation, OHSS does not occur unless an ovulatory dose of hCG is administered [14,15]. Exogenous hCG induces massive luteinization of granulosa cells, which leads to the production of vasoactive substances such as VEGF that increase vascular permeability. (See 'VEGF/vascular permeability' below.)
Such massive luteinization is usually not observed when the final steps of oocyte maturation are achieved with drugs other than hCG (eg, gonadotropin-releasing hormone [GnRH] agonists) . The effect of hCG is related to its high biological activity, which is six to seven times that of endogenous LH (because of hCG's longer half-life) . (See "Prevention of ovarian hyperstimulation syndrome".)
VEGF/vascular permeability — A number of substances have been proposed as the cause of increased vascular permeability post-hCG administration, but vascular endothelial growth factor (VEGF) appears to play the main role [16,18-24]. VEGF is a member of the family of heparin-binding proteins that act directly on endothelial cells to induce proliferation and angiogenesis. VEGF mRNA and protein are expressed by granulosa and theca cells late in follicular development and after ovulation. Studies on ascitic fluid from patients with severe OHSS have demonstrated that VEGF is the major capillary permeability agent .
VEGF serum concentrations are positively correlated with the risk of developing OHSS and with the severity of its form [26-28]. The presence of VEGF receptor 2 (VEGFR-2) in granulosa-lutein cells after hCG administration has been confirmed in humans .
Increased capillary permeability and fluid shift to the third space are usually confined to the ovaries and abdomen . Additionally, patients who get pregnant after oocyte donation do not have OHSS, despite high free VEGF levels .
Very little is known about the steps through which the VEGF-VEGFR-2 complex increases vascular permeability, but potential downstream elements involved in endothelial cell-to-cell junctions may play a role [31-33].
Rare causes — Rarely, OHSS may be seen in the absence of exogenous gonadotropin administration. In these cases, OHSS may be the consequence of the high production of endogenous gonadotropins (hCG) or gonadotropin-like molecules (thyroid-stimulating hormone [TSH]), or enhanced sensitivity to endogenous gonadotropins (mutations in the follicle-stimulating hormone [FSH] receptor).
●Previous episode of OHSS [2,35].
●Polycystic ovary syndrome (PCOS) [2,11,36-38]. In a meta-analysis of 10 studies, women with PCOS were at higher risk for OHSS than women with other infertility diagnoses (odds ratio [OR] 6.8, 95% CI 4.9-9.6) .
●Potential biomarkers of risk – Basal serum anti-müllerian hormone (AMH) concentration >3.3 ng/mL and an antral follicle count (AFC) >8. These were predictors of OHSS risk in a retrospective study of 41 women who developed OHSS compared with an age-matched control group who did not develop OHSS .
●Secondary risk factors related to ovarian response :
•Number of follicles (risk rises with increasing number of follicles >20 over 10 mm in diameter).
•High (or rapidly rising) serum estradiol concentration. In one report, the incidence of OHSS in women with preovulatory serum estradiol concentrations >3500 pg/mL (12,850 pmol/L) or >6000 pg/mL (22,028 pmol/L) was 1.5 and 38 percent, respectively . The role of serum estradiol monitoring for preventing OHSS is discussed separately. (See "Prevention of ovarian hyperstimulation syndrome".)
•Number of oocytes retrieved in in vitro fertilization (IVF) cycle (risk increases with increasing number of oocytes) .
•Administration of human chorionic gonadotropin (hCG) rather than progesterone for luteal phase support .
•Pregnancy, which increases not only the risk of late OHSS, but also the duration and severity of OHSS (due to the persistent stimulation by endogenous hCG) .
Although younger age and low body weight have been reported as possibly associated with OHSS, neither is a good predictor of risk [2,35,37,42-44].
CLINICAL MANIFESTATIONS — Clinical manifestations of OHSS are the consequence of the processes that define the syndrome: enlarged ovaries (which may cause abdominal discomfort) and increased vascular permeability, resulting in fluid accumulation in the abdomen .
Onset — "Early" OHSS is usually mild to moderate and begins four to seven days after the ovulatory dose of human chorionic gonadotropin (hCG). "Late" OHSS typically begins at least nine days after the ovulatory dose of hCG in the setting of a conception cycle. Late OHSS is more severe because the rising hCG of pregnancy exacerbates the course of OHSS. Early symptoms include abdominal distension and possibly pain due to ovarian enlargement and accumulation of abdominal fluid.
Classification — OHSS may be classified into four stages based upon the severity of symptoms, signs, and laboratory findings (table 1).
●Mild OHSS – Mild OHSS is characterized by bilateral ovarian enlargement with multiple follicular and corpus luteum cysts, abdominal distention and discomfort, mild nausea, and, less frequently, vomiting and diarrhea. There are no biochemical abnormalities (table 1).
Mild OHSS is frequently seen after ovarian stimulation with gonadotropins for in vitro fertilization (IVF) in women with a strong ovarian response. Typically, no special care is necessary, but surveillance of the patient is indicated.
●Moderate OHSS – The clinical features of moderate OHSS include those of mild OHSS plus ultrasonographic evidence of ascites. Ovaries are frequently enlarged up to 12 cm in their longest dimension. Abdominal discomfort and gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea) are more frequent and intense than in mild OHSS. A sudden increase in weight of more than 3 kg (6.6 lbs) may be an early sign of moderate OHSS (table 1).
Laboratory features include a hematocrit above 41 percent and white blood cell concentration (WBC) above 15,000/microL, with hypoproteinemia.
●Severe OHSS – In addition to the findings of moderate OHSS, severe OHSS is defined by the presence of clinical evidence of ascites with severe abdominal pain and, in some patients, pleural effusion. Women with severe OHSS can gain as much as 15 to 20 kg (33 to 44 lbs) over 5 to 10 days and display progressive leukocytosis. Ascites and pleural effusion may compromise pulmonary function, resulting in hypoxia (table 1) .
Hypovolemia, oliguria or anuria, and intractable nausea and/or vomiting are frequently present. Creatinine levels are above 1.6 mg/dL. Reduced liver perfusion affects its function; anticlotting factors are among the first to be depleted, and transaminases are increased . Other laboratory findings include a hematocrit >55 percent, WBC >25,000/microL, and electrolyte imbalance (hyponatremia, hyperkalemia) [48-50]. Hemoconcentration increases the risk for thromboembolism.
In a study of 20 cases of OHSS, intraabdominal pressure (IAP) was measured and was increased in all of them, including cases of moderate OHSS . Based upon these data, the study authors proposed that OHSS should be managed as a secondary abdominal compartment syndrome (ACS) . ACS is defined as a persistently elevated intraabdominal hypertension that leads to compromised end-organ function.
●Critical OHSS – In critical OHSS, the function of vital organs and systems is seriously compromised. Anuria with acute renal failure, cardiac arrhythmia, respiratory insufficiency, and disseminated intravascular coagulation (venous and arterial thrombosis) may result in death. Pleural effusion becomes a massive hydrothorax, accompanied by pericardial effusion. Sepsis and acute respiratory distress syndrome (ARDS) may further complicate the clinical picture. In one study of 209 patients with severe/critical OHSS, eight (4 percent) had pneumonia, four (2 percent) ARDS, and four (2 percent) had pulmonary thromboembolism (table 1) .
Investigators doing clinical trials in this area have proposed a different set of criteria for the diagnosis and classification of OHSS as follows:
●Mild OHSS – Women presenting with mild OHSS signs/symptoms are classified as "ovarian hyperresponders."
●Moderate, severe, or critical OHSS – Those presenting with moderate or more severe OHSS signs/symptoms are classified as "OHSS," which can be further classified into:
•"Self-limited OHSS" – No catastrophic events
•"OHSS with significant comorbidities" – At least one of the following events: venous thromboembolism; acute respiratory distress syndrome; cerebral edema, acute ischemia, encephalopathy; kidney injury; liver failure 
Specific complications — Other potential complications that may be seen in the setting of OHSS include:
●Ovarian torsion – Whenever ovarian volume is increased, there is a risk of ovarian torsion. This complication is characterized by ovarian enlargement, abdominal pain, nausea, vomiting, hypotension, progressive leukocytosis, and anemia. Ovarian torsion may demand surgical correction .
●Thromboembolism – Thromboembolic events are infrequent, but among the most serious, complications of OHSS. Thromboses can be either arterial (25 percent) or venous (75 percent) and may lead to permanent neurologic injury or death [55-57].
The occurrence of these events is likely related not only to hemoconcentration but also to hypercoagulation associated with elevated serum estrogen concentrations. In one report, high levels of factor V, platelets, fibrinogen, profibrinolysin, fibrinolytic inhibitors, and increased thromboplastin generation were observed in women with OHSS .
Thromboembolic complications of OHSS have been reported in the internal jugular, subclavian, axillary, and mesenteric vessels [46,59]. In one series of five cases of internal jugular vein thrombosis presenting at 7 to 10 weeks gestation after IVF, two occurred in women who had not had OHSS but had an underlying thrombophilia, while three occurred in women with severe OHSS and no underlying thrombophilia . Cerebrovascular thrombosis typically presents as an ischemic infarct.
Some experts advise that women with an underlying thrombophilia (eg, antithrombin III deficiency, factor V mutation, and protein C or S deficiency) should receive prophylaxis (such as low-dose heparin therapy) prior to ovulation induction, to prevent thromboembolic complications . (See "Overview of the causes of venous thrombosis" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Selecting thromboprophylaxis'.)
Because thromboembolic complications are rare, we do not suggest routine screening for thrombophilia in women planning to undergo ovarian stimulation.
DIAGNOSIS — The diagnosis of OHSS is made by clinical history and transvaginal ultrasound (table 1) (see 'Classification' above). There should be a history of ovarian stimulation followed by administration of human chorionic gonadotropin (hCG). The number of collected oocytes, peak serum estradiol, and number of transferred embryos are predictors of the presence of OHSS.
Differential diagnosis — The diagnosis of OHSS is usually straightforward, as the syndrome occurs in a specific setting: ovarian stimulation with exogenous gonadotropins followed by hCG injection. However, other disorders resulting in pelvic pain and possibly free fluid include ectopic pregnancy, hemorrhagic cyst, ruptured ovarian cyst, and ovarian torsion. These disorders, when associated with hemoperitoneum (or hemoperitoneum due to oocyte retrieval) may be similar to OHSS (enlarged ovaries, free fluid [blood], abdominal distension, and pain). However, hemoconcentration is not present (there is a fall in hemoglobin and hematocrit). (See "Ectopic pregnancy: Clinical manifestations and diagnosis" and "Ovarian and fallopian tube torsion".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian hyperstimulation syndrome".)
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SUMMARY AND RECOMMENDATIONS
●Ovarian hyperstimulation syndrome (OHSS) is an exaggerated ovarian response to ovulation induction, particularly in the setting of in vitro fertilization (IVF). It occurs almost exclusively in the setting of ovarian stimulation with exogenous gonadotropins, and only if human chorionic gonadotropin (hCG) is administered to trigger ovulation. (See 'Pathogenesis' above.)
●Mild OHSS is a condition that is almost always seen as an iatrogenic complication of ovarian stimulation performed during assisted reproductive technologies (ART). It can be strictly defined as the shift of serum from the intravascular space to the third space, mainly to the abdominal cavity, in the context of enlarged ovaries due to follicular stimulation. In its very severe form, OHSS is a life-threatening condition (table 1). (See 'Pathogenesis' above.)
●The incidence of moderate and severe OHSS while undergoing IVF has decreased in the last decade due to modern approaches in prevention strategies: use of gonadotropin-releasing hormone (GnRH) agonist triggering, dopamine agonists, and others. (See 'Epidemiology' above.)
●A number of substances have been proposed as the cause of increased vascular permeability post-hCG administration, but vascular endothelial growth factor (VEGF) appears to play the main role. (See 'VEGF/vascular permeability' above.)
●Risk factors include the presence of polycystic ovary syndrome (PCOS), previous OHSS, luteal phase hCG support, number of follicles, and high serum estradiol concentrations. Pregnancy increases the risk, duration, and severity of OHSS (due to the persistent stimulation by endogenous hCG) (table 2). (See 'Risk Factors' above.)
●The diagnosis of OHSS is based upon clinical history and transvaginal ultrasound. There should be a history of ovarian stimulation followed by ovulation or administration of hCG (see 'Diagnosis' above). The signs and symptoms of mild, moderate, severe, and critical OHSS are described above. (See 'Classification' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Bruno Lunenfeld, MD and the late Vaclav Insler, MD, who contributed to earlier versions of this topic review.
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