Ovarian Hyperstimulation Syndrome

Updated: Feb 18, 2016
  • Author: Richard Scott Lucidi, MD, FACOG; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Overview

Background

Ovarian hyperstimulation syndrome (OHSS) is a rare, iatrogenic complication for ovarian stimulation by assisted reproduction technology and other infertility treatments. Following gonadotropin therapy, OHSS usually develops several days after oocyte retrieval or assisted ovulation. This syndrome is characterized by ovarian enlargement due to multiple ovarian cysts and an acute fluid shift into the extravascular space. Complications of OHSS include ascites, hemoconcentration, hypovolemia, and electrolyte imbalances (see the image below). (See Pathophysiology and Etiology.)

Ultrasonographic presentation of ovarian hyperstim Ultrasonographic presentation of ovarian hyperstimulation syndrome.

The prevalence of therapy employing assisted reproduction technology is increasing. Therefore, gynecologists, internists, and emergency physicians must become familiar with OHSS and its myriad clinical presentations, which can cause multiorgan dysfunction and, potentially, death. (See Prognosis, Presentation, Treatment, and Medication.) [1]

Classification

To understand OHSS and its management, one must first be aware of its various grades of severity, (1) mild OHSS, (2) moderate OHSS, and (3) severe OHSS. (See Presentation and Workup) [2]

Mild OHSS is classified as follows:

  • Grade 1 - Abdominal distention and discomfort
  • Grade 2 - Grade 1 disease plus nausea, vomiting, and/or diarrhea, as well as ovarian enlargement of 5-12 cm

Moderate OHSS is classified as follows:

  • Grade 3 - Features of mild OHSS plus ultrasonographic evidence of ascites

Severe OHSS is classified as follows:

  • 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
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Pathophysiology

Abdominal pain, nausea, and vomiting

Enlargement of the ovaries causes abdominal pain, nausea, and vomiting. The enlargement is sometimes as much as 25 cm.

Ascites and tense distention

Another consequence of ovarian hyperstimulation syndrome (OHSS) is discomfort resulting from increased intra-abdominal pressure due to ascites. [3, 4]

Ascites and tense abdominal distention occur because of extravasation and increased leakage of protein-rich fluid from the intravascular space into the abdominal cavity, owing to an osmolar differential.

In addition, leakage of fluid from large follicles, increased capillary permeability (due to the release of vasoactive substances), or frank rupture of follicles can all contribute to ascites. [3]

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 vascular endothelial growth factor (VEGF), which is thought to increase vascular permeability, escape into the peritoneal cavity.

Blood vessels within and outside the ovary become functionally impaired, resulting in the leakage of fluid through those vessels and a massive fluid shift from the intravascular to the extravascular compartment. This process results in intravascular hypovolemia with the concomitant development of edema, ascites, hydrothorax, and/or hydropericardium. [5]

Hypotension and/or hypovolemia are also caused by compression of the inferior vena cava because of enlarged cysts or ascites. As a result, venous return and preload decrease. Eventual outcomes are reduced 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. [6]

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. [7]

Acute renal failure

Hypovolemia in OHSS leads to hemoconcentration and creates a hypercoagulable state. Microthrombi form in tubules, leading to decreased renal perfusion. Acute renal failure may result.

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Etiology

The pathogenesis of ovarian hyperstimulation syndrome (OHSS) is unknown, but the process is related to increased vascular permeability in the region surrounding the ovaries and their vasculature. [8] Beta human chorionic gonadotropin (hCG) and its analogs, as well as estrogen, estradiol, prolactin, histamine, and prostaglandins, have been implicated in the past.

Vasoactive substances such as interleukins, tumor necrosis factor (TNF)-alpha, endothelin-1, and VEGF secreted by the ovaries have been implicated in increasing vascular permeability. [9, 10]

Human chorionic gonadotropin

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. [11] Exogenous and endogenous gonadotropins from molar pregnancy, gonadotroph adenomas, and even pregnancy can aggravate OHSS. [12] These changes in the ovarian vasculature are exaggerated responses to normal luteinizing hormone (LH).

Indeed, 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. [9]

Exogenous recombinant hCG precipitates OHSS more than endogenous agents (gonadotropin-releasing hormone [GnRH] analogs) do. Other precipitating factors for OHSS are induction in a hyperestrogenic state and poor timing.

Risk factors

Age younger than 35 years, low body mass index (BMI), gonadotropin treatment, high estradiol concentrations, large number of follicles, history of polycystic ovarian syndrome, administration of exogenous hCG, and endogenous hCG from treatments resulting in pregnancy increase a patient’s risk of developing OHSS. [13]

According to Martin et al, if the pre-hCG estradiol amount is greater than 6000 mcg and/or if more than 30 follicles are present, the rate of severe OHSS approaches 80%. [14]

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Epidemiology

The incidence of ovarian hyperstimulation syndrome (OHSS) depends on definitions, risk factors, stimulation protocols, and conception. Rates of occurrence have been estimated as follows [4] :

  • 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 an increased number of follicles on ultrasonography. The incidence rises when protocols combine GnRH agonists and gonadotropins, as compared with gonadotropins alone, to induce ovulation. [4]

Only women of childbearing age are affected by ovarian hyperstimulation syndrome.

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Prognosis

The prognosis in mild or moderate cases of ovarian hyperstimulation syndrome (OHSS) is excellent. However, morbidity may be clinically significant in cases of severe OHSS, and fatalities do occur. However, the prognosis is optimistic in severe OHSS if proper (or adequate) treatment is given.

Death from OHSS is largely due to hypovolemic shock and electrolyte imbalance, hemorrhage, and thromboemboli (hypercoagulability may endanger the patient). Estimated fatality rates are 1 per 400,000-500,000 stimulated cycles.

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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 should report urinary output of less than 1000mL in any 24-hour period.

Patients are also instructed 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.

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