Ovarian Hyperstimulation Syndrome 

Definition

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation for 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. Results include ascites, hemoconcentration, hypovolemia, and electrolyte imbalances.

The prevalence of therapy with assisted reproduction technology is increasing. Therefore, gynecologists, internists, and emergency physicians must be aware of this rare condition and its myriad clinical presentations, which can cause multiorgan dysfunction and, potentially, death.^[1]

Classification

To understand OHSS and its management, one must first be aware of its classifications of severity. Grades of OHSS are as follows:^[2]

• 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

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.^[3] 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.^[4]

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.^[5] 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.^[4]

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.^{[6, 7]}

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.^[6]

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.^[8]

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.^[9]

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.^[10]

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

International

The rate of ovarian hyperstimulation syndrome depends on definitions, risk factors, stimulation protocols, and conception.

Rates of OHSS are as follows:^[7]

• 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 gonadotropin-releasing hormone (GnRH) agonists and gonadotropins, as compared with gonadotropins alone, to induce ovulation.^[7]

In the ideal situation, induction should stimulate the ovaries to a desired level. However, the unpredictable response of the ovaries to induction make the prediction and prevention of OHSS difficult.^[7] Hence, heightened clinical suspicion and early intervention are paramount for decreasing morbidity and mortality.

Women of young age, as well as those with low body weight, polycystic ovarian syndrome, or previous episodes of hyperstimulation are all at increased risk for developing OHSS. In addition, an increased number of small- and medium-sized follicles and elevated estradiol levels around the assumed time of ovulation increase the incidence.

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%.^[11]

Mortality/Morbidity

Morbidity may be clinically significant in cases of severe and critical ovarian hyperstimulation syndrome, and fatalities do occur. (See also Prognosis.)

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.