The pathophysiology of ovarian hyperstimulation syndrome: an unrecognized compartment syndrome

Abstract

Objective

To compare and contrast the pathophysiology of ovarian hyperstimualtion syndrome (OHSS) with known syndromes of increased intraabdominal pressure (IAP), and to explore the relationship of increased IAP with symptom severity in OHSS.

Design

Literature review.

Main Outcome Measure(s)

Correlation of OHSS symptoms with IAP; effects of paracentesis on IAP in patients with OHSS.

Setting

Academic Research Institution.

Intervention(s)

None.

Result(s)

OHSS involves a rapid accumulation of volume (from 1.5–17 liters) in the peritoneal cavity that can lead to organ dysfunction, including respiratory impairment and oliguria. In published reports of 20 moderate-to-severe OHSS patients in whom IAP was measured, IAP was found to be elevated to a pathologic range. The increased IAP indicates that OHSS may be considered a compartment syndrome and meets criteria for abdominal compartment syndrome in advanced cases. For this reason, management of OHSS should include reduction of pressure by paracentesis to avoid morbidity and syndrome progression. In addition, measurement of IAP may help to classify the stage of OHSS.

Conclusion(s)

IAP was found to be elevated in the few cases of OHSS in which it was measured, substantiating the conclusion that OHSS may be considered a compartment syndrome. An understanding of the pathophysiology of increased intrabdominal pressure is useful in the management of OHSS.

Moderate to severe ovarian hyperstimulation syndrome (OHSS) has been calculated to occur in 0.2% to 2% of all ovarian stimulation cycles (1, 2). Risk factors include young age, low body weight, polycystic ovarian syndrome, previous OHSS, pregnancy, high follicle count, and elevated serum estradiol (3, 4). Stimulation protocols using hCG for luteal phase support also increase the risk (3). Additional causes include follicle stimulating hormone (FSH) mutations that were first reported by both Vasseur et al. (5) and Smits et al. (6).

Conventional OHSS staging has relied upon clinical symptoms and laboratory findings to categorize severity of disease. The first classification was proposed by Rabau et al. (7) in 1967, and was later modified by Schenker and Weinstein (8); it included three categories of mild, moderate, and severe, as well as six grades of severity. Golan et al. (9) modified the classification, using only five grades, although some argued the severe category warranted further distinction. Navot et al. (3) further contributed to the classification, based on clinical criteria and by reviewing and comparing risk factors and previous treatment strategies. Although the current classification of OHSS includes specific laboratory values, the major areas of the classification rely on qualitative clinical findings (10), reviewed in ref. (11). The timing of the emergence of OHSS symptoms is a consideration in classification of OHSS. Early-onset OHSS occurs within 9 days after oocyte retrieval and is related to hyperresponse of the ovaries to gonadotropin stimulation and exogenous hCG. Late-onset OHSS appears after this 10-day period and is associated with hCG produced by an implanted embryo(s) (12–14).

PATHOGENESIS OF OHSS

OHSS has been intensely studied, but the pathogenesis remains controversial. Serum estradiol (E₂) was initially suspected to play a large role in OHSS because of the high levels of E₂ present in most OHSS patients (15), yet cases of OHSS have been reported in patients with low E₂ levels because of hypogonadotrophic hypogonadism (16) and congenital adrenal hyperplasia (17). Additionally, OHSS was reported not to occur when hCG was withheld, regardless of a high E₂ level (18). However, E₂ did not appear to be the cause of the circulatory dysfunction (19), and the E₂ molecule itself did not exhibit direct vasoactive effects (20). Nevertheless, circulating E2 levels have been suggested to be of predictive value for OHSS, regardless of whatever the actual role of estrogen in pathogenesis may be (21). Recently, more data on the effects of cystic fibrosis transmembrane conductance regulator (CFTR), which is upregulated by the effects of estradiol, has been found in conjunction with OHSS. CTFR function has been shown to increase channel activity in most exocrine glands, as well as in the peritoneal activity, causing excessive fluid shift and accumulation and offers a potential explanation for the involvement of estradiol in this syndrome (22).

The role of a variety of cytokines and growth factors, including interleukins (IL) IL-2, IL-6, IL-8, IL-10, IL-18, and vascular endothelial growth factor (VEGF) have been detected in the peritoneal fluid of women with OHSS and have been the focus of molecular research involving the pathogenesis of OHSS (23). In the past, renin–angiotensin, histamine, prolactin, prostaglandins, and other substances have also been considered for their possible role in OHSS (24).

At this time, current research supports a major role of VEGF in OHSS, as reviewed by Soares et al. (23). An increase in vascular permeability (VP) was found in ascitic fluid from women with OHSS implicating VEGF in the pathogenesis, and conversely, incubation with rhVEGF antiserum significantly decreased the VP activity (25). Using a rat model it was found that VEGF mRNA levels and VP increased following gonadotropin stimulation (26), and that gonadotropins increased ovarian VEGF receptor 2 (VEGFR-2) mRNA expression (27). Immunohistochemical staining localized VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the corpus luteum (26). In humans, hCG administration increased VEGF expression in granulosa-lutein cells (28) and VEGF blood levels predicted the development of OHSS and its severity (29).

HEMODYNAMIC PATHOPHYSIOLOGY OF OHSS

Vascular endothelial growth factor increases VP, and transcapillary fluid dynamics studies in OHSS patients confirmed a reduction in the colloid osmotic gradient favoring leakage to the extravascular space (30). This “third spacing” leads to depletion of the intravascular volume, ultimately resulting in hypotension. The large fluid shift can cause tension ascites that can be transmitted into the thoracic cavity leading to pleural effusions as first described by Mozes et al. (31), other pulmonary manifestations (32), or dependent edema (33).

Because hypotension leads to decreased venous pressure and reduced venous return, a decreased cardiac output (CO) might be expected; however, studies have found the CO was increased in OHSS (19, 34). In one study CO was found to increase to 2.6 L/min, mean arterial pressure decreased by 16.6 mmHg, and peripherial vascular resistance was decreased (34). These findings led to the determination that there is accompanying arterial vasodilation in OHSS (19). The hypotension also affects organ function because of the decreased perfusion. Reduced perfusion of the kidney leads to a decreased glomerular filtration rate (GFR), and can result in oliguria. In addition, changes in perfusion can affect liver function (35), including synthesis of proteins, of which anticlotting factors are among the first to become depleted. This, along with the hemocon centration because of depleted intravascular volume can lead to thromboses, not infrequently in the upper extremities (36). Both arterial thromboses (37) and venous thromboses in sites such as the superior vena cava (38), internal jugular vein (39–41), and subclavian vein (42) have been reported in patients with OHSS. Many affected patients had no other risk factors for thrombosis. Hemoconcentration may partially explain the increase in white blood cells and platelets, although some believe these elevations may be because of demargination associated with stress (43).

Collectively, the hemodynamic changes associated with OHSS strongly resemble those of an abdominal compartment syndrome, but there is only one case report of abdominal compartment syndrome (ACS) as a unique outcome of OHSS (44). Because of the rapid increase of pressure in a the abdominal compartment, leading to hemodynamic changes and ultimately organ dysfunction, we hypothesize that moderate to severe cases of OHSS should be considered as an abdominal compartment syndrome. We review evidence supporting this hypothesis and discuss the potential importance of intraabdominal pressure (IAP) in classification of the severity of OHSS.

INTRAABDOMINAL HYPERTENSION (IAH) AND THE ACS

The abdomen is a closed compartment in which the elasticity of the walls and the contents of the cavity determine the IAP (Fig. 1). The IAP is affected by the volume of the organs and viscera, the presence of fluid or space-occupying lesions within the cavity, and respiration (45). The IAP can be measured directly or indirectly via several methods. Transvesicular pressure via a bladder catheter is most commonly used and has been validated (46). Normal IAP is typically subatmospheric or 0 mmHg (<5 mmHg) although pressure may be chronically elevated (10–15 mmHg) in morbidly obese patients (47). Increased IAP is defined (Table 1) as IAH, and is graded as follows: grade 1: IAP 12–15 mmHg; grade 2: IAP 16–20 mmHg; grade 3: IAP 21–25 mmHg; grade 4: >25 mmHg (45). Directly relevant to the degree of IAH is the ACS grading: I (10–15 mmHg IAP), II (16–25 mmHg IAP), III (26–35 mmHg IAP), IV (>35 mmHg IAP). The IAH can be classified as acute when there is an increase in IAP over hours, as may occur in surgical patients (45). The IAH is termed subacute when the increase occurs over a period of days as may occur in medical patients, such as those with pancreatitis. Abdominal perfusion pressure (APP) is equal to the mean arterial pressure minus the IAP. An APP below 60 mmHg is the threshold that predicts inadequate visceral perfusion, and conversely, an APP >60 mmHg has been correlated with improved survival in cases of IAH (45).

FIGURE 1.

Nomenclature of terms and conditions associated with increased intraabdominal pressure (IAP). Intraabdominal pressure is normally <5 mmHg. Increased IAP is defined as IAP R12 mmHg, and is associated with symptoms (shown in Table 1). ACSis IAP >20–25 mmHg with organ dysfunction (see Table 1) and is treated by decompression.

TABLE 1.

IAH and ACS grading and physiology.

Symptoms	IAH physiologic effects	IAH gradea (IAP in mmHg)	ACS gradeb (IAP in mmHg)	ACS physiologic effects
None	None	Normal = <12	Normal = <10	None
	Renal impairmentd	I = 12–15	I = 10–15	No ACS effectsc
	Venous stasisd
Oliguriac	Splanchnic BF ↓e	II = 16–20	II = 16–25	PAP ↑c
	Lung compliance ↓d			Urine output ↓c
		III = 21–25
Anuriac	CPP ↓	IV = >25	III = 26–35	Urine output ↓↓c
				Cardiac output ↓c
			IV = >35	DO2I ↓b
				SVR ↑b
				Coagulopathy ↑b

Note: IAH = intraabdominal hypertension; IAP = intraabdominal pressure; ACS, abdominal compartment syndrome; PAP = peak airway pressure; CPP = cerebral perfusion pressure; DO₂I = oxygen delivery index (mL O₂/min/m²); SVR = systemic vascular resistance; BF = blood flow; renal impairment = decreased glomerular filtration rate.

^aMalbrain et al. (45).

^bMeldrum et al. (48).

^cMoore et al. (49).

^dSugrue et al. (67).

^eIvatury et al. (68).

Abdominal compartment syndrome is formally defined as a sustained IAP >20 mmHg (with or without APP <60 mmHg) with accompanying organ dysfunction (Table 1). Malbrain and colleagues (45) described a triad with ACS as a pathologic state caused by acute increase in IAP above 20 to 25 mmHg that adversely affects end-organ function and in which abdominal decompression has beneficial effects. Although grading classifications were proposed (48, 49), as detailed in Table 1, ACS may be considered an all-or-nothing phenomenon according to the most recent guidelines from the 2004 Second World Congress on Abdominal Compartment Syndrome (45). Primary ACS is abdominal or pelvic in origin, with etiologies including trauma and surgery. Secondary ACS includes other etiologies, such as capillary leak syndromes. The pathophysiology and effects of ACS described in the literature (Table 1) are either identical to the effects observed in patients with OHSS (Table 2), or are remarkably similar. Note that organ dysfunction in both ACS and OHSS syndromes is accompanied by similar increases in abdominal pressure, in agreement with the conclusion that OHSS may be considered a form of secondary ACS.

TABLE 2.

Comparison of OHSS to IAH by OHSS staging.

Symptoms/signs of OHSS	Stage	Measured IAP in OHSS (mmHg)
Abdominal distension/discomforta	Milda	No documented IAH
Ovaries enlarged to 5–12 cm
Ascites seen on ultrasound	Moderatea	12.9b=Grade I IAH
Nausea or vomiting
Oliguriaa
Difficulty breathinga
Tachycardia
Hemoconcentration
Severe hemoconcentrationa	Severea	40c=Grade IV IAH
Coagulation abnormalitiesa
Organ dysfunctiona
Anuriaa

Note: OHSS grading adapted from Golan et al. (9), Whelan et al. (10). IAP = intraabdominal pressure; OHSS = ovarian hyperstimulation syndrome; IAH = intraabdominal hypertension.

^aSimilar to IAH.

^bMaslovitz et al. (50). Mean IAP in OHSS patients (n=19).

^cCil et al. (44). IAP in OHSS patient (n=1).

OHSS IS A COMPARTMENT SYNDROME

Current evidence supports the hypothesis that OHSS is a compartment syndrome even in moderate cases, with severe OHSS cases representing a form of ACS characterized by an increased IAP and organ dysfunction. By definition an increased IAP includes effects of the volume of the organs and viscera and the presence of fluid or space-occupying lesions within the cavity (45), which includes IAP increases in OHSS as the ovaries enlarge and ascitic fluid accumulates. Increased IAP has been documented for 20 OHSS patients in the literature (44, 50), with increased IAP reported in moderate and severe OHSS cases. Cil et al. (44) documented an IAP of 54 cm H₂O by bladder catheter (44), equivalent to 40 mmHg, which satisfies criteria for ACS. Another study found mean IAP of 17.5±1.24 cm H₂O, equal to 12.9±0.91 mmHg, in 19 OHSS patients with varying symptoms including decline in respiratory function, tense ascites, oliguria, or a combination of these (50). These IAP measurements are consistent with grade 1 IAH (Fig. 1, Table 1), and it should be noted that a rapid increase in IAP may affect symptomatology. Based upon these observations, and the well-established link between IAH and organ dysfunction, it is logical to consider how IAP measurement may correlate with the disease severity in OHSS patients (Table 2).

The pathophysiology and accompanying clinical presentation of ACS is virtually identical to a severe case of OHSS, consistent with a role of increased IAP in OHSS. The ACS consists of a clinical triad (47). The first component is respiratory compromise as increased IAP elevates the diaphragm thus affecting respiration. This is observed in OHSS (32), as many patients complain of dyspnea and pleural effusions can occur. The second component of the ACS triad involves decreased venous return as increased pressure compresses the inferior vena cava (IVC), impeding blood return to heart. Although studies in patients with tense ascites have documented increased IVC pressure (51), no studies have specifically quantified IVC compression in OHSS patients. The last component of the ACS triad is intestinal obstruction because of compression of viscera, which can lead to decreased appetite and then nausea/vomiting as is observed in OHSS. Beyond this described triad there are effects on renal, liver, and hematologic parameters that are common to both syndromes. Specific effects of increased IAP documented in IAH and ACS are summarized in Table 1. Table 2 summarizes symptoms used to classify OHSS severity with documented IAP measurements from the literature. Comparison of Tables 1 and 2 indicates that the severity of OHSS and associated symptoms occur at levels of increased IAP accompanied by organ dysfunction virtually identical to that observed in IAH leading to ACS.

In OHSS, IAH, and ACS, the rapid increase in volume and/or pressure exceeds the abdominal wall compliance because there is no time for tissue adaptation. A compliance curve for the abdomen has been described in for acute changes in volume in chronic dialysis patients (52), which further correlates with the described effects of rapid increase in volume (ascites) in OHSS patients. The curve was found to consist of three phases when fluid was injected into the abdomen. The initial phase during which fluid injection was begun showed a slight increase in IAP. The middle phase had minimal further increase in IAP to a volume of about 3 L, but was associated with a progressive increase in abdominal girth and mild abdominal discomfort. The last phase revealed a linear increase in IAP when volume was >3 L and was associated with intense abdominal discomfort but not much greater increase in abdominal girth. These findings corroborate the clinical observations in OHSS patients, although the experiment was done in chronic dialysis patients (52) who may have greater abdominal compliance than a previously healthy OHSS patient.

PHYSIOLOGIC BENEFITS OF PARACENTESIS

If the pathophysiology of OHSS is largely due to the rapid increase in abdominal pressure, as we suggest, then paracentesis to reduce IAP in OHSS would be expected to result in immediate beneficial effects. Notably, improvement after intervention is a criterion for ACS in patients with elevated IAP for other reasons. The beneficial physiologic effects of paracentesis have been documented for massive ascites, including cases of OHSS. Knauer and Lowe (51) found that paracentesis for tense ascites in cirrhotic patients reduced IAP and IVC pressure and led to an increase in CO and stroke volume. Similarly, Guazzi et al. (53) found paracentesis decreased IAP, which led to increased venous return and improved filling of the heart. Thaler and colleagues (54) were the first to describe the benefits of paracentesis in the OHSS patients, and reported a dramatic clinical improvement after fluid removal. Renal effects after paracentesis in OHSS include decreased renal artery resistance (50), improved GFR (50), and ultimately increased urine production (50, 54–56), with one study finding a 65% increase in urine production within 1 day of fluid removal (50). Pulmonary symptoms, including severe respiratory compromise, were improved after paracentesis (57) in OHSS patients. Hemoconcentration was decreased in OHSS patients after paracentesis, with hematocrit and leukocyte counts significantly lowered (55). As many patients with OHSS are pregnant, possible effects of paracentesis on the pregnancy may be of concern. No adverse effects on pregnancy outcome have been attributed to paracentesis (58), and paracentesis could even be beneficial because it increases uterine perfusion (58). Collectively, the improvement in organ function resembles that observed with IAH and ACS after pressure reduction, and supports the view that OHSS is, at least in advanced cases, an abdominal compartment syndrome.

The fact that a decrease in IAP was noted after paracentesis in OHSS patients is further evidence that OHSS is an ACS best treated by pressure reduction. One study reported the IAP decreased from 17.5±1.24 cm H₂O (12.9±0.91 mmHg) to 10±1.22 cm H₂O (7.4±0.90 mmHg) after paracentesis for OHSS (50). The reduction in pressure led to less abdominal discomfort and easier breathing (50), which can be explained physiologically by the direct effects of pressure reduction because of fluid removal. It was noted that most of the decrease in IAP was seen after initial drainage of 2,000 mL, with additional drainage having negligible effect on the pressure (50), whereas improved urine output occurred with drainage of less fluid. This supports the notion that the dramatic effects of fluid removal are not linearly related to the amount removed, but rather to the decompression per se, as an immediate substantial clinical improvement is observed even following the removal of small amounts. This finding strongly suggests that the reduction in pressure is responsible for the beneficial effects that result from paracentesis, as opposed to other possible mechanisms.

One goal of OHSS management is to prevent progression in disease severity. Current parameters for paracentesis are based upon symptomatic complaints of dyspnea, abdominal distension and pain, or oliguria. The timing, method, and aggressiveness of paracentesis is institution and physician dependent. Some investigators (59–61) have advocated early intervention by aggressive paracentesis because they have noted dramatic clinical improvement and shortened hospital stay in OHSS patients (59). Others (10, 62) have proposed paracentesis is indicated only when conservative management has failed because of rare complications, including damage to hypervascularized and enlarged ovaries, bowel, and post paracentesis vulvar edema (63, 64). If OHSS is considered to be a compartment syndrome, then early intervention with paracentesis even for mild to moderate cases where ascites is found would seem the most logical plan of care.

REVISITING THE MANAGEMENT OF OHSS

A proposed management incorporating the view of OHSS as a compartment syndrome is outlined in Figure 2. This is a proposed management scheme for a future clinical study. Symptoms including abdominal discomfort or distension, difficulty lying flat, dyspnea, and/or nausea/vomiting warrant evaluation for OHSS in the at-risk patient. An ultrasound to assess for the presence or absence of ascites is key to distinguish mild OHSS from more advanced states of OHSS. In the presence of ascites, the patient's specific symptoms, exam, and lab values provide substantial aid to the physician and help the provider to classify the severity of OHSS. Moderate disease is characterized by ascites, nausea or vomiting, oliguria, difficulty in breathing, hemoconcentration, and tachycardia, whereas severe hemoconcentration, coagulation abnormalities, organ dysfunction, and anuria are the hallmarks of the severe stage. IAP measurement may be indicated if the distinction between moderate and severe OHSS is not clear. IAP is measured via a transvesicular indirect method in which a pressure transducer is attached to the Foley catheter (46, 65). Increased IAP measurements have been found in patients with moderate and severe OHSS (Table 2). Based on existing literature for the management of IAH and ACS, an IAP >20 mmHg warrants decompression (45), which in OHSS patients is accomplished by paracentesis. For OHSS patients, intervention by paracentesis to relieve the pressure before reaching this critical IAP may prevent disease progression and complications. By including IAP measurement as a method of assisting in classification of the severity of OHSS, the correlation between IAP and symptoms, classification, and outcome of OHSS might be further established.

FIGURE 2.

Proposed management of OHSS. Ovarian hyperstimualtion syndrome management includes evaluation of symptoms, labs, ultrasound, and possibly IAP measurement to determine the severity of the OHSS presentation and treat as indicated. Liver function tests might not be helpful in early diagnosis of OHSS, but could serve as a baseline reference in case ascites occur later or that liver function becomes impaired. It is our practice to send electrolytes before intervention, in case nausea or dehydration caused electrolyte abnormalities. CBC=complete blood count; LFT=liver function tests; LMWH=low molecular weight heparin.

Paracentesis is the most important factor in management of patients with moderate or severe OHSS as the presence of tense ascites accompanied by symptoms and hemodynamic changes are defining features for more advanced stages of disease. Transvaginal ultrasound guided paracentesis is the first choice for most patients. Ascitic fluid seen on imaging in patients with moderate to severe OHSS symptoms should be removed, with typical volumes equaling 2–3 liters (59, 61); however, anecdotally, we note that significant improvement can be seen with removal of smaller volumes, perhaps because of reduction in hydrostatic pressure at a “tipping point” where the patients become symptomatic. Patients should be well hydrated before paracentesis and fluid status should be evaluated after the procedure. Repeat paracentesis may be indicated for fluid reaccumulation in patients with moderate or severe disease who again become symptomatic, typically in 1 or 2 days, because this is the usual period that fluid accumulates (unpublished observation).

Outpatient management with vaginal paracentesis at early stages of OHSS, with simultaneous presence of ascites has been proposed (61), and has recently been shown to be cost effective (66). Multiple culdocenteses (and IV albumin) were used alternatively to hospitalization to manage patients who met criteria for moderate to severe OHSS (61), with reaccumulation of fluid. The average fluid removed was 1910±59 mL, with an average 3.4 outpatient treatments. In aggressively treating OHSS with paracentesis before the development of symptoms including weight gain, hemoconcentration, electrolyte imbalance, or renal abnormality, only 9.4% of patients ultimately required hospitalization (61) for repetitive culdocenteses.

Anticoagulation is an important tenet of management because of the increased risk of thrombosis in OHSS patients. OHSS patients are considered to be at great risk for thromboembolic disease (36); therefore they should be treated prophylactically (35). Unfortunately, evidence-based protocols have not been established for dosage, when to initiate treatment, or for the duration of preventative anticoagulation. As many patients may be pregnant, warfarin is avoided. Low molecular weight heparin (LMWH) has been favored over unfractionated heparin because of ease of administration and lack of monitoring needed. One empiric-based strategy is to initiate prophylaxis with LMWH 40 mg twice a day at the time of paracentesis and have patients remain on this dose for 2 to 3 weeks after the last paracentesis. Additionally, all patients are encouraged to be mobile, but if this is not possible, sequential compressive devices or compressive stockings may be used in addition to anticoagulation with LMWH. A point to be reinforced is that sequential compressive devices or compressive stockings alone are not as likely to be effective, as many thromboses often occur in the upper extremities of OHSS patients (36).

Other elements of management include fluid and electrolyte management as needed. Patients should be frequently reassessed for improvement or deterioration by reviewing symptoms, exam, lab values, and ultrasound as needed. Serial IAP measurements may prove to be helpful in monitoring severe cases. Most cases should be able to be successfully managed on an outpatient basis, which has been found to be the most cost-effective approach (66), whereas patients who fail to tolerate oral fluids, are dehydrated or require supportive care, such as pain control, should be hospitalized.

An accurate classification of disease severity early in the OHSS presentation, combined with paracentesis when ascites is present on ultrasound, might minimize disease progression and complications of OHSS.

In conclusion, advanced stages of OHSS share a hemodynamic pathophysiology with abdominal compartment syndromes. In the 20 cases of OHSS where an IAP was documented, an elevated IAP was found to be present. Many pathophysiologic effects of an elevated IAP reported in the surgical literature strongly resemble those reported for OHSS patients. The important and integral role that increased abdominal pressure plays in OHSS should be considered in classification of disease severity and management of patients with OHSS. Current evidence supports early intervention to prevent progression of disease and severe complications. Studies are needed to investigate the correlation of IAP in OHSS patients with symptoms, severity, and outcome of OHSS.