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Ovarian hyperstimulation syndrome
Crit Care Clin 20 (2004) 679 – 695
Ovarian hyperstimulation syndrome Jaime F. Avecillas, MDa, Tommaso Falcone, MDb, Alejandro C. Arroliga, MDc,d,* a
Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA b Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA c Section of Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA d Fellowship Program, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication that is associated with modern techniques for in vitro fertilization (IVF). This entity increasingly is recognized because of the high number of women undergoing assisted reproductive techniques. The syndrome typically is associated with regimens of exogenous gonadotrophins but also can be seen, albeit rarely, during administration of clomiphene citrate for ovulation induction or spontaneously during pregnancy [1,2]. Extensive efforts have been made to understand the pathophysiology of OHSS and to improve the management of this entity. The severe and life threatening forms of OHSS are still challenging for critical care physicians. Patients with the severe or life-threatening forms of OHSS can be critically ill and require aggressive medical intervention. These patients are at risk for a variety of complications, which may lead to increased morbidity and mortality rates. This clinical situation is emotionally difficult because, a large number of these infertile patients are pregnant at the time of their acute illness. Intensivists should be familiar with the different clinical manifestations and potential complications of this entity. Critical care physicians should be able to recognize the patient population who are at risk for OHSS and should be aware of the current principles of management. This article focuses on a general * Corresponding author. Section of Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue (G-62), Cleveland, OH 44195. E-mail address: [email protected] (A.C. Arroliga). 0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2004.05.003
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approach to the evaluation and initial management of the severe and lifethreatening forms of OHSS in the intensive care unit (ICU). The pathogenesis, epidemiology, classification, clinical manifestations, and complications of OHSS are reviewed. The different therapeutic options also are discussed, and a stepwise approach for the management of these patients is provided. The authors’ recommendations are based on an extensive review of the medical literature and experience at their institution.
Pathogenesis IVF techniques include the use of gonadotropin-releasing–hormone (GnRH) agonists or antagonists and gonadotrophin drugs to stimulate the ovaries and human chorionic gonadotrophin (hCG) to initiate ovulation and sometimes maintain the luteal phase. These changes allow an increase in the number of oocytes retrieved, embryos obtained, and pregnancy rates. Ovarian stimulation in these circumstances may result in an excessive ovarian response, which may lead to OHSS. This syndrome is associated with the presence of hCG through exogenous administration or the presence of pregnancy [3]. It consists of ovarian enlargement accompanied by overproduction of ovarian hormones and a host of other ovarian vasoactive substances (eg, cytokines, angiotensin, vascular endothelial growth factor), which alone or in concert may produce a state of increased capillary hyperpermeability [4]. The pathophysiology of the syndrome remains unknown. The clinical manifestations of OHSS are believed to be the result of increased capillary permeability, which in turn leads to a loss of protein-rich fluid from the intravascular compartment into the interstitial space resulting in ascites, hydrothorax, and anasarca [5,6]. OHSS produces a hyperdynamic circulatory dysfunction state, similar to that observed in other conditions associated with edema formation (eg, high-output heart failure, cirrhosis), that is characterized by arterial hypotension, increased cardiac output, reduced peripheral vascular resistance, and intense stimulation of the renin–angiotensin and sympathetic nervous systems and antidiuretic hormone [7]. Although the development of OHSS usually is associated with the use of IVF techniques, the spontaneous occurrence of this entity has been reported in rare instances during pregnancy, most often when there is a supraphysiologic production of chorionic gonadotropin (eg, multiple gestations, molar pregnancies) [8]. Familial cases of recurrent, spontaneous, pregnancy-associated OHSS have been described in the literature [2,9]. Mutations in the follicle-stimulating–hormone (FSH) receptor have been identified in these cases [2,9].
Epidemiology and risk factors The prevalence of moderate to severe OHSS ranges from 1% to 10% in major IVF programs [10]. Early reports on IVF found severe cases of this syndrome in
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Table 1 Risk factors associated with OHSS High risk
Low risk
Young (b35 years) PCOS-like Asthenic habitus High serum estradiol Multiple follicles Necklace sign Pregnancy hCG luteal supplementation GnRH-agonist protocol
Older (N36 years) Hypogonadotrophic Heavy build Low serum estradiol Few follicles Quiescent ovary Barren cycle Progesterone or no supplementation Clomiphene citrate and/or HMG protocol
Abbreviation: HMG, human menopausal gonadotropin. Data from Navot D. Severe ovarian hyperstimulation syndrome. In: Gardner DK, editor. Textbook of assisted reproductive techniques: laboratory and clinical perspectives. 1st editon. London: Martin Dunitz; 2001. p. 645–54.
approximately 2% of all IVF cycles [5]. There is variation in the reported incidence of OHSS between different studies. This discrepancy could be explained by the use of different OHSS classifications and IVF stimulation protocols in the populations studied. Increased awareness of the risk factors of OHSS has lead to a decrease in the incidence of the syndrome. Risk factors that are associated with the development of OHSS include (Table 1): 1. Age: Different studies have shown an association between younger age and the development of OHSS [11–14]. In a retrospective multicentric study, Delvigne et al [11] found that patients with OHSS were significantly younger than controls (age, 30.2 F 3.5 and 32.0 F 4.5 years, respectively). In a prospective cohort study involving 428 patients who underwent IVF, Enskog et al [13] found that all of the patients with OHSS were significantly younger than those without OHSS. Possible explanations are that the ovaries of younger women have a higher density of gonadotropin receptors, making them more responsive to gonadotropins, or that they have a larger number of follicles that are able to respond to gonadotropins [12]. 2. Body mass index (BMI): In a prospective study, Navot et al [14] found that patients with OHSS had a significantly lower mean weight than did a control population. Other studies have concluded that BMI or total body weight does not influence markedly the response to ovarian hyperstimulation in women with normal cycles [11,15]. There is still controversy about the inclusion of a low BMI in the list of variables influencing the incidence of OHSS. 3. Presence of polycystic ovary syndrome (PCOS): PCOS is a common endocrinopathy that is associated with a menstrual abnormality, such as oligoovulation and clinical or biochemical markers of increased androgens. This syndrome is associated with a variety of metabolic abnormalities, such as insulin resistance and lipid disorders [16]. It is believed to be a risk factor in
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patients with OHSS [12]. Among OHSS cases, Delvigne et al [11] found a higher frequency of parameters that normally are associated with PCOS (hyperandrogenism, anovulation, elevated ratio of luteinizing hormone to FSH). Other studies also have shown this association [17–19]. A higher incidence of OHSS has been observed in patients who have an ultrasonographic phenotype of PCOS [12]. This phenotype is characterized by the presence of 10 or more cysts, each measuring less than 10 mm in diameter, in a single plane (necklace sign). 4. Allergies: Patients with severe OHSS had an increased prevalence of atopy (56% versus 21%) in a prospective study by Enskog et al [13]. These investigators hypothesized that general immunologic mechanisms may have a role in the development of an inflammatory response in other non– allergy-induced situations and that differences in the immunologic sensitivity of patients may be a predictive sign of OHSS [13]. 5. Parameters that are specific to the IVF cycle: There is no difference in the occurrence of OHSS with the use of urinary-derived gonadotropins or recombinant FSH. A meta-analysis that compared the effectiveness of both modalities showed no difference in the incidence of OHSS [20]. The use of GnRH antagonists rather than GnRH agonists has been reported to be associated with a decreased incidence of OHSS [21]. Rapidly rising serum estradiol levels or an estradiol concentration above 2500 pg/mL are associated with increased risk for OHSS [22]. A large number of medium-sized follicles that are recruited during ovarian stimulation or a large number of oocytes (N14) that are obtained at oocyte retrieval are associated with an increased incidence of OHSS. As stated previously, hCG has a pivotal role in the development of OHSS. Pregnancy prolongs and increases the severity of disease. Preventive measures have been suggested when high-risk parameters are identified during a stimulation cycle. These measures include delaying the administration of hCG until an acceptable level of estradiol is obtained, use of progesterone instead of hCG in the luteal phase, and prophylactic use of intravenous 25% albumin (20–50 g) [22]. The administration of albumin might prevent one case of severe OHSS for every 18 at-risk cases that receive this treatment [22].
Classification In 1967, Rabau et al [23] classified OHSS into three clinical categories (mild, moderate, severe) and six grades, based on the severity of the symptoms, signs, and laboratory findings. These grades are defined as follows: Mild OHSS Grade 1: These patients have laboratory findings of hyperstimulation (urinary estrogen level, N150 mg/24 h; urinary pregnanediol level, N10 mg/24 h) but no palpable cysts or enlargement of ovaries.
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Grade 2: The laboratory findings of grade 1 are present, as is enlargement of ovaries with or without palpable cyst formation. (Currently, urinary steroids are no longer measured, mild OHSS is defined as enlarged ovaries, and the grades 1 and 2 are no longer used.) Moderate OHSS Grade 3: Grade 3 is defined as abdominal distention and nausea, in addition to laboratory findings of hyperstimulation and enlargement of ovaries with or without palpable cysts formation. Grade 4: These patients present with the criteria of grade 3 along with vomiting or diarrhea. Severe OHSS Grade 5: This condition involves the same symptoms as grade 4, plus large ovarian cysts, ascites, or hydrothorax. Grade 6: In addition to the symptoms of grade 5, grade 6 involves changes in blood viscosity. Additional features, which upgrade OHSS from moderate to severe, include: hepatic dysfunction, evidence of hemoconcentration (hematocrit, N45%), white blood cell count greater than 15,000 cells/mL, evidence of renal dysfunction (oliguria or a creatinine level of 1.0–1.5 mg/dL), and anasarca [4]. In 1992, Navot el al [24] proposed a new stage: critical or life-threatening OHSS. Criteria for this stage are variable enlarged ovary, adult respiratory distress syndrome (ARDS), tense ascites, hydrothorax, pericardial effusion, oliguria, creatinine level of at least 1.6 mg/dL, creatinine clearance less than 50 mL/min, severe hemoconcentration (hematocrit, N55%), profound leucocytosis (z25,000 cells/mL), and thromboembolic phenomena (Table 2) [24]. The types of OHSS that are clinically relevant are the moderate, severe, and life-threatening forms. Most
Table 2 Criteria that define the severe and life-threatening stages of OHSS Severe OHSS
Life-threatening OHSS
Variably enlarged ovary Massive ascites with or without hydrothorax Hematocrit N45% WBC count N15,000 Oliguria Creatinine level 1.0–1.5 mg/dL Creatinine clearance z50 mL/min Liver dysfunction Anasarca
Variably enlarged ovary Tense ascites with or without hydrothorax Hematocrit N55% WBC count N25,000 Oliguria Creatinine level z1.6 mg/dL Creatinine clearance b50 mL/min Renal failure Thromboembolic phenomena ARDS
Abbreviation: WBC, white blood cell. Data from Rabau E, David A, Serr DM, Mashiach S, Lunenfeld B. Human menopausal gonadotropins for an ovulation and sterility. Am J Obstet Gynecol 1967;98(1):92–8; and Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992;58(2):249–61.
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patients with OHSS that the authors see in the ICU present with the severe or lifethreatening form of this condition. OHSS also has been classified by the time of onset. Early-onset OHSS occurs 3 to 7 days after the administration of the ovulatory dose of hCG and is caused by excessive preovulatory ovarian response to stimulation [25]. Late-onset OHSS is believed to be caused by a pregnancy-related increase in hCG level, presents more than 1 week after this increase, is likely to be clinically severe, and only is related poorly to preovulatory events [25].
Clinical features The basic pathologic mechanism responsible for the clinical features of OHSS seems to be a fluid shift from the intravascular to extravascular space as a result of increased capillary permeability [26]. This massive accumulation of extravascular exudates can manifest clinically as ascites, pleural or pericardial effusions, electrolyte imbalances, oliguria, hemoconcentration, or hypovolemia with or without hypovolemic shock [3,7,27]. Symptoms usually begin with a sensation of bloating and abdominal discomfort and proceed to nausea, vomiting, and diarrhea. The onset of vomiting or diarrhea within 48 hours of hCG administration, shortness of breath, or reduced urine output indicating accumulation of ascites suggest potentially severe disease [3]. If patients present with acute abdominal pain, torsion of an adnexa should be considered. Physical examination of patients with OHSS may reveal weight gain, increased abdominal girth, oliguria or anuria, and signs of hypovolemia. The ovaries are enlarged greatly and are easily palpable in the abdomen [27]. In severe cases, respiratory compromise or multiorgan failure can be seen, as can the sequelae of thromboembolic events [28,29]. Laboratory data are characterized by electrolyte abnormalities, including hyperkalemia and dilutional hyponatremia [3,7,30]. This reduction in the serum sodium level is associated with low serum osmolality. Hemoconcentration (hematocrit, N45%) frequently is seen [7], and a hematocrit greater than 55% heralds a life-threatening situation. The white blood cell and platelet counts also are increased in OHSS, but the coagulation parameters are normal in most patients [7]. In severe and life-threatening OHSS, an elevated serum creatinine level can be seen; however, in most cases of OHSS, the creatinine levels are within normal limits [7,30]. Abnormalities of liver function tests are seen in approximately 30% of patients with severe OHSS [30] and are characterized by mild-to-moderate increases in transaminases, which are associated in some cases with increases in levels of g-glutamil transpeptidase or alkaline phosphatase [30]. Hypoalbuminemia commonly is seen [31]. Significantly lower levels of immunoglobulin, specifically IgG and IgA, have been detected in the plasma of patients with severe OHSS [31]. Serum IgG in patients with severe OHSS exudes into their peritoneal cavity, making them immunodeficient and at potential increased risk for infection [32,33]. Patients
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with OHSS have high plasma levels of endogenous vasoactives substances (renin activity, aldosterone, norepinephrine, antidiuretic hormone, atrial natriuretic peptide) [7,30]. Lower baseline levels of these vasoactive substances seem to correlate with an early response to treatment with albumin and diuretics [7]. At diagnosis, most patients have low urinary sodium excretion and urine volume [30]. Analysis of the ascitic fluid obtained from patients with OHSS reveals a high protein concentration, low leukocyte count, and relatively high number of red blood cells [30]. Respiratory distress in patients with OHSS most likely results from lung restriction caused by ascites, large cystic ovaries, or pleural or pericardial effusions [34]. Pulmonary manifestations of severe OHSS include acute hydrothorax [35,36], ARDS [28,37], pulmonary embolism [29], pulmonary edema [26], atelectasis [34], and intra-alveolar hemorrhage [26]. Pleural effusions develop in approximately 20% of patients with severe OHSS [34]. The pleural effusions are usually bilateral and associated with ascites [34,38] or other signs and symptoms of OHSS. Cases of unilateral hydrothorax as the only extraovarian manifestation of OHSS have been reported [35,36,39]. In patients with OHSS, the hydrothorax is usually right sided when unilateral [35,36,39]. Severe ascites may contribute to fluid accumulation in the chest because of ascitic abdominal fluid that traverses the diaphragm by way of the thoracic duct on the right side of the aortic hiatus [1]. A case of a compressive right pleural effusion producing shock caused by compression of the mediastinum has been reported in a patient with OHSS [40]. Sudden respiratory arrest caused by massive pulmonary edema, intra-alveolar hemorrhage, and pleural effusion without evidence of pulmonary thromboembolism on autopsy also has been reported in OHSS [26]. OHSS can be accompanied by thromboembolic disease [41,42]. The exact cause of OHSS-associated vascular thrombosis is not understood completely; however, the OHSS characteristics of high estrogen concentrations, hemoconcentration, and reduced circulating blood volume are believed to explain partly the occurrence of this phenomenon [42]. Immobility and decreased venous return because of enlarged ovaries also may have roles. Elevated levels of coagulation factors, fibrinolytic inhibitors, and platelets have been reported in conjunction with OHSS [41,43]. Stewart et al [42] examined a total of 54 cases of thromboembolic disease (associated with ovulation induction and assisted conception treatment) that were reported in the medical literature. Sixty-six percent of these thromboembolic events were associated with OHSS, and 84% were associated with pregnancy [42]. Although most thromboses were venous sites (75%), there were cases of spontaneous arterial thromboses [42]. Sixty percent of the venous thrombotic events were located in the upper limb and neck and head veins, whereas most of the arterial thromboses were intracerebral [42]. Other reported locations for arterial thrombotic events in patients with OHSS include femoropopliteal, carotid, subclavian, iliac, ulnar, and mesenteric arteries and the aorta [42,43]. Central retinal artery occlusion with irreversible visual impairment has been described [44]. In Stewart’s series [42], 29% of patients with OHSS and lower-extremity deep vein thrombosis developed pulmonary embo-
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lism; the frequency of pulmonary embolism was lower in patients with upperextremity deep vein thrombosis and those with arterial thrombosis (4% and 8%, respectively). Thromboembolic events in patients with OHSS can be seen in association with other hypercoagulable states (eg, antiphospholipid antibody syndrome, activated protein C resistance, antithrombin III deficiency, low protein S levels) [42,45]. Any hereditary factor should be excluded that could make thromboembolic events more likely to occur in patients selected for ovarian stimulation. Kodama et al [46] determined hemostastic markers in the serum of 23 patients with OHSS, including a patient with thromboembolism. This patient demonstrated marked leukocytosis and higher levels of activation in the blood markers related to the fibrinolytic system (a2-plasmin inhibitor, plasmin-a2–antiplasmin complexes, d-dimers) before the onset of the episode. These laboratory abnormalities may be the sign of imminent thromboembolism in patients with OHSS. Another complication seen in patients with OHSS is the presence of infections, which in severe cases can present as sepsis [29,33]. To define the incidence and causes of fever in severe and critical OHSS, Abramov et al [33] reviewed the medical records of 196 patients with severe OHSS and 13 patients
Fig. 1. A markedly enlarged ovary with multiple cystic formations in a patient with OHSS.
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Fig. 2. Ascites surrounding the uterus of a patient with OHSS.
with critical OHSS. The incidence of febrile morbidity was 82.3%, and 20.5% of these cases were attributed to urinary tract infection, 3.8% to pneumonia, 3.3% to upper respiratory tract infection, 2.0% to intravenous-line phlebitis, 1.0% to cellulites at an abdominal puncture site, 1.0% to postoperative wound infections, and 0.5% to a gluteal abscess at the site of progesterone injection [33]. Proteus mirabilis, Klepsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Morganella morganii, and Proteus vulgaris were the most common causatives organisms [33]. Hypoglobulinemia was recorded in most patients, whereas ascitic and pleural fluids that were aspirated from these patients contained high concentrations of globulin [33]. IgG and IgA levels increased as patients improved clinically [33]. Ultrasound examination of patients with OHSS discloses enlarged ovaries with numerous follicular cysts and ascites (Figs. 1 and 2). Abdominal CT can be used in patients with OHSS; the CT findings of OHSS are also multiple variablesized cystic enlargements in the ovaries and associated ascites [47].
Management There is no specific treatment for OHSS, and therapy is mainly supportive until the condition resolves. The syndrome is self-limiting, and resolution parallels the decline in serum hCG levels (about 7 days in nonpregnant patients
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and 10–20 days in pregnant patients) [3]. Most patients have been diagnosed with OHSS by the time they arrive to the ICU and already have received outpatient management. Outpatient management of this condition includes daily monitoring of weight and urine output; avoidance of strenuous physical activity and sexual intercourse; oral fluid intake with more than 1 L of electrolyte-supplemented drinks (sports drinks); and serial follow-up of hematocrit concentration, electrolytes, and creatinine. Although the moderate form of OHSS usually subsides spontaneously with bed rest for 2 to 3 weeks, patients in this category may progress rapidly to the severe form, especially if conception occurs [27]. Close observation is warranted, and conception has to be confirmed by serial estimation of b-hCG levels in blood as soon as possible. In patients with moderate or severe OHSS, the pelvic examination must be avoided to decrease the likelihood of ovarian cyst rupture that may result in intraperitoneal hemorrhage [6,27]. The assessment of hemodynamic and respiratory status is the first step in the initial management of patients with severe or life-threatening OHSS. A full physical examination must be performed, with careful examination of all four extremities and the head and neck to look for deep vein thrombosis. An intravenous access needs to be established promptly. These patients need placement of two large-bore peripheral intravenous catheters or a central venous catheter. If the use of a central venous catheter is required, the authors prefer to use subclavian venous catheterization, because it carries the lowest risk for catheterrelated thrombosis [48,49]. One of the main advantages of placing a central venous catheter is that it allows measurement of the central venous pressure, which is helpful in fluid management. An indwelling urinary bladder catheter should be introduced for close monitoring of the urine output. Because the presence of an indwelling urinary bladder catheter is a modifiable risk factor for the development of infections, clinicians must evaluate the need for continued catheterization in the ICU on a daily basis. All patients with severe or life-threatening OHSS must have daily blood tests to measure white blood cell count, hemoglobin concentration, hematocrit, and levels of serum electrolytes, and liver enzymes. The creatinine clearance must be calculated on a daily basis. Prothrombin time and partial thromboplastin time are useless in predicting thrombotic events [1]. An abdominal ultrasound is required to measure the ovaries and to determine the presence of ascites. Because the use of CT may imply transportation of critically ill patients to a CT scanner (placing them at additional risks), the authors rarely use this diagnostic tool in these patients. If patients are short of breath, a chest radiograph, oxygen saturation by pulse oximetry, and blood gases must be obtained. A ventilationperfusion lung scan is required to rule out pulmonary embolism if the chest radiograph does not reveal the presence of pleural effusions or pulmonary infiltrates. If the respiratory status worsens or respiratory failure develops, endotracheal intubation with mechanical ventilation may be necessary. It is important to be aware of the possibility of pregnancy in patients with OHSS if a chest radiograph or CT is contemplated. When a pericardial effusion is suspected, an echocardiogram should be obtained.
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Medical treatment of severe OHSS should be directed to maintain circulatory function and to mobilize the intra-abdominal fluid by creating a net negative balance of sodium and water [7]. Initially, the goal is to replace fluids in the vascular compartment sufficient to counter hemoconcentration and allow sufficient urine production. Normal saline with or without glucose is the crystalloid of choice, and potassium-containing fluids should be avoided, because patients with OHSS could develop hyperkalemia. In more severe cases with significant hypovolemia, hemoconcentration (hematocrit, N45%), hypoalbuminemia (serum albumin level, b3.0 g/dL), or severe ascites, albumin can be given as a plasma expander [3]. Serial hematocrits are obtained to ensure that the hemoconcentration is reversed. Once the hematocrit is brought within 36% to 38%, furosemide may be given to assess renal response [1]. Premature or overzealous use of diuretics may aggravate hypovolemia and hemoconcentration, increasing the risk for thromboembolism [22]. In addition to albumin, other intravascular volume expanders, such as dextran [37] and fresh frozen plasma [50], have been used in patients with severe OHSS. Fresh frozen plasma does not offer any advantage over albumin, and the use of dextran in patients with OHSS has been associated with the development of ARDS [37]. Patients with severe OHSS who do not have hemodynamic or respiratory compromise can be treated safely with a conservative approach. In a prospective longitudinal study involving 25 women with ascites caused by severe OHSS, Balasch et al [7] assessed the value of a conservative medical therapeutic approach (bed rest, low-sodium diet, plasma-volume expansion with albumin, diuretics) in the management of this syndrome. After 2 days of therapy, there was marked improvement in clinical symptoms, standard laboratory parameters, diuresis, and urinary sodium excretion in all patients [7]. The length of treatment with albumin plus furosemide ranged between 2 and 6 days (average, 3.3 days), and it correlated directly with the severity of the syndrome [7]. Conservative observation is the usual treatment of hydrothorax in OHSS [35]. If there is progression of respiratory symptoms, thoracentesis should be performed. If ARDS develops and mechanical ventilation is required, lungprotective strategies must be used. In these patients, the use of lower tidal volumes (6 mL/kg of predicted body weight) and a plateau pressure of less than or equal to 30 cm of water may decrease the mortality rate and increase the number of days without ventilator use [51]. Because patients with OHSS are at increased risk for infections [33], a careful investigation for possible infectious causes of ARDS must be performed. Fluid management could be problematic in patients with OHSS and ARDS. A reasonable approach is maintenance of the intravascular volume at the lowest level that is consistent with adequate systemic perfusion, as assessed by metabolic acid–base balance and renal function [52]. Data about the use of glucocorticoids in ARDS are inconclusive [52]; however, prompt regression of ARDS after steroid pulse treatment (initiated on days 6 and 7 of the clinical course) has been reported in life-threatening OHSS [28]. In severe cases of OHSS, administration of prophylactic anticoagulation should be part of routine care [1,3]. If a thrombotic or thromboembolic event is suspected,
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therapeutic anticoagulation must be initiated. The use of prophylactic full anticoagulation therapy in patients with OHSS who also have a second hypercoagulable or thrombogenic state may be considered. The indications for paracentesis in patients with OHSS include the need for symptomatic relief, a tense ascites, oliguria, increasing creatinine or decreasing creatinine clearance, and hemoconcentration that is unresponsive to medical therapy [6,32]. In this situation, ultrasound-guided paracentesis (transabdominal or transvaginal) may produce a dramatic improvement in renal function [6]. It is believed that the decrease in intra-abdominal pressure postparacentesis leads to an increase in renal vein blood flow, venous return, and cardiac output. The transvaginal ultrasonographic approach affords a more thorough fluid evacuation, because ascitic fluid accumulates dependently in the posterior uterine cul-de-sac and allows needle access into a fluid pocket that is not likely to be obstructed by bowel [1]. The markedly increased size of the ovaries in these patients makes paracentesis difficult to perform. The use of ultrasound guidance during abdominal paracentesis to avoid ovarian puncture may be indicated. When paracentesis is not required, the ascites resolve after a negative sodium balance is achieved with sodium restriction alone or in combination with diuretics [30]. In cases of severe ascites associated with OHSS, treatment may require drainage of fluid twice to three times weekly. A prospective trial involving 26 patients with severe OHSS showed that the percutaneous placement of a pigtail catheter is a safe and effective treatment modality for severe OHSS [53]. This treatment may represent an attractive alternative to multiple paracentesis for the management of ascites in these patients. The use of continuous autotransfusion system of ascites (CATSA) might be effective in controlling the ascites and improving hypoimmunoglobulinemia by the use of the peritoneo-venous shunt [32]. Takamizawa et al [32] studied 10 patients with severe OHSS who were treated with CATSA. Before the treatments, serum IgG concentrations in patients with severe OHSS were significantly lower than those in controls (15 infertile women who did not develop OHSS after the same superovulation protocol) [32]. After CATSA treatment, the concentration of IgG increased in the sera, whereas it decreased in the peritoneal fluid [32]. Because the administration of exogenous immunoglobulins may decrease the rate of bacterial infections in other protein-loss entities (eg, nephrotic syndrome) [54], the same therapeutic intervention may be beneficial in patients with severe and critical OHSS. Further studies are necessary to validate this therapeutic intervention. A low threshold to start empiric antibiotic therapy is suggested when the possibility of an infectious process is considered in patients who are critically ill and hemodynamically unstable. The authors, however, try to alter the antibiotic regimen as soon as bacteriologic data are available. Empiric therapy must be guided by information about the patient’s indigenous flora, severity of disease, risks factors for infection, and patterns of antibiotic resistance in the ICU. Empiric antibiotic therapy should be directed at the most likely pathogens involved in this type of infections, which are P mirabilis, K pneumoniae, P aeruginosa, E coli, and P vulgaris [33]. Because Abramov et al [33] was not able to find an infectious
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cause in 50% of patients with OHSS who presented with fever, other causes of febrile morbidity, which may be related to the syndrome itself, must be considered in these patients. To decrease the risk for infections in patients with OHSS, invasive interventions (eg, abdominal paracentesis, thoracentesis, laparoscopy, laparotomy) should be performed only when strictly necessary. Reports have shown that the therapeutic administration of low-dose dopamine is safe and effective in managing patients with severe OHSS [55]. The rationale for this therapeutic approach is to increase renal blood flow and glomerular filtration; however, continuous intravenous infusion of low-dose dopamine did not confer clinically significant protection for renal dysfunction in a multicenter, placebo-controlled trial of 328 critically ill patients with clinical evidence of early renal dysfunction [56]. In the authors’ practice, the use of low-dose dopamine is not favored in critically ill patients. Nonsteroidal anti-inflammatory drugs (specifically indomethacin), antihistaminics, and angiotensin-converting–enzyme (ACE) inhibitors have been mentioned in the medical literature as potential alternative therapeutic regimens for OHSS; however, most of the information regarding these drugs comes from animal studies or small, uncontrolled studies. An animal study by Pride et al [57] suggested that prostaglandins might have a role in the development of OHSS. Another animal study by the same authors showed that indomethacin is not effective in suppressing the ovarian enlargement and ascites formation in OHSS [58]. A retrospective study involving 33 patients with OHSS revealed no differences in symptoms, signs, or time spent in the hospital between indomethacin users and nonusers [50]. One theory about the pathogenesis of the OHSS is that this syndrome is mediated by the release of histamine or histaminelike substances from the ovary [59]. The presence of allergies has been recognized as a possible risk factor for the development of OHSS [13]. In animal studies, antihistaminics prevented the occurrence of OHSS and caused a more rapid reduction in size of the hyperstimulated ovary compared with controls [59–61]. Prospective, randomized trials are needed to determine the real value of antihistaminics in the treatment of OHSS. Angiotensin II has been considered one of the probable pathogenic factors for OHSS, and the possibility of using ACE inhibitors as a therapeutic agent for OHSS has been raised. These drugs are teratogenic, however, and contraindicated in pregnancy [4]. Surgical intervention may be necessary in the presence of adnexal torsion, ovarian cyst rupture, or ovarian cyst hemorrhage. A decreasing hematocrit in this context may be a sign of hemorrhage rather than resolving hemoconcentration. Adnexal torsion is a rare but recognized complication that can occur in pregnant patients with OHSS and present as acute lower abdominal pain with the presence of an abdominal tender mass [62]. Laparoscopic unwinding of the affected ovary is a simple and effective technique that can be used in this situation [62]. Early diagnosis and prompt surgical intervention are necessary for a successful outcome [62]. Late diagnosis often results in a devitalized ovary that is beyond salvage, requiring laparotomy. In rare circumstances in which the syndrome increases in severity despite all interventions, termination of the pregnancy should
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be considered to decrease hCG levels. Medical termination can be accomplished with the use of mifepristone.
Summary Treatment of severe and life-threatening OHSS remains controversial, mainly because the cause of this syndrome is unknown. The authors think that there is enough available data in the medical literature to support the use of aggressive intravenous hydration, intravascular expanders, and prophylactic anticoagulation. They also support the use of ultrasound-guided paracentesis and empiric antibiotic therapy when appropriate. Awareness of the potential complications of OHSS allows critical care physicians to provide an optimal therapy to patients with this syndrome. Knowledge of the risk factors that predispose women to the development of OHSS is important to make an early diagnosis, which allows intensivists to provide aggressive medical intervention in a timely fashion.
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[54] Ogi M, Yokoyama H, Tomosugi N, Hisada Y, Ohta S, Takaeda M, et al. Risk factors for infection and immunoglobulin replacement therapy in adult nephrotic syndrome. Am J Kidney Dis 1994;24(3):427 – 36. [55] Ferraretti AP, Gianaroli L, Diotallevi L, Festi C, Trounson A. Dopamine treatment for severe ovarian hyperstimulation syndrome. Hum Reprod 1992;7(2):180 – 3. [56] Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Lancet 2000;356:2139 – 43. [57] Pride SM, Yuen BH, Moon YS. Clinical, endocrinologic, and intraovarian prostaglandin F responses to H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model. Am J Obstet Gynecol 1984;148:670 – 4. [58] Pride SM, Yuen BH, Moon YS, Leung PC. Relationship of gonadotropin-releasing hormone, danazol, and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome in the rabbit. Am J Obstet Gynecol 1986;154(5):1155 – 60. [59] Gergely RZ, Paldi E, Erlik Y, Makler A. Treatment of ovarian hyperstimulation syndrome by antihistamine. Obstet Gynecol 1976;47(1):83 – 5. [60] Knox GE, Dowd AJ, Spiesel SA, Hong R. Antihistamine blockade of the ovarian hyperstimulation syndrome: II. possible role of antigen-antibody complexes in the pathogenesis of the syndrome. Fertil Steril 1975;26(5):418 – 21. [61] Knox GE. Antihistamine blockade of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1974;118(7):992–4. [62] Chew S, Ng SC. Laparoscopic treatment of a twisted hyperstimulated ovary after IVF. Singapore Med J 2001;42(5):228 – 9.
Ovarian hyperstimulation syndrome Jaime F. Avecillas, MDa, Tommaso Falcone, MDb, Alejandro C. Arroliga, MDc,d,* a
Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA b Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA c Section of Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA d Fellowship Program, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication that is associated with modern techniques for in vitro fertilization (IVF). This entity increasingly is recognized because of the high number of women undergoing assisted reproductive techniques. The syndrome typically is associated with regimens of exogenous gonadotrophins but also can be seen, albeit rarely, during administration of clomiphene citrate for ovulation induction or spontaneously during pregnancy [1,2]. Extensive efforts have been made to understand the pathophysiology of OHSS and to improve the management of this entity. The severe and life threatening forms of OHSS are still challenging for critical care physicians. Patients with the severe or life-threatening forms of OHSS can be critically ill and require aggressive medical intervention. These patients are at risk for a variety of complications, which may lead to increased morbidity and mortality rates. This clinical situation is emotionally difficult because, a large number of these infertile patients are pregnant at the time of their acute illness. Intensivists should be familiar with the different clinical manifestations and potential complications of this entity. Critical care physicians should be able to recognize the patient population who are at risk for OHSS and should be aware of the current principles of management. This article focuses on a general * Corresponding author. Section of Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue (G-62), Cleveland, OH 44195. E-mail address: [email protected] (A.C. Arroliga). 0749-0704/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2004.05.003
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approach to the evaluation and initial management of the severe and lifethreatening forms of OHSS in the intensive care unit (ICU). The pathogenesis, epidemiology, classification, clinical manifestations, and complications of OHSS are reviewed. The different therapeutic options also are discussed, and a stepwise approach for the management of these patients is provided. The authors’ recommendations are based on an extensive review of the medical literature and experience at their institution.
Pathogenesis IVF techniques include the use of gonadotropin-releasing–hormone (GnRH) agonists or antagonists and gonadotrophin drugs to stimulate the ovaries and human chorionic gonadotrophin (hCG) to initiate ovulation and sometimes maintain the luteal phase. These changes allow an increase in the number of oocytes retrieved, embryos obtained, and pregnancy rates. Ovarian stimulation in these circumstances may result in an excessive ovarian response, which may lead to OHSS. This syndrome is associated with the presence of hCG through exogenous administration or the presence of pregnancy [3]. It consists of ovarian enlargement accompanied by overproduction of ovarian hormones and a host of other ovarian vasoactive substances (eg, cytokines, angiotensin, vascular endothelial growth factor), which alone or in concert may produce a state of increased capillary hyperpermeability [4]. The pathophysiology of the syndrome remains unknown. The clinical manifestations of OHSS are believed to be the result of increased capillary permeability, which in turn leads to a loss of protein-rich fluid from the intravascular compartment into the interstitial space resulting in ascites, hydrothorax, and anasarca [5,6]. OHSS produces a hyperdynamic circulatory dysfunction state, similar to that observed in other conditions associated with edema formation (eg, high-output heart failure, cirrhosis), that is characterized by arterial hypotension, increased cardiac output, reduced peripheral vascular resistance, and intense stimulation of the renin–angiotensin and sympathetic nervous systems and antidiuretic hormone [7]. Although the development of OHSS usually is associated with the use of IVF techniques, the spontaneous occurrence of this entity has been reported in rare instances during pregnancy, most often when there is a supraphysiologic production of chorionic gonadotropin (eg, multiple gestations, molar pregnancies) [8]. Familial cases of recurrent, spontaneous, pregnancy-associated OHSS have been described in the literature [2,9]. Mutations in the follicle-stimulating–hormone (FSH) receptor have been identified in these cases [2,9].
Epidemiology and risk factors The prevalence of moderate to severe OHSS ranges from 1% to 10% in major IVF programs [10]. Early reports on IVF found severe cases of this syndrome in
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Table 1 Risk factors associated with OHSS High risk
Low risk
Young (b35 years) PCOS-like Asthenic habitus High serum estradiol Multiple follicles Necklace sign Pregnancy hCG luteal supplementation GnRH-agonist protocol
Older (N36 years) Hypogonadotrophic Heavy build Low serum estradiol Few follicles Quiescent ovary Barren cycle Progesterone or no supplementation Clomiphene citrate and/or HMG protocol
Abbreviation: HMG, human menopausal gonadotropin. Data from Navot D. Severe ovarian hyperstimulation syndrome. In: Gardner DK, editor. Textbook of assisted reproductive techniques: laboratory and clinical perspectives. 1st editon. London: Martin Dunitz; 2001. p. 645–54.
approximately 2% of all IVF cycles [5]. There is variation in the reported incidence of OHSS between different studies. This discrepancy could be explained by the use of different OHSS classifications and IVF stimulation protocols in the populations studied. Increased awareness of the risk factors of OHSS has lead to a decrease in the incidence of the syndrome. Risk factors that are associated with the development of OHSS include (Table 1): 1. Age: Different studies have shown an association between younger age and the development of OHSS [11–14]. In a retrospective multicentric study, Delvigne et al [11] found that patients with OHSS were significantly younger than controls (age, 30.2 F 3.5 and 32.0 F 4.5 years, respectively). In a prospective cohort study involving 428 patients who underwent IVF, Enskog et al [13] found that all of the patients with OHSS were significantly younger than those without OHSS. Possible explanations are that the ovaries of younger women have a higher density of gonadotropin receptors, making them more responsive to gonadotropins, or that they have a larger number of follicles that are able to respond to gonadotropins [12]. 2. Body mass index (BMI): In a prospective study, Navot et al [14] found that patients with OHSS had a significantly lower mean weight than did a control population. Other studies have concluded that BMI or total body weight does not influence markedly the response to ovarian hyperstimulation in women with normal cycles [11,15]. There is still controversy about the inclusion of a low BMI in the list of variables influencing the incidence of OHSS. 3. Presence of polycystic ovary syndrome (PCOS): PCOS is a common endocrinopathy that is associated with a menstrual abnormality, such as oligoovulation and clinical or biochemical markers of increased androgens. This syndrome is associated with a variety of metabolic abnormalities, such as insulin resistance and lipid disorders [16]. It is believed to be a risk factor in
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patients with OHSS [12]. Among OHSS cases, Delvigne et al [11] found a higher frequency of parameters that normally are associated with PCOS (hyperandrogenism, anovulation, elevated ratio of luteinizing hormone to FSH). Other studies also have shown this association [17–19]. A higher incidence of OHSS has been observed in patients who have an ultrasonographic phenotype of PCOS [12]. This phenotype is characterized by the presence of 10 or more cysts, each measuring less than 10 mm in diameter, in a single plane (necklace sign). 4. Allergies: Patients with severe OHSS had an increased prevalence of atopy (56% versus 21%) in a prospective study by Enskog et al [13]. These investigators hypothesized that general immunologic mechanisms may have a role in the development of an inflammatory response in other non– allergy-induced situations and that differences in the immunologic sensitivity of patients may be a predictive sign of OHSS [13]. 5. Parameters that are specific to the IVF cycle: There is no difference in the occurrence of OHSS with the use of urinary-derived gonadotropins or recombinant FSH. A meta-analysis that compared the effectiveness of both modalities showed no difference in the incidence of OHSS [20]. The use of GnRH antagonists rather than GnRH agonists has been reported to be associated with a decreased incidence of OHSS [21]. Rapidly rising serum estradiol levels or an estradiol concentration above 2500 pg/mL are associated with increased risk for OHSS [22]. A large number of medium-sized follicles that are recruited during ovarian stimulation or a large number of oocytes (N14) that are obtained at oocyte retrieval are associated with an increased incidence of OHSS. As stated previously, hCG has a pivotal role in the development of OHSS. Pregnancy prolongs and increases the severity of disease. Preventive measures have been suggested when high-risk parameters are identified during a stimulation cycle. These measures include delaying the administration of hCG until an acceptable level of estradiol is obtained, use of progesterone instead of hCG in the luteal phase, and prophylactic use of intravenous 25% albumin (20–50 g) [22]. The administration of albumin might prevent one case of severe OHSS for every 18 at-risk cases that receive this treatment [22].
Classification In 1967, Rabau et al [23] classified OHSS into three clinical categories (mild, moderate, severe) and six grades, based on the severity of the symptoms, signs, and laboratory findings. These grades are defined as follows: Mild OHSS Grade 1: These patients have laboratory findings of hyperstimulation (urinary estrogen level, N150 mg/24 h; urinary pregnanediol level, N10 mg/24 h) but no palpable cysts or enlargement of ovaries.
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Grade 2: The laboratory findings of grade 1 are present, as is enlargement of ovaries with or without palpable cyst formation. (Currently, urinary steroids are no longer measured, mild OHSS is defined as enlarged ovaries, and the grades 1 and 2 are no longer used.) Moderate OHSS Grade 3: Grade 3 is defined as abdominal distention and nausea, in addition to laboratory findings of hyperstimulation and enlargement of ovaries with or without palpable cysts formation. Grade 4: These patients present with the criteria of grade 3 along with vomiting or diarrhea. Severe OHSS Grade 5: This condition involves the same symptoms as grade 4, plus large ovarian cysts, ascites, or hydrothorax. Grade 6: In addition to the symptoms of grade 5, grade 6 involves changes in blood viscosity. Additional features, which upgrade OHSS from moderate to severe, include: hepatic dysfunction, evidence of hemoconcentration (hematocrit, N45%), white blood cell count greater than 15,000 cells/mL, evidence of renal dysfunction (oliguria or a creatinine level of 1.0–1.5 mg/dL), and anasarca [4]. In 1992, Navot el al [24] proposed a new stage: critical or life-threatening OHSS. Criteria for this stage are variable enlarged ovary, adult respiratory distress syndrome (ARDS), tense ascites, hydrothorax, pericardial effusion, oliguria, creatinine level of at least 1.6 mg/dL, creatinine clearance less than 50 mL/min, severe hemoconcentration (hematocrit, N55%), profound leucocytosis (z25,000 cells/mL), and thromboembolic phenomena (Table 2) [24]. The types of OHSS that are clinically relevant are the moderate, severe, and life-threatening forms. Most
Table 2 Criteria that define the severe and life-threatening stages of OHSS Severe OHSS
Life-threatening OHSS
Variably enlarged ovary Massive ascites with or without hydrothorax Hematocrit N45% WBC count N15,000 Oliguria Creatinine level 1.0–1.5 mg/dL Creatinine clearance z50 mL/min Liver dysfunction Anasarca
Variably enlarged ovary Tense ascites with or without hydrothorax Hematocrit N55% WBC count N25,000 Oliguria Creatinine level z1.6 mg/dL Creatinine clearance b50 mL/min Renal failure Thromboembolic phenomena ARDS
Abbreviation: WBC, white blood cell. Data from Rabau E, David A, Serr DM, Mashiach S, Lunenfeld B. Human menopausal gonadotropins for an ovulation and sterility. Am J Obstet Gynecol 1967;98(1):92–8; and Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992;58(2):249–61.
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patients with OHSS that the authors see in the ICU present with the severe or lifethreatening form of this condition. OHSS also has been classified by the time of onset. Early-onset OHSS occurs 3 to 7 days after the administration of the ovulatory dose of hCG and is caused by excessive preovulatory ovarian response to stimulation [25]. Late-onset OHSS is believed to be caused by a pregnancy-related increase in hCG level, presents more than 1 week after this increase, is likely to be clinically severe, and only is related poorly to preovulatory events [25].
Clinical features The basic pathologic mechanism responsible for the clinical features of OHSS seems to be a fluid shift from the intravascular to extravascular space as a result of increased capillary permeability [26]. This massive accumulation of extravascular exudates can manifest clinically as ascites, pleural or pericardial effusions, electrolyte imbalances, oliguria, hemoconcentration, or hypovolemia with or without hypovolemic shock [3,7,27]. Symptoms usually begin with a sensation of bloating and abdominal discomfort and proceed to nausea, vomiting, and diarrhea. The onset of vomiting or diarrhea within 48 hours of hCG administration, shortness of breath, or reduced urine output indicating accumulation of ascites suggest potentially severe disease [3]. If patients present with acute abdominal pain, torsion of an adnexa should be considered. Physical examination of patients with OHSS may reveal weight gain, increased abdominal girth, oliguria or anuria, and signs of hypovolemia. The ovaries are enlarged greatly and are easily palpable in the abdomen [27]. In severe cases, respiratory compromise or multiorgan failure can be seen, as can the sequelae of thromboembolic events [28,29]. Laboratory data are characterized by electrolyte abnormalities, including hyperkalemia and dilutional hyponatremia [3,7,30]. This reduction in the serum sodium level is associated with low serum osmolality. Hemoconcentration (hematocrit, N45%) frequently is seen [7], and a hematocrit greater than 55% heralds a life-threatening situation. The white blood cell and platelet counts also are increased in OHSS, but the coagulation parameters are normal in most patients [7]. In severe and life-threatening OHSS, an elevated serum creatinine level can be seen; however, in most cases of OHSS, the creatinine levels are within normal limits [7,30]. Abnormalities of liver function tests are seen in approximately 30% of patients with severe OHSS [30] and are characterized by mild-to-moderate increases in transaminases, which are associated in some cases with increases in levels of g-glutamil transpeptidase or alkaline phosphatase [30]. Hypoalbuminemia commonly is seen [31]. Significantly lower levels of immunoglobulin, specifically IgG and IgA, have been detected in the plasma of patients with severe OHSS [31]. Serum IgG in patients with severe OHSS exudes into their peritoneal cavity, making them immunodeficient and at potential increased risk for infection [32,33]. Patients
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with OHSS have high plasma levels of endogenous vasoactives substances (renin activity, aldosterone, norepinephrine, antidiuretic hormone, atrial natriuretic peptide) [7,30]. Lower baseline levels of these vasoactive substances seem to correlate with an early response to treatment with albumin and diuretics [7]. At diagnosis, most patients have low urinary sodium excretion and urine volume [30]. Analysis of the ascitic fluid obtained from patients with OHSS reveals a high protein concentration, low leukocyte count, and relatively high number of red blood cells [30]. Respiratory distress in patients with OHSS most likely results from lung restriction caused by ascites, large cystic ovaries, or pleural or pericardial effusions [34]. Pulmonary manifestations of severe OHSS include acute hydrothorax [35,36], ARDS [28,37], pulmonary embolism [29], pulmonary edema [26], atelectasis [34], and intra-alveolar hemorrhage [26]. Pleural effusions develop in approximately 20% of patients with severe OHSS [34]. The pleural effusions are usually bilateral and associated with ascites [34,38] or other signs and symptoms of OHSS. Cases of unilateral hydrothorax as the only extraovarian manifestation of OHSS have been reported [35,36,39]. In patients with OHSS, the hydrothorax is usually right sided when unilateral [35,36,39]. Severe ascites may contribute to fluid accumulation in the chest because of ascitic abdominal fluid that traverses the diaphragm by way of the thoracic duct on the right side of the aortic hiatus [1]. A case of a compressive right pleural effusion producing shock caused by compression of the mediastinum has been reported in a patient with OHSS [40]. Sudden respiratory arrest caused by massive pulmonary edema, intra-alveolar hemorrhage, and pleural effusion without evidence of pulmonary thromboembolism on autopsy also has been reported in OHSS [26]. OHSS can be accompanied by thromboembolic disease [41,42]. The exact cause of OHSS-associated vascular thrombosis is not understood completely; however, the OHSS characteristics of high estrogen concentrations, hemoconcentration, and reduced circulating blood volume are believed to explain partly the occurrence of this phenomenon [42]. Immobility and decreased venous return because of enlarged ovaries also may have roles. Elevated levels of coagulation factors, fibrinolytic inhibitors, and platelets have been reported in conjunction with OHSS [41,43]. Stewart et al [42] examined a total of 54 cases of thromboembolic disease (associated with ovulation induction and assisted conception treatment) that were reported in the medical literature. Sixty-six percent of these thromboembolic events were associated with OHSS, and 84% were associated with pregnancy [42]. Although most thromboses were venous sites (75%), there were cases of spontaneous arterial thromboses [42]. Sixty percent of the venous thrombotic events were located in the upper limb and neck and head veins, whereas most of the arterial thromboses were intracerebral [42]. Other reported locations for arterial thrombotic events in patients with OHSS include femoropopliteal, carotid, subclavian, iliac, ulnar, and mesenteric arteries and the aorta [42,43]. Central retinal artery occlusion with irreversible visual impairment has been described [44]. In Stewart’s series [42], 29% of patients with OHSS and lower-extremity deep vein thrombosis developed pulmonary embo-
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lism; the frequency of pulmonary embolism was lower in patients with upperextremity deep vein thrombosis and those with arterial thrombosis (4% and 8%, respectively). Thromboembolic events in patients with OHSS can be seen in association with other hypercoagulable states (eg, antiphospholipid antibody syndrome, activated protein C resistance, antithrombin III deficiency, low protein S levels) [42,45]. Any hereditary factor should be excluded that could make thromboembolic events more likely to occur in patients selected for ovarian stimulation. Kodama et al [46] determined hemostastic markers in the serum of 23 patients with OHSS, including a patient with thromboembolism. This patient demonstrated marked leukocytosis and higher levels of activation in the blood markers related to the fibrinolytic system (a2-plasmin inhibitor, plasmin-a2–antiplasmin complexes, d-dimers) before the onset of the episode. These laboratory abnormalities may be the sign of imminent thromboembolism in patients with OHSS. Another complication seen in patients with OHSS is the presence of infections, which in severe cases can present as sepsis [29,33]. To define the incidence and causes of fever in severe and critical OHSS, Abramov et al [33] reviewed the medical records of 196 patients with severe OHSS and 13 patients
Fig. 1. A markedly enlarged ovary with multiple cystic formations in a patient with OHSS.
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Fig. 2. Ascites surrounding the uterus of a patient with OHSS.
with critical OHSS. The incidence of febrile morbidity was 82.3%, and 20.5% of these cases were attributed to urinary tract infection, 3.8% to pneumonia, 3.3% to upper respiratory tract infection, 2.0% to intravenous-line phlebitis, 1.0% to cellulites at an abdominal puncture site, 1.0% to postoperative wound infections, and 0.5% to a gluteal abscess at the site of progesterone injection [33]. Proteus mirabilis, Klepsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Morganella morganii, and Proteus vulgaris were the most common causatives organisms [33]. Hypoglobulinemia was recorded in most patients, whereas ascitic and pleural fluids that were aspirated from these patients contained high concentrations of globulin [33]. IgG and IgA levels increased as patients improved clinically [33]. Ultrasound examination of patients with OHSS discloses enlarged ovaries with numerous follicular cysts and ascites (Figs. 1 and 2). Abdominal CT can be used in patients with OHSS; the CT findings of OHSS are also multiple variablesized cystic enlargements in the ovaries and associated ascites [47].
Management There is no specific treatment for OHSS, and therapy is mainly supportive until the condition resolves. The syndrome is self-limiting, and resolution parallels the decline in serum hCG levels (about 7 days in nonpregnant patients
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and 10–20 days in pregnant patients) [3]. Most patients have been diagnosed with OHSS by the time they arrive to the ICU and already have received outpatient management. Outpatient management of this condition includes daily monitoring of weight and urine output; avoidance of strenuous physical activity and sexual intercourse; oral fluid intake with more than 1 L of electrolyte-supplemented drinks (sports drinks); and serial follow-up of hematocrit concentration, electrolytes, and creatinine. Although the moderate form of OHSS usually subsides spontaneously with bed rest for 2 to 3 weeks, patients in this category may progress rapidly to the severe form, especially if conception occurs [27]. Close observation is warranted, and conception has to be confirmed by serial estimation of b-hCG levels in blood as soon as possible. In patients with moderate or severe OHSS, the pelvic examination must be avoided to decrease the likelihood of ovarian cyst rupture that may result in intraperitoneal hemorrhage [6,27]. The assessment of hemodynamic and respiratory status is the first step in the initial management of patients with severe or life-threatening OHSS. A full physical examination must be performed, with careful examination of all four extremities and the head and neck to look for deep vein thrombosis. An intravenous access needs to be established promptly. These patients need placement of two large-bore peripheral intravenous catheters or a central venous catheter. If the use of a central venous catheter is required, the authors prefer to use subclavian venous catheterization, because it carries the lowest risk for catheterrelated thrombosis [48,49]. One of the main advantages of placing a central venous catheter is that it allows measurement of the central venous pressure, which is helpful in fluid management. An indwelling urinary bladder catheter should be introduced for close monitoring of the urine output. Because the presence of an indwelling urinary bladder catheter is a modifiable risk factor for the development of infections, clinicians must evaluate the need for continued catheterization in the ICU on a daily basis. All patients with severe or life-threatening OHSS must have daily blood tests to measure white blood cell count, hemoglobin concentration, hematocrit, and levels of serum electrolytes, and liver enzymes. The creatinine clearance must be calculated on a daily basis. Prothrombin time and partial thromboplastin time are useless in predicting thrombotic events [1]. An abdominal ultrasound is required to measure the ovaries and to determine the presence of ascites. Because the use of CT may imply transportation of critically ill patients to a CT scanner (placing them at additional risks), the authors rarely use this diagnostic tool in these patients. If patients are short of breath, a chest radiograph, oxygen saturation by pulse oximetry, and blood gases must be obtained. A ventilationperfusion lung scan is required to rule out pulmonary embolism if the chest radiograph does not reveal the presence of pleural effusions or pulmonary infiltrates. If the respiratory status worsens or respiratory failure develops, endotracheal intubation with mechanical ventilation may be necessary. It is important to be aware of the possibility of pregnancy in patients with OHSS if a chest radiograph or CT is contemplated. When a pericardial effusion is suspected, an echocardiogram should be obtained.
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Medical treatment of severe OHSS should be directed to maintain circulatory function and to mobilize the intra-abdominal fluid by creating a net negative balance of sodium and water [7]. Initially, the goal is to replace fluids in the vascular compartment sufficient to counter hemoconcentration and allow sufficient urine production. Normal saline with or without glucose is the crystalloid of choice, and potassium-containing fluids should be avoided, because patients with OHSS could develop hyperkalemia. In more severe cases with significant hypovolemia, hemoconcentration (hematocrit, N45%), hypoalbuminemia (serum albumin level, b3.0 g/dL), or severe ascites, albumin can be given as a plasma expander [3]. Serial hematocrits are obtained to ensure that the hemoconcentration is reversed. Once the hematocrit is brought within 36% to 38%, furosemide may be given to assess renal response [1]. Premature or overzealous use of diuretics may aggravate hypovolemia and hemoconcentration, increasing the risk for thromboembolism [22]. In addition to albumin, other intravascular volume expanders, such as dextran [37] and fresh frozen plasma [50], have been used in patients with severe OHSS. Fresh frozen plasma does not offer any advantage over albumin, and the use of dextran in patients with OHSS has been associated with the development of ARDS [37]. Patients with severe OHSS who do not have hemodynamic or respiratory compromise can be treated safely with a conservative approach. In a prospective longitudinal study involving 25 women with ascites caused by severe OHSS, Balasch et al [7] assessed the value of a conservative medical therapeutic approach (bed rest, low-sodium diet, plasma-volume expansion with albumin, diuretics) in the management of this syndrome. After 2 days of therapy, there was marked improvement in clinical symptoms, standard laboratory parameters, diuresis, and urinary sodium excretion in all patients [7]. The length of treatment with albumin plus furosemide ranged between 2 and 6 days (average, 3.3 days), and it correlated directly with the severity of the syndrome [7]. Conservative observation is the usual treatment of hydrothorax in OHSS [35]. If there is progression of respiratory symptoms, thoracentesis should be performed. If ARDS develops and mechanical ventilation is required, lungprotective strategies must be used. In these patients, the use of lower tidal volumes (6 mL/kg of predicted body weight) and a plateau pressure of less than or equal to 30 cm of water may decrease the mortality rate and increase the number of days without ventilator use [51]. Because patients with OHSS are at increased risk for infections [33], a careful investigation for possible infectious causes of ARDS must be performed. Fluid management could be problematic in patients with OHSS and ARDS. A reasonable approach is maintenance of the intravascular volume at the lowest level that is consistent with adequate systemic perfusion, as assessed by metabolic acid–base balance and renal function [52]. Data about the use of glucocorticoids in ARDS are inconclusive [52]; however, prompt regression of ARDS after steroid pulse treatment (initiated on days 6 and 7 of the clinical course) has been reported in life-threatening OHSS [28]. In severe cases of OHSS, administration of prophylactic anticoagulation should be part of routine care [1,3]. If a thrombotic or thromboembolic event is suspected,
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therapeutic anticoagulation must be initiated. The use of prophylactic full anticoagulation therapy in patients with OHSS who also have a second hypercoagulable or thrombogenic state may be considered. The indications for paracentesis in patients with OHSS include the need for symptomatic relief, a tense ascites, oliguria, increasing creatinine or decreasing creatinine clearance, and hemoconcentration that is unresponsive to medical therapy [6,32]. In this situation, ultrasound-guided paracentesis (transabdominal or transvaginal) may produce a dramatic improvement in renal function [6]. It is believed that the decrease in intra-abdominal pressure postparacentesis leads to an increase in renal vein blood flow, venous return, and cardiac output. The transvaginal ultrasonographic approach affords a more thorough fluid evacuation, because ascitic fluid accumulates dependently in the posterior uterine cul-de-sac and allows needle access into a fluid pocket that is not likely to be obstructed by bowel [1]. The markedly increased size of the ovaries in these patients makes paracentesis difficult to perform. The use of ultrasound guidance during abdominal paracentesis to avoid ovarian puncture may be indicated. When paracentesis is not required, the ascites resolve after a negative sodium balance is achieved with sodium restriction alone or in combination with diuretics [30]. In cases of severe ascites associated with OHSS, treatment may require drainage of fluid twice to three times weekly. A prospective trial involving 26 patients with severe OHSS showed that the percutaneous placement of a pigtail catheter is a safe and effective treatment modality for severe OHSS [53]. This treatment may represent an attractive alternative to multiple paracentesis for the management of ascites in these patients. The use of continuous autotransfusion system of ascites (CATSA) might be effective in controlling the ascites and improving hypoimmunoglobulinemia by the use of the peritoneo-venous shunt [32]. Takamizawa et al [32] studied 10 patients with severe OHSS who were treated with CATSA. Before the treatments, serum IgG concentrations in patients with severe OHSS were significantly lower than those in controls (15 infertile women who did not develop OHSS after the same superovulation protocol) [32]. After CATSA treatment, the concentration of IgG increased in the sera, whereas it decreased in the peritoneal fluid [32]. Because the administration of exogenous immunoglobulins may decrease the rate of bacterial infections in other protein-loss entities (eg, nephrotic syndrome) [54], the same therapeutic intervention may be beneficial in patients with severe and critical OHSS. Further studies are necessary to validate this therapeutic intervention. A low threshold to start empiric antibiotic therapy is suggested when the possibility of an infectious process is considered in patients who are critically ill and hemodynamically unstable. The authors, however, try to alter the antibiotic regimen as soon as bacteriologic data are available. Empiric therapy must be guided by information about the patient’s indigenous flora, severity of disease, risks factors for infection, and patterns of antibiotic resistance in the ICU. Empiric antibiotic therapy should be directed at the most likely pathogens involved in this type of infections, which are P mirabilis, K pneumoniae, P aeruginosa, E coli, and P vulgaris [33]. Because Abramov et al [33] was not able to find an infectious
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cause in 50% of patients with OHSS who presented with fever, other causes of febrile morbidity, which may be related to the syndrome itself, must be considered in these patients. To decrease the risk for infections in patients with OHSS, invasive interventions (eg, abdominal paracentesis, thoracentesis, laparoscopy, laparotomy) should be performed only when strictly necessary. Reports have shown that the therapeutic administration of low-dose dopamine is safe and effective in managing patients with severe OHSS [55]. The rationale for this therapeutic approach is to increase renal blood flow and glomerular filtration; however, continuous intravenous infusion of low-dose dopamine did not confer clinically significant protection for renal dysfunction in a multicenter, placebo-controlled trial of 328 critically ill patients with clinical evidence of early renal dysfunction [56]. In the authors’ practice, the use of low-dose dopamine is not favored in critically ill patients. Nonsteroidal anti-inflammatory drugs (specifically indomethacin), antihistaminics, and angiotensin-converting–enzyme (ACE) inhibitors have been mentioned in the medical literature as potential alternative therapeutic regimens for OHSS; however, most of the information regarding these drugs comes from animal studies or small, uncontrolled studies. An animal study by Pride et al [57] suggested that prostaglandins might have a role in the development of OHSS. Another animal study by the same authors showed that indomethacin is not effective in suppressing the ovarian enlargement and ascites formation in OHSS [58]. A retrospective study involving 33 patients with OHSS revealed no differences in symptoms, signs, or time spent in the hospital between indomethacin users and nonusers [50]. One theory about the pathogenesis of the OHSS is that this syndrome is mediated by the release of histamine or histaminelike substances from the ovary [59]. The presence of allergies has been recognized as a possible risk factor for the development of OHSS [13]. In animal studies, antihistaminics prevented the occurrence of OHSS and caused a more rapid reduction in size of the hyperstimulated ovary compared with controls [59–61]. Prospective, randomized trials are needed to determine the real value of antihistaminics in the treatment of OHSS. Angiotensin II has been considered one of the probable pathogenic factors for OHSS, and the possibility of using ACE inhibitors as a therapeutic agent for OHSS has been raised. These drugs are teratogenic, however, and contraindicated in pregnancy [4]. Surgical intervention may be necessary in the presence of adnexal torsion, ovarian cyst rupture, or ovarian cyst hemorrhage. A decreasing hematocrit in this context may be a sign of hemorrhage rather than resolving hemoconcentration. Adnexal torsion is a rare but recognized complication that can occur in pregnant patients with OHSS and present as acute lower abdominal pain with the presence of an abdominal tender mass [62]. Laparoscopic unwinding of the affected ovary is a simple and effective technique that can be used in this situation [62]. Early diagnosis and prompt surgical intervention are necessary for a successful outcome [62]. Late diagnosis often results in a devitalized ovary that is beyond salvage, requiring laparotomy. In rare circumstances in which the syndrome increases in severity despite all interventions, termination of the pregnancy should
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be considered to decrease hCG levels. Medical termination can be accomplished with the use of mifepristone.
Summary Treatment of severe and life-threatening OHSS remains controversial, mainly because the cause of this syndrome is unknown. The authors think that there is enough available data in the medical literature to support the use of aggressive intravenous hydration, intravascular expanders, and prophylactic anticoagulation. They also support the use of ultrasound-guided paracentesis and empiric antibiotic therapy when appropriate. Awareness of the potential complications of OHSS allows critical care physicians to provide an optimal therapy to patients with this syndrome. Knowledge of the risk factors that predispose women to the development of OHSS is important to make an early diagnosis, which allows intensivists to provide aggressive medical intervention in a timely fashion.
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