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REVIEW ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 4  |  Page : 475-479

Ovarian hyperstimulation syndrome


Department of Anesthesia and ICU, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission01-Sep-2014
Date of Acceptance18-Sep-2014
Date of Web Publication28-Nov-2014

Correspondence Address:
Hatem S Abdel Hamid
Department of Anesthesia and ICU, Faculty of Medicine, Ain Shams University, Cairo, 11566
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.145665

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  Abstract 

Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation induction (OI) therapy. Severe OHSS is estimated to occur in around 1% of all gonadotropin cycles. It is characterized by cystic enlargement of the ovaries and transudation of fluid and proteins from the intravascular compartment into the third space due to increased capillary permeability, considered as a potentially fatal complication of ovarian stimulation. This article aims to revise recent data and trends in the diagnosis and treatment of this potentially serious complication of a rapidly expanding therapy.

Keywords: hyperstimulation, induction of ovulation, gonadotropins


How to cite this article:
Abdel Hamid HS, Moharram A, Magdy R. Ovarian hyperstimulation syndrome . Ain-Shams J Anaesthesiol 2014;7:475-9

How to cite this URL:
Abdel Hamid HS, Moharram A, Magdy R. Ovarian hyperstimulation syndrome . Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2019 Sep 17];7:475-9. Available from: http://www.asja.eg.net/text.asp?2014/7/4/475/145665


  Introduction Top


Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation induction (OI) therapy [1]. OHSS is a rare, iatrogenic complication of ovarian stimulation with follicle-stimulating hormone medications. OHSS was first described in 1943 (Rydberg et al., 1943; Davis et al., 1944), and the first fatal cases were documented in 1951 by Gotzsche (Esteban-Altirriba, 1961) and later also in 1958 (Figueroa-Casas et al. 1958). Severe OHSS is estimated to occur in ~1% of all gonadotropin cycles [2]. It is characterized by cystic enlargement of the ovaries and transudation of fluid and proteins from the intravascular compartment into the third space due to increased capillary permeability, considered as a potentially fatal complication of ovarian stimulation [3]. The syndrome is almost exclusively associated with exogenous gonadotropin stimulation and is only rarely observed after clomiphene citrate treatment or spontaneous ovulation [4].


  Pathophysiology Top


Severe OHSS is a systemic condition thought to result from vasoactive peptides released from the granulosa cells in hyperstimulated ovaries [4]. Clinically, the fundamental physiologic change in severe OHSS is an increase in vascular permeability resulting in a fluid shift from intravascular to third-space compartments such as the peritoneal and thoracic cavities [5]. Studies have shown serum vascular endothelial growth factor levels to correlate with the severity of OHSS [6]. In addition, human chorionic gonadotropin (hCG) has been shown to increase vascular endothelial growth factor (VEGF) expression in human granulosa cells, which in turn raises serum VEGF concentration [7]. Other mediators, such as angiotensin II, insulin-like growth factor 1, epidermal growth factor, tumor growth factor, basic fibroblast growth factor, platelet-derived growth factor, interleukin 1b, and interleukin 6, have also been implicated in the disease process [8].

Receptor mutation and genetic predisposition also appear to be important pathogenic factors. Spontaneous OHSS has been reported to develop between 8 and 14 weeks of normal pregnancies. Mutations of follicle-stimulating hormone receptors have been implicated as a cause for spontaneous OHSS [9].


  Risk factors Top


There are many well-known and clearly documented risk factors for the development of OHSS, including young age, low BMI, polycystic ovarian syndrome (PCOS), allergic history, high antral follicle count, high doses of gonadotropins, high or rapidly rising estradiol levels, large numbers of large and medium-sized follicles, large numbers of eggs retrieved, high or repeated doses of hCG, pregnancy, and prior OHSS [10].


  Clinical picture Top


In the initial form of OHSS, the increase in size of the ovaries is accompanied by abdominal discomfort. In a more advanced form, the ovaries have become cystic ([Figure 1], [Figure 2], [Figure 3] and [Table 1]) and this will often result in abdominal distension and pain, nausea, vomiting, and sometimes diarrhea. These digestive symptoms may be present as soon as 48 h after hCG administration, but they become most severe between days 7 and 10 after hCG [11].

The clinical features found in each organ system can also be identified, and patients with OHSS of increasing severity will experience increased numbers of affected organ systems. Gastrointestinal system findings include ascites (third-spacing of fluid) ([Figure 2]), paralytic ileus, and enlarged ovaries. Pulmonary system findings include pleural effusions ([Figure 3]), restrictive lung disease from ascites or paralytic ileus, and ARDS. Cardiovascular system findings include decreased intravascular volume, decreased blood pressure, decreased central venous perfusion, and compensatory increased heart rate and cardiac output with arterial vasodilation. Coagulation abnormalities include hemoconcentration, increased estrogen level leading to hypercoagulability, and thrombosis (venous>arterial).
Figure 1: Ultrasound fi nding of multiple ovarian cysts in case of OHSS. OHSS, ovarian hyperstimulation syndrome.

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Table 1 Clinical grading system for ovarian hyperstimulation syndrome (Humaidan et al., 2010)

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Figure 2" Abdominal ultrasound showing ascitis as a complication of severe OHSS. OHSS, ovarian hyperstimulation syndrome.

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Figure 3: Right-sided pleural effusion in chest radiograph as a complication of severe OHSS. OHSS, ovarian hyperstimulation syndrome.

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Renal system findings include decreased renal perfusion with subsequent oliguria or renal failure. Hepatic system findings may include hepatic edema. Constitutional symptoms occur as well, with 50% of severe cases presenting with elevated temperature of noninfectious etiology. The etiology of hyperthermia is presently unclear and may be due to cytokines or prostaglandins. Hematologic findings include increased hematocrit (secondary to increased capillary permeability and fluid loss) and elevated white blood cell count, a multifactorial finding associated with elevated estrogen level, prostaglandins, and dilution. Gynecologic findings include enlarged ovaries, which may develop torsion or rupture. Finally, electrolyte findings classically include hyponatremia (secondary to increased antidiuretic hormone due to decreased intravascular volume) and hyperkalemia (secondary to the renal sodium/potassium pump alterations) [10].


  Prevention Top


The keys to preventing OHSS are experience with OI therapy and recognition of risk factors for OHSS. OI regimens should be highly individualized, carefully monitored, and use the minimum dose and duration of gonadotropin therapy necessary to achieve the therapeutic goal. Withholding further gonadotropin stimulation and delay in hCG administration until E2 levels plateau or decrease significantly can reduce risks for OHSS [12]. Prophylactic intravenous administration of 25% albumin (20-50 g) at time of oocyte retrieval has been suggested as a means to reduce risk for OHSS [13].

Albumin infusion may be expected to prevent one case of severe OHSS for every 18 women at risk who are treated [14].


  Management Top


Severe OHSS must be regarded as a potentially fatal complication requiring immediate therapy as well as close monitoring. Careful clinical examination should be performed to detect the presence of secondary complications. Therapy should remain supportive and conservative, aiming at refilling the arteriolar bed, mobilizing fluid from the third space back to the vessels, maintaining circulatory hemodynamics, and preventing hemoconcentration. Volume replacement may begin with intravenous crystalloid fluids (normal saline solution) at 125 ± 150 ml/h. Plasma expanders (colloids) can be used if necessary. However, if plasma expanders themselves are transported to the peritoneal cavity, their use may be counterproductive [15]. Albumin has often been used (at 200 ml of 25% albumin solution over 4 h), as have dextran, mannitol, and fresh-frozen plasma. Recently, the effect of 6% hydroxyaethyl starch was compared with that of albumin in a small series of patients suffering from severe OHSS. Results appeared in favor of hydroxyaethyl starch in terms of higher urine output, fewer paracentesis procedures, and shorter hospital stays [16].

Bed rest and careful monitoring of urinary output are mandatory, especially when oliguria occurs. Dopamine may be helpful in restoring renal perfusion [17]. Diuretics are contraindicated when patients display hemoconcentration, hypotension, or hyponatremia. Their use should be restricted to cases in which hemodilution is achieved while oliguria persists [18]. Nevertheless, intravenous 20% albumin associated with frusemide at 20 mg every 6 h under careful monitoring was successfully used in patients with prerenal azotemia resistant to other therapeutic measures [19].

Abdominal paracentesis is the most frequent intervention in severe cases of OHSS. This therapeutic approach induces a marked improvement of creatinine clearance and of urine volume as well as weight loss [20]. Others confirmed a significant decrease in hematocrit and blood osmolality [21].

Evaluation of dyspneic patients with severe OHSS includes physical examination, chest radiography, and arterial blood gas analysis. It is essential to evaluate accurately any pulmonary and ventilation disturbances and resulting hypoxia and to apply appropriate treatment. Oxygen supplementation and early removal of fluid from the third space reduce the risk for hypoxia. Thoracocentesis is not necessary in all cases, but a marked improvement in clinical status was noted after paracentesis. The need for repeat thoracocentesis is rare, even in cases of reaccumulated effusion. The installation of a chest drainage tube for bilateral effusion has been suggested [22].

The surgical approach should be avoided, unless a hemorrhage due to follicular rupture or torsion of the ovary is suspected ([Figure 4]). In all cases, this surgery should be conservative, with a minimum of invasive manipulations and careful hemostasis to preserve ovarian integrity as much as possible. One group [23] recommended aspiration of the cysts, believing that elimination of their contents may reduce the ovarian production of OHSS mediators; however, this should be balanced against the risk of causing bleeding of the frail ovaries, which may lead to ovariectomy and infertility [24].
Figure 4: Surgical intervention for adenexal torsion as a complication of severe OHSS. OHSS, ovarian hyperstimulation syndrome.

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Thromboembolism prevention is critical given the hypercoagulatory state of OHSS, and both venous support stockings and anticoagulants such as unfractionated or low-molecular-weight heparins are recommended [25].

Specific agents

Insulin-sensitizing agents

Insulin resistance with compensatory hyperinsulinemia is thought to play a pathophysiological role in the ovarian dysfunction and hyperandrogenism associated with PCOS. Metformin has been widely used in OI as monotherapy or in combination with other OI drugs and also as pretreatment before intrauterine insemination or IVF/intracytoplasmic sperm injection in women with PCOS. A meta-analysis of eight randomized-controlled trials of metformin coadministration during gonadotropin-stimulated OI or IVF in women with PCOS found little benefit of metformin treatment in terms of improved ovulation or clinical outcome in this population but did note a significant positive effect on the incidence of OHSS [26].

Dopamine agonist administration

Cabergoline inhibits partially the VEGF receptor 2 phosphorylation levels and associated vascular permeability without affecting luteal angiogenesis and reduces the 'early'(within the first 9 days after hCG) onset of OHSS. Even using cabergoline, the OHSS incidence may be as high as 10.8% [27].

Nonsteroidal anti-inflammatory administration

A large randomized-controlled trial demonstrated that low-dose aspirin was associated with reduction in the OHSS incidence (0.25 vs. 8.4%) in a high-risk group with similar pregnancy rates [28]. Meloxicam was capable of reducing the OHSS-associated ovarian weight and expression of VEGF in an animal model [29] ([Figure 4]).


  Conclusion Top


OHSS continues to be a serious complication of assisted reproductive techniques (ART) and conclusions are lacking in the literature regarding the best method of prevention. However, experience with OI therapy and knowledge of OHSS pathophysiology, risk factors, and clinical features are key for prevention and management.


  Acknowledgements Top


 
  References Top

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  In this article
   Abstract
  Introduction
  Pathophysiology
  Risk factors
  Clinical picture
  Prevention
  Management
  Conclusion
  Acknowledgements
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