Sindromul de hiperstimulare ovariană

Introduction

Ovarian hyperstimulation syndrome (OHSS) is a potentially severe iatrogenic complication associated with controlled ovarian stimulation during assisted reproductive technology (ART).

Although the incidence of severe forms has decreased significantly in recent decades due to therapeutic advancements, mild and moderate forms remain common, significantly impacting patient quality of life and fertility treatment outcomes⁽¹⁾.

The clinical recognition of ovarian hyperstimulation syndrome dates back to the 1960s, coinciding with the growing use of exogenous gonadotropins for ovulation induction⁽²⁾. Early reports linked the condition to the administration of human chorionic gonadotropin (hCG), which was commonly used to trigger ovulation following controlled ovarian stimulation⁽³⁾.

As the application of assisted reproductive technologies became more widespread, concerns about the risks associated with ovarian stimulation emerged. This led to increased awareness and the gradual development of preventive strategies⁽⁴⁾.

In recent years, a deeper understanding of the syndrome’s underlying mechanisms – particularly, the role of vascular endothelial growth factor (VEGF) – has enabled clinicians to significantly reduce the incidence and severity of OHSS through more tailored and patient-specific treatment protocols^(5-9).

Incidence of OHSS in IVF cycles

The incidence of ovarian hyperstimulation syndrome in case of in vitro fertilization (IVF) cycles varies depending on the stimulation protocol used and the severity of the syndrome.

• A large Danish cohort study analyzing 186,168 IVF/ICSI cycles between 2001 and 2017 reported an annual OHSS incidence of approximately 1.2%, with no significant trend over time⁽¹⁰⁾.
• A nationwide Chinese study that included 1,581,703 oocyte retrieval cycles from 2013 to 2017 reported a mean annual OHSS incidence of 1.14%, with a decreasing trend observed in recent years⁽¹¹⁾.
• In a prospective Australian study involving 1801 patients undergoing 2524 IVF cycles using a GnRH antagonist protocol, the incidence of OHSS was 2.1%, with 1.2% early OHSS and 0.9% late OHSS⁽¹²⁾.

These data indicate that OHSS develops in approximately 1-2% of IVF treatment cycles. However, the incidence may vary depending on individual patient factors, including age, the presence of polycystic ovary syndrome (PCOS), the number of antral follicles, and serum levels of anti-Müllerian hormone (AMH).

Effective prevention of OHSS relies on the early identification of patients at increased risk before starting controlled ovarian stimulation (COS). This can be achieved by tailoring stimulation protocols to each patient’s profile and, when necessary, implementing a “freeze-all” approach to defer embryo transfer and reduce the likelihood of OHSS onset⁽¹³⁾.

Despite significant advancements in assisted reproductive technology protocols and preventive strategies, ovarian hyperstimulation syndrome continues to be a clinical concern. This is primarily because of its potentially unpredictable nature and the fact that even mild or moderate cases can impact patient well-being, delay treatment and increase healthcare utilization. Moreover, severe forms of OHSS, though less frequent, are associated with serious complications such as thromboembolism, renal impairment and respiratory distress, which may require hospitalization and intensive care. The variability in individual patient response to stimulation, coupled with the biological complexity of ovarian physiology, makes it challenging to eliminate OHSS entirely. As such, continuous vigilance, patient-tailored protocols, and updated clinical guidelines remain essential components of safe and effective fertility care⁽¹⁴⁾.

Pathophysiology of ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome arises as a result of an excessive biological response to controlled ovarian stimulation, particularly following the administration of human chorionic gonadotropin. The key driver of this condition is the significant release of vascular endothelial growth factor by luteinized granulosa cells, which promotes increased vascular permeability through activation of endothelial VEGF receptors, especially VEGFR-2⁽¹⁵⁾.

This abnormal vascular response leads to:

• Plasma leakage from the intravascular space into third spaces such as the peritoneal and pleural cavities, resulting in ascites and, occasionally, pleural effusion.
• Concentration of blood components due to fluid loss (hemoconcentration), reduced circulating volume and decreased renal perfusion.
• Disturbances in electrolyte balance, including hyponatremia and hyperkalemia.
• A heightened risk of thrombosis due to hemoconcentration and changes in coagulation profiles⁽¹⁶⁾.

Beyond VEGF, several other mediators contribute to the pathogenesis of OHSS, including interleukins (IL-6, IL-8), platelet-activating factor (PAF), angiopoietins and elements of the ovarian renin-angiotensin system, all of which amplify vascular permeability and inflammation. The clinical severity of OHSS is closely linked to the magnitude of ovarian response and the degree of activation of these molecular pathways. Although severe OHSS is now less frequent due to improved protocols, it can still result in critical complications such as renal dysfunction, respiratory distress and thromboembolic events, underscoring the importance of preventive strategies and individualized patient care⁽¹⁷⁾.

The central role of VEGF in OHSS pathophysiology

Vascular endothelial growth factor plays a central role in the onset and progression of ovarian hyperstimulation syndrome. After the administration of human chorionic gonadotropin (hCG), which is used to trigger final oocyte maturation, luteinized granulosa cells in the ovaries begin to produce elevated levels of VEGF. This growth factor exerts its effects by binding to endothelial receptors, primarily VEGFR-2, initiating a cascade that increases vascular permeability⁽¹⁷⁾.

Increased capillary permeability

Through the activation of VEGFR-2, VEGF disrupts the integrity of the endothelial barrier by loosening intercellular junctions and promoting the formation of transendothelial channels. As a result, fluid and plasma proteins move out of the blood vessels and into the surrounding tissues⁽¹⁷⁾.

Fluid accumulation in third spaces

This vascular leak results in the accumulation of fluid in third spaces such as the abdominal cavity (ascites) and pleural space, which can lead to abdominal distension and respiratory symptoms. The intravascular fluid loss contributes to hemoconcentration, hypovolemia and reduced kidney perfusion, increasing the risk of electrolyte disturbances and thromboembolic complications⁽¹⁷⁾.

In summary, VEGF is the key mediator in OHSS, and its regulation remains a major focus in strategies to prevent moderate and severe forms of the syndrome.

Risk factors associated with ovarian hyperstimulation syndrome

A retrospective analysis of 4894 assisted reproductive technology cycles conducted by Delvigne et al. (2015) aimed to identify clinical and biological risk factors associated with the occurrence of ovarian hyperstimulation syndrome, as well as to assess their impact on embryological and clinical outcomes⁽¹⁸⁾. The main risk factors identified were:

• Younger age – women under the age of 30 were found to be more prone to developing OHSS, likely due to higher ovarian reserve and stronger response to gonadotropin stimulation.
• Low Body Mass Index (BMI) – patients with a lower BMI demonstrated increased susceptibility to OHSS, suggesting a heightened sensitivity to hormonal treatment in this subgroup.
• Polycystic ovary syndrome (PCOS) – the presence of PCOS was strongly associated with a higher likelihood of OHSS, consistent with the elevated follicular response seen in this population.
• High antral follicle count (AFC) – a larger number of antral follicles at baseline served as a reliable predictor of an exaggerated ovarian response.
• Elevated estradiol levels – supraphysiologic levels of estradiol prior to ovulation triggering correlated with a higher risk of OHSS.
• Greater number of retrieved oocytes – the risk of OHSS increased proportionally with the number of oocytes collected, reflecting the extent of ovarian stimulation.

Using GnRH agonist (buserelin) for triggering final oocyte maturation eliminated the occurrence of OHSS in this study cohort. However, this approach was associated with lower oocyte maturation rates and reduced clinical pregnancy rates when compared to the standard hCG trigger, suggesting a trade-off between safety and reproductive outcomes⁽¹⁸⁾.

The Australian & New Zealand Journal of Obstetrics & Gynaecology published in 2016 a clinical study which evaluated medical records of patients hospitalized with OHSS, aiming to identify clinical and biochemical factors associated with both the occurrence and severity of OHSS. The analysis revealed significant risk factors for the development of OHSS⁽¹⁹⁾:

• Age – younger women were more likely to experience moderate to severe forms of OHSS.
• High estradiol levels – elevated E₂ levels were strongly correlated with increased OHSS severity.
• Number of oocytes retrieved – a higher oocyte yield was associated with a greater risk of severe OHSS.

Classification of ovarian hyperstimulation syndrome

The Golan system, introduced in a landmark review published in Obstetrical & Gynecological Survey, organizes OHSS into five grades of severity, categorized as mild (grades 1-2), moderate (grade 3) and severe (grades 4-5). This classification is based primarily on clinical symptoms and ultrasound findings, such as abdominal discomfort, distention, ovarian size and the presence or absence of ascites. In more advanced stages, patients may exhibit significant hemoconcentration and enlarged ovaries exceeding 12 cm in diameter⁽²⁰⁾.

While Golan’s system is straightforward and well-suited for rapid clinical triage, it does not clearly differentiate between severe OHSS and the most life-threatening manifestations that may require intensive care.

In response to the limitations of the Golan system, Navot et al. proposed a more comprehensive classification framework in 1992. This system incorporates clinical signs along with laboratory values (e.g., serum creatinine, hematocrit, urine output) and respiratory function parameters. Notably, Navot et al. introduced a distinct category termed “critical OHSS”, which encompasses serious complications such as renal failure, pleural effusions, thromboembolic events and hemodynamic instability – conditions that often necessitate intensive care management⁽²¹⁾.

Navot et al. classification enables a more nuanced evaluation of OHSS severity, making it particularly useful in hospital settings where high-risk patients require careful monitoring and complex therapeutic interventions.

In their 2010 publication, Navot, Bergh and Laufer articulate the need for a refined and standardized framework for classifying ovarian hyperstimulation syndrome. They classify the clinical forms into mild, moderate, severe and critical – based on symptomatology, ultrasonographic findings and systemic complications⁽²²⁾. The authors emphasize the necessity for a universally accepted classification of OHSS that can be endorsed by professional reproductive medicine societies. Given the life-threatening nature of complications such as thromboembolism, renal impairment and respiratory distress, the authors recommend that what they term “critical OHSS” be formally integrated as an extension of the severe category, rather than as a separate class. This would reflect the full clinical spectrum of advanced OHSS more appropriately. The article concludes with a strong recommendation for interdisciplinary alignment in the application of this classification system. Standardization not only facilitates improved clinical outcomes but also underpins evidence-based protocols and clinical trials⁽²²⁾.

Clinical presentation and diagnosis

The clinical presentation of ovarian hyperstimulation syndrome is primarily driven by increased vascular permeability, which leads to fluid shifts and is accompanied by concurrent enlargement of the ovaries and uterus^(23,24).

The initial clinical manifestations typically emerge progressively, characterized by abdominal distension and mild discomfort, which are attributable to the enlargement of reproductive organs accompanied by cyst formation^(24,25).

In certain cases, the cystic ovaries can enlarge significantly, reaching dimensions of 12 to 25 cm, with an associated risk of rupture or hemorrhage, which may subsequently result in peritonitis⁽²⁶⁾. Likewise, these patients exhibit an elevated risk of ovarian torsion^(23,27). The earliest clinical sign of ovarian hyperstimulation syndrome is typically the development of ascites, resulting from increased vascular permeability⁽²³⁾.

The measurement of albumin levels in the context of ovarian hyperstimulation syndrome is an important aspect of the evaluation and management of this complication, especially in moderate and severe forms. Low albumin levels may indicate a severe form of OHSS, and require hospital monitoring and treatment^(23,24).

The accumulation of fluid in the peritoneal cavity contributes to progressive abdominal distension, pain and elevated intraabdominal pressure (IAP)⁽²⁸⁾. As IAP rises beyond 12 mmHg, intraabdominal hypertension (IAH) may occur, and in more severe presentations, it can evolve into abdominal compartment syndrome (ACS), defined by sustained IAP exceeding 20 mmHg in conjunction with new-onset organ dysfunction or failure^(28-30). Impaired venous drainage under increased IAP leads to organ congestion and edema, particularly affecting the kidneys, liver and intestines⁽²⁸⁾. Clinically, this is reflected in early oliguria, hepatic injury, paralytic ileus and intestinal edema, often manifesting with severe vomiting and diarrhea^(23,31). Furthermore, tissue hypoxia may develop as a result of compromised hepatic and splanchnic perfusion^(28,29).

Biochemical abnormalities, such as elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are observed in approximately 30% of severe OHSS cases, occasionally accompanied by increases in g-glutamyl transpeptidase or alkaline phosphatase^(23,32). Renal involvement is also marked by dilutional hyponatremia, stemming from low serum osmolality and decreased urinary sodium excretion^(23,33). This electrolyte imbalance can precipitate neurological complications, including cerebral edema and altered mental status⁽³⁴⁾. Additional metabolic disturbances, including hyperkalemia and metabolic acidosis, may further exacerbate the clinical picture in critically ill patients⁽³⁵⁾.

Hemoconcentration represents a characteristic laboratory abnormality in ovarian hyperstimulation syndrome, indicative of intravascular volume depletion resulting from significant fluid extravasation into third spaces. This phenomenon is typically reflected by elevated hematocrit values (commonly exceeding 41-45%) and increased hemoglobin levels^(36,37). In addition, leukocytosis may be observed, generally reflecting a nonspecific inflammatory response rather than an underlying infectious process⁽²³⁾.

Patients affected by ovarian hyperstimulation syndrome commonly develop a prothrombotic state, characterized by elevated fibrinogen concentrations, reactive thrombocytosis, and increased platelet aggregability. When compounded by hemoconcentration and prolonged immobilization, these hematological alterations substantially heighten the risk of thromboembolic complications, notably deep vein thrombosis and pulmonary embolism⁽³⁸⁾.

Regarding imaging investigations, transvaginal ultrasonography constitutes the main diagnostic modality for the evaluation of ovarian hyperstimulation syndrome, offering superior sensitivity in detecting ovarian enlargement, cystic degeneration, and the presence of ascitic fluid⁽³⁷⁾. Complementary imaging through abdominal and thoracic ultrasonography may assist in identifying free fluid accumulation within the peritoneal and pleural cavities, commonly associated with more advanced stages of the syndrome. In clinically complex or ambiguous presentations, advanced cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) may be warranted to evaluate for abdominal compartment syndrome or to exclude potentially life-threatening thromboembolic events⁽³⁹⁾.

Management of ovarian hyperstimulation syndrome

The management of ovarian hyperstimulation syndrome requires a tiered approach tailored to the severity of clinical manifestations and the patient’s individual risk of systemic complications. Contemporary literature emphasizes a framework that integrates preventive strategies, conservative care and targeted interventions in severe cases⁽⁴⁰⁾.

Prevention remains the cornerstone of OHSS management, particularly in high-risk patients such as those with polycystic ovary syndrome (PCOS) or elevated anti-Müllerian hormone levels. Evidence-based prophylactic measures include:

• Individualized ovarian stimulation protocols, favoring GnRH antagonist regimens and minimizing or avoiding the use of hCG for luteal phase support^(37,41).
• Implementation of “coasting”, which involves temporary cessation of gonadotropins when estradiol levels are excessively high⁽⁴²⁾.
• Administration of cabergoline, a dopamine agonist that mitigates VEGF-mediated vascular permeability⁽⁴³⁾.
• Use of progesterone rather than hCG for luteal phase support to reduce the risk of OHSS progression⁽⁴⁰⁾.

In mild to moderate cases of ovarian hyperstimulation syndrome, the treatment is primarily conservative and supportive, with a focus on monitoring and preventing progression to severe forms. Key elements of management include:

• Correction of fluid and electrolyte imbalances – this is typically achieved through careful intravenous fluid administration, often using isotonic crystalloids such as normal saline or Ringer’s lactate. The goal is to restore intravascular volume, maintain hemodynamic stability, and prevent renal compromise. Electrolyte levels (especially sodium and potassium) should be regularly monitored and corrected as needed⁽³⁶⁾.
• Intravenous albumin administration – albumin can be administered to improve plasma oncotic pressure and counteract the third-spacing of fluids, which is characteristic of OHSS. The increased vascular permeability mediated by vascular endothelial growth factor leads to a shift of protein-rich fluid into the extravascular compartment. Albumin, as a plasma expander, may help draw fluid back into the intravascular space, reducing ascites and the risk of hypovolemia. While its use remains somewhat controversial due to mixed evidence on efficacy and potential effects on implantation rates, it is still considered in moderate cases where hypoalbuminemia and hemoconcentration are present⁽⁴⁴⁾.
• Monitoring of urinary output – close monitoring of fluid balance is crucial. Oliguria ((44).
• Thromboprophylaxis and early ambulation – OHSS increases the risk of thromboembolic events due to hemoconcentration and immobilization. Prophylactic low-molecular-weight heparin may be administered, especially in hospitalized patients or those with additional risk factors for venous thromboembolism. Early mobilization is also encouraged to reduce the risk of clot formation⁽⁴⁵⁾.

Severe or critical presentations necessitate invasive procedures and intensive monitoring:

• Ultrasound-guided paracentesis to evacuate ascitic fluid, thereby relieving intraabdominal pressure⁽⁴⁶⁾.
• Placement of a pigtail catheter for continuous peritoneal drainage in cases of recurrent or refractory ascites⁽⁴⁶⁾.
• Intensive care unit (ICU) support for patients presenting with organ dysfunction, including renal or respiratory compromise⁽³⁷⁾.
• Timely anticoagulation therapy to prevent or manage thromboembolic complications, following risk-adjusted protocols⁽³⁸⁾.

Conclusions

Ovarian hyperstimulation syndrome remains a significant and potentially serious complication in assisted reproductive technologies, despite advances in prevention and treatment. While the incidence of severe cases has decreased through individualized stimulation protocols and the use of safer ovulation triggers like GnRH agonists, mild or moderate forms of ovarian hyperstimulation syndrome continue to affect pa­tient outcomes and safety. A thorough understanding of OHSS pathophysiology, particularly the central role of VEGF in vascular permeability, alongside careful risk assessment and early intervention, is essential for optimizing management.

Effective treatment ranges from supportive care in mild cases to invasive procedures and intensive monitoring in severe presentations. Continued research and standardized clinical guidelines are vital to further reduce OHSS incidence and improve fertility treatment safety.

Autor corespondent: Alina Mareș, e-mail: georgiana-alina.mares@rez.umfcd.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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