Ovarian Hyperstimulation Syndrome: Comprehensive Overview
Definition and Epidemiology
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation that complicates up to 30% of assisted reproductive technology (ART) cycles, with severe forms occurring in approximately 0.5-4% of cases. 1, 2 The syndrome results from an excessive ovarian response to pharmacologic stimulation, leading to a systemic capillary leak syndrome with potentially life-threatening complications 2.
Risk Factors
Patient-Specific Risk Factors
- Age < 35 years is a significant predictor of OHSS development 1
- Polycystic ovary syndrome (PCOS) substantially increases OHSS risk compared to women without PCOS 3, 4
- High antral follicle count at baseline assessment predicts increased susceptibility 3, 5
- Previous history of OHSS in prior stimulation cycles 1
- Underlying thrombophilia specifically raises the likelihood of severe OHSS 3, 5
- Presence of antiphospholipid antibodies warrants special consideration as thrombophilia amplifies severe OHSS risk 3, 5
Cycle-Related Risk Factors
- Elevated estradiol levels during stimulation 3, 5
- Pregnancy occurrence after stimulation, as pregnancy prolongs and worsens the syndrome 3, 1
- Use of hCG trigger for final oocyte maturation (versus GnRH agonist trigger) 4
- More than 2 dominant follicles > 15 mm or more than 5 follicles > 10 mm at trigger time 3
Clinical Presentation and Severity Grading
Key Clinical Features
- Oliguria reflects acute kidney injury secondary to intravascular volume depletion from third-spacing 3
- Shortness of breath indicates pleural effusion caused by capillary leak and fluid redistribution 3
- Abdominal distension from ascites, which can progress to tense ascites 3
- Hemoconcentration manifested by elevated hematocrit/hemoglobin 3
Initial Assessment Parameters
Immediate evaluation must include 3:
- Serial abdominal girth measurements
- Assessment for tense ascites
- Respiratory examination for pleural effusion
- Hematocrit and hemoglobin levels
- Renal function tests (creatinine, BUN)
- Coagulation studies to gauge thrombotic risk
Severity Classification
While specific grading criteria vary, severity is generally categorized as:
- Mild OHSS: Abdominal bloating and discomfort without significant fluid shifts
- Moderate OHSS: Ultrasound evidence of ascites with nausea, vomiting, and diarrhea
- Severe OHSS: Clinical ascites, oliguria, hemoconcentration (Hct > 45%), hyponatremia, elevated creatinine, and potential for critical complications 1, 2
Life-Threatening Complications
Emergency physicians must evaluate for 1, 2:
- Abdominal compartment syndrome
- Acute respiratory distress syndrome
- Thromboembolic disease (both venous and arterial)
- Renal dysfunction progressing to acute kidney injury
- Hemodynamic instability
Thrombotic Risk: The Most Critical Complication
Magnitude of Risk
In severe OHSS, the incidence of venous thromboembolism reaches 4.1% (95% CI 1.1-13.7%), representing a 20-fold increase over uncomplicated IVF cycles. 6, 3 This translates to a number needed to treat (NNT) of 39 with LMWH prophylaxis to prevent one VTE 6, 3.
Unique Thrombotic Pattern
Unlike typical VTE presentations, 67-75% of IVF-related thromboses are venous, and approximately 80% of these venous events involve the upper body (neck and arm veins) rather than lower extremities. 6, 5 This atypical distribution leads to missed diagnoses when clinicians search only for lower-extremity DVT 6.
Temporal Pattern
- Venous events occur at a median of 42 days after embryo transfer (range: 2 days to 11 weeks after OHSS resolution) 6, 3, 5
- Arterial events occur earlier, at a median of 11 days after embryo transfer 6, 3
- OHSS is present in 90% of arterial and 78% of venous thrombotic events associated with ART 6, 5
- 98% of IVF-related thrombotic events occur after ovulation induction, highlighting the stimulation phase as the critical risk period 6
Clinical Monitoring for Thrombosis
- Upper-extremity or neck swelling should prompt immediate evaluation for venous thrombosis 6
- Maintain high clinical suspicion for thrombosis even weeks after apparent OHSS resolution 6, 3
Prevention Strategies
Protocol Selection (Primary Prevention)
For patients identified as high-risk for OHSS, use a GnRH-antagonist stimulation protocol combined with a GnRH-agonist trigger for final oocyte maturation, as this approach markedly reduces the incidence of severe OHSS. 6, 3, 4
Additional protocol modifications include:
- Co-treatment with metformin in GnRH agonist cycles for women with PCOS 4
- Progestin-primed ovarian stimulation (PPOS) protocols as an alternative 4
- Aromatase inhibitor incorporation to yield lower peak estrogen levels 5
Gonadotropin Dosing
- Use gonadotropin dosing ≤ 75 IU per day; higher doses increase multiple pregnancy rates without improving overall pregnancy rates 3
- Consider clomiphene citrate or tamoxifen as alternatives to gonadotropins, acknowledging a modest reduction in live-birth rates but lower multiple-pregnancy rates 3
Trigger Management
- Withhold hCG trigger when > 2 dominant follicles > 15 mm or > 5 follicles > 10 mm are present to reduce severe OHSS risk 3
- Perform aspiration of excess follicles at hCG administration as an alternative to cycle cancellation 3
Embryo Management
Freeze all embryos (elective cryopreservation) when OHSS is present, as pregnancy prolongs and can worsen the syndrome. 6, 3 This "freeze-all" strategy is one of the most effective interventions for preventing progression to severe late OHSS 4.
Alternative Approaches
- In vitro maturation (IVM) offers an alternative with no risk of OHSS, though it currently has lower cumulative live birth rates than conventional IVF 4
- Dopamine agonist treatment after oocyte collection can reduce OHSS severity 4
Management by Severity Level
Mild OHSS (Outpatient Management)
Pain Management
NSAIDs (naproxen 550 mg or ibuprofen 600-800 mg) are first-line analgesia for mild-to-moderate OHSS. 3, 5 Aspirin should be avoided before oocyte retrieval due to increased bleeding risk, though it may be considered post-retrieval 5.
Monitoring
- Serial assessment of symptoms
- Instruction to report worsening abdominal distension, decreased urine output, or dyspnea
- No routine thromboprophylaxis needed (baseline VTE risk only 0.2%, NNT = 781) 6, 3
Moderate-to-Severe OHSS (Hospitalization Required)
Thromboprophylaxis (Highest Priority Intervention)
Initiate low-molecular-weight heparin (enoxaparin 40 mg subcutaneously once daily) immediately upon diagnosis of moderate-to-severe OHSS. 6, 3, 5 This intervention prevents approximately 26 VTEs per 1,000 treated women without increasing clinically significant bleeding risk 6, 3.
Duration of thromboprophylaxis:
- Continue for at least 3 months after symptom resolution if no pregnancy occurs 6, 3, 5
- Continue throughout pregnancy and the postpartum period if pregnancy occurs 6, 3, 5
The prolonged duration is critical because thrombotic events can occur 2 days to 11 weeks after OHSS resolution 6, 3, 5.
Special Populations: Thrombophilia
- For patients with known thrombophilia or antiphospholipid syndrome, start thromboprophylaxis at the beginning of ovarian stimulation 5
- For patients with established thrombotic antiphospholipid syndrome on therapeutic anticoagulation, transition to therapeutic-dose LMWH (enoxaparin 1 mg/kg subcutaneously every 12 hours) 3, 5
Fluid Management
- Intravenous fluid resuscitation for intravascular volume depletion 7
- Avoid aggressive fluid administration that may worsen third-spacing 2
- Monitor for signs of abdominal compartment syndrome 1
Paracentesis
- Perform therapeutic paracentesis for tense ascites causing respiratory compromise or abdominal compartment syndrome 7
- Serial paracentesis may be required 2
Renal Support
- Monitor renal function closely with serial creatinine and urine output 3
- Optimize intravascular volume to support renal perfusion 2
Respiratory Support
- Supplemental oxygen for hypoxemia secondary to pleural effusion 1
- Thoracentesis if pleural effusion causes significant respiratory compromise 2
Critical OHSS (ICU-Level Care)
Multidisciplinary Approach
Critical patients should be evaluated in the resuscitation bay, and consultation with the primary obstetrics/gynecology team is needed, which improves patient outcomes. 1 Involve critical care medicine early for patients with hemodynamic instability, respiratory failure, or renal failure 1, 2.
Advanced Interventions
- Mechanical ventilation for acute respiratory distress syndrome 1, 2
- Renal replacement therapy for acute kidney injury unresponsive to conservative management 2
- Vasopressor support for hemodynamic instability 2
- Continued aggressive thromboprophylaxis with LMWH 6, 3
Common Pitfalls and How to Avoid Them
Pitfall 1: Missing Upper-Body Thrombosis
Assuming that IVF-related VTE follows the classic lower-extremity DVT pattern leads to missed diagnoses; the predominant pattern is upper-body venous thrombosis (neck/arm). 6, 5 Always examine and inquire about upper-extremity and neck swelling in OHSS patients 6.
Pitfall 2: Premature Discontinuation of Thromboprophylaxis
Discontinuing LMWH prophylaxis too early can result in thrombotic events occurring up to 11 weeks after OHSS resolution. 6 Maintain prophylaxis for the full 3-month duration after symptom resolution, or throughout pregnancy if conception occurs 6, 3.
Pitfall 3: Indiscriminate Prophylaxis
Applying routine prophylaxis to all IVF patients rather than targeting those with OHSS or additional risk factors provides little benefit and may expose patients to unnecessary medication. 6 Reserve LMWH for moderate-to-severe OHSS or patients with additional thrombotic risk factors 6, 3.
Pitfall 4: Allowing Fresh Embryo Transfer in Active OHSS
Proceeding with fresh embryo transfer when OHSS is developing will prolong and worsen the syndrome 3. Always freeze all embryos and defer transfer 6, 3.
Pitfall 5: Inadequate Pre-Treatment Risk Assessment
Failure to identify high-risk patients (PCOS, high antral follicle count, thrombophilia) before stimulation prevents implementation of preventive strategies 3, 5, 4. Perform thorough risk stratification before initiating any ovarian stimulation protocol 5.
Evidence Quality Considerations
The thromboprophylaxis recommendations are based on low-quality evidence due to indirectness (extrapolated from orthopedic surgery populations) and imprecision in risk estimates 8. However, the magnitude of benefit in severe OHSS (NNT = 39) combined with no increased bleeding risk makes LMWH prophylaxis a clear recommendation despite the evidence limitations 8, 6, 3. The American College of Chest Physicians endorses this approach based on the favorable risk-benefit profile 8, 5.