What are the risk factors, clinical presentation, severity grading, management, and prevention of ovarian hyperstimulation syndrome in a woman undergoing IVF who develops abdominal distension, pain, nausea, vomiting, rapid weight gain, oliguria, and shortness of breath after a human chorionic gonadotropin trigger?

Ovarian Hyperstimulation Syndrome (OHSS) in IVF

Risk Factors

Women with polycystic ovary syndrome (PCOS), high antral follicle counts, elevated estradiol levels, or underlying thrombophilia are at substantially increased risk for developing OHSS. 1, 2, 3

• PCOS patients face the highest risk among all IVF populations 3
• High antral follicle counts predict excessive ovarian response 1
• Underlying thrombophilia increases risk of severe OHSS 2
• Patients with antiphospholipid antibodies require special consideration as thrombophilia amplifies severe OHSS risk 1

Clinical Presentation

OHSS manifests with abdominal distension, pain, nausea, vomiting, rapid weight gain, oliguria, and shortness of breath after hCG trigger, caused by cystic ovarian enlargement and massive fluid shift from intravascular space to third compartments. 4, 5

• Ovarian enlargement causes abdominal pain, nausea and vomiting 4
• Increased capillary permeability leads to ascites (potentially tense), hydrothorax, and hydropericardium 4
• Intravascular hypovolemia develops with concomitant third-spacing 4
• Oliguria results from acute kidney injury due to intravascular volume depletion 6
• Shortness of breath indicates pleural effusion 6

Severity Grading and Assessment

Immediate assessment must include abdominal girth measurement, evaluation for tense ascites, respiratory status for pleural effusion, hemoconcentration markers, renal function (creatinine and BUN), and coagulation studies. 6

• Measure abdominal girth serially 6
• Check for tense ascites requiring drainage 6
• Evaluate respiratory status for pleural effusion 6
• Assess hemoconcentration (hematocrit, hemoglobin) 6
• Check renal function including creatinine and BUN to assess for acute kidney injury 6
• Obtain coagulation studies to evaluate thrombotic risk given the hypercoagulable state 6

Thrombotic Risk

OHSS creates a severe hypercoagulable state with VTE risk reaching 4.1% in severe cases, with most events occurring in neck and arm veins, and thrombosis can develop from 2 days to 11 weeks after OHSS resolution. 7, 1

• Severe OHSS carries up to 4.1% (95% CI: 1.1%-13.7%) incidence of thrombosis 7
• 90% of arterial and 78% of venous thrombotic events associated with assisted reproductive technology occur with OHSS 1
• 49 of 61 reported venous thrombosis cases involved neck and arm veins 1
• Venous events are delayed compared to arterial (average 42.4 days post-embryo transfer vs 10.7 days) 7, 1
• Hemoconcentration, elevated estrogen, and immobility all contribute to thrombotic risk 6, 1

Management

Thromboprophylaxis (Highest Priority)

Initiate LMWH (enoxaparin 40 mg subcutaneously daily) immediately in moderate-to-severe OHSS and continue for 3 months post-resolution of symptoms or throughout pregnancy and postpartum if pregnancy occurs. 6, 1

• Start thromboprophylaxis immediately upon diagnosis of moderate-to-severe OHSS 1
• LMWH prophylaxis prevents 26 VTE per 1,000 women treated (NNT of 39) in severe OHSS 7
• No increased risk of significant bleeding with LMWH prophylaxis 7
• Continue for 3 months after resolution of clinical OHSS symptoms 1
• If pregnancy occurs, extend prophylaxis throughout pregnancy and into postpartum period 7
• In patients with established thrombotic antiphospholipid syndrome on therapeutic anticoagulation, transition to therapeutic-dose LMWH (enoxaparin 1 mg/kg subcutaneously every 12 hours) 1

Critical caveat: In women without OHSS, baseline VTE risk is only 0.2%, making LMWH prophylaxis of very limited value (NNT 781), so thromboprophylaxis should be reserved for those with actual OHSS. 7

Pain Management

Use NSAIDs (naproxen 550 mg or ibuprofen 600-800 mg) for pain control in mild-to-moderate OHSS. 6, 1

• NSAIDs are first-line for pain management 6, 1
• Avoid aspirin before oocyte retrieval due to bleeding risk 1

Fluid Management

Outpatient culdocentesis should be considered for prevention of disease progression in severe OHSS with tense ascites. 8

• Culdocentesis can prevent progression of severe OHSS 8
• Albumin or other plasma expanders at time of egg retrieval are NOT recommended for OHSS prevention 8

Cycle Management

Freeze all embryos if not already done, as pregnancy will prolong and worsen OHSS. 6, 1

• Pregnancy causes prolonged severe OHSS 6
• Cryopreservation of all embryos prevents this complication 6, 1
• Avoiding pregnancy by freezing all embryos prevents severe prolonged OHSS in high-risk patients 8

Prevention Strategies

Protocol Selection

GnRH antagonist protocols with GnRH agonist trigger for final oocyte maturation are recommended for patients at high risk for OHSS, as this approach significantly reduces severe OHSS risk. 8, 3

• GnRH antagonist protocols reduce OHSS incidence compared to agonist protocols 8, 4
• GnRH agonist trigger as substitute for hCG in antagonist protocols reduces severe OHSS risk 8
• GnRH antagonist protocol with GnRH agonist trigger is recommended for donor oocyte and fertility preservation cycles 8
• Pregnancy rates are not affected when using GnRH agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer 8

Adjunctive Medications

Metformin should be added in PCOS patients undergoing IVF as it reduces OHSS incidence. 8, 3

• Metformin co-treatment in GnRH agonist cycles reduces OHSS risk in PCOS patients 8, 3

Cabergoline starting from day of hCG reduces OHSS incidence in higher-risk patients without lowering pregnancy rates. 8

• Cabergoline inhibits VEGF receptor 2 phosphorylation and associated vascular permeability 4
• Reduces early onset OHSS (within first 9 days after hCG) 4

Gonadotropin Management

Gonadotropin dosing must be carefully individualized based on age, body mass, antral follicle count, and previous response to gonadotropins. 8

• Low-dose gonadotropin protocols reduce risks in PCOS patients 4
• Coasting may reduce severe OHSS incidence but coasting >3 days reduces pregnancy rates 8

Luteal Support

Progesterone, rather than hCG, should be used for luteal phase support. 8

• Progesterone avoids additional hCG exposure that worsens OHSS 8

Embryo Transfer Strategy

Elective single embryo transfer is recommended in patients at high risk for OHSS. 8

• Reduces risk of pregnancy-related OHSS prolongation 8