Ovarian Hyperstimulation Syndrome

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation. It is characterised by enlarged, multiple follicular ovaries and a shift of fluid from the intravascular compartment into the third space (ascites, pleural effusions). Incidence of moderate to severe OHSS is 1 to 5 percent of IVF cycles, and critical OHSS about 0.1 to 0.5 percent.

Increased capillary permeability drives the fluid shift. Vascular endothelial growth factor is released from the corpora lutea after human chorionic gonadotrophin (hCG) exposure.

• Early OHSS occurs within 3 to 7 days after the hCG trigger and is related to the exogenous hCG.
• Late OHSS occurs after 10 days and is driven by endogenous hCG from a pregnancy. It is more severe and prolonged, particularly in multiple pregnancy.

Risk factors:

• Young age (below 35) and low body weight.
• Polycystic ovary syndrome or polycystic ovarian morphology.
• High antral follicle count (above 24) and more than 20 follicles.
• High anti-Müllerian hormone (above 3.4 ng/mL).
• High oestradiol on the day of trigger (above 3,500 pg/mL or 13,000 pmol/L).
• A previous episode, and use of hCG for luteal support.

Classification:

• Mild: abdominal bloating, ovarian size up to 5 cm.
• Moderate: nausea, vomiting, ascites on ultrasound, ovaries 5 to 12 cm.
• Severe: clinical ascites, hydrothorax, haemoconcentration with haematocrit above 45 percent, white cell count above 15 x 10^9/L, oliguria below 300 mL/day, creatinine above 1.2 mg/dL, hypoalbuminaemia, ovaries above 12 cm.
• Critical: tense ascites, haematocrit above 55 percent, white cell count above 25 x 10^9/L, oliguria or anuria, renal failure, thromboembolism, adult respiratory distress syndrome.

• Abdominal distension and discomfort, nausea, vomiting, diarrhoea, weight gain (above 1 kg per day or 3 kg over 3 days), and reduced urine output.
• Dyspnoea and tachypnoea from ascites or pleural effusion; tachycardia, hypotension in severe disease.
• Abdominal tenderness, distension, shifting dullness, reduced breath sounds at the bases.
• Complications: hypovolaemia and renal failure, venous and arterial thromboembolism (especially in the upper limbs and cerebral), ovarian torsion, cyst rupture and haemoperitoneum, hepatic dysfunction, electrolyte disturbance (hyponatraemia, hyperkalaemia), respiratory distress, and rarely death.

• History of stimulation (gonadotrophins, trigger with hCG or luteinising hormone agonist) with timing.
• Ultrasound: enlarged ovaries with multiple cysts (up to 10 to 15 cm), free fluid in the pelvis and abdomen, and pleural effusion; measure ovarian size.
• Laboratory: full blood count (haemoconcentration; haematocrit, white cell count), electrolytes (low sodium below 135 mmol/L, high potassium above 5 mmol/L), creatinine and urea, liver function tests, albumin (below 35 g/L), coagulation, and urinalysis; hCG to check for pregnancy.
• Daily weight and abdominal girth, fluid balance monitoring, and oxygen saturation.
• Exclusion of differential diagnoses: ectopic pregnancy, ovarian torsion, appendicitis, and pelvic infection.

Prevention

• Individualise the dose of gonadotrophins, with a low starting dose (100 to 150 IU) in high responders.
• Use a gonadotrophin releasing hormone antagonist protocol.
• In high responders, trigger with a gonadotrophin releasing hormone agonist (triptorelin 0.2 mg subcutaneously, or leuprolide 1 mg) instead of hCG.
• Freeze all embryos for transfer in a later cycle. This almost eliminates early and late OHSS.
• Cabergoline 0.5 mg orally daily for 8 days, starting on the day of trigger, reduces VEGF-mediated permeability and reduces risk by about 50 percent.
• Metformin 500 to 850 mg twice daily in women with PCOS.
• Coasting (withholding gonadotrophins) in selected cases, and luteal support with progesterone rather than hCG.
• Aspirin and low-molecular-weight heparin in high risk cases.

Mild to moderate (outpatient)

• Oral fluids to thirst (2 to 3 L daily, with electrolyte containing drinks).
• Paracetamol 1 g every 6 hours, and antiemetics (ondansetron 4 mg every 8 hours).
• Avoid non-steroidal anti-inflammatory drugs (renal effects), and avoid strenuous exercise and intercourse (risk of torsion and rupture).
• Daily weight and urine monitoring. Review every 2 to 3 days with ultrasound and blood tests.

Severe (inpatient)

• Admit, with daily weight, abdominal girth, strict fluid balance and 4-hourly vital signs.
• Intravenous crystalloid (normal saline 0.9 percent, 1 L over 1 to 2 hours then 125 to 150 mL per hour) restores volume. Avoid overload.
• Give albumin 20 to 25 percent, 50 to 100 g infused over 4 hours, repeated every 4 to 12 hours, or hydroxyethyl starch 6 percent 500 to 1,000 mL. Use these when haematocrit is above 45 percent or oliguria persists after crystalloid.
• Diuretics are used only when haemodilution is achieved and oliguria persists (furosemide 20 to 40 mg intravenously).
• Thromboprophylaxis: enoxaparin 40 mg subcutaneously daily (or 60 mg in obese women), with compression stockings. Continue throughout and for 2 to 6 weeks after (and for 12 weeks if pregnancy is achieved).
• Ascites drainage: ultrasound guided paracentesis for tense ascites with respiratory distress, oliguria, or pain. Drain 1 to 3 L slowly (up to 5 L), with albumin cover. Transvaginal drainage may also be used.
• Thoracocentesis for large symptomatic pleural effusions.
• Cabergoline 0.5 mg orally daily for 2 to 3 weeks, and oral or intravenous dopamine agonists, reduce symptoms.
• Intensive care for renal failure, respiratory distress, or thromboembolism; renal replacement therapy if indicated.
• Antibiotics for fever or infection. Avoid ovarian puncture except if necessary. Laparoscopy for torsion (with detorsion, not oophorectomy) or haemorrhage.
• Termination of pregnancy is rarely needed for life threatening disease unresponsive to all treatment.

Prognosis: early OHSS resolves in 7 to 10 days, late OHSS persists 2 to 3 weeks or longer when pregnancy is established. Pregnancy outcome is generally good, but monitoring for multiple pregnancy and prolonged symptoms is required.