Ovarian Hyperstimulation Syndrome

Ovarian hyperstimulation syndrome (OHSS) is the most serious consequence of induction of ovulation as part of assisted conception techniques.

It follows stimulation of the ovaries into superovulation with drugs such as human chorionic gonadotrophin (hCG) and human menopausal gonadotrophin. It is rare with clomiphene except in polycystic ovary disease.

Many women with OHSS will be seen by doctors unfamiliar with the condition. This is because assisted conception treatment frequently takes place outside hospitals and also because serious OHSS is uncommon. Hence education and good communication are particularly important in providing safe and effective care to women with OHSS.¹

• In OHSS the ovaries may form 20 follicles or more and swell following an increase in serum levels of hCG. This results in very high levels of oestrogen production.
• OHSS may be classified as mild, moderate or severe (see below). Severe cases can be life-threatening.
• OHSS would appear to be an acute inflammatory condition with elevated levels of c-reactive protein (CRP).²

This table shows the range of severity and the clinical features associated.¹

• Despite careful monitoring, a mild degree of OHSS occurs in as 33% of IVF cycles.¹
• A moderate degree occurs in as many as in 3 to 5% of treatment cycles.
• It may be severe in 1 or 2% of IVF cycles.

Risk factors

• Polycystic ovary disease (greatly increases the risk)
• Younger women are at greater risk
• High oestrogen levels and a large number of follicles
• Administration of GnRh agonist
• The use of hCG for luteal phase support

Gonadotrophin releasing hormone (GnRH) antagonists can be used within the treatment cycle to suppress the production of gonadotrophins and in doing so they shorten the treatment cycle. A Cochrane review compared the short and long protocols and concluded that whilst the short protocol had a lower incidence of severe OHSS, it also had a lower pregnancy rate and so couples need to be counselled about the relative risks and benefits of each.³

• The diagnosis of OHSS is based on clinical criteria and therefore clinicians should be aware of the signs and symptoms.¹
• Symptoms usually appear 4 or 5 days after harvesting of eggs.
• There is abdominal pain and distension due to accumulation of fluid.
• In 1 or 2% of cases with very enlarged ovaries, the patient is ill with severe pain, nausea and vomiting.
• There may also be pleural effusions with fluid passing from the abdomen into the pleural cavity.
• Extravasation of fluid can cause haemoconcentration and hypercoagulability with risk of thrombosis.

If a woman who is undergoing IVF treatment presents with severe bloating, nausea and vomiting, shortness of breath and reduced urine output, admission to hospital is required.

Careful monitoring of the ovaries during treatment is mandatory. The rate of growth of follicles is measured and treatment is cut back if stimulation seems excessive. Despite such care, OHSS will still occur at times.
In severe OHSS investigations include:

• Ultrasound of ovaries and abdomen for fluid. A possible risk in this condition is torsion of the ovary and U/S may suggest this.
• FBC as there may be haemoconcentration. Serious findings are haematocrit above 45% and white cell count above 15x10⁹/L.
• U&E and creatinine as renal function may be impaired. Serious findings are sodium below 135 mmol/l or potassium above 5.0 mmol/l.
• Coagulation screen
• LFTs
• CXR and lateral (to assess any pleural effusion)
• Measure abdominal girth daily

This often involves a multidisciplinary approach and should follow agreed protocols.
The gold standard for management of OHSS is outlined in the guideline from the Royal College of Obstetricians and Gynaecologists.¹

• If blood oestrogens and ultrasound scans show a high risk of severe OHSS, hCG should be withheld.
• Egg collection and insemination may occur but any viable embryos should be frozen. Fresh embryo transfer should not occur in that cycle but frozen embryo transfer may take place in a subsequent treatment cycle. Routine freezing rather than fresh transfer as a matter of routine was not supported by a Cochrane review.⁴
• "Coasting" is the term used for stopping the gonadotropin stimulation and continuing the agonist suppression until oestrogen levels decline to acceptable values before proceeding to egg collection.

Severity

• In mild cases, analgesia and increased oral fluids will suffice. The condition will settle rapidly unless pregnancy occurs when it will take longer to subside.
• In moderate cases, admission to hospital for thromboprophylaxis and monitoring may be judicious.
• Severe cases require very careful monitoring of fluid balance.
  • An initial bolus of a litre of fluid IV should be followed by enough to maintain urine output of 30 to 40 ml an hour. Give a diuretic if urine output is inadequate.
  • Aspiration of ascites or pleural effusion can relieve symptoms.
  • Albumin may be given to replace circulating volume and it may need to be given periodically. The American guidelines listed at the end recommend against the use of dextran as it can cause adult respiratory distress syndrome but there is evidence that dextran 40 may be more effective than albumin.⁵
  • Clear guidance on the management of the acute, severe condition is not available⁶ but each aspect is tackled as required and intensive care may be required.

Ovarian torsion and renal damage may both occur.

Authors recognise that this is a condition that can be fatal but figures for death rates are not available. It is a cause for concern that a paper from 2000 stated, "To the best of our knowledge, this is the first autopsy report of a patient with severe OHSS."⁷ We should be learning from such tragedies, whenever they occur. A case with cerebral infarction was reported from New Zealand.⁸ Death is very rare but it seems that few of the cases are reported in the literature.

This is an iatrogenic condition for what may be seen as a voluntary and non-essential treatment.

Techniques such as reducing the ovarian stimulus, coasting and cryopreservation are sometimes advocated to reduce the risk of OHSS. Other more experimental strategies include follicular aspiration, in-vitro maturation of immature oocytes, the use of gonadotrophin-releasing hormone (GnRH) agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch.⁹ A Cochrane review¹⁰ concluded that the evidence about the efficacy of "coasting" was inadequate as good trials have not been forthcoming.

Intravenous albumin on the day of oocyte retrieval has been suggested as a useful method of reducing the risk of OHSS but a RCT showed that it is of no benefit.¹¹ However, a Cochrane review concluded that it is of benefit but with a NNT of 18.¹² They felt that treating 18 women to prevent 1 case was a rather high number.

In women with PCOS, short term treatment with metformin did not improve the response to stimulation but it did improve the pregnancy outcome and reduced the incidence of OHSS.¹³