Ovarian Hyperstimulation Syndrome

PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

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

It may occur after stimulation of the ovaries into superovulation with drugs such as human chorionic gonadotrophin (hCG) and human menopausal gonadotrophin. It is rare with clomifene except in polycystic ovarian syndrome (PCOS).

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. Education and good communication are particularly important in providing safe and effective care to women with OHSS.[1]

  • Ovarian hyperstimulation syndrome (OHSS) is an acute inflammatory condition with elevated levels of C-reactive protein (CRP).[2]
  • 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.
  • It may be classified as mild, moderate or severe (see under 'Classification', below) and severe cases can be life-threatening.
Grade and associated clinical features[1]
Moderate OHSS
  • Moderate abdominal pain.
  • Nausea ± vomiting.
  • Ultrasound evidence of ascites.
  • Ovarian size usually 8-12 cm*.
Severe OHSS
  • Clinical ascites (occasionally hydrothorax).
  • Oliguria.
  • Haemoconcentration haematocrit ›45%.
  • Hypoproteinaemia.
  • Ovarian size usually ›12 cm*.
Critical OHSS
  • Despite careful monitoring, a mild degree of ovarian hyperstimulation syndrome (OHSS) occurs in 33% of in vitro fertilisation (IVF) cycles.[1]
  • A moderate degree occurs in as many as 3-5% of treatment cycles.
  • It may be severe in 1 or 2% of IVF cycles.

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Risk factors

  • Polycystic ovarian syndrome (PCOS) greatly increases the risk.[3]
  • Younger women are at greater risk.
  • High oestrogen levels and a large number of follicles.
  • The use of hCG for luteal phase support.
  • Administration of gonadotrophin-releasing hormone (GnRH) agonist. 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.[4]

The diagnosis of ovarian hyperstimulation syndrome (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, urgent assessment in hospital is required.

Careful monitoring of the ovaries by ultrasound during treatment is mandatory. The rate of growth of follicles is measured and treatment is cut back if stimulation seems excessive.
In severe ovarian hyperstimulation syndrome (OHSS) investigations include:

  • Ultrasound of the ovaries and abdomen for fluid. A possible risk in this condition is torsion of the ovary and ultrasound scan may suggest this.
  • FBC,as there may be haemoconcentration. Serious findings are haematocrit above 45% and white cell count above 15 x 109/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).
  • Measurement of abdominal girth daily.

This often involves a multidisciplinary approach and should follow agreed protocols.
The gold standard for management of ovarian hyperstimulation syndrome (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.[5]
  • 'Coasting' is the term used for stopping the gonadotrophin stimulation and continuing the agonist suppression until oestrogen levels decline to acceptable values before proceeding to egg collection.

Management principles by 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:
    These require very careful monitoring of fluid balance:
    • An initial bolus of a litre of fluid intravenously (IV) should be followed by enough to maintain urine output of 30 to 40 ml an hour.
    • A diuretic should be given 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 advise against the use of dextran, as it can cause adult respiratory distress syndrome.
      • However, there is evidence that dextran 40 may be more effective than albumin.[6]
    • Clear guidance on the management of the acute, severe condition is not available but each aspect is tackled as required and intensive care may be required.[7]

Ovarian torsion and renal damage may both occur.

Most authors recognise this condition can be fatal but figures for death rates are not available.

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 ovarian hyperstimulation syndrome (OHSS). Other more experimental strategies include follicular aspiration, in vitro maturation of immature oocytes, the use of GnRH agonists to trigger ovulation and the use of volume expanders such as hydroxyethyl starch.[8] A Cochrane review concluded that the evidence for the efficacy of 'coasting' was inadequate.[9]

IV albumin on the day of oocyte retrieval has been suggested as a useful method of reducing the risk of OHSS but an RCT showed that it is of no benefit.[10] However, a Cochrane review concluded that it is of benefit but with an NNT of 18.[11]

In women with polycystic ovarian syndrome (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.[12]

Further reading & references

  1. Management of Ovarian Hyperstimulation Syndrome, Royal College of Obstetricians and Gynaecologists (2006)
  2. Levin I, Gamzu R, Pauzner D, et al; Elevated levels of CRP in ovarian hyperstimulation syndrome: an unrecognised potential hazard? BJOG. 2005 Jul;112(7):952-5.
  3. Nader S; Infertility and pregnancy in women with polycystic ovary syndrome. Minerva Endocrinol. 2010 Dec;35(4):211-25.
  4. Al-Inany H, Abou-Setta A, Aboulghar M; Al-Inany HG, Abou-Setta AM, Aboulghar M; Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2006 Jul 19;3:CD001750.
  5. D'Angelo A, Amso N; Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD002806.
  6. Endo T, Kitajima Y, Hayashi T, et al; Low-molecular-weight dextran infusion is more effective for the treatment of hemoconcentration due to severe ovarian hyperstimulation syndrome than human albumin infusion. Fertil Steril. 2004 Nov;82(5):1449-51.
  7. Delvigne A, Rozenberg S; Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update. 2003 Jan-Feb;9(1):77-96.
  8. Chen D, Burmeister L, Goldschlag D, et al; Ovarian hyperstimulation syndrome: strategies for prevention. Reprod Biomed Online. 2003 Jul-Aug;7(1):43-9.
  9. D'Angelo A, Brown J, Amso NN; "Coasting" (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;(6):CD002811.
  10. Bellver J, Munoz EA, Ballesteros A, et al; Intravenous albumin does not prevent moderate-severe ovarian hyperstimulation syndrome in high-risk IVF patients: a randomized controlled study. Hum Reprod. 2003 Nov;18(11):2283-8.
  11. Aboulghar M, Evers JH, Al-Inany H; Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review. Hum Reprod. 2002 Dec;17(12):3027-32.
  12. Tang T, Glanville J, Orsi N, et al; The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun;21(6):1416-25. Epub 2006 Feb 24.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Richard Draper
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1358 (v23)
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