Ovarian hyperstimulation syndrome

It occurs when the ovaries are hyperstimulated and enlarged due to fertility treatments and results in the shift of plasma from the intravascular space to third spaces, predominantly the peritoneal cavity.

In most cases the symptoms are mild tend to be self limiting (typically lasting 10-14 days) and will do well with supportive treatment, however in a small number of cases it can be severe and even life threatening.

The syndrome is more prolonged and more severe in women who are pregnant.

It is more frequently seen in:

●          Younger patients, (less than 35 years)

●          Patients less than 60 kgms.

●          Patients with polycystic ovarian syndrome.

The syndrome is characterized clinically by

1.         Ovarian enlargement.

2.         Increased vascular permeability.

The condition tends to be more severe if the patient is pregnant.

Epidemiology

The incidence of OHSS is approximately low at approximately 5 % following ovulation induction with exogenous gonadotrophins.

The World Health Organization (WHO) has estimated the incidence of severe OHSS to be 0.2 to 1 % of all stimulation cycles. ¹

Pathophysiology

The pathophysiology of OHSS is not fully understood, but increased capillary permeability with the resulting loss of fluid into third spaces is its main feature.

In the susceptible individuals, gonadotrophins administration for final follicular maturation and triggering of ovulation appears to be the pivotal stimulus for OHSS, leading to:

●          Excessive production of vascular endothelial growth factor (VEGF) in the ovary

●          Release into the circulation of vasoactive-angiogenic substances that lead to          increased vascular permeability, with loss of fluid to third spaces

Risk factors:

It is more frequently seen in:

1.         Patients with polycystic ovarian syndrome.

2.         Patients with a previous episode of OHSS

3.         High (or rapidly rising) serum estradiol concentrations

4.         Pregnancy:

●          Which increases not only the risk of late OHSS, but also the duration and             severity of OHSS (due to the persistent stimulation by endogenous hCG).

Less certainly:

5.         Younger patients, (less than 35 years)

6.         Patients less than 60 kgms.

Complications

These include:

1.         Hypotension:

Due to contracted intravascular space, with transudate fluid losses into third spaces, including:

●          Peritoneal space (most commonly)

●          Pleural space (uncommon)

●          Pericardial space (rarely).

2.         Dehydration/ electrolyte disturbances:

            ●          Due to vomiting

3.         Renal impairment/ failures

4.         Respiratory distress:

            ●          ARDS

5.         Increased risk of ovarian torsion.

6.         Increased susceptibility to sepsis

7.         Increased susceptibility to thromboembolic disease.

●          The occurrence of these events is likely to be related to hemoconcentration            and to hypercoagulation associated with elevated serum estrogen            concentrations.

            ●          These events may be arterial or venous.

Classification of the Severity of OHSS

OHSS can be classified as mild, moderate, severe and critical as follows:

Mild

●          Mild abdominal pain

●          No clinically apparent ascites.

●          No Abdominal ascites detected on ultrasound.

●          Ovarian size < 8 cm

●          No clinically important laboratory findings.

Moderate

●          Moderate abdominal pain

●          Abdominal ascites detected ultrasound examination.

●          Nausea and vomiting

●          Ovarian size 8 – 12 cm

●          Hematocrit > 41 % up to 0.45 and WCC > 15,000

●          Estradiol levels, 10,000 – 20,000 pmol/L

Severe

●          Moderate to severe abdominal pain

●          Abdominal ascites detected clinically.

●          Pleural effusion

●          Intractable nausea and vomiting

●          Ovarian size >12 cm

●          Hematocrit > 0.55 and WCC > 25,000

●          Elevated liver enzymes

●          Estradiol levels, 20,000 – 30,000 pmol/L

●          Oliguria

Critical

In critical OHSS, the function of vital organs and systems is compromised

●          Moderate to severe abdominal pain

●          Abdominal ascites detected clinically.

●          Intractable nausea and vomiting

●          Ovarian size >12 cm

●          Hematocrit as above and worsening.

●          Estradiol levels, 20,000 – 30,000 pmol/L or higher

 Together with clinical complications:

●          Renal failure

●          Pleural and pericardial effusions, causing dyspnea and hypotension.

●          Thrombo-embolic events.

●          Cardiovascular collapse

●          ARDS

Clinical Features

The OHSS syndrome is essentially characterized clinically by:

1.         Ovarian enlargement.

2.         Increased vascular permeability.

The diagnosis of (OHSS) is made by a combination of:

1.         History of ovarian stimulation followed by ovulation or administration of       human chorionic gonadotropin (hCG).

2.         Typical clinical features

3.         Transvaginal ultrasound findings (enlarged ovaries

Once the diagnosis of ovarian hyperstimulation syndrome is made, disease severity should be classified as mild, moderate, severe, or critical (see above).

Important points of History:

Patients will most commonly present with:

1.         Abdominal pain.

2.         Abdominal distension.

Less commonly with:

3.         Shortness of breath.

If the condition is severe:

4.         Cardiovascular collapse

            Note that intravascular fluid loss may be:

            ●          Occult or “third space”

            ●          Co-existent with peripheral and pulmonary edema.

5.         Thrombo-embolic events.

Important points of Examination:

1.         Vital signs:

            ●          Check for signs of sepsis (fever) and/ or circulatory compromise.

●          In addition to the usual vital signs; monitoring and measurement of weight             and abdominal circumference should also be done, (in the ward these will subsequently be re-measured on a daily basis)

2.         Abdominal tenderness which is mild and diffuse:

            Note that if there is significant local tenderness / guarding / peritonism found on    examination, other important differential diagnoses or secondary complications        will need to be considered including:

            ●          Ectopic pregnancy

            ●          Ovarian torsion or bleeding.

            ●          Other intra-abdominal sepsis.

3.         Asses for signs of third space complications:

●          Ascites

●          Pleural effusion.

●          Cardiac tamponade

4.         PV:

●          If this is considered necessary, care should be taken (as it should for a        vaginal ultrasound) so as not to rupture large ovarian cysts.

Investigations

These will be guided by the clinical severity of the presentation and not all will be necessary in all cases, but the following will need to be considered:

Blood tests:

1.         FBE:

            ●          Especially for hematocrit and WCC.

2.         CRP

3.         U&Es / glucose

4.         Beta HCG

5.         Clotting profile.

●          Include a thromobphilia screen in patients with thromboembolic events.

6.         LFTs

7.         Estradiol (E2) levels.

Ultrasound:

This is the most important investigation.

●          Ovarian size is measured.

●          To assist in ruling out alternative diagnoses, (bleed into a cyst or torsion of a cyst,             ectopic pregnancy)

●          Detect ascites.

CXR:

This should be done if there are significant respiratory symptoms or pleural effusion is suspected.

Appropriate shielding should be provided.

ECG:

If the patient is significantly unwell or pericardial effusion is suspected.

Echocardiography:

This should be done if pericardial effusion is suspected.

It will confirm the presence of pericardial fluid and detect any evidence of cardiac tamponade.

Management

Treatment is predominantly supportive and most cases will be mild and self-limiting and can be managed as outpatients.

Mild OHSS can progress to moderate or severe OHSS, particularly if pregnancy has occurred.

Therefore, women with mild disease should be observed closely for worsening abdominal pain, excessive weight gain (>1 kg/day), and increasing abdominal girth

Those with more severe symptoms and/ or complications will of course require inpatient management.

In general terms:

1.         Attend to any immediate resuscitation as required:

2.         Analgesia as clinically indicated.

●          Paracetamol is suitable for milder symptoms.

3.         Heparin/ enoxaparin:

            ●          In moderate or more severe hospitalized cases, anticoagulation       prophylaxis may be considered (after ruling out any hemorrhagic             complications) – but this should be discussed with the O&G Unit.

4.         Diuretics should be avoided due to the contracted intravascular volume.

Management can be complex in severe cases and will need close input and coordination with both the ICU and the obstetrics units.

5.         Fluid management will involve:

●          Optimizing the intra-vascular volume with normal saline to:

            ♥          Maintaining urine output of at least 30 mls per hour

            ♥          Returning the hematocrit to normal.

●          A CVC and urinary catheter should be placed to help monitor fluid therapy.

7.         ARDS may require CPAP

8.         Paracentesis:

            ●          Ascites may cause significant discomfort, impairment to respiration and                             impairment of venous return (by compression of the IVC)

●          Ultrasound guided paracentesis should be considered in extreme cases of             tense ascites.

Ultrasound-guided culdocentesis can be performed (even on an outpatient basis) in women with tense ascites

9.         Cardiovascular collapse may require inotropic support in addition to fluid management.

Disposition:

All actual or suspected  cases of OHSS must be referred to the O&G Unit

Severe or critical cases will also need an ICU referral.

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References

FOAMed

• Nickson C. Ovarian Hyperstimulation Syndrome. CCC

Publications

• Nastri CO, Ferriani RA, Rocha IA, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology and prevention. J Assist Reprod Genet. 2010 Feb;27(2-3):121-8.