Prevention and Management of Ovarian Hyperstimulation Syndrome (OHSS)

I)   Prevention of OHSS:

Patient Counselling

·  It is recommended to counsel patients with elevated anti-müllerian hormone levels, polycystic ovary syndrome (PCOS), and anticipated high oocyte yields that they are at increased risk for ovarian hyperstimulation syndrome (OHSS). Interventions to reduce OHSS risk should be focused on this patient population.

(Strong Recommendation, high grade evidence) (15).

During Ovarian Stimulation:

GnRH Antagonists

· It is recommended to dose gonadotropins based on individualized ovarian reserve testing to decrease the risk of OHSS (Strong Recommendation, high grade evidence) (16).

Lower Starting Dose

·  Consider lowering the starting dose of gonadotropins and/or supplementing with oral ovulation-inducing medications (clomiphene citrate and/or letrozole) to decrease the risk of OHSS (Conditional Recommendation, moderate grade evidence) (18).

GnRH Agonist Trigger

·  Use a GnRH agonist to trigger oocyte maturation as a first-line strategy to reduce the risk of moderate-to-severe OHSS (Strong Recommendation, high grade evidence) (19).

Coasting

·  Coasting is generally not recommended as a primary strategy to reduce the risk of moderate-to-severe OHSS. However, when other more effective strategies are not available, coasting in combination with cabergoline and a freeze-only strategy may mitigate the risk (Conditional recommendation, low grade evidence) (23).

Luteal Support:

Adequate Luteal Support

·  Provide adequate luteal support when using a GnRH agonist as a trigger and planning a fresh embryo transfer (Strong Recommendation, high grade evidence) (20).

Dopamine Agonist:

Cabergoline

· In patients at risk for moderate-to-severe OHSS, start a dopamine agonist such as cabergoline on the day of the hCG trigger or soon after that and continue for several days (Strong Recommendation, high grade evidence) (21).

Freeze-All Strategy:

Freeze-Only Cycle

·  Consider a freeze-only cycle and subsequent frozen embryo transfer in patients at risk for OHSS based on a high ovarian response or elevated serum estradiol levels. Multiple high-quality studies have reported a significant reduction in rates of moderate or severe OHSS when this strategy is employed (Strong Recommendation, high grade evidence) (22).

Trigger:

hCG-Only Trigger

·  Do not use a lower dose for the human chorionic gonadotropin (hCG)-only trigger as a strategy to reduce the risk of moderate-to-severe OHSS (Conditional Recommendation, low grade evidence) (24).

Adjuvants During Luteal Phase:

Letrozole

·  Do not administer letrozole as an intervention to reduce rates of moderate-to-severe OHSS (Conditional Recommendation, moderate grade evidence) (25).

Luteal GnRH Antagonist

· Do not administer a luteal GnRH antagonist alone to reduce rates of moderate-to-severe OHSS. Most studies report no reduction in rates of moderate-to-severe OHSS or associated signs or symptoms. Some low-quality evidence suggests modest symptomatic improvement in women with OHSS who received a GnRH antagonist after the hCG trigger (Conditional Recommendation, low grade evidence) (26).

Aspirin

·  Do not use aspirin as a primary strategy to reduce the incidence of OHSS (Conditional Recommendation, low grade evidence) (27).

Metformin

·  Do not administer metformin for the sole purpose of reducing the incidence of OHSS in GnRH antagonist cycles. Most studies do not report a significant reduction in OHSS rates in women with PCOS who were given metformin. However, metformin may be considered for OHSS risk reduction among women with PCOS using a GnRH-agonist protocol (Conditional Recommendation, moderate grade evidence) (28).

Ineffective Medications

· Do not administer medications such as mifepristone, myoinositol, D-chiro-inositol, or glucocorticoids to reduce rates of OHSS as studies have shown these interventions to be ineffective (Conditional Recommendation, low grade evidence) (29).

Volume Expanders

·  Do not use volume expanders such as albumin, hydroxyethyl starch, or mannitol in patients at high risk of developing moderate or severe OHSS (Conditional Recommendation, low grade evidence) (30).

II)  Outpatient management of OHSS:

Assessment of OHSS Symptoms:

· Clinicians need to be aware of the symptoms and signs of OHSS, as the diagnosis is based on clinical criteria. (Conditional Recommendation, low grade evidence) (8). Table 4

·  Women presenting with symptoms suggestive of OHSS should be assessed face-to-face by a clinician. In women presenting with severe abdominal pain or pyrexia, extra care should be taken to rule out other causes of the patient’s symptoms. The input of clinicians experienced in the management of OHSS should be obtained in such cases. (Conditional Recommendation, low grade evidence) (8).

Classification of OHSS Severity:

·  It is recommended that once the diagnosis of OHSS is established, the severity of the disease should be classified as mild, moderate, severe, or critical according to the standardized classification scheme included. (Conditional Recommendation, low grade evidence) (32). Table 5

Outpatient Management of OHSS:

Outpatient Management

·  Outpatient management is recommended for women who have mild or moderate OHSS and only in selected cases with severe OHSS when the physician can ensure that the patient can follow clinical guidelines and ensure that a system is in place to assess the condition every 1 to 2 days. (Conditional Recommendation, low grade evidence) (33).

· Women undergoing outpatient management of OHSS should be appropriately counselled and provided with information regarding fluid intake and output monitoring. In addition, they should be provided with contact details to access advice. (Conditional Recommendation, low grade evidence) (30).

Fluid Replacement in Outpatient Management

·  Fluid replacement by the oral route, guided by thirst, is the most physiological approach to correcting intravascular dehydration. (Conditional Recommendation, low grade evidence) (30).

 Thromboprophylaxis in outpatient management

· Women with moderate OHSS should be evaluated for predisposing risk factors for thrombosis and prescribed either antiembolism stockings or LMWH if indicated. (Conditional Recommendation, low grade evidence) (34).

·  Women with severe OHSS being managed on an outpatient basis should receive thromboprophylaxis with low molecular weight heparin (LMWH). The duration of treatment should be individualised, taking into account risk factors and whether or not conception occurs. (Conditional Recommendation, low grade evidence) (35).

Follow up & Review in Outpatient Management

· Women with OHSS being managed on an outpatient basis should be reviewed urgently if they develop symptoms or signs of worsening OHSS. In the absence of these, a review every 2–3 days is likely to be adequate. (Conditional Recommendation, low grade evidence) (36).

·   Baseline laboratory investigations should be repeated if the severity of OHSS is thought to be worsening. Haematocrit is a useful guide to the degree of intravascular volume depletion. (Conditional Recommendation, low grade evidence) (36)Table 6

Paracentesis in Outpatient Management

·  Outpatient paracentesis/culdocentesis of ascitic fluid by the abdominal or transvaginal route under ultrasound guidance may be considered for prevention of disease progression in cases of moderate to severe OHSS. (Conditional Recommendation, moderate grade evidence) (8).

III)  Inpatient management of OHSS:

Hospital Admission

·  Hospital admission should be considered for women who:

·   are unable to achieve satisfactory pain control

·   are unable to maintain adequate fluid intake due to nausea

·  show signs of worsening OHSS despite outpatient intervention

·  are unable to attend for regular outpatient follow-up

·   have critical OHSS.
(Conditional Recommendation, low grade evidence) (23).

Intravenous Hydration for Severe OHSS

· Women with severe and critical OHSS should be hospitalized for intravenous hydration and observation. (Conditional Recommendation, low grade evidence) (36).

·  Intravenous hydration with crystalloid solution should be implemented to prevent hemoconcentration and provide adequate organ perfusion targets. When the use of a crystalloid solution does not allow the maintenance of such an infusion, an alternative colloidal solution should be administered. (Conditional Recommendation, moderate grade evidence) (37).

Daily Assessment of Hospitalized OHSS Patients

·  Women admitted with OHSS should be assessed at least once daily. More frequent assessment is appropriate for women with critical OHSS and those with complications. (Conditional Recommendation, low grade evidence) (38).

Use of Antiemetics in OHSS

·  Antiemetics may be used in women with OHSS, avoiding medicines contraindicated in pregnancy. (Conditional Recommendation, low grade evidence) (39).

Invasive Monitoring for Persistent Haemoconcentration

·  Women with persistent haemoconcentration despite volume replacement with intravenous colloids may need invasive monitoring, and this should be managed with anaesthetic input. (Conditional Recommendation, low grade evidence) (40).

Intensive Care Consideration for Critical OHSS

· Features of critical OHSS should prompt consideration of the need for intensive care. Multidisciplinary assistance should be sought for the care of women with critical OHSS and severe OHSS who have persistent haemoconcentration and dehydration. A clinician experienced in the management of OHSS should remain in overall charge of the woman’s care. Intravenous colloid therapy should be considered for women who have large volumes of fluid removed by paracentesis. (Conditional Recommendation, low grade evidence) (40).

Pain Management in Hospitalized OHSS Patients

·  In hospitalized patients, pain relief should be conducted with acetaminophen and/or opioid analgesics. (Conditional Recommendation, low grade evidence) (41).

Thromboprophylaxis for Hospitalized OHSS Patients

·  Prophylactic doses of anticoagulants should be considered in women who have severe ovarian hyperstimulation syndrome. The duration of LMWH prophylaxis should be individualized according to patient risk factors and outcome of treatment. (Conditional Recommendation, moderate grade evidence) (42).

Paracentesis

· Paracentesis should be performed to alleviate discomfort in hospitalized patients with tense ascites. (Conditional Recommendation, moderate grade evidence) (8)

Indications for paracentesis include the following:

-   severe abdominal distension and abdominal pain secondary to ascites

-   shortness of breath and respiratory compromise secondary to ascites and increased intra-abdominal pressure

-    oliguria despite adequate volume replacement, secondary to increased abdominal pressure causing reduced renal perfusion.

Suspected Thromboembolism with Neurological Symptoms

·  In addition to the usual symptoms and signs of venous thromboembolism (VTE), thromboembolism should be suspected in women with OHSS who present with unusual neurological symptoms, even if they present several weeks after apparent improvement in OHSS. (Conditional Recommendation, moderate grade evidence) (43)

Surgery for OHSS

·  Surgery is only indicated in patients with OHSS if there is a coincident problem such as adnexal torsion, ovarian rupture, or ectopic pregnancy, and should be performed by an experienced surgeon. (Conditional Recommendation, low grade evidence) (40)

Medication considerations in OHSS:

NSAIDs in Pain Management

·   Non-steroidal anti-inflammatory drugs with antiplatelet properties shouldn't be used for pain relief as they may compromise renal function. (Conditional Recommendation, low grade evidence) (40).

Diuretics

·  Diuretics should be avoided as they further deplete intravascular volume, but they may have a role in a multidisciplinary setting if oliguria persists despite adequate fluid replacement and drainage of ascites. (Conditional Recommendation, low grade evidence) (40).

GnRH Antagonists or Dopamine Agonists

·   There is insufficient evidence to support the use of gonadotrophin-releasing hormone antagonists or dopamine agonists in treating established OHSS. Those drugs should not be used as routine management of OHSS. (Conditional Recommendation, low grade evidence) (21).

• IMPLEMENTATION CONSIDERATIONS

- Patient Information: Fertility clinics should provide verbal and written information concerning OHSS to all women undergoing fertility treatment and notify each patient of her risk of OHSS to which she is exposed. Information should include a 24-hour contact telephone number of a team member who has relevant experience. Special attention for ART patients who have a higher risk of developing OHSS and to patients who are in areas where they do not have easy access to physicians who are knowledgeable in the diagnosis and management of OHSS. (Strength of evidence: LOW; strength of recommendation: conditional) (23).

- OHSS Protocols for Acute and Emergency Units: All acute/emergency units where women with suspected OHSS are likely to present should establish agreed local protocols for the assessment and management of these women and ensure they have access to appropriately skilled clinicians with experience in the management of this condition. (Strength of evidence: LOW; strength of recommendation: conditional) (44).

- Liaison Between Fertility Treatment Centres and Emergency Units: Licensed centres that provide fertility treatment should ensure close liaison and coordination with acute/emergency units where their patients may present. (Strength of evidence: LOW; strength of recommendation: conditional) (8).