Ovarian Hyperstimulation Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

Iatrogenic physiologic complication of controlled ovarian hyperstimulation (most often related to treatment for infertility)Results in ovarian enlargement, increased vascular permeability with resulting 3rd-space loss and intravascular fluid depletion, electrolyte imbalance, hemoconcentration, and ascitesClassification of OHSS is based on clinical symptoms and ultrasound findings. Mild: Abdominal distension and discomfortModerate: Abdominal distension, enlarged ovaries (8–10 cm3) and ascites on ultrasound (largest pocket <3 cm)Severe: Clinical evidence of ascites and/or hydrothorax, hemoconcentration >45%Critical: hemoconcentration >55%, creatinine clearance <50 mL/min, renal failure, thromboembolism, ARDSSymptoms of OHSS may occur early (within 10 days of hCG administration) or late (more than 10 days after hCG administration). Late OHSS is usually associated with a pregnancy and may often be more severe.

Epidemiology

Incidence

Predominant age: Women of reproductive ageWith controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF): Mild OHSS: 20–33% of cyclesModerate OHSS: 3–6% of cyclesSevere OHSS: 0.1–2% of cycles

Risk Factors

Previous history of OHSSYoung ageLow body weightPolycystic ovary syndrome (PCOS) or polycystic ovaries on ultrasoundLarge number of resting follicles (>10 follicles between 2 and 8 mm) per ovaryHigh doses of gonadotropinsLarge number of intermediate-sized folliclesNumber of oocytes retrievedRapidly rising estradiol levelsHigh estradiol levels >3000/4000 pg/mLUse of human chorionic gonadotropin (hCG) for luteal supportAchievement of a pregnancyMultiple pregnancy

General Prevention

Patients who have had OHSS are more at risk for OHSS in the future, and this should be taken into consideration in subsequent treatment cycles. Patients need to inform their health care providers of a history of OHSS when considering further assisted reproductive technology treatment.If a patient is noted to be at high risk of OHSS, the stimulation and monitoring protocol may be modified to reflect this risk. In some circumstances, consideration should be given to canceling the stimulation by withholding the preovulatory injection of hCG, proceeding with a lower dose of hCG, the use of a GnRH agonist to trigger ovulation in GnRH antagonist cycles, “coasting” or withholding stimulatory drugs for several days to allow for estradiol levels to plateau or decrease, avoiding the use of hCG for luteal supporting, or freezing all viable embryos without proceeding with an embryo transfer (1)[B].Recent evidence suggests that the off-label use of dopamine agonists (cabergoline 0.5 mg) after hCG administration may decrease the incidence of OHSS (2)[A].

Pathophysiology

Ovarian hyperstimulation leads to increased capillary permeability and intravascular fluid shifts.Fluid shifts can lead to ascites and pleural effusions.Intravascular volume depletion can lead to hemoconcentration, decreased renal perfusion, and thrombosis.The ovarian renin–angiotensin system, cytokines, and other inflammatory mediators such as vascular endothelial growth factor (VEGF) may play a role in the pathophysiology of OHSS.

Etiology

OHSS is an iatrogenic syndrome that occurs during controlled ovarian hyperstimulation (COH) for infertility treatment.Generally, OHSS is associated with the use of exogenous gonadotropins such as recombinant or purified follicle-stimulating hormone (FSH).OHSS rarely has been associated with types of ovarian stimulation such as clomiphene citrate.

Commonly Associated Conditions

InfertilityPCOSAssisted reproductive technologies

Diagnosis

OHSS is a clinical diagnosis based on history, physical exam, ultrasound findings, and laboratory results.

History

Details of stimulation cycle: Medications usedDate of oocyte retrieval and embryo transferSymptoms of dehydrationAbdominal pain and distensionNausea, vomiting, diarrheaShortness of breathLoss of appetiteWeight changesFluid intakeLethargyRisks factors such as PCOS or previous OHSS

Physical Exam

Vital signs, including O2 saturation if shortness of breathWeight (daily)Monitoring of ins and outs (daily or more often as needed)Chest and cardiovascular examAbdominal circumference measured at the umbilicus (daily)Gentle abdominal exam to detect ascites

Alert

Pelvic and bimanual examinations are contraindicated to avoid ovarian hemorrhage or rupture.

Diagnostic Tests & Interpretation

Lab

Initial lab tests

CBC Hemoconcentration (hematocrit >45% indicates severe disease, >55% indicates critical disease)WBC >15,000 indicates severe diseaseElectrolytes to look for hyponatremia and hyperkalemiaRenal function testsLiver enzymesCoagulation profileß-hCG

Follow-Up & Special Considerations

For patients with mild or moderate OHSS being monitored as an outpatient, CBC and electrolytes should be performed every 1–2 days, until improvement in symptoms.

Imaging

Initial approach

Abdominal/pelvic ultrasound to assess ovarian size, ovarian torsion or rupture, and abdominal ascitesCXR to evaluate pleural effusion in presence of shortness of breath

Follow-Up & Special Considerations

Repeat abdominal/pelvic ultrasound as needed to assess ascites and guide management for paracentesis.

Pathological Findings

Ovarian enlargementDecreased renal perfusionThromboembolismAbdominal ascitesPleural effusionsPericardial effusions

Differential Diagnosis

Hemorrhagic ovarian cystOvarian torsionEctopic pregnancyPelvic infection

Treatment

Medication

Heparin 5,000 units SC every 8–12 hours; all hospitalized patients should be on anticoagulation prophylaxis and graduated compression stockings to prevent thrombotic events (3)[C].Full anticoagulation therapy should be started if there is evidence of a thromboembolic event.

Additional Treatment

General Measures

Mild to moderate OHSS: Generally managed as outpatient Oral fluid intake of at least 1 L daily of a balanced electrolyte solution (sports drinks) (3)[C].Monitor daily weight, abdominal circumference, and urine output (3)[C].Avoid physical exertion or abdominal trauma.Monitor for development of further symptoms.Frequent follow-up is required.For moderate OHSS, frequent assessments every 1–2 days including a physical examination and blood work should occur.Consider hospitalization with worsening signs or symptoms: Severe abdominal painSevere oliguria or anuriaTense ascitesDyspnea or tachypneaHypotension, dizziness, or syncopeSevere electrolyte imbalance: Hyponatremia <135 mEq/L, hyperkalemia >5 mEq/L, hemocrit >45%Severe OHSS: Should be managed as an in-patient. Daily weight and abdominal circumferenceFrequent monitoring of vital signs every 2–8 hoursStrict monitoring of input and output to maintain urine output of 20–30 cc/hourBed rest or reduced activity; the enlarged ovaries are at risk of torsion and ovarian hemorrhage either spontaneously or from injury or trauma.With severe illness, oral fluids should be limited and rehydration provided with IV fluids until evidence of symptom resolution such as spontaneous diuresis.IV fluids should be administered to maintain urine output to 20–30 mL/hour. Normal saline with 5% dextrose is preferred to Ringer’s lactate (3)[C].Once 3rd-space edema reenters the intravascular space, hemoconcentration reverses, and the patient begins to diurese spontaneously.Monitor leukocyte count, hematocrit and hemoglobin, electrolytes, creatinine, and liver enzymes.Thrombosis prophylaxis (3)[C]Intensive monitoring may be required for pulmonary support in cases of acute respiratory distress syndrome, thromboembolic events, or for renal failure.

Issues for Referral

Consultation with a reproductive endocrinology specialist or a gynecologist with experience in the management of OHSS and its complications.

Surgery/Other Procedures

Paracentesis/thoracentesis may be required for symptomatic control and for pulmonary and/or renal compromise. An ultrasound-guided approach for paracentesis is recommended to avoid the enlarged ovaries. Indications for paracentesis include severe discomfort or pain, respiratory compromise, evidence of hydrothorax, or persistent oliguria/anuria despite adequate fluid replacement.Surgery should be avoided whenever possible in these patients.When ovarian hemorrhage is suspected, surgery may be necessary. The goal should be hemostasis, and the ovaries should be conserved when possible.In a situation of ovarian torsion, surgery may be performed to attempt to revascularize the ovary by unwinding the adnexa.

In-Patient Considerations

Inpatients should have a CBC and electrolytes daily. Renal function, liver enzymes, and coagulation profile should be repeated as needed.

Initial Stabilization

Vital signs and O2 saturation

Admission Criteria

Abdominal pain suspicious of torsion or hemorrhageIntolerance of food or liquidsHypotensionSignificant ascites or plural effusionsHemoconcentration: Hematocrit >50%; white blood cell (WBC) count >25,000Hyponatremia (Na <135 mEq/L)Hyperkalemia (K >5.0 mEq/L)

IV Fluids

With severe illness, IV fluid rehydration should be used. After an initial bolus of 500–1,000 mL, fluid administration should continue to maintain a urine output of at least 20–30 mL/hour. D5NS is preferred over Ringer’s lactate because of the risk of hyponatremia.Albumin 25% (50–100 g) should be reserved for situations in which IV fluids are inadequate to maintain hemodynamic stability or urine output.Diuretics should be used cautiously and only after intravascular volume has been restored. Diuretics may aggravate hypovolemia and hemoconcentration.

Discharge Criteria

Tolerating oral liquids and dietResolution of hemoconcentration and electrolyte imbalancesAdequate urine output

Ongoing Care

Follow-Up Recommendations

Patients discharged from the hospital should be followed with frequent health care provider contact until symptom resolution.

Patient Monitoring

Patients who have conceived should have an early ultrasound to confirm pregnancy and rule out multiple gestations and then routine antenatal care as indicated by their pregnancy.

Diet

Consume 1.0–1.5 L daily of a balanced salt solution, such as a sports drink, until resolution of symptoms.

Patient Education

Monitor oral intake and urinary output.Reduce activity to avoid abdominal trauma or impact.www.acog.org

Prognosis

OHSS is a self-limiting disease that will run its course over 10–14 days in the absence of an ensuing pregnancy and may persist for weeks in a pregnant patient. Supportive treatment is initiated to prevent further deterioration of the patient’s condition.

Complications

Ovarian hemorrhageOvarian torsionArterial and venous thrombosisAcute respiratory distress syndromeLiver failureRenal failure

Pregnancy Considerations

Patients who conceive a multiple gestation are at higher risk of OHSS.Studies have shown an increased risk of prematurity, low birth weight, pregnancy-induced hypertension, and gestational diabetes in women who had severe OHSS (4)[B].

References

1. Vloeberghs V, Peeraer K, Pexsters A, et al. Ovarian hyperstimulation syndrome and complications of ART. Best Pract Res Clin Obstet Gynaecol. 2009;23:691–709.

2. Youssef MA, van Wely M, Hassan MA, et al. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis.Human reproduction update. 2010

3. Practice Committee of American Society for Reproductive Medicine. Ovarian hyperstimulation syndrome. Fertil Steril. 2008;90:S188–93.

4. Raziel A, Schachter M, Friedler S, et al. Outcome of IVF pregnancies following severe OHSS. Reprod Biomed Online. 2009;19:61–5.

Codes

ICD9

256.1 Other ovarian hyperfunction

Snomed

213201002 hyperstimulation of ovaries (disorder)129635004 ovarian hyperstimulation syndrome (disorder)

Clinical Pearls

Patients who have had OHSS are more at risk for OHSS in the future, and this should be taken into consideration in subsequent treatment cycles.Abdominal and pelvic exams are contraindicated in patients with OHSS to avoid ovarian hemorrhage or rupture.OHSS is a self-limiting disease that will run its course over 10–14 days in the absence of an ensuing pregnancy and may persist for weeks in a pregnant patient. Management is mainly supportive to prevent and identify complications until resolution of symptoms.