Definition:

Ovarian hyperstimulation syndrome (OHSS) resulting from supraphysiological stimulation of the ovaries, usually during ovulation induction by gonadotropins. The syndrome can developed only after luteinization i.e. following the administration of Human Chorionic Gonadotropin (hCG). In its severe form, OHSS induces massive ovarian enlargement with multiple cycts, hemoconcentration, and third space accumulation of fluid in the forms of ascites, pleural and pericardial effusion, and anasarca. The full blown clinical syndrome may be complicated by renal failure and oliguria, hypovolemic shock, thromboembolic phenomena, adult respiratory distress syndrome (ARDS) and even death.
The syndrome is self-limiting phenomena that resolve spontaneously after several days if the patient is not pregnant. In case of pregnancy, the syndrome may persist longer and increase in its severity.

Ovarian hyperstimulation syndrome. Multiple large anechoic cysts are visualized in both ovaries in this image.

Pathopysiology

The severity of the symptoms related to OHSS results from an increase capillary permeability which case a fluid shift from the intravascular space to the third space compartments. It was shown that hCG along with Vascular Endothelial Growth Factor (VEGF), Angiotensin II, Epithelial Growth Factor (EGF), Insulin like Growth Factor I (IGF-I), Transforming Growth Factor (TGF), Platelet-derived Growth Factor (PDGF), Interleukin-1beta and others may play a role in this syndrome.

Classification:

Although the severity of OHSS forms a continuous spectrum and a woman’s condition may improve or deteriorate with time, various attempts have been made to classify the degree of severity.

Whereas in the case of those who have OHSS following ovulation induction the size of the ovaries is a useful indicator of the severity of the condition, this does not apply to women who had undergone follicular aspiration, in whom the severe forms of the condition may coexist with relatively minor ovarian enlargement. Thus, ovarian size, the most important factor when ovulation induction is the only technique, is not definitive with assisted reproductive technology (ART) procedures, and the classification of OHSS in patients undergoing ART cycles should rely more on the clinical picture and laboratory parameters and not on ovarian enlargement.

OHSS is classified as (1) mild (2) moderate (3) severe. The severe form may be further sub-classified based on the severity into a critical state.

Mild OHSS is characterized by cystic ovarian enlargement up to 5 cm.

Moderate OHSS is defined by ovarian enlargement between 5 and 12 cm accompanied by: Gastrointestinal symptoms such as bloating,
Abdominal distension with tenderness, nausea, vomiting and/or  diarrhea.
Dyspnea at some degree
US examination of the pelvis often reveals moderate amounts of fluid.

Severe OHSS comprises massive ovarian enlargement greater than 12 cm, and/or symptoms and signs of moderate OHSS which are more pronounced  and often associated with clinical evidence of intravascular fluid loss. One or more of the following clinical signs are present: Ascites,
Pleural effusion,
Pericardial effusion,
Anasarca,
Abdominal pain,
Electrolyte imbalance,
Hypovolemia,
Oliguria,
ARDS,
Thromboembolic phenomena,
Hypovolemic shock.

Critical, life-threatening OHSS. Generalized edema (anasarca) and liver dysfunction are considered additional signs of severe OHSS, and ARDS, tense ascites, severe hemoconcentration (hematocrit > 55%), and profound leukocytosis (>25,000 cells/mm3) are signs of the most severe, life threatening form.

  The normal pleural space contains approximately 1 mL of fluid, representing the balance between (1) hydrostatic and oncotic forces in the visceral and parietal pleural vessels and (2) extensive lymphatic drainage. Pleural effusions result from disruption of this balance.

Clinical signs and laboratory criteria of OHSS

Strategies for Prevention of OHSS

The first step in prevention of OHSS is proper identification of the population at risk. Since this protocol deals mainly with management of OHSS once it has developed, preventive measures will only be described briefly. Patients at high risk are generally:

- Young (<35 years="" span="">

-  Low body weight

- PCOD or PCO-like ovaries

- Asthenic habitus

- High serum E2 (>7000 pmol/L)

- Multiple follicles

- Pregnancy

- hCG luteal supplementation

- GnRH-agonist protocol for pituitary down-regulation

- Previous history of OHSS

When the patient is considered at high risk for development of OHSS several preventive steps can be undertaken:

- Alteration of ovarian response; individually tailored gonadotropin regimen.

- Strict monitoring of cycles.

- Reducing the hCG dose (usually to 5,000 IU)

- Triggering the final stage of ovulation with GnRH-agonist (if the patient has not been 
down-regulated).

- Avoidance of hCG for luteal support.

- Withhold the ovulatory dose of hCG.

- Prolonged coasting or ‘drift period’.

Additional measures should be considered:

- Prophylactic infusion of human albumin solution at the time of egg collection.

- Elective embryo cryopreservation (avoidance of pregnancy).

 Initial Diagnosis and Evaluation

On admission, a carefully taken history is mandatory. Particular attention should be paid to the medications used, their dosage and exact dates of administration. In addition, a history of evaluation procedures of infertility, infertility treatments as well as previous OHSS should be elucidated.

A general physical examination should be performed with special emphasis placed on accurate measurement of:
Blood pressure,
Pulse
Respiratory rate,
Careful auscultation of the heart and lungs.
Abdominal examination including signs of ascites (shifting dullness) and acute abdomen
If possible, no speculum examination or palpation of the ovaries and uterus should be performed.
Ultrasound (US) scan of the pelvis is more informative, much safer and therefore, the preferred examination modality.
Accurate measurement of body weight and abdominal circumference at the umbilical level.

Initial investigations should include:
Hematocrit and hemoglobin
White blood cell count,
Urea, creatinine, serum electrolytes,
Liver function tests,
Coagulation profile.
An US scan will assess ovarian size and degree of ascites.
If chest pathology is suspected, a chest X-ray may be helpful.
If the woman is tachypneic, or dyspneic, oxygen saturation and arterial blood gases should be measured.
If the woman is oliguric, she should be catheterized and hourly urine output recorded. Observations and investigation results, recorded on a flow chart, help to identify subsequent trends.

On presentation, the patient may be given symptomatic relief following critical assessment of state of hydration, hemodynamic status, and evidence of ascites, pleural effusion, pericardial effusion, and thromboembolism. Pain may be significant with OHSS causing diagnostic confusion if acute cyst complications are suspected. Paracetamol or dipyrone (optalgin) may be given for pain relief. The use of non-steroidal anti inflammatory drugs is controversial. Nausea may be lessened with metoclopramide (Pramin).

Management:

OHSS usually becomes evident 3 to 6 days after hCG administration and lasts longer if the patient conceived in that cycle. The clinical features of OHSS usually disappear rather quickly. Its course is self-limited and usually subsides within two weeks if the patient does not conceive.

As long as the pathogenesis of OHSS remains enigmatic, the treatment of OHSS remains largely empiric.

Mild OHSS:

Uncomplicated mild OHSS requires little more than reassuring the patient that, in the absence of pregnancy, her symptoms should resolve within two weeks after the administration of hCG. This condition does not require hospitalization. However, if the patient conceives, the symptoms may progress, but rarely more than one degree in severity. Clinical follow up and pelvic US once a week in order to detect further ovarian enlargement should be performed.

Moderate OHSS

In case of moderate OHSS, i.e., patients with moderate ascites and mild hemoconcentration     (hematocrit 45% or a 30% increment over baseline) and accumulation of ascitic fluid. The latter indicates that OHSS has entered the category of severe OHSS and that hospitalization and IV fluid therapy are required.  If asymptomatic, moderate OHSS is followed up ambulatory until resolution or deterioration occurs. Two parameters are of major importance when treatment options are considered: the clinical picture accompanying gradually accumulating ascites, and laboratory signs of hemoconcentration. Any deterioration such as abdominal pain and/or severe gastrointestinal symptoms should be managed under hospitalization according to the guidelines for severe OHSS. If the patient’s compliance or ability to communicate with the caring physician are in doubt, hospitalization is recommended as well. A pregnancy test (-hCG) should be performed approximately ten days after embryo transfer since pregnancy-derived hCG may induce a more severe and protracted course of OHSS.

Transvaginal ultrasound image of a woman with moderate ovarian hyperstimulation syndrome. Both ovaries are observed in the posterior cul-de-sac. The ovaries are in close contact and displace the uterus anteriorly. Both ovaries contain several large unruptured follicles.

Severe OHSS

Severe OHSS requires hospitalization and prompt treatment, especially if the cycle is conceptual. The basic disturbance in this phase is an acute shift of fluids from the intravascular compartment to the peritoneal and pleural cavity and sometimes pericardial effusion.

Ultrasound picture of a hyperstimulated ovary and free fluid in the abdomen

Hemoconcentration:

The dramatic and rapid shift of intravascular fluid into the third spaces is primarily responsible for the morbidity and occasional mortality of OHSS. This disturbance in normal hemodynamics has a wide range of serious consequences, including ascites and pleural effusions, electrolyte imbalance, liver and kidney damage, and thromboembolic phenomena. This wide range of systemic effects resulting from OHSS is ultimately derived from a rapid depletion of intravascular plasma volume. The single most important parameter that indicates the severity of OHSS is hemoconcentration as reflected in the hematocrit. The magnitude of change in the hematocrit, however, is not directly proportional to the change in plasma volume. Small changes in hematocrit may reflect significant changes in plasma volume in face of a constant red blood cell volume. The percentage change in plasma volume is best described by the product of a proportionality factor and the percentage difference between the original and final hematocrit ratios as illustrated by the following equation:

%ΔP =    100 X     100 (H1-H2) %
(100 - H1)                 H2

where %ΔP is the percentage change in plasma volume, H1 is the initial hematocrit and H2 is the final hematocrit.  Any increase in the hematocrit as it approaches 45% does not accurately reflect the magnitude of plasma volume depletion and thus the seriousness of the patient’s condition. Similarly, in the face of hemoconcentration, small drops in the hematocrit may represent a significant improvement in plasma volume.

An additional measure of hemoconcentration is the magnitude of leukocytosis; WBC counts as high as 35,000/mm3 may be seen. This massive neutrophylia may to some extent be attributed to a generalized stress reaction. Thus the concurrent finding of an elevated WBC count (stress and hemoconcentration) becomes helpful in the clinical assessment of OHSS. In addition to plasma electrolytes and kidney function tests, it is imperative to assess periodically the patient’s coagulation profile and liver enzymes.

Fluid therapy

Crystalloids, although seldom sufficient in restoring homeostasis when administered alone, remain the mainstay of fluid therapy. Because of the tendency for hyponatremia, sodium chloride (Normal Saline, NaCl) with or without glucose is the crystalloid of choice. The daily volume infused may vary from 1.5 L to > than 3.0 L.

The five parameters essential for maintaining fluid balance are:
Urine output,
Body weight,
Hematocrit,
Abdominal girth
Oral and IV fluid intake

Intra vascular volume replacement should result in improved renal perfusion before it escapes into the third space. However, this transient hemodilution is achieved at the expense of increasing ascites. Although some advocate the use of fluid restriction in preventing this worsening third spacing, this line of therapy is extremely hazardous and should be avoided.

Whenever adequate fluid balance cannot be restored by crystalloids alone, plasma expanders should be utilized. IV dextran (Rheomacrodex), fresh-frozen plasma, human albumin, hemaccel and mannitol have all been utilized successfully as plasma expanders through restoration of oncotic pressure.

At present, both North American and European investigators agree that as albumin is the protein that is lost in OHSS, and is safe from viral contamination, low-salt albumin is the preferred volume expander. Albumin has a low mulecular weight (approximately 69,000), and its average normal half-life is 17 to 20 days. Approximately 60% of albumin is found in the extravascular spaces, but plasma albumin is still the most abundant circulating protein. Albumin has both osmotic and transport functions. It contributes approximately 75% of the plasma oncotic pressure, and administration of 50 g of human albumin solution will draw more than 800 mL of extracellular fluid into the circulation within 15 minutes, reducing hemoconcentration and blood viscosity for many hours. This amount of albumin is osmotically equivalent to approximately 1,000 mL of normal citrated plasma. The major drawback of albumin is its relatively high price. However, albumin in doses of 25 to 50 g, repeated every 2 to 12 hours, is an extremely effective plasma expander in OHSS. Hematocrit is rapidly improved and restored to normal, and diuresis is resumed with IV albumin.

Plasma therapy in an era of high prevalence of HIV and hepatitis should be avoided.

Dextran, a synthetic colloid, has been implicated in severe ARDS and may theoretically occlude the renal tubules.

Hemaccel has been implicated in severe allergic reactions.

Mannitol, the experience so far is extremely limited.

Tense Ascites

At a relatively advanced stage of OHSS secondary to crystalloid and colloid therapy, gradual hemodilution is obtained at the expense of a tightening abdominal wall with the rapid accumulation of ascitic fluid. At this stage of relatively restored intravascular volume and improved renal perfusion, there is a sudden paradoxic onset of oliguria, increasing serum creatinine, and rapidly falling creatinine clearance. The most likely interpretation of this phenomenon is that this sudden deterioration in fluid balance is a result of a significant rise in intraabdominal pressure produced by tense ascites, which may impede renal venous outflow, causing congestion, renal edema, and possibly thrombosis. This  problem may be approached by either a medical or a surgical approach.

Diuretics

Although highly controversial, diuretics continue to have a role in treatment of severe OHSS. When oliguria persists, despite evidence of adequate therapeutic hemodilution, IV furosemide (Lasix) at 10 mg or higher dose is often beneficial. In practice, an albumin-furosemide chase protocol seems to yield the best results. Twenty-five to 50 g of albumin is followed immediately by furosemide every 2 to 4 hours. Furosemide should never be used in the presence of hemoconcentration or hypotension.

Paracentesis

The single most important treatment modality in life-threatening OHSS that cannot be controlled by medical therapy is paracentesis. It is a safe and exceptionally beneficial procedure. Dramatic improvements in the clinical symptoms of severe OHSS, with almost instantaneous diuresis and weight loss were reported. The indications for paracentesis include the need for symptomatic relief, tense ascites, oligoanuria, rising creatinine or falling creatinine clearance, and hemoconcentration unresponsive to medical therapy. Paracentesis should only be performed with US guidance. It is contraindicated in the patient who is hemodinamically unstable or if there is suspected hemoperitoneum. Paracentesis should be performed aseptically by means of a small gauge needle or a Z puncture technique in the abdominal wall to avoid continuous leakage. US guidance is obligatory, as is careful monitoring of hemodynamic stability. Abdominal paracentesis has the advantage that the drain may be left in situ for several days avoiding the need for repeated puncture in cases with massive persistent ascites. However, transvaginal US-guided aspiration of ascitic fluid has been reported as an effective and equally safe method.
In case of anuria and dyspnea in the presence of tense ascites abdominal paracentesis should be done as urgent procedure.

  Picture showing paracentesis being done for OHSS enlarged ovary at left, top of the vagina at V, the needle is the white line at the left of the red X

Life-threatening complications of OHSS

The critical form of OHSS is often complicated by mutiple system failure. The most severe consequences of OHSS are renal failure, heart failure, thromboembolic phenomena, and ARDS. The role of the caring physician is to identify impending organ failure and hypercoagulability. Patients in such a critical condition should be monitored and treated in an intensive care unit.

The therapy remains largely empiric with the goal to maintain vital systems. The first signs of impending renal failure are oliguria, gradually declining creatinine clearance, and rising serum creatinine, usually in the face of rapidly accumulating tense ascites. When all the measures used to treat the severe form of the syndrome have failed to reinstate proper renal perfusion, dopamine drip may be helpful. Intensive monitoring, including central venous pressure and pulmonary wedge pressure may be required. Once frank renal failure has occured, hemodialysis may be necessary. At this stage, if the patient is pregnant, the painful alternative of pregnancy termination should be strongly considered.

Increased capillary permeability may result in several cardio-respiratory problems. Diaphragmatic movement may be restricted by tense ascites, compromising respiratory function. Cardiac output may be impaired by reduced venous return resulting from reduction of the intravascular volume and ascitic pressure on the inferior vena cava. Cardiac output is initially maintained by compensatory tachycardia, but subsequently hypotension may result. Paracentesis combined with careful expansion of the intravascular compartment with albumin needs critical monitoring of the hemodynamic status. Pleural effusions only require drainage if symptomatic, and pericardial effusions are probably best managed conservatively.

Thromboembolic complications
Infrequently phenomena in OHSS, however, they are an important concern and potentially fatal. Although abnormalities of the coagulation system have been identified in OHSS and mild abnormalities of liver function tests are common, there is no coagulation abnormality in most patients. The increased risk of thromboembolism probably relates to frequent occurrence of hemoconcentration. To reduce the risk, patients should be encouraged to move their legs; anti thrombotic stockings may be worn, and low-dose SC heparin or Low Molecular Weight Heparin (LMWH) like Celxan may be helpful.

Posteroanterior and lateral chest radiograph findings are normal, which is the usual finding in patients with pulmonary embolism.

A pulmonary angiogram shows the abrupt termination of the ascending branch of the right upper-lobe artery, confirming the diagnosis of pulmonary embolism

Surgical management:

Surgical management is reserved only for acute cyst complications such as hemorrhage or torsion, and for ruptured ectopic pregnancy or abortion.

Two main complications of OHSS requiring immediate diagnosis and emergency treatment are ovarian torsion and actively bleeding ovarian cyst rupture. It should be remembered that both conditions are rare but require surgery by an experienced gynecologist.

Diagnosis of ovarian torsion may be difficult and should be suspected in patients with signs of acute abdomen. Simple unwinding of the ovarian torsion may save the ovary even if signs of ischemia are noted. A sudden decline of the patient’s hematocrit may be an important indicator of an intra-abdominal hemorrhage. At surgery, maximum care must be taken not to cause further damage, and the extent of surgery should be the minimal necessary. In case of actively bleeding ovarian rupture, electrocoagulation may suffice and save the ovary.

In case of unruptured ectopic gestation, expectant management (in face of falling -hCG levels) or chemotherapy (methotrexate, systemic or locally injected under US guidance) should be the preferred treatment modalities. Because of the severe ascites and massive ovarian enlargement, laparoscopy is contraindicated and surgery should be best avoided.

Summary: Guidelines for management of severe OHSS:

The following measures are taken as soon as the patient is hospitalized:

1. In every case, on admission, an IV infusion of normal saline solution should be set up. As a primary treatment 400-500 mL are usually sufficient. Baseline fluid intake should be maintained at 2 to 3 L/day. There is no  place for strict fluid restriction in the management of severe OHSS. Potassium should be given only if hypokalemia is present, and special care should be given if renal function is impaired. A central line should be strongly considered in order to monitor the fluid balance accurately, especially if hypotension and tachycardia are present.

2. An intensive care chart should be opened. Fluid balance should be monitored by strict input/output charts, together with at least daily measurements of hematocrit, electrolytes, weight and abdominal girth.

3. After consultation, colloids like albumin or hemacel are recommended in addition to crystaloids in order to prevent hemoconcentration and to raise the intravascular oncotic pressure. Colloid administration should be considered in the following situations: pleural or pericardial effusion, anasarca, ascites, hematocrit above 45 or if the patient is oliguric.

4. Fluid intake and output are carefully assessed and recorded.

5. Body weight and abdominal circumference are recorded every day.

6. Basal blood studies are ordered including: CBC, PT, PTT, fibrinogen, and a clot observation test set up on the spot, renal function tests, electrolytes, plasma proteins, blood osmolarity and liver function tests (bilirubin, sGOT, sGPT, alkaline phosphatase).

7. 24 hours collected urine is evaluated for creatinine, osmolarity and urine analysis.

8. The hematocrit is one of the best indicators of hemoconcentration and should be taken at least twice a day until stabilization. All the other blood and urine tests are ordered daily, and every 2-3 days afterwards.

9. Ultrasonography is performed as soon as possible after admission and repeated 2-3 times a week. The ovaries should be scanned and accurately measured.

10. Blood pressure should be measured, pulse rate, respirations and urine output should be taken and carefully  recorded. All these values combined with central venous pressure will help to estimate fluid balance and rate of rehydration.

11. X-ray is ordered, ECG is performed. If signs of pleural effusion or pulmonary edema are noted or the patient has dyspnea blood gases are evaluated and pleural puncture is performed. In this case, a central line is mandatory in order to evaluate fluid balance accurately.

12. Abdominal paracentesis is recommended for symptomatic relief of abdominal discomfort or dyspnea caused by pronounced ascites.

13. In case of oliguria, careful hydration of the patient with frequent CVP measurements should be performed. If the CVP rises above 15 cm H2O and the urinary output is still not satisfactory, IV furosemide (5-10 mg) with careful hydration may be recommended until urinary output improves.

14.  Avoid vaginal examinations, as the risk of rupturing an ovarian cyst outweighs its merits.

15.  Do not restrict salt and water intake, as further hypovolemia can be induced.

16.  Encourage the patient to move her legs, and perscribe anti thrombotic stockings and/or low-dose SC heparin or LMWH if ambulation is unlikely.

17.  Anticoagulant therapy in the form of IV heparin is required only when evidence of thromboembolism appears.

18. Surgery is indicated only when torsion or rupture of an ovarian cyst occurs. With massive ascites and ovarian enlargement laparoscopy is contraindicated.

The purpose of the measures elaborated in points 1-18 is to bring the patient to a satisfactory clinical condition until spontaneous resolution of OHSS.

Ovarian ligament with doppler blood flow shown by red and blue colors

Ovarian hyperstimulation syndrome - therapeutic approach