Ovarian Hyperstimulation Syndrome Treatment & Management

In the ideal situation, the ovaries should be stimulated to the desired level when ovulation is induced. However, the unpredictable response of the ovaries to induction makes the prediction and prevention of OHSS difficult. ^[4] Hence, heightened clinical suspicion and early intervention are paramount to the reduction of morbidity and mortality.

Treatment should include the following:

• Maintenance of a high degree of clinical suspicion and a low threshold for admission

• Early surgical intervention in cases of ovarian torsion or hemorrhage

• Paracentesis to address ascites - This decreases pressure on the inferior vena cava and diaphragm

• Placement of a transthoracic tube to manage pleural effusions

Treatment should not include the following:

• Aggressive palpation of the abdomen - This can precipitate follicular rupture

• Early surgical intervention - Early surgery may cause extensive bleeding from ovarian cysts; as stated above, however, surgery is mandated if torsion or rupture causing hemorrhage has occurred

• Neglect of organ and system deterioration - Remember that OHSS is a syndrome of multiorgan dysfunction

Surgery

Ovarian hyperstimulation syndrome is a self-limiting disease. Therefore, treatment should be conservative and directed at symptoms, with medical therapy being sufficient for most patients. Women with severe symptoms often require intensive medical care.

Surgical management further aggravates electrolyte imbalances and increases morbidity. Indeed, surgery is necessary only in extreme cases, such as in the case of ovarian torsion, a ruptured cyst, or an internal hemorrhage. Ascites can be tapped by means of paracentesis. Laparotomy during torsion and intraperitoneal hemorrhage is lifesaving and recommended.

Consultations

In severe cases of OHSS, consultation with a physician specializing in fluid and electrolyte imbalances is warranted. For some cases, aggressive treatment in the surgical intensive care unit may be required.

Diet

Ensure that the patient receives plenty of hydration.

Activity

Patient activity should be minimal.

Conservative management in the outpatient setting is appropriate for mild-to-moderate ovarian hyperstimulation syndrome (OHSS) until spontaneous resolution occurs. However, management in the inpatient setting should be considered if any of the following criteria are present:

• Inability to tolerate oral food or hydration

• Severe abdominal pain

• Unclear diagnosis

• Hypotension

• Shortness of breath

• Tense ascites

• Peritoneal signs

• Hematocrit greater than 48%

• Sodium less than 135 mEq/L

• Potassium greater than 5 mEq/L

• Creatinine greater than 1.2 mg/dL

Mild hyperstimulation

Treatment for OHSS is supportive. Mild ovarian hyperstimulation can develop into moderate or severe disease, especially if conception ensues. Therefore, women with mild disease should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least 2 weeks or until menstrual bleeding occurs.

Moderate hyperstimulation

The treatment of moderate OHSS consists of observation, bed rest, the provision of adequate fluids, and ultrasonographic monitoring of the size of cysts. Serum electrolyte concentrations, hematocrits, and creatinine levels should also be evaluated.

Some physicians have their outpatients keep track of their fluid intake and output. Intake or output of less than 1000 mL daily or a discrepancy in fluid balance of greater than 1000 mL daily is a cause for concern. ^[20]

The beginning of the resolution of OHSS is apparent when the cysts shrink, as seen on 2 consecutive ultrasonographic examinations, and when clinical symptoms recede. In contrast, early detection of progression to the severe form of the syndrome is marked by continuous weight gain (≥2 lb daily), increased severity of existing symptoms, or the appearance of new symptoms (eg, vomiting, diarrhea, or dyspnea). ^[19]

Severe hyperstimulation

Clinician experience with severe OHSS is mandatory for appropriate treatment. One should transfer the patient to a different center if no one who is experienced in managing severe OHSS is available at the present location.

Severe OHSS is not common, but it is dangerous. Severe and critical forms of OHSS are potentially fatal disorders, and history taking and physical examination are paramount at the time of admission. In most clinical situations, patients require bed rest. Daily physical examination should consist of measuring the patient's weight and abdominal girth. Fluid balance must be assessed every 4 hours.

Medical treatment of severe hyperstimulation is directed at maintaining intravascular blood volume. Simultaneous goals are correcting the disturbed fluid and electrolyte balance, relieving secondary complications of ascites and hydrothorax, and preventing thromboembolic phenomena.

The main interventions are fluid management and correction of hypovolemia. These measures consist of initial intravenous (IV) administration of 1 L normal saline over 1 hour. Dextrose 5% in normal saline or normal saline is then infused at a rate of 125-150mL/h, with 4-hour tabulations of urine production. If urine production is restored or improved, IV hydration at a maintenance rate of 125-150 mL/h is continued.

If urine output is unsatisfactory, hyperosmolar IV therapy is indicated, with an infusion of 50-200 mL of 25% human albumin every 6 hours. The use of diuretics in patients with low urine production and intravascular volume depletion is counterproductive and dangerous. ^[19] Adequate intravascular volume as evidenced by normalizing hematocrit levels should be present before diuretics are used.

Close surveillance of fluid management is necessary. IV fluid administration is stopped when urine production, appetite, or interest in drinking increases and when overall clinical improvement is observed. In the resolution phase of severe OHSS, the patient's fluid intake should be restricted to avoid renewed hemodilution.

To prevent thrombosis, subcutaneous heparin 5000-7500 U daily is begun on the first day of admission. It is stopped after adequate ambulation is achieved.

To manage ascites, ultrasonographically guided abdominal or vaginal paracentesis is indicated if the patient has severe discomfort or pain or if she has pulmonary or renal compromise. ^[24] The vaginal procedure entails the same setup as that used for transvaginal follicular puncture. Whelan and Vlahos advise that an anesthesiologist be present. Paracentesis may be repeated if necessary. ^[20] Use of an indwelling pig-tail catheter may be considered for extended drainage.

Critical hyperstimulation

Grade 5 OHSS may include renal failure, hepatic damage, thromboembolic phenomena, ARDS, and multiorgan failure. ^[25] Its management and treatment require intensive care in a critical care unit. Such care should include invasive monitoring of circulatory indicators, including venous pressure and wedge pressure. The patient may need extra oxygenation (assisted ventilation).

If renal failure is present, an IV dopamine regimen should be started. To treat thromboembolism, therapeutic doses of anticoagulants should be administered. Thoracocentesis should be performed in cases of severe hydrothorax. Finally, if a pregnancy is maintaining a life-threatening OHSS, therapeutic abortion must be considered.

After several days, third-space fluid begins to reenter the intravascular space, hemoconcentration reverses, and natural diuresis ensues. IV fluids may be tapered as the patient's oral intake increases. Complete resolution typically takes 10-14 days from the onset of initial symptoms.

Careful maintenance of blood volume, correction of electrolyte imbalances, and relief of secondary complications of ascites and hydrothorax are generally sufficient to support the patient during the severe phase of ovarian hyperstimulation. If these treatments are promptly administered, anticoagulant therapy is usually unnecessary. Blood coagulation may be monitored because of the danger of disseminated intravascular clotting.

Ovarian hyperstimulation syndrome (OHSS) is a self-limiting disease of the luteal phase. Without luteinizing hormone (LH) or its imitator, hCG, ovulation or the luteal phase does not occur. Avoidance of hCG during ovarian stimulation offers an opportunity to prevent OHSS in high-risk patients. However, those patients do not conceive. Other options are delaying hCG (coasting) for 1-3 days until estradiol levels plateau or decline (< 2500 pg/mL), using a GnRH agonist to induce ovulation, or lowering doses of hCG. ^[19]

The best preventive method is to adapt the treatment and closely monitor patients at risk. Remember that women at risk are those with high levels of estrogen and many follicles at the assumed time of ovulation. Patients with polycystic ovarian syndrome should be closely monitored as well.

Two trials, involving 230 women with moderate risk of bias, found evidence that a daily oral dose of 0.5 mg of the dopamine agonist cabergoline may reduce the risk of ovarian hyperstimulation in high-risk women, with no influence on pregnancy outcome. ^[26]

Laboratory findings of a serum estradiol concentration of greater than 2000 pg/mL and a progesterone concentration of greater than 30 ng/mL in the early part of the luteal phase are warning signs of developing OHSS. ^[23]

Vaginal intercourse is restricted in women with any grade of OHSS because of the risk of rupturing a cyst. Patients should also avoid impact-type activities or strenuous exertion.

Prevention guidelines

A 2014 clinical practice guideline from the Society of Obstetricians and Gynaecologists of Canada (SOGC), The Prevention of Ovarian Hyperstimulation Syndrome, includes the following recommendations ^[27] :

• The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization, because it may reduce the incidence of OHSS

• Gonadotropin dosing should be carefully individualized, taking into account the patient’s age, body mass, antral follicle count, and previous response to gonadotropins

• Cycle cancellation before administration of hCG is an effective strategy for the prevention of OHSS, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled

• GnRH antagonist stimulation protocols are recommended in patients at high risk for OHSS; the risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for hCG to trigger final oocyte maturation

• A GnRH antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles

• Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of OHSS

• Elective single-embryo transfer is recommended in patients at high risk for OHSS

• Progesterone, rather than hCG, should be used for luteal-phase support

• Outpatient culdocentesis should be considered for the prevention of disease progression in severe OHSS