Management of ovarian hyperstimulation syndrome

INTRODUCTION — Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian hyperstimulation (COH) for assisted reproduction. It is characterized by a broad spectrum of signs and symptoms that includes abdominal distention and discomfort, enlarged ovaries, ascites, and other complications of enhanced vascular permeability. The syndrome can be strictly defined as the shift of serum from the intravascular space to the third space, mainly to the abdominal cavity, in the context of enlarged ovaries due to follicular stimulation. In its very severe form, OHSS is a life-threatening condition.

The management of OHSS will be reviewed here. The pathogenesis, clinical manifestations, and prevention of OHSS are discussed separately. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome" and "Prevention of ovarian hyperstimulation syndrome".)

BACKGROUND — OHSS is an iatrogenic and potentially life-threatening condition that affects young, healthy females [1,2]. In addition, there is an important economic burden associated with OHSS due to absence from work, bed rest, or hospitalization and intensive medical management of severe cases.

The pathophysiology of OHSS is not fully understood, but increased capillary permeability with the resulting loss of fluid into the third space is its main feature. In the susceptible patient, human chorionic gonadotropin (hCG) administration for final follicular maturation and triggering of ovulation is the pivotal stimulus for OHSS, leading to overexpression of vascular endothelial growth factor (VEGF) in the ovary, release of vasoactive-angiogenic substances, increased vascular permeability, loss of fluid to the third space, and full-blown OHSS (algorithm 1).

There are two clinical forms of OHSS, both hCG related: the early-onset form (occurring on the first eight days after exogenous hCG administration) and the late-onset form (occurring nine or more days after hCG administration, related to pregnancy-induced hCG production) [3]. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome", section on 'Onset'.)

PREVENTION — The keys to preventing OHSS are to identify the potential risk for the individual patient and to plan appropriate strategies to avoid its occurrence. The main steps include recognizing risk factors, using individualized ovarian stimulation regimens for assisted reproduction, modifying treatment when indicators for increasing OHSS risk develop, and using an alternative to standard-dose human chorionic gonadotropin (hCG) agonist for final oocyte maturation. The use of GnRH agonists for final oocyte maturation are associated with much lower risks of OHSS than hCG [4]. These strategies, as well as other interventions that are thought to be ineffective (eg, intravenous albumin), are reviewed in detail separately. (See "Prevention of ovarian hyperstimulation syndrome".)

APPROACH TO MANAGEMENT — The management of established OHSS should be conservative and directed at symptoms and/or signs of worsening; many females can be managed as outpatients. However, females with severe or critical OHSS require hospitalization (in some cases in the intensive care unit [ICU]). OHSS is a self-limited disease, although symptoms may be prolonged if pregnancy has occurred.

The general approach to managing the patient with OHSS is outlined in the algorithm (algorithm 2).

Our approach is similar to the American Society of Reproductive Medicine, the Royal College of Physicians of Ireland, and the Joint Society of Obstetricians and Gynecologists of Canada-Canadian Fertility and Andrology Society, all of whom have published clinical practice guidelines for OHSS [5-7].

Mild OHSS — Most ovarian hyperstimulation syndrome (OHSS) cases are mild or moderate and can be managed on an outpatient basis (table 1). Normally, these cases are self-limited and can be managed conservatively, with a goal of relieving symptoms.

Mild OHSS is seen in many females undergoing ovarian stimulation for assisted reproduction. For mild OHSS, analgesics (acetaminophen rather than nonsteroidal anti-inflammatory drugs [NSAIDs]) and avoidance of heavy physical activity are usually enough. Patients should be instructed to call for any signs or symptoms of worsening (oliguria, abdominal distention, shortness of breath, or weight gain [a sign of fluid accumulation]) (table 1 and algorithm 2).

Mild OHSS can progress to become moderate or severe, particularly if pregnancy has occurred. Therefore, females with mild disease should be observed for worsening abdominal pain, weight gain (>1 kg/day), and increasing abdominal girth for at least two weeks or until menstrual bleeding occurs.

Moderate OHSS — For females with moderate ovarian hyperstimulation syndrome (OHSS), recommendations include (table 1 and algorithm 2):

●Oral fluid intake of 1 to 2 liters per day. Diuretics are contraindicated because they can worsen decreased intravascular volume.

●Ambulate, but avoid other physical activity. Avoid sexual intercourse.

•Bed rest is sometimes necessary

●Daily weights, abdominal circumference measurements, and urinary output recordings.

●Monitoring for signs of progression is performed at the time of initial presentation and every 48 hours thereafter (or daily if worsening symptoms develop):

•Physical examination

•Transvaginal ultrasound (TVUS)

•Laboratory testing (complete blood count [CBC], electrolytes, creatinine, serum albumin, and liver enzymes)

●Daily communication with patient:

•Is hydration adequate?

•Document weight, abdominal circumference, and urine output

•Report any signs or symptoms of worsening

●Pregnant patients must be followed very closely as they are likely to worsen (or present with more severe symptoms) because of the rising levels of endogenous human chorionic gonadotropin (hCG) [6]. Pregnant patients with severe OHSS take longer to recover than nonpregnant patients (who typically experience resolution of symptoms within 10 to 14 days).

Ascites/culdocentesis — Although transabdominal paracentesis is reported to be successful [8], most in vitro fertilization (IVF) centers are more experienced with transvaginal aspiration of the ascitic fluid from the cul-de-sac, guided by TVUS. Ultrasound-guided culdocentesis is often performed (even on an outpatient basis) in females with tense ascites, orthopnea, rapid increase of abdominal fluid, or any other sign that may indicate progression of illness [7]. Removal of ascitic fluid provides symptomatic relief; females without other complications can then continue to be monitored as outpatients.

The volume of fluid to be removed is not well established, but after aspiration of 500 mL of ascitic fluid, patients typically report resolution of abdominal discomfort. In one report of 19 females with OHSS, after aspiration of 2000 mL of ascites, a reduction in intra-abdominal pressure and renal artery resistance was seen, followed by an increase in urine output [9]. Removal of more than 4 liters of fluid is not recommended. Blind paracentesis should not be done, because of the potential risk of bowel or vessel puncture.

Dopamine agonists (DA) — In females at high risk for OHSS undergoing ovarian stimulation, the rate of developing moderate and severe OHSS can be significantly reduced with cabergoline (0.5 mg/day orally), beginning on the day of hCG administration or oocyte retrieval. Less is known about the efficacy of DA for the treatment of OHSS once it is established. However, some small studies suggest it may diminish clinical symptoms and severity [10-13]. (See "Prevention of ovarian hyperstimulation syndrome".)

Severe and critical OHSS

Hospitalization — Hospitalization is mandatory in females with severe ovarian hyperstimulation syndrome (OHSS) and any of the following criteria: a hematocrit >55 percent, leukocytes >25,000/L, and creatinine >1.6 mg/dL. Females with severe abdominal pain, intractable vomiting, severe oliguria/anuria, tense ascites, dyspnea or tachypnea, hypotension, dizziness or syncope, severe electrolyte imbalance, or abnormal liver function tests must also be hospitalized (table 1 and algorithm 2).

We suggest that females be hospitalized in a facility with extensive OHSS experience. Inpatient care consists of supportive care, monitoring, and prevention and treatment of complications.

Medical treatment of severe hyperstimulation is directed at maintaining intravascular blood volume. Although isotonic crystalloid solutions (eg, normal saline, Ringer's lactate) are typically used for intravenous hydration in patients with severe OHSS, some clinicians use intravenous albumin in critically ill, volume-depleted patients. However, available evidence suggests that intravenous albumin provides no additional benefit when compared with crystalloid solutions. (See "Treatment of severe hypovolemia or hypovolemic shock in adults", section on 'Normal saline (crystalloid)'.)

Simultaneous goals are correcting the disturbed fluid and electrolyte balance, relieving secondary complications of ascites and hydrothorax, and preventing thromboembolic phenomena. We suggest thromboprophylaxis in all hospitalized patients with OHSS. (See 'Prophylaxis for thromboembolic events' below.)

In addition to volume management and prophylaxis for thromboembolism, patients should also be monitored for signs of infection. Bacterial peritonitis has been described in occasional patients [14]; other potential sources of infection include indwelling catheters and procedures to drain pleural and ascitic fluid. If bacterial infection is suspected, we suggest broad-spectrum empiric antibiotic therapy while awaiting culture results. We typically use a third- or fourth-generation cephalosporin in combination with metronidazole [15].

Critical OHSS cases should be managed in an intensive care unit (ICU) [16]. Routine ICU care will not be reviewed here. However, aspects of daily monitoring that are particularly important for females with OHSS include (table 1 and algorithm 2) [6,16]:

●Assessment of fluid balance (daily or more often)

●Weights and measurement of abdominal circumference

●CBC

●Electrolytes, blood urea nitrogen (BUN), creatinine

●Serum hCG measurements (to determine if patient has conceived)

●Invasive monitoring of central venous pressure

●Pelvic ultrasound as needed to evaluate ovarian size and ascites

●Chest radiograph and echocardiogram when pleural or pericardial effusion is suspected (as often as needed)

The management of severe complications such as massive hydrothorax, pericardial effusion, arterial thrombosis, pulmonary embolism, sepsis, acute renal failure, acute respiratory distress syndrome (ARDS), and disseminated intravascular coagulation (DIC) are reviewed in their relevant topics. (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)

Prophylaxis for thromboembolic events — We suggest prophylaxis for thromboembolism in the following settings [17]:

●All hospitalized patients with OHSS. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

●Females with OHSS being managed as outpatients with two to three additional risk factors (in addition to OHSS): age >35 years, obesity, immobility, elevated hematocrit, personal or family history of thrombosis, thrombophilias, and pregnancy. For those in whom bed rest is suggested, an intermittent pneumatic compression device is typically recommended. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Intermittent pneumatic compression'.)

●We use prophylactic low molecular weight heparin, 20 mg subcutaneously every 12 hours, or heparin 5000 units subcutaneously every 12 hours [5-7].

Resolution and prognosis — The pathophysiological process of OHSS is self-limited, and increased vascular permeability regresses spontaneously. Those who have not conceived recover over 10 to 14 days from the onset of initial symptoms. Third-space fluid begins to re-enter the intravascular space, hemoconcentration reverses, and natural diuresis ensues.

Clinical evidence of resolution includes:

●Normalization of hematocrit

●Progressive reduction of ascites on ultrasound

●Alleviation of clinical symptoms

If pregnancy occurs, resolution may take longer [18]. As described above, OHSS may worsen initially as hCG levels rise. Some studies have suggested that OHSS pregnancies are associated with a higher rate of miscarriage and later complications, such as gestational diabetes and pregnancy-associated hypertension [19,20]. However, in a retrospective chart review of females undergoing IVF, similar rates of gestational diabetes and preeclampsia were seen in those who did and did not develop OHSS [21].  

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian hyperstimulation syndrome".)

SUMMARY AND RECOMMENDATIONS

●Ovarian hyperstimulation syndrome (OHSS) – OHSS is the most serious complication of controlled ovarian hyperstimulation (COH) for assisted reproduction. It is a broad spectrum of signs and symptoms that include abdominal distention and discomfort, enlarged ovaries, ascites, and other complications of enhanced vascular permeability. (See 'Background' above.)

OHSS is a self-limited disease, although symptoms may be prolonged if pregnancy has occurred. Management should be conservative and directed at symptoms; many females can be managed as outpatients. However, females with severe or critical OHSS require hospitalization (in some cases to the intensive care unit [ICU]). (See 'Background' above.)

•Mild OHSS – Females with mild OHSS (table 1) should receive outpatient management that includes analgesics (acetaminophen) and avoidance of heavy physical activity. Patients should be instructed to call for any signs or symptoms of worsening (oliguria, abdominal distention, shortness of breath, or weight gain [a sign of fluid accumulation]). Females should also avoid sexual intercourse (which could cause discomfort and increase the risk of ovarian rupture). (See 'Mild OHSS' above.)

Mild OHSS can progress to moderate or severe OHSS, particularly if pregnancy has occurred. Therefore, females with mild disease should be observed for worsening abdominal pain, weight gain (>1 kg/day), and increasing abdominal girth for at least two weeks or until menstrual bleeding occurs (table 1 and algorithm 2). (See 'Mild OHSS' above.)

•Moderate OHSS – Females with moderate OHSS should receive outpatient management that includes avoidance of physical activity, oral hydration (1 to 2 liters per day), and a baseline transvaginal ultrasound (TVUS) and complete blood count (CBC) to look for ascites and hemoconcentration, respectively. In addition, daily communication with the patient is done to monitor daily weights and abdominal circumference and to report any worsening signs and symptoms (oliguria, abdominal distention, shortness of breath, weight increase). Other monitoring for signs of progression should be done every 48 hours (or daily if symptoms are worsening), including physical and ultrasound examinations and laboratory testing (CBC, electrolytes, creatinine, serum albumin, and liver enzymes) (table 1 and algorithm 2). (See 'Moderate OHSS' above.)

Pregnant patients must be followed very closely as they are likely to worsen (or present with more severe symptoms) because of the rising levels of endogenous human chorionic gonadotropin (hCG) [6]. Pregnant patients take longer to recover than nonpregnant patients (who typically experience resolution of symptoms within 10 to 14 days). (See 'Moderate OHSS' above.)

Ultrasound-guided culdocentesis is often performed (even on an outpatient basis) in females with tense ascites, orthopnea, rapid increase of abdominal fluid, or any other sign that may indicate progression of illness. (See 'Ascites/culdocentesis' above.)

•Severe OHSS – Females with severe OHSS and any of the following criteria: a hematocrit >45 percent, leukocytes >25,000/L, and creatinine >1.6 mg/dL should be hospitalized. Females with severe abdominal pain, intractable vomiting, severe oliguria/anuria, tense ascites, dyspnea or tachypnea, hypotension, dizziness or syncope, severe electrolyte imbalance, and abnormal liver function tests must also be hospitalized (table 1 and algorithm 2). (See 'Hospitalization' above.)

We suggest thromboembolism prophylaxis for all hospitalized patients with OHSS (Grade 2C). In addition, we suggest prophylaxis for those managed as outpatients with two to three additional risk factors (in addition to OHSS): age >35 years, obesity, immobility, elevated hematocrit, personal or family history of thrombosis, thrombophilias, and pregnancy. (See 'Prophylaxis for thromboembolic events' above.)

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 events (table 1 and algorithm 2). (See 'Hospitalization' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Bruno Lunenfeld, MD and the late Vaclav Insler, MD, who contributed to earlier versions of this topic review.