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## Complete Summary

#### GUIDELINE TITLE

Ovarian hyperstimulation syndrome.

#### BIBLIOGRAPHIC SOURCE(S)

Ovarian hyperstimulation syndrome. Fertil Steril 2003 Nov;80(5):1309-14.
\[53 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14607613)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [February 28, 2008, Heparin Sodium
    Injection](http://www.fda.gov/medwatch/safety/2008/safety08.htm#HeparinInj2):
    The U.S. Food and Drug Administration (FDA) informed the public that
    Baxter Healthcare Corporation has voluntarily recalled all of their
    multi-dose and single-use vials of heparin sodium for injection and
    their heparin lock flush solutions. Alternate heparin manufacturers
    are expected to be able to increase heparin production sufficiently
    to supply the U.S. market. There have been reports of serious
    adverse events including allergic or hypersensitivity-type
    reactions, with symptoms of oral swelling, nausea, vomiting,
    sweating, shortness of breath, and cases of severe hypotension.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Ovarian hyperstimulation syndrome (OHSS)

#### GUIDELINE CATEGORY

Management\
Prevention

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Obstetrics and Gynecology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To present guidelines that discuss the pathophysiology of ovarian
hyperstimulation syndrome (OHSS) and its risk factors, clinical
features, management, and prevention

#### TARGET POPULATION

Women with ovarian hyperstimulation syndrome

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Evaluation/Prevention**

1.  Evaluation of clinical features and risk factors for developing
    ovarian hyperstimulation syndrome (OHSS)

2.  Experience with ovulation induction therapy

3.  Evaluation and laboratory assessments of hospitalized patients with
    OHSS

**Management**

1.  Outpatient management

2.  Hospitalization

3.  Intravenous fluid management, including monitoring renal and
    pulmonary function

4.  Ultrasound-guided paracentesis

#### MAJOR OUTCOMES CONSIDERED

-   Progression of illness

-   Hospitalization

-   Life-threatening complications including renal failure, adult
    respiratory distress syndrome (ARDS), hemorrhage from ovarian
    rupture, and thromboembolism

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review\
Review of Published Meta-Analyses

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**[Risk Factors]{.underline}**

The following factors increase the risk independently for developing
ovarian hyperstimulation syndrome (OHSS):

-   Young age

-   Low body weight

-   Polycystic ovary syndrome (PCOS)

-   Higher doses of exogenous gonadotropins

-   High absolute or rapidly rising serum estradiol levels

-   Previous episodes of OHSS

In addition, risk rises with the number of developing ovarian follicles,
and the number of oocytes retrieved in assisted reproductive technology
(ART) cycles. Risk increases when higher or repeated doses of exogenous
human chorionic gonadotropin (hCG) are administered in superovulation
and ART cycles (for ovulation induction or luteal phase support) and
decreases when exogenous progesterone, rather than hCG, is used to
support the luteal phase. Pregnancy increases the likelihood, duration,
and severity of OHSS symptoms.

**[Clinical Features]{.underline}**

The OHSS has traditionally been classified as mild, moderate, or severe.
However, the clinical symptoms and signs of OHSS exhibit a continuum of
scope and severity that defies attempts at specific classification or
staging.

Mild manifestations of OHSS are relatively common and include:

-   Transient lower abdominal discomfort

-   Mild nausea

-   Vomiting

-   Diarrhea

-   Abdominal distention (observed in up to a third of superovulation
    cycles)

Onset of symptoms typically occurs soon after ovulation (in
superovulation cycles) or after oocyte retrieval in ART cycles, but it
may be delayed.

Progression of illness is recognized when symptoms persist, worsen, or
include ascites that may be demonstrated by increasing abdominal girth
or ultrasound evaluation. Serious illness exists when pain is
accompanied by one or more of the following:

-   Rapid weight gain

-   Tense ascites

-   Hemodynamic instability (orthostatic hypotension, tachycardia)

-   Respiratory difficulty (tachypnea)

-   Progressive oliguria

-   Laboratory abnormalities

Hypotension results from extravasation of protein-rich fluid and
contraction of the vascular volume, oliguria/anuria from reduced renal
perfusion due to decreased vascular volume and/or tense ascites, and
pulmonary compromise from an elevated diaphragm and/or hydrothorax. Risk
of thromboembolism is increased as a result of hemoconcentration,
diminished peripheral blood flow, and inactivity due to abdominal
distension and pain. Life-threatening complications of OHSS include
renal failure, adult respiratory distress syndrome (ARDS), hemorrhage
from ovarian rupture, and thromboembolism.

**[Management]{.underline}**

**Outpatient Management**

Patients with mild manifestations of OHSS can be managed on an
outpatient basis. Treatment usually requires only oral analgesics and
counseling regarding the signs and symptoms of progressing illness.
Intercourse is best avoided as it may be painful and may increase the
risk of ovarian rupture.

Treatment of worsening OHSS typically requires antiemetics and more
potent analgesics. Most patients still can be effectively managed and
monitored on an outpatient basis, but they require more careful
evaluation including frequent physical and ultrasound examinations (to
detect increasing ascites), daily weight measurements, and serial
laboratory determinations of hematocrit, electrolytes, and serum
creatinine. Careful monitoring is essential and should include at least
daily communication, if not examination, to ensure that progression to
more severe disease is promptly recognized.

Recommendations for the outpatient management of persistent and
worsening OHSS include:

-   Oral fluid intake should be maintained at no less than 1 L per day;
    any of the commercially available electrolyte-supplemented drinks is
    preferable to other beverages.

-   Strenuous physical activity should be avoided as risk of ovarian
    torsion increases when the ovaries are significantly enlarged. Light
    physical activity should be maintained to the extent possible.
    Strict bed rest is unwarranted and may increase risk of
    thromboembolism.

-   Weight should be recorded daily, as well as the frequency and/or
    volume of urine output. Weight gain of [\>]{.underline}2 pounds per
    day or decreasing urinary frequency should prompt repeated physical
    examination, ultrasound, and laboratory evaluation to include
    hematocrit, electrolytes, and serum creatinine.

-   Pregnant patients with OHSS must be monitored very closely because
    risk of progressing to severe disease is particularly high for those
    further stimulated by rapidly rising serum concentrations of hCG.

-   In ART cycles, it may be necessary to consider cryopreserving all
    embryos and deferring transfer to a subsequent cycle after symptoms
    have completely resolved. Although pregnancy rates in frozen embryo
    transfer cycles are generally lower than in fresh cycles, this
    approach may reduce the risk for developing severe OHSS without a
    marked decrease in pregnancy rates per cycle.

**Hospitalization**

Serious illness requiring hospitalization is relatively uncommon but by
no means rare. Hospitalization may be required based on severity of
symptoms, analgesic requirements, and other social considerations
(availability of responsible adult supervision, support, and assistance
with child care).

Given the scope and severity of symptoms and the potential for
complications, most women with OHSS who are seriously ill merit
hospitalization for more careful monitoring and aggressive treatment. No
one symptom or sign is an absolute indication, but hospitalization
should be considered when one or more of the following are present:

-   Severe abdominal pain or peritoneal signs

-   Intractable nausea and vomiting that prevents ingestion of food and
    adequate fluids

-   Severe oliguria or anuria

-   Tense ascites

-   Dyspnea or tachypnea

-   Hypotension (relative to baseline), dizziness, or syncope

-   Severe electrolyte imbalance (hyponatremia, hyperkalemia)

-   Hemoconcentration

-   Abnormal liver function tests

Laboratory findings in women with serious illness resulting from OHSS
include:

-   Hemoconcentration (hematocrit \>45%)

-   Leukocytosis (white blood cell count \>15,000)

-   Electrolyte imbalances (hyponatremia: sodium \<135 mEq/L;
    hyperkalemia: potassium \>5.0 mEq/L)

-   Elevated liver enzymes

-   Decreased creatinine clearance (serum creatinine \>1.2; creatinine
    clearance \<50 mL/min)

Recommendations for the evaluation and monitoring of hospitalized
patients with OHSS include the following:

-   Vital signs (every 2--8 hours, according to clinical status)

-   Weight (recorded daily)

-   Complete physical examination (daily, avoiding bimanual examination
    of the ovaries due to risk of ovarian rupture)

-   Abdominal circumference (at the navel, recorded daily)

-   Monitoring of fluid intake and output (daily, or more often as
    needed)

-   Ultrasound examination (ascites, ovarian size), repeated as
    necessary to guide management or paracentesis (see below)

-   Chest x-ray and echocardiogram (when pleural or pericardial effusion
    is suspected), repeated as necessary

-   Pulse oximetry (for patients with symptoms of pulmonary compromise)

-   Complete blood count (daily, or more often as needed to guide fluid
    management)

-   Electrolytes (daily)

-   Serum creatinine or creatinine clearance, urine specific gravity,
    repeated as necessary

-   Liver enzymes, repeated as necessary

Careful and frequent reevaluation of the hospitalized patient with
severe OHSS is essential. Complaints of increasing abdominal pain and
distension demand immediate attention, remaining mindful that pain and
ascites can easily mask ovarian rupture and acute intra-abdominal
hemorrhage. Serial clinical and laboratory evaluations provide the means
to monitor progression of illness, to judge the response to treatment,
and to recognize evidence of resolution.

**Fluid Management**

Hospitalized patients require intravenous (IV) fluid management to
address the acute need for volume expansion while also considering the
marked increase in vascular permeability that accompanies severe OHSS.
Renal and pulmonary function must be carefully monitored. Guidelines for
fluid management for patients hospitalized with severe illness relating
to OHSS include the following:

-   Strict monitoring of fluid intake and urine output is essential
    until symptoms improve or diuresis begins.

-   Oral fluid intake should be carefully recorded and limited to those
    amounts necessary to maintain the patient\'s comfort.

-   Rapid initial hydration may be accomplished with a bolus of IV fluid
    (500--1,000 mL). Thereafter, fluids should be administered
    judiciously, in the volumes necessary to maintain adequate urine
    output (\>20--30 mL/h) and reverse hemoconcentration. Five percent
    dextrose in normal saline is preferable to lactated Ringer\'s
    solution, given the tendency to hyponatremia. Correction of
    hypovolemia, hypotension, and oliguria has highest priority,
    accepting that fluid administration may contribute to the
    accumulation of ascites.

-   Albumin (25%) in doses of 50--100 g, infused over 4 hours and
    repeated at 4- to 12-hour intervals as necessary, is an effective
    plasma expander when infusion of normal saline fails to achieve or
    maintain hemodynamic stability and adequate urine output. In
    general, albumin is the preferred plasma expander, although others
    (e.g., mannitol, fresh frozen plasma) may be used. Dextran has been
    associated with development of adult respiratory distress syndrome
    (ARDS) and is best avoided.

-   Treatment with diuretics (e.g., furosemide, 20 mg IV) may be
    considered after an adequate intravascular volume has been restored
    (hematocrit \<38%). Premature or overzealous use of diuretics will
    aggravate hypovolemia, and hemoconcentration, thereby increasing
    risk of thromboembolism.

-   Intravenous fluid administration should be sharply curtailed and
    oral fluid intake increased when there is evidence that the syndrome
    is resolving, generally heralded by improving symptoms and onset of
    a brisk diuresis.

-   Hyperkalemia is associated with risk of cardiac dysrhythmias. Acute
    management involves treatments that move potassium into the
    intracellular space (insulin and glucose, sodium bicarbonate,
    albuterol) or protect the heart from the effects of elevated
    potassium levels (calcium gluconate). Electrocardiographic
    manifestations of hyperkalemia (prolonged PR and QRS intervals, ST
    segment depression, tall peaked T waves) indicate the need for
    immediate treatment with calcium gluconate. Kayexalate is a cation
    exchange resin that removes potassium from the body but works more
    slowly (onset of action 1--2 hours); it may be administered orally
    or rectally as a retention enema.

**Paracentesis**

Ultrasound-guided paracentesis may be indicated for patients with
ascites that causes pain, compromised pulmonary function (e.g.,
tachypnea, hypoxia, hydrothorax), or oliguria/anuria that does not
improve with appropriate fluid management. A transvaginal or
transabdominal approach may be used, under gentle ultrasound guidance.
The optimal volume of fluid that should be removed on any one occasion,
and over what interval of time, is not well established. Whereas rapid
removal of large volumes of ascitic fluid has been observed to trigger
dangerous compensatory fluid shifts in elderly patients with malignant
ascites, the risk of such complications in young, otherwise healthy
women with OHSS is generally small. Nevertheless, it is prudent to
remove fluid at a deliberate pace until the desired effect is achieved,
while carefully monitoring the patient´s response. Serial paracentesis
may be required to maintain adequate renal and pulmonary function.
Severe ascites may be associated with hydrothorax, most commonly on the
right, resulting from transfer of abdominal fluid to the chest via the
thoracic duct. Paracentesis will generally be effective in resolving
hydrothorax and thoracentesis may be reserved for those with bilateral
or severe pleural effusions that persist.

Thromboembolism is a life-threatening complication of severe OHSS, and
prophylactic measures are warranted. Full-length venous support
stockings are recommended, and prophylactic heparin therapy (5,000 U
subcutaneously \[SC\], every 12 hours) should be seriously considered.
The use of an intermittent pneumatic compression device is prudent when
symptoms prevent ambulation and confine the patient to bed. Signs and
symptoms suggesting thromboembolism demand prompt additional diagnostic
measures (arterial blood gas measurements, ventilation/perfusion scan)
and therapeutic anticoagulation when the diagnosis is confirmed or
strongly suspected.

Intensive care may be required for management of thromboembolic
complications, renal failure, or pulmonary compromise that does not
respond to supportive care and paracentesis. Renal failure will often
respond to low-dose dopamine therapy (0.18 mg/kg/h) that will dilate
renal vessels and increase renal blood flow. Invasive monitoring of
central venous pressure or pulmonary capillary wedge pressure and even
short-term dialysis may be required. Pulmonary intensive care may
involve oxygen supplementation, thoracentesis, and assisted ventilation
when more conservative measures fail. Patients with severe OHSS who may
require surgery for a ruptured ovarian cyst with hemorrhage, torsion, or
an ectopic pregnancy present a unique challenge for the anesthesiologist
who is unlikely to be familiar with the pathophysiology of the syndrome
and must be quickly educated to minimize the additional risks involved.

**[Prevention]{.underline}**

The keys to preventing OHSS are experience with ovulation induction
therapy and recognition of risk factors for OHSS. Ovulation induction
regimens should be highly individualized, carefully monitored, and use
the minimum dose and duration of gonadotropin therapy necessary to
achieve the therapeutic goal.

Caution is indicated when any of the following indicators for increasing
risk of OHSS are present:

-   Rapidly rising serum estradiol levels

-   An estradiol concentration in excess of 2,500 pg/mL

-   The emergence of a large number of intermediate sized follicles
    (10--14 mm)

Withholding further gonadotropin stimulation and delaying hCG
administration until estradiol levels plateau or decrease significantly
can reduce risks of OHSS. Available evidence suggests that such
\"coasting\" does not adversely affect outcome in in vitro fertilization
(IVF) cycles unless it is prolonged (\>3 days).

Given the evidence suggesting that hCG may play a pivotal role in the
development of OHSS, a lower dose of hCG (e.g., 5,000 IU vs. the
standard 10,000 IU dosage) may be prudent for patients judged to be at
high risk for OHSS. Alternatively, a GnRH agonist (e.g., leuprolide
0.5--1.0 mg SC) rather than hCG might be used to stimulate an endogenous
LH surge to promote final oocyte maturation and induce ovulation. This
approach would be useful only in cycles not involving previous
down-regulation with longer term agonist treatment or use of a GnRH
antagonist (e.g., ganirelix, cetrorelix).

Regardless whether hCG or a GnRH agonist is administered at midcycle,
the use of exogenous progesterone (e.g., 50 mg progesterone in oil IM,
100 mg progesterone vaginal suppositories, or 8% progesterone vaginal
gel, daily) for luteal phase support rather than supplemental doses of
hCG, may further reduce risks of OHSS. When symptoms of OHSS emerge even
before administration of hCG, cycle cancellation and less aggressive
stimulation in a subsequent cycle should be seriously considered.

Although evidence indicates that meticulous follicle aspiration will
reduce corpus luteum P production, it cannot be relied on to prevent
development or progression of OHSS in ART cycles.

Prophylactic IV administration of 25% albumin (20--50 g) at time of
oocyte retrieval has been suggested as a means to reduce risk of OHSS
when E~2~ levels are markedly elevated or there is history of a previous
episode of OHSS. Studies of its efficacy have had mixed results, and
albumin treatment risks exacerbation of ascites, allergic reactions, and
virus/prion transmission. However, a recent meta-analysis of five
randomized controlled trials demonstrated that prophylactic albumin
administration significantly reduced risk of developing OHSS (odds ratio
\[OR\] 0.28, 95% confidence interval \[CI\] 0.11, 0.73); albumin
infusion may be expected to prevent one case of severe OHSS for every 18
women at risk who are treated.

**[Summary]{.underline}**

-   Experience with ovulation induction therapy and knowledge of ovarian
    hyperstimulation syndrome (OHSS) pathophysiology, risk factors, and
    clinical features are key to preventing and managing OHSS.

-   Mild manifestations of OHSS are fairly common, occurring in up to a
    third of exogenous gonadotropin-induced superovulation cycles.

-   Worsening symptoms of OHSS can still usually be managed on an
    outpatient basis, but frequent monitoring and evaluation are
    essential.

-   Serious illness resulting from OHSS is much less common, but it can
    be life-threatening.

-   Hospitalization may be necessary for patients with serious illness
    resulting from OHSS.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is not specifically stated for each
recommendation.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Effective prevention, management, and treatment of ovarian
hyperstimulation syndrome

#### POTENTIAL HARMS

Not stated

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Ovarian hyperstimulation syndrome. Fertil Steril 2003 Nov;80(5):1309-14.
\[53 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14607613)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2003 Nov

#### GUIDELINE DEVELOPER(S)

American Society for Reproductive Medicine - Private Nonprofit
Organization

#### SOURCE(S) OF FUNDING

American Society for Reproductive Medicine

#### GUIDELINE COMMITTEE

The Practice Committee of the American Society for Reproductive Medicine

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

Not stated

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [American Society for Reproductive
Medicine Web site](http://www.asrm.org/Media/Practice/practice.html).

Print copies: Available from American Society for Reproductive Medicine,
1209 Montgomery Highway, Birmingham, Alabama 35216-2809; Phone: (205)
978-5000; Fax: (205) 978-5005; E-mail: <asrm@asrm.org>; Web site:
[www.asrm.org](http://www.asrm.org/).

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on August 23, 2004. This summary
was updated by ECRI Institute on June 22, 2007 following the U.S. Food
and Drug Administration (FDA) advisory on heparin sodium injection. This
summary was updated by ECRI Institute on March 13, 2008 following the
updated FDA advisory on heparin sodium injection.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008