Ovarian hyperstimulation syndrome (OHSS)

In the unlikely event that you experience symptoms that require emergency hospitalization, you will please take this written information with you and pass it on to your doctor.
Severe forms of ovarian hyperstimulation syndrome are very rare and most specialists have no experience in such cases.
Therefore, the Gynera Clinic decided to provide this specialized information to all patients who have risk factors for ovarian hyperstimulation, to support physicians and serve as an up-to-date reference.

Ovarian hyperstimulation syndrome in short
(References: American Society for Reproductive Medicine, 2011, www.asrm.org)

• It is an exaggerated reaction of the body to the use of ovulation-inducing medication
• Increased capillary permeability causes fluid loss, bloating, nausea and bloating.
• Mild manifestations of OHSS are common after IVF stimulation, occurring in one-third of cases.
• Moderate forms are treated on an outpatient basis with: effort reduction, hydration, monitoring of urine volume.
• Severe forms require hospitalization and intravenous hydration.
• Symptoms appear after HCG administration and disappear spontaneously, usually within a week.
• In pregnant women, symptoms persist for 2-3 weeks or more and then gradually decrease.
• Gynecological examination is not recommended because enlarged ovaries and cysts can rupture under pressure.
• Oral monitoring and hydration are sufficient in most cases.

Ovarian hyperstimulation syndrome (OHSS)

1.1. Definition
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of the luteal phase and / or early pregnancy after induction of ovulation (causing ovulation in women with anovulatory cycle), or ovarian stimulation (in the context of intrauterine insemination or in vitro fertilization).

1.2. Essential features
The essence of OHSS is represented by the enlargement of the ovaries with the formation of cysts and the passage of fluids from the space.
intravascular in the third space, due to increased capillary permeability and ovarian angiogenesis. His appearance is dependent on the administration of human chorionic gonadotropin (HCG). Without HCG, OHSS occurs extremely rarely.
The impact on the patient’s health can be very important. Occasionally, fatal cases have been reported.

1.3. Early and late forms of OHSS
The early form of OHSS, although triggered by HCG, is linked to an exaggerated ovarian response to stimulation with
gonadotropin, while the late form is mainly due to placental secretion of HCG. The latest definition of OHSS (Mathur et al., 2000) still relies on the mentioned etiology, but makes a clear distinction between the early form (<10 days after induction of ovulation with HCG) and the late form (≥ 10 days after HCG administration).
Especially the cases that constitute a combination of the two forms and are followed by pregnancy are more severe and with long evolution (Papanikolaou et al., 2004).

2. Analysis of available information

2.1. Incidence
The exact figures of the OHSS incidence are not known due to the lack of systematic reporting. Light forms of OHSS occurs in 8-23% of stimulated cycles, moderate forms in <1-7% of cycles, and severe forms in ~ 0.5% of
stimulated cycles (Golan et al., 1989; Navot et al., 1992). Because of this severe OHSS is perceived by to gynecologists as a relatively rare complication. However, the total annual number worldwide is estimated at several thousand. The incidence has almost certainly increased over the years (Abramov et al., 1999). There are also fatal cases, though these are almost always not reported.

2.2. Symptoms
The most common signs and symptoms:
• Distension of the lower abdomen
• Progressive increase in abdominal circumference (measured at the navel)
• Enlargement of the ovaries up to over 12 cm
• Nausea and vomiting that impede nutrition and hydration
• Dyspnoea and breathing problems due to ascending diaphragm and hydrothorax
• Diarrhea
• Rapid weight gain

More severe signs and symptoms:
• Ascites
• Hypotension
• Pleural effusion (most common on the right side)
• Pericardial effusion
• Adult form of respiratory distress syndrome
• Oliguria and anuria
• Multiple organ failure
• Death (1 / 500,000 cycles) (Brinsden et al., 1995)

Changes in biological constants:
• Changes in electrolyte concentration (Na <136 mEq / l; K> 5 mEq / l)
• Hypovolemia
• Hemoconcentration (hematocrit> 45%)
• Leukocytosis> 15000 / mm3
• Creatinine clearance <50 ml / minute; serum creatinine> 1.2 mg / dl
• Increased liver enzymes
• Hypercoagulability
• Hypoproteinemia and hypoalbuminemia (<30 g / l)

Other complications:
• Ovarian torsion
It causes sudden and extremely violent abdominal pain and nausea; the incidence is 1/5000 cycles
stimulated, but increases if OHSS and pregnancy are associated (Mashiach et al., 1990)
• Ovarian bleeding
Occurs due to ovarian rupture or intraovarian bleeding, caused by pressure or bimanual examination;
manifests itself with signs of acute hemorrhage (hypotension, nausea, sudden decrease in hematocrit)
• Episodes of thromboembolism
They were described with both venous (65.7%) and arterial localization; 83% of them occur at the level
head, neck and arm, but can also occur in the vessels of the lower body (Delvigne et al., 2003);
pulmonary thromboembolism occurs in 4-12% of cases (Stewart et al., 1997). Venous embolisms were
described at the level of the humeral vein, subclavian, internal jugular and cavities, and the arterial at the level of the artery
subclavian, ulnar, internal carotid, middle cerebral, and coronary arteries.

2.3. Primary risk factors
• Polycystic ovary syndrome (PCOS)
• Patients with some of the characteristics of PCOS:
❖ Large number of follicles in both ovaries before stimulation (> 10 follicles of 4-10 mm in each ovary)
❖ LH / FSH ratio> 2
❖ Hyperandrogenism
• History of OHSS
• Young patient
• Weak women
• Atopic terrain (predisposition to allergies)

2.4. Secondary risk factors
• Maximum serum estradiol value> 3000-4000 pg / ml
❖ No clear cut-off value
❖ Relatively low predictive value (max. 73%)
❖ Estradiol itself is not a mediator, since OHSS may occur in patients with low blood pressure.
serum estradiol (in case of stimulation with recombinant FSH)
❖ The increase in serum estradiol is the main risk factor, and is more important than the level
maximum reached (predictive value of 77%)
• The number of follicles on each ovary> 20-25
❖ No clear cut-off value (10-35)
❖ Variable depending on the operator and technique
• Measurements of serum VEGF concentration are not useful for individual prediction (Mathur et al., 2002)

OHSS classification after the Golan (1989)

OHSS light form

  • Grade 1: Abdominal distension and discomfort
  • Grade 2: Grade 1 criteria: Nausea, vomiting and / or diarrhea; Larger ovaries, 5-12cm

Moderate OHSS

  • Grade 3: OHSS criteria easy form
  • Ascites ultrasound examination

OHSS sever

  • Grade 4: Moderate OHSS Criteria + Clinical Signs of Ascites and / or Hydrothorax and Respiratory Disorders
  • Grade 5: Grade 4 criteria + Changes in blood volume and viscosity, hemoconcentration, coagulation disorders; Low renal function
  • Grade 6: Life-threatening forms

Subsequently, two clarifications were introduced:
Critical OHSS (Navot et al., 1992) and severe OHSS group C (Rizk and Aboulghar, 1999), which describe the same
life-threatening clinical entity: severe reduction in circulating blood volume, severe haemoconcentration,
multiple organ failure (kidney, liver, heart) and / or thromboembolism symptoms. Both are considered as
grade 6 in the modern Golan classification. It is essential to understand that these degrees are not strictly separate entities
and that a moderate OHSS can progress rapidly to a severe OHSS.
The most important criterion for immediate hospitalization is hematocrit> 45%.

4. Clinical management

4.1.Hospitalization criteria:
• Hematocrit> 45%
• Any sign of severe OHSS

4.2. Elements of outpatient follow-up of the patient:
• Daily liquid balance
• Daily weighing
• Increased abdominal circumference in the navel
• Instructions for contacting the clinic for any signs of damage
• Control every 48-72 hours with blood tests and ultrasound examination

4.3. Patient monitoring in the hospital:
• Heart rate
• Blood pressure
• Daily liquid balance
• Ultrasound elements: volume of ascites fluid, size of the ovaries
• Chest radiography (in dyspnea patients) for the diagnosis of pleural effusion
• ECG (to exclude pericardial effusion)
• Blood tests: hematocrit, blood count, electrolytes, kidney function testing, liver enzymes, tests
coagulation, serum concentration of total proteins and albumin

4.4. Therapeutic conduct

4.4.1. Maintaining diuresis!
Liquid management:
• Intravenous administration of lactated Ringer’s solution
• In the first 24 hours: 1500-3000 ml; some centers restrict total fluid intake (including oral) to
1500 ml, to prevent fluid overload
• In the following days: liquid intake depending on the liquid balance
• Combinations: Lactated Ringer + 5% Dextrose or 0.9% NaCl + 5% Dextrose (standard solutions)
Increase in plasma volume:
• HEAS solution 6% in isotonic NaCl
• Maximum daily dose: 33 ml / kg in 250-500 ml / day, administered slowly, to avoid pulmonary congestion
Albumin administration
• It is given only if hypoalbuminemia (<28 mg / dl) is demonstrated, due to the risk of
hepatitis, overdose, kidney dysfunction and high cost
• It must be administered when draining the ascites fluid, because it
causes a massive loss of protein.

4.4.2. Anticoagulant therapy
Low molecular weight heparin is preferable to be administered in all cases of severe OHSS with
hospitalization, but must be administered in the following cases:
• Clinical signs of thromboembolic complications
• Documented thrombophilia
• History of hypercoagulability or thromboembolic episodes
• Uncorrected blood concentration after 48 hours of usual intravenous treatment
To prevent thromboembolic complications, low-dose aspirin has been suggested in
especially in immobilized patients due to obesity or other reasons. When paracentesis is performed, it must
weighed and appreciated the risk of bleeding.

4.4.3. Drainage of ascites fluid
It can be performed abdominally or vaginally (Padilla et al., 190; Aboulghar et al., 1990), but
always under ultrasound control. It is indicated when there is severe abdominal discomfort and dyspnea
severe and leads to a rapid improvement in the patient’s symptoms. It also leads to increased return
venous flow, cardiac output, diuresis, creatinine clearance and pulmonary ventilation. It must be done
graded: maximum 4 liters in 24 hours. Removing large amounts of fluid means massive losses of
proteins that need to be replaced. One liter of ascites fluid contains 3-3.5 g of albumin; is recommended
daily administration of 30-50 g of albumin.
Outpatient management of OHSS patients follows strict rules. When signs of
deterioration, hospitalization should be considered, preferably in an experienced center. Hospitalized patients
should be visited frequently by the same doctor, because the clinical picture can change quickly (during a single
days) and the doctor can and must ascertain this. In the case of critical OHSS, the patient must be admitted to a ward
intensive care. In very severe cases, discontinuation of an early pregnancy should be considered.

4.5. Pregnancy after OHSS
The pregnancy rate in patients with OHSS is higher than average. This is due to the fact that these patients are
usually young women in the first cycles of assisted reproduction, with many quality oocytes and embryos. More
authors reported an increase in the percentage of miscarriages in patients with OHSS (Raziel et al., 2002;
Papanikolaou et al., 2004).