Ovarian Hyperstimulation Syndrome

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OHSS is the major serious and potentially life-threatening complication of ovulation induction in IVF-ET treatment. It is characterized by transudation of protein-rich fluid from the vascular space into the peritoneal cavity and to a less extent, pleural and pericardial cavities. The basic pathophysio-logic event in OHSS is an acute increase in capillary permeability; however, the exact factors responsible for this phenomenon have, until recently, not been clear.

Because intensity of the OHSS is related to the degree of ovarian response to ovulation induction therapy, OHSS is probably an exaggeration of normal ovarian physiology. Part of the angiogenic response, which occurs in the follicle at the time of ovulation, is increased vascular permeability VEGF. VEGF stimulates endothelial cell mitogenesis and renders capillaries highly permeable to high-molecular-weight protein (59). VEGF has been identified in rat (60) and primate ovaries predominantly after the LH surge. Luteal-phase treatment with GnRH agonist, to suppress LH secretion, decreased VEGF messenger-RNA expression, implying such expression is dependent on LH. We first reported the role of VEGF in OHSS (61). We have demonstrated that VEGF is the major capillary permeability factor in OHSS ascites. Although other capillary permeability factors may not have been detected, 70% of the capillary permeability activity in OHSS ascites was neutralized by recombinant human VEGF antiserum. Abramov et al. (62) subsequently followed the kinetics of VEGF in the plasma of seven patients with severe OHSS from the time of admission to the hospital until clinical resolution. They found that compared with normo-responders, IVF patients suffering OHSS had VEGF plasma levels which were significantly higher and correlated to the clinical picture. Ascitic fluid obtained from OHSS patients contained high VEGF levels.

The incidence of OHSS after induction of ovulation varies between 1% and 30%, as reported in various publications. This variation is probably due to the difference in the definition of OHSS. OHSS is classically divided into three categories:

1. Mild OHSS, with high serum E2 levels, mild abdominal distension, and large ovaries of about 5 cm due to the presence of multiple fol-licular and corpus luteal cysts.

2. Moderate OHSS, characterized by more abdominal distension, mild ascites, and gastrointestinal symptoms such as nausea, vomiting, and less frequently, diarrhea, some gain in weight, and ovaries enlarged up to 12 cm.

3. Severe OHSS which can be a life-threatening situation, characterized by pronounced abdominal distension, ascites, pleural effusion, hemoconcentration, electrolyte imbalance, oliguria/ anuria, and sometimes disseminated intravascular coagulation and hypovolemic shock. The ovaries are enlarged to more than 12 cm in diameter.

The treatment of OHSS is conservative. Bed rest and symptomatic relief are usually sufficient for mild and moderate OHSS. In mild cases, symptoms subside usually within a few days, whereas in moderate cases, symptoms can require up to 3 wk to subside. When pregnancy occurs, OHSS will last longer.

Severe OHSS can be life-threatening and patients, therefore, should be hospitalized and monitored closely. Patients are put on bed rest; daily body weight and fluid balance monitoring are necessary; hematocrit, coagulation and kidney functions, serum electrolyte, and albumin studies are obtained daily, as well as ultrasound scan of the pelvis and chest; oxygen saturation measurements (using an oximeter while breathing air and if less than 85% using blood gases) should be performed if dyspnoea is notified; and pelvic examination should be avoided because of the fragility of the enlarged ovaries and ovarian surgery is relatively contraindicated.

Hypovolemia and hemoconcentration need immediate corrections. When necessary, intravenous crystalloid infusion or plasma expanders are given to maintain central venous pressure. Replacement may require central venous pressure monitoring. Diuretics should not be given with, as the fluids in the abdominal and thoracic cavity are not responsive to diuretics and the further intravascular depletion can cause hypotension, shock, and thrombosis. Administration of low-dose heparin to prevent thromboembolism needs to be balanced against the risk of ovarian bleeding, possible need for paracentesis, and the possibility of heparian-induced thrombocytopenia. Most of our hospitalized patients are commenced on heparin 5000 U x 2/day subcutaneously on admission and reviewed after 24 hr. Heparin should be continued until discharge from the hospital if the patient has risk factors or past history of thrombosis, family history of thromboembolism, smoking, obesity, or varicose veins. Heparin should also be continued if there is hemoconcentration, tense ascites with inferior vena cava (IVC) compression, and late presentation with possible multiple pregnancies. Abdominal paracentesis under ultrasonographic guidance is recommended where there are ascites with IVC compression and edema of the lower limbs. Indomethacin has been shown to have beneficial effects on hyperstimulation syndrome, but its safety in early pregnancy is unknown (63).

The acute clinical manifestation of the severe form of OHSS usually disappears within several days if there are no complications. If pregnancy does not occur, the ovarian enlargement subsides usually within 30-40 days. If, however, pregnancy occurs, the high serum E2 levels will continue to the end of the first trimester.

Prevention of OHSS is vital. Low body mass index and PCOS are two clinical predictors and gonadotropin dosage should be reduced in such patients. When OHSS is suspected before hCG injection (as when serum E2 >25,000 nmol/L), hCG should be withheld. If, however, OHSS is diagnosed after oocyte retrieval, embryos should be frozen in order to avoid conception and replaced later in a natural cycle (64) or with estrogen/progesterone therapy. This approach also allows GnRH agonist administration to be renewed immediately after oocyte retrieval and maintained until the onset of subsequent menstruation, further reducing the risk of significant OHSS (65). We use hCG at a dose of 5000 IU rather than 10,000 IU for final oocyte maturation before retrieval in all our IVF patients to help prevent OHSS.

In 1993, Asch et al. (66) claimed that prevention of severe OHSS was possible by administration of intravenous albumin at a dose of 5% in ringer lactate in doses of 500 ml during oocytes retrieval and 500 ml immediately thereafter. Subsequent prospective randomized trials by Shoham et al. (67), Shalev et al. (68), and Shaker et al. (69) all showed that the frequency and degree of OHSS developed in patients treated with intravenous albumin were not different than in control patients. However, the pregnancy rate was significantly higher in patients who had all embryos cryopreserved to be transferred subsequently in hormonally manipulated cycle than in patients treated with albumin and fresh ET.

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