- Ovarian hyperstimulation syndrome (OHSS) ranges from mild ovarian enlargement to severe multisystem failure, with death occurring in approximately 1 in 400,000 to 500,000 superovulation cycles.
- The basic features of OHSS are enlarged multicystic ovaries and increased vascular permeability, with intravascular fluid loss into the third space.
- Mild to moderate OHSS is treated expectantly on an outpatient basis, while women with severe OHSS should be hospitalized.
- Severe OHSS has been reported in 0.1% to 2% of superovulation and assisted reproductive technology (ART) cycles.
- Risk factors for severe OHSS include young age, lean habitus, high 17ß-estradiol (E2) levels, pregnancy, and a greater follicle number.
Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of the medical treatment of infertile women. This potentially life-threatening iatrogenic condition has challenged physicians since the inception of ovulation induction more than 30 years ago. Despite a great deal of basic science and clinical research, its etiology eludes us. Thus, OHSS is difficult—though not necessarily impossible—to prevent and predict, and treatment remains supportive and symptom-directed.
OHSS ranges from mild ovarian enlargement to severe multisystem failure, with death occurring in approximately 1 in 400,000 to 500,000 superovulation cycles.1 Of the several staging systems that have been developed to help guide patient management, the one by Navot et al is most useful, as it introduces a fourth category of critical disease (Table 1).2 In general, mild to moderate OHSS is treated expectantly on an outpatient basis, while women with severe OHSS should be hospitalized. Critical patients are best managed in an intensive-care setting in consultation with other specialists. This article focuses primarily on OHSS requiring hospitalization.
|Grade 1||Same as mild stage plus ascites on ultrasonography||Ovaries >12 cm*||Ovaries >12 cm*|
|Abdominal distention and/or discomfort||Massive ascites with or without hydrothorax||Tense ascites with orwithout hydrothorax Hematocrit >55|
|Grade 2||Hematocrit >45†||WBC ≥25,000|
|Above plus nausea, vomiting, and/or diarrhea||WBC >15,000 Oliguria Creatinine 1-1.5 mg/dL||Oliguria Creatinine >1.6 mg/dL Creatinine clearance|
|Ovaries 5-12 cm||Creatinine clearance ≥50 mL/min Liver dysfunction Anasarca||<50 mL/min Renal failure Thromboembolic ARDS|
|*Ovarian size after follicle aspiration is not definitive, as the ovaries are not as large as after superovulation alone.|
|† Or 30% increase over baseline|
|Source: Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril. 1992;58:249-261.|
There appear to be 3 underlying pathophysiological processes leading to OHSS: angiogenesis, increased vascular permeability, and vasodilation. OHSS originates in the ovaries. Its basic features are enlarged multicystic ovaries and increased vascular permeability, with intravascular fluid loss into the third space. Study of the hyperstimulated ovaries reveals multiple hemorrhagic follicular and corpus luteum cysts, stromal edema, and neovascularization. The ascites of OHSS is a transudate/exudate from the peritoneum and is not derived from the ovarian surface. OHSS only occurs following ovulation.
The true incidence of OHSS is difficult to ascertain, due in part to the use of different classification systems. The wide variation in patient selection and the degree of aggressiveness in superovulation regimens also has a bearing, as do differences in the diagnosis of milder forms of the syndrome. It is likely that some degree of OHSS occurs in nearly all patients treated with gonadotropins. Thus, mild disease perhaps should be considered an accepted consequence of ovulation induction,3 while severe disease has been reported in only about 0.1% to 2% of superovulation and assisted reproductive technology (ART) cycles.1,4
In rare instances, severe OHSS has been reported with spontaneous pregnancies and with the use of clomiphene citrate. It also has occurred during pituitary down-regulation with gonadotropin-releasing hormone (GnRH) agonists. For all practical purposes, however, human chorionic gonadotropin (hCG) as the ovulation trigger is a prerequisite for the development of OHSS.1 In fact, the risk of OHSS is greater, and the condition is more severe and protracted, if conception occurs due to stimulation of the ovaries by endogenous hCG.1,5 (Endogenous luteinizing-hormone [LH] surges rarely cause OHSS unless pregnancy occurs.) Early OHSS, described by Lyons et al, presents 3 to 7 days after exogenous hCG is given to trigger ovulation, while late OHSS develops 12 to 17 days after the administration of hCG and then only in pregnant cycles.6 With late OHSS, a rate of severe disease of 71.4% has been reported, while the rate of severe disease with early OHSS is 14.3%.5
Pregnancy rates appear to be about 3 times higher in cycles involving severe OHSS than in OHSS-free cycles, probably due to the greater number of ovulated oocytes. However, the very high levels of 17ß-estradiol (E2) associated with OHSS may have an adverse effect on oocyte quality and endometrial receptivity. This may account for the greater risk of spontaneous abortion (SAB) seen with the disorder (33.5% to more than 50%).7