Ovarian hyperstimulation syndrome

Abstract

Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation induction therapy. The OHSS is typically associated with exogenous gonadotropin stimulation and is only rarely observed with use of other agents (clomiphene citrate [CC] and gonadotropin-releasing hormone [GnRH]). Clinicians who prescribe ovulation-inducing agents must be prepared to recognize and manage OHSS (1Blankstein J. Shalev J. Saadon T. Kukia E.E. Rabinovici J. Pariente C. et al.Ovarian hyperstimulation syndrome prediction by number and size of preovulatory ovarian follicles.Fertil Steril. 1987; 47: 597-602Abstract Full Text PDF PubMed Google Scholar, 2McArdle C. Siebel M. Hann L.E. Weinstein F. Taymor M. The diagnosis of ovarian hyperstimulation (OHS) the impact of ultrasound.Fertil Steril. 1983; 39: 464-467Abstract Full Text PDF PubMed Google Scholar, 3Pride S.M. James C.S.J. Yuen B.H. The ovarian hyperstimulation syndrome.Semin Reprod Endocrinol. 1990; 8: 247-260Crossref Scopus (60) Google Scholar). OHSS is a self-limiting disorder that usually resolves spontaneously within several days, but may persist for longer durations, particularly in conception cycles. The syndrome has a broad spectrum of clinical manifestations, from mild illness needing only careful observation to severe disease requiring hospitalization and intensive care. This guideline will discuss the pathophysiology of OHSS and its risk factors, clinical features, management, and prevention. The hallmark of OHSS is an increase in capillary permeability resulting in a fluid shift from the intravascular space to third space compartments (4Tollan A. Holst N. Forsdahl F. Fadnes H.O. Oian P. Maltau J.M. Transcapillary fluid dynamics during ovarian stimulation for in vitro fertilization.Am J Obstet Gynecol. 1990; 162: 554-558Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 5Goldsman M.P. Pedram A. Dominguez C.E. Ciuffardi I. Levin E. Asch R.H. Increased capillary permeability induced by human follicular fluid a hypothesis for an ovarian origin of the hyperstimulation syndrome.Fertil Steril. 1995; 63: 268-272Abstract Full Text PDF PubMed Google Scholar). Factors that have been implicated in the process include: •increased secretion or exudation of protein-rich fluid from enlarged ovaries or peritoneal surfaces (6Bergh P.A. Navot D. Ovarian hyperstimulation syndrome a review of pathophysiology.J Assist Reprod Genet. 1992; 9: 429-438Crossref PubMed Scopus (95) Google Scholar, 7Koninckx P.R. Heyns W. Verhoeven G. Van Baelen H. Lissens W.D. et al.Biochemical characterization of peritoneal fluid in women during the menstrual cycle.J Clin Endocrinol Metab. 1980; 51: 1239-1244Crossref PubMed Scopus (95) Google Scholar, 8Koninckx P.R. Renaer M. Brosens I.A. 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Schalekamp M.A. High concentrations of immunoreactive renin, prorenin and enzymatically-active renin in human ovarian follicular fluid.Br J Obstet Gynaecol. 1987; 94: 4-9Crossref PubMed Scopus (67) Google Scholar)•angiotensin-mediated changes in capillary permeability (11Derkx F.H. Alberda A.T. Zeilmaker G.H. Schalekamp M.A. High concentrations of immunoreactive renin, prorenin and enzymatically-active renin in human ovarian follicular fluid.Br J Obstet Gynaecol. 1987; 94: 4-9Crossref PubMed Scopus (67) Google Scholar, 12Lightman A. Tarlatzis B.C. Rzasa P.J. Culler M.D. Caride V.J. Negro-Vilar A.F. et al.The ovarian renin-angiotensin system renin-like activity and angiotensin II/III immunoreactivity in gonadotropin-stimulated and unstimulated human follicular fluid.Am J Obstet Gynecol. 1987; 156: 808-816Abstract PubMed Google Scholar) Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has emerged as one of the factors most likely involved in the pathophysiology of OHSS (13Geva E. Jaffe R.B. Role of vascular endothelial growth factor in ovarian physiology and pathology.Fertil Steril. 2000; 74: 429-438Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). VEGF is an angiogenic cytokine that is a potent stimulator of the vascular endothelium and appears to play an integral role in follicular growth, corpus luteum function, and ovarian angiogenesis. The VEGF levels correlate with the severity of OHSS (14Levin E.R. Rosen G.F. Cassidenti D.L. Yee B. Meldrum D. Wisot A. et al.Role of vascular endothelial cell growth factor in ovarian hyperstimulation syndrome.J Clin Invest. 1998; 102: 1978-1985Crossref PubMed Scopus (146) Google Scholar), and recombinant VEGF produces effects similar to those of OHSS that can be reversed with a specific antiserum (15McClure N. Healy D.L. Rogers P.A. Sullivan J. Beaton L. Haning R.V. et al.Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome.Lancet. 1994; 344: 235-236Abstract PubMed Scopus (342) Google Scholar, 16Neulen J. Yan Z. Raczek S. Weindel K. Keek C. Weich H.A. et al.Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells importance in ovarian hyperstimulation syndrome.J Clin Endocrinol Metab. 1995; 80: 1967-1971Crossref PubMed Google Scholar). Recent studies also indicate that hCG increases VEGF expression in human granulosa cells and raises serum VEGF concentrations (16Neulen J. Yan Z. Raczek S. Weindel K. Keek C. Weich H.A. et al.Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells importance in ovarian hyperstimulation syndrome.J Clin Endocrinol Metab. 1995; 80: 1967-1971Crossref PubMed Google Scholar, 17Pellicer A. Albert C. Mercader A. Bonilla-Musoles F. Remohi J. Simon C. The pathogenesis of ovarian hyperstimulation syndrome in vivo studies investigating the role of interleukin-1β, interleukin-6, and vascular endothelial growth factor.Fertil Steril. 1999; 71: 482-489Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Numerous other factors may be involved, acting directly or indirectly via VEGF, including angiotensin II, insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), transforming growth factors (TGF) α and β, basic fibroblast growth factor (BFGF), platelet-derived growth factor (PDGF), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (13Geva E. Jaffe R.B. Role of vascular endothelial growth factor in ovarian physiology and pathology.Fertil Steril. 2000; 74: 429-438Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 19Warren R.S. Yuan H. Matli M.R. Ferrara N. Donner D.B. Induction of vascular endothelial growth factor by insulin-like growth factor I in colorectal carcinoma.J Biol Chem. 1996; 271: 483-488Google Scholar, 20Ferrara N. Davis-Smyth T. The biology of vascular endothelial growth factor.Endocrinol Rev. 1997; 18: 4-25Crossref PubMed Scopus (3655) Google Scholar). The following factors increase the risk independently for developing OHSS (18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 21Navot D. Relou A. Birkenfeld A. Rabinowitz R. Brzezinski A. Margalioth E.J. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome.Am J Obstet Gynecol. 1988; 159: 210-215Abstract PubMed Google Scholar, 22Delvigne A. Demoulin A. Smitz J. Donnez J. Koinckx P. Dhont M. et al.The ovarian hyperstimulation syndrome in in-vitro fertilization a Belgian multicentric study. I. Clinical and biological features.Hum Reprod. 1993; 8: 1353-1360PubMed Google Scholar, 23MacDougall M.J. Tan S.L. Jacobs H.S. In-vitro fertilization and the ovarian hyperstimulation syndrome.Hum Reprod. 1992; 7: 597-600Crossref PubMed Scopus (186) Google Scholar, 24Buyalos R.P. Lee C.T. Polycystic ovary syndrome pathophysiology and outcome with in vitro fertilization.Fertil Steril. 1996; 65: 1-10PubMed Google Scholar, 25Forman R.G. Frydman R. Egan D. Ross C. Barlow D.H. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization a European series and a proposal for prevention.Fertil Steril. 1990; 53: 502-509Abstract Full Text PDF PubMed Google Scholar, 26Mizunuma H. Andoh K. Yamada K. Takagi T. Kamijo T. Ibuki Y. Prediction and prevention of ovarian hyperstimulation by monitoring endogenous luteinizing hormone release during purified follicle-stimulating hormone therapy.Fertil Steril. 1992; 58: 46-50PubMed Google Scholar, 27Mordel N. Schenker J.G. Gonadotrophin-releasing hormone agonist and ovarian hyperstimulation syndrome in assisted reproduction.Hum Reprod. 1993; 8: 2009-2014PubMed Google Scholar, 28Haning Jr, R.V. Austin C.W. Carlson I.H. Kuzma D.L. Shapiro S.S. Zweibel W.J. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins.Fertil Steril. 1983; 40: 31-36Abstract Full Text PDF PubMed Scopus (131) Google Scholar): •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 (1Blankstein J. Shalev J. Saadon T. Kukia E.E. Rabinovici J. Pariente C. et al.Ovarian hyperstimulation syndrome prediction by number and size of preovulatory ovarian follicles.Fertil Steril. 1987; 47: 597-602Abstract Full Text PDF PubMed Google Scholar, 29Enskog A. Henriksson M. Unander M. Nilsson L. Brannstrom M. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization.Fertil Steril. 1999; 71: 808-814Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar), and the number of oocytes retrieved in assisted reproductive technology (ART) cycles (23MacDougall M.J. Tan S.L. Jacobs H.S. In-vitro fertilization and the ovarian hyperstimulation syndrome.Hum Reprod. 1992; 7: 597-600Crossref PubMed Scopus (186) Google Scholar, 29Enskog A. Henriksson M. Unander M. Nilsson L. Brannstrom M. Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization.Fertil Steril. 1999; 71: 808-814Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Risk increases when higher or repeated doses of exogenous 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 (25Forman R.G. Frydman R. Egan D. Ross C. Barlow D.H. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization a European series and a proposal for prevention.Fertil Steril. 1990; 53: 502-509Abstract Full Text PDF PubMed Google Scholar). Pregnancy increases the likelihood, duration, and severity of OHSS symptoms. 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) (30Golan A. Ron-el R. Herman A. Soffer Y. Weinraub Z. Caspi E. Ovarian hyperstimulation syndrome an update review.Obstet Gynecol Surv. 1989; 44: 430-440Crossref PubMed Scopus (729) Google Scholar) 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 (18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 31Zosmer A. Katz Z. Lancet M. Konichezky S. Schwartz-Shoham Z. Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome.Fertil Steril. 1987; 47: 524-526Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 32Abramov Y. Elchalal U. Schenker J.G. Pulmonary manifestations of severe ovarian hyperstimulation syndrome a multicenter study.Fertil Steril. 1999; 71: 645-651Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). 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 anti-emetics 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 ≥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 (33Pattinson H.A. Hignett M. Dunphy B.C. Fleetham J.A. Outcome of thaw embryo transfer after cryopreservation of all embryos in patients at risk of ovarian hyperstimulation syndrome.Fertil Steril. 1994; 62: 1192-1196PubMed Google Scholar, 34Shaker A.G. Zosmer A. Dean N. Bekir J.S. Jacobs H.S. Tan S.L. Comparison of intravenous albumin and transfer of fresh embryos with cryopreservation of all embryos for subsequent transfer in prevention of ovarian hyperstimulation syndrome.Fertil Steril. 1996; 65 ([see comments, Fertil Steril 1997;67:587–9.]): 992-996Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 35Ferraretti A.P. Gianaroli L. Magli C. Fortini D. Selman H.A. Feliciani E. Elective cryopreservation of all pronucleate embryos in women at risk of ovarian hyperstimulation syndrome efficiency and safety.Hum Reprod. 1999; 14: 1457-1460Crossref PubMed Scopus (116) Google Scholar). 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 (18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 36Navot D. Bergh P.A. Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies prevention and treatment.Fertil Steril. 1992; 58: 249-261Abstract Full Text PDF PubMed Google Scholar, 37Borenstein R. Elhalah U. Lunenfeld B. Schwartz Z.S. Severe ovarian hyperstimulation syndrome a reevaluated therapeutic approach.Fertil Steril. 1989; 51: 791-795Abstract Full Text PDF PubMed Scopus (110) Google Scholar): •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 re-evaluation 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. Hospitalized patients require 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 (18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 36Navot D. Bergh P.A. Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies prevention and treatment.Fertil Steril. 1992; 58: 249-261Abstract Full Text PDF PubMed Google Scholar, 37Borenstein R. Elhalah U. Lunenfeld B. Schwartz Z.S. Severe ovarian hyperstimulation syndrome a reevaluated therapeutic approach.Fertil Steril. 1989; 51: 791-795Abstract Full Text PDF PubMed Scopus (110) Google Scholar): •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 (25Forman R.G. Frydman R. Egan D. Ross C. Barlow D.H. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization a European series and a proposal for prevention.Fertil Steril. 1990; 53: 502-509Abstract Full Text PDF PubMed Google Scholar), 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 (31Zosmer A. Katz Z. Lancet M. Konichezky S. Schwartz-Shoham Z. Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome.Fertil Steril. 1987; 47: 524-526Abstract Full Text PDF PubMed Scopus (59) Google Scholar).•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. Kayexelate 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. Ultrasound-guided paracentesis may be indicated for patients with ascites that causes pain, compromised pulmonary function (e.g., tachypnea, hypoxia, hydrothorax) (32Abramov Y. Elchalal U. Schenker J.G. Pulmonary manifestations of severe ovarian hyperstimulation syndrome a multicenter study.Fertil Steril. 1999; 71: 645-651Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar), or oliguria/anuria that does not improve with appropriate fluid management. A transvaginal or transabdominal approach may be used, under gentle ultrasound guidance (38Aboulghar M.A. Mansour R.T. Serour G.I. Amin Y. Ultrasonically guided vaginal aspiration of ascites in the treatment of severe ovarian hyperstimulation syndrome.Fertil Steril. 1990; 53 ([erratum appears in Fertil Steril 1990;54:957.]): 933-935Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 39Rizk B. Aboulghar M. Modern management of ovarian hyperstimulation syndrome.Hum Reprod. 1991; 6: 1082-1087PubMed Google Scholar). 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 (32Abramov Y. Elchalal U. Schenker J.G. Pulmonary manifestations of severe ovarian hyperstimulation syndrome a multicenter study.Fertil Steril. 1999; 71: 645-651Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 40Rinaldi M.L. Spirtos N.J. Chest tube drainage of pleural effusion correcting abdominal ascites in a patient with severe ovarian hyperstimulation syndrome a case report.Fertil Steril. 1995; 63 ([comment Fertil Steril 1995;64:1228–9.]): 1114-1117Abstract Full Text PDF PubMed Scopus (28) Google Scholar). 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 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 (41Ferraretti A.P. Gianaroli L. Diotallevi L. Festi C. Trounson A. Dopamine treatment for severe ovarian hyperstimulation syndrome.Hum Reprod. 1992; 7 ([comments Hum Reprod 1992;7:1181.]): 180-183PubMed Google Scholar). 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 (42Reed A.P. Tausk H. Reynolds H. Anesthetic considerations for severe ovarian hyperstimulation syndrome.Anesthesiology. 1990; 73: 1275-1277Crossref PubMed Scopus (14) Google Scholar). 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 (43Grochowski D. Wolczynski S. Kuczynski W. Domitrz J. Szamatowicz J. Szamatowicz M. Correctly timed coasting reduces the risk of ovarian hyperstimulation syndrome and gives good cycle outcome in an in vitro fertilization program.Gynecol Endocrinol. 2001; 15: 234-238Crossref PubMed Scopus (24) Google Scholar, 44Al-Shawaf T. Zosmer A. Hussain S. Tozer A. Panay N. Wilson C. et al.Prevention of severe ovarian hyperstimulation syndrome in IVF with or without ICSI and embryo transfer a modified “coasting” strategy based on ultrasound for identification of high-risk patients.Hum Reprod. 2001; 16: 24-30Crossref PubMed Scopus (75) Google Scholar). Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>3 days) (45Ulug U. Bahceci M. Erden H.F. Shalev E. Ben-Shlomo I. The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles.Hum Reprod. 2002; 17: 310-313Crossref PubMed Scopus (71) Google Scholar). 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 (18Whelan 3rd, J.G. Vlahos N.F. The ovarian hyperstimulation syndrome.Fertil Steril. 2000; 73: 883-896Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). 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 (46Lewitt N. Kol S. Manor D. Itskovitz-Eldor J. Comparison of gonadotrophin-releasing hormone analogues and human chorionic gonadotrophin for the induction of ovulation and prevention of ovarian hyperstimulation syndrome a case-control study.Hum Reprod. 1996; 11: 1399-1402Crossref PubMed Scopus (55) Google Scholar). 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 an 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 (25Forman R.G. Frydman R. Egan D. Ross C. Barlow D.H. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization a European series and a proposal for prevention.Fertil Steril. 1990; 53: 502-509Abstract Full Text PDF PubMed Google Scholar). 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 (47Friedman C.I. Schmidt G.E. Chang F.E. Kim M.H. Severe ovarian hyperstimulation following follicular aspiration.Am J Obstet Gynecol. 1984; 150: 436-437PubMed Google Scholar). 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 E2 levels are markedly elevated or there is history of a previous episode of OHSS (48Asch R.H. Ivery G. Goldsman M. Frederick J.L. Stone S.C. Balmaceda J.P. The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome.Hum Reprod. 1993; 8 ([comments Hum Reprod 1994;9:753–4 and Hum Reprod 1995;10:2750–2.]): 1015-1020PubMed Google Scholar, 49Shoham Z. Weissman A. Barash A. Borenstein R. Schachter M. Insler V. Intravenous albumin for the prevention of severe ovarian hyperstimulation syndrome in an in vitro fertilization program a prospective, randomized, placebo-controlled study.Fertil Steril. 1994; 62: 137-142Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 50Shalev E. Giladi Y. Matilsky M. Ben-Ami M. Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous albumin a prospective study.Hum Reprod. 1995; 10: 1373-1376Crossref PubMed Scopus (64) Google Scholar). Studies of its efficacy have had mixed results, and albumin treatment risks exacerbation of ascites, allergic reactions, and virus/prion transmission (51Ng E. Leader A. Claman P. Domingo M. Spence J.E. Intravenous albumin does not prevent the development of severe ovarian hyperstimulation syndrome in an in-vitro fertilization programme.Hum Reprod. 1995; 10 ([comments Hum Reprod 1996;11:460–1.]): 807-810PubMed Google Scholar, 52Ben-Chetrit A. Eldar-Geva T. Gal M. Huerta M. Mimom T. Algur N. et al.The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme a randomized placebo-controlled trial.Hum Reprod. 2001; 16: 1880-1884Crossref PubMed Scopus (49) Google Scholar). 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 (53Aboulghar M, Evers JH, Al-Inany H. Intra-venous albumin for preventing severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;2:CD001302Google Scholar). •Experience with ovulation induction therapy and knowledge of 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.