Human Reproduction vol.6 no.8 pp.1082-1087, 1991
REVIEW
Modern management of ovarian hyperstimulation syndrome
Botros Rizk1 and Mohamed Aboulghar2 Academic Department of Obstetrics and Gynaecology, University of Cambridge and Department of Obstetrics and Gynaecology, Norfolk and Norwich Hospital, Norwich, UK 2
Academic Department of Obstetrics and Gynaecology, Cairo University and the Egyptian IVF—ET Centre, Cairo, Egypt. 'To whom correspondence should be addressed
The number of women receiving ovulation induction has markedly increased with the advent of medically assisted reproduction. Consequently, ovarian hyperstimulation syndrome (OHSS) has become a frequent clinical problem. It is a potentially life-threatening situation. In its severe forms it is complicated by haemoconcentration, hypovolaemia, hypotension, acute renal insufficiency and thromboembolism. The pathophysiology of OHSS is poorly understood. The occurrence of OHSS correlates well with the level of oestradiol, the number of follicles, and administration of human chorionic gonadotrophin (HCG). The risk is increased in polycystic ovarian disease. The aim of this paper is to review critically the published literature on prediction, prevention and modern management of OHSS. Complete prevention of OHSS is not possible although several methods are used to predict and reduce its occurrence. Endocrine profile and ultrasonic follkular monitoring are the mainstays of prediction. The presence of a large number of small and intermediate size follicles at sonography is a risk factor. Witholding HCG, continuation of gonadotrophin-releasing hormone analogues and cryopreservation of embryos are optional courses of action for prevention. Mild OHSS is usually self-limiting and requires no active therapy. Moderate and severe cases are treated by correction of fluid and electrolyte imbalance, and by prevention of thromboembolism. The use of surgery is limited to cases of torsion or rupture of ovarian cysts, or the presence of concomitant ectopic pregnancy. Aspiration of the ascitic fluid, preferably by the transvaginal route, is recommended in cases with severe ascites. Key words: management/OHSS/prediction/prevention
Introduction Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction. In severe forms, the syndrome is characterized by ovarian enlargement, ascites, hydrothorax, electrolyte imbalance, hypovolaemia, oliguria and 1082
thromboembolism (Schenker and Weinstein, 1978; Thaler et al., 1981; Borenstein et al., 1989; Rizk et al, 1990). There is a great discrepancy in the incidence of ovarian hyperstimulation syndrome reported in the literature (Schenker and Weinstein, 1978; McArdle et al., 1983; Aboulghar et al., 1989; Borenstein et al., 1989). This could be due to a multitude of factors: variation among different authors in defining and diagnosing the severity of OHSS, the use of different stimulation protocols and the difference between centres in applying strict criteria for prevention. Schenker and Weinstein (1978) reported that the incidence varied from 8 to 23% in mild, < 1 to 7% in moderate and < 1 to 1.8% in its severe forms. The incidence does not seem to have decreased in recent years. In our experience, moderate OHSS occurred in 5.8% and severe OHSS in 1.8% of patients undergoing ovulation induction for in-vitro fertilization (IVF). As assisted conception utilizing ovarian superstimulation becomes more widely available, the occurrence of OHSS will probably increase. Hence, the importance is clear of intensifying the studies which might clarify the obscure pathogenesis of the syndrome, improve the methods of prevention and introduce more effective lines of treatment.
Pathogenesis The probability of occurrence of OHSS correlates well with the level of oestradiol (EJ and the number of follicles on the day of human chorionic gonadotrophin (HCG) administration (Schenker and Weinstein, 1978; Haning et al., 1983; Blankstein et al., 1987). A decrease in the fraction of mature follicles and an increase in the fraction of small ones on the day of HCG injection is associated with a high risk of OHSS (Blankstein et al., 1987). Administration of HCG is critical for the development of OHSS except in sporadic cases (Schenker and Weinstein, 1978). It is more common in conceptional cycles (Tyler, 1968; Rizk, 1991). Borenstein et al. (1989) reported a 35% pregnancy rate in cases of severe OHSS. The risk is also increased in patients with polycystic ovarian disease (PCOD) (Charbonnel et al., 1987). The pathophysiology of ovarian hyperstimulation is poorly understood. There are data suggesting that increased capillary permeability is the pathogenetic mechanism (Thaler et al., 1981). It may be caused by excessively high oestrogen levels and it is probably mediated through increased production of prostaglandin (Schenker and Polishuk, 1975). Recently it has been suggested that the cause of increased capillary permeability and fluid shifting in OHSS is the increased activity of the rerun-angiotensin-aldosterone systems. A direct © Oxford University Press
Management of ovarian hyperstimulation
correlation between plasma renin activity and the severity of OHSS has been found. The renin-angiotensin cascade is implicated in new vessel formation. Angiogenesis is associated with a rapid increase in capillary permeability (Navot et al., 1987). Hyperstimulated ovaries seem to be the main source of this hyperreninism (Sealey etai, 1986). In the case report presented by Balasch et al. (1990), extremely high plasma levels of renin, aldosterone and antidiuretic hormone were found in the patient. However, the authors emphasized that the increased capillary permeability of OHSS is essentially only seen in the ovarian vessels. Rare cases where ovarian hyperstimulation presented solely as isolated acute pleural effusion in the absence of ascites or ovarian enlargement make it debatable that increased permeability of the ovarian vessels is the only mechanism in the pathogenesis of OHSS (Jewelewicz and Vande Wiede, 1975; Kingsland etai, 1989). Classification of OHSS Rabau et al. (1967) suggested the first classification for OHSS. The syndrome was classified into three categories and six grades. Mild OHSS included laboratory changes in the form of increased oestrogen and pregnanediol secretion in the urine with ovarian enlargement. Moderate OHSS included the features of mild OHSS plus abdominal distension, nausea, vomiting, diarrhoea and ovarian enlargement more than 5 cm. Severe OHSS included manifestations of moderate OHSS plus ascites or hydrothorax, and it could be associated with changes in the blood volume, blood viscosity, coagulation abnormality and decreased renal perfusion. If we apply this classification, almost all patients who receive human menopausal gonadotrophin (HMG) will be diagnosed as having mild OHSS. A more recent classification was proposed by Golan et al. (1989): mild OHSS, grade 1: abdominal distension and discomfort; grade 2: features of grade 1 plus nausea, vomiting and/or diarrhoea, ovaries are enlarged 5 - 1 2 cm; moderate OHSS, grade 3: features of mild OHSS plus ultrasonic evidence of ascites; severe OHSS, grade 4: features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or breathing difficulties; grade 5: all of the above plus change in the blood volume, increased blood viscosity due to haemoconcentration, coagulation abnormalities and diminished renal perfusion and function. We hope that the European Society of Human Reproduction devotes one of its symposia to achieving a standard international classification to enable different centres to compare results. Risks and complications The ovarian hyperstimulation syndrome is a potentially lifethreatening situation (Balasch et al., 1990). In its severe forms, it is complicated by haemoconcentration, hypovolaemia, hypotension, decreased renal perfusion and acute renal insufficiency (Shapiro et al., 1977; Haning et al., 1985; Bider et al., 1989; Balasch et al., 1990). A rare complication is the occurrence of thromboembolism which is related to haemoconcentration (Mozes et al., 1965; Schenker and Weinstein 1978; Borenstein et al., 1989; Rizk et al., 1990). Zosmer et al.
(1987) described a rare case of OHSS complicated by adult respiratory distress syndrome. Several cases of liver dysfunction associated with OHSS have been reported recently (Sueldo et al., 1988; Younis et al., 1988; Balasch et al., 1990; Forman et al., 1990). The mild hepatocellular and cholestatic damage described in patients with OHSS is possibly due to the high level of E2 (Balasch et al., 1990). Management of OHSS Prediction and Prevention There are no completely curative therapies for the treatment of OHSS. Therefore, the most effective treatment of OHSS is still prevention. However, complete prevention of OHSS does not seem possible with the currently available means (Borenstein etai., 1989). Several methods have been used to reduce the incidence of predicted OHSS (Figure 1). It can be reduced by monitoring oestrogen levels (Tulandi etai., 1984). Plasma E2 was far superior to urinary oestrogen determination for prediction of OHSS (Haning et al., 1983; Varma and Patel, 1988; Golan et al., 1989). There is no agreement concerning the Ej level above which HCG injection should be withheld. The limits suggested were 800 pg/ml by Schenker and Weinstein (1978), 1700 pg/ml by Blankstein et al. (1986) and 4000 pg/ml by Haning et al. (1983). Tal et al. (1985) found a correlation between the number of immature follicles and OHSS. Blankstein et al. (1987) found a correlation between the increased number of small and intermediate follicles and OHSS. In severe OHSS, the small follicles predominated. More recently, Salat-Baroux etai. (1989) suggested that PCOD pattern of ovarian response to gonadotrophin-releasing hormone agonist analogue (GnRH-a) before HMG stimulation could be used prospectively to define a subgroup of patients who are at risk of developing OHSS. In our experience we have found that a combination of serum E2 and ultrasonography offers a better chance for prediction of OHSS. Golan etai. (1989) considered this combination to be the ideal one. Rabau et al. (1967) stated that there is no correlation between the severity of OHSS and HMG dosage. Animal experiments showed direct correlation between OHSS and the dose of HMG. However, this was not demonstrated in the human (Schenker and Weinstein, 1978). It seems that the sensitivity of the ovaries and to a lesser extent the doses and duration of HMG therapy are determinants in the causation of OHSS (Golan et al., 1988). Patients with PCOD syndrome form a high risk group for OHSS. It was suggested that stimulation by pure follicle stimulating hormone (FSH) might result in a lower incidence of ovarian hyperstimulation compared to stimulation by HMG (Rabinovici etai., 1987). Gonadotrophin-releasing hormone agonists (GnRH-a) are now widely used in conjunction with HMG for ovulation induction in assisted conception. The incidence of moderate and severe OHSS varied between 0.6% and 14% in different centres using different GnRH-a protocols for pituitary desensitization, different dosages of HMG and different luteal phase supports (B.Rizk and 1083
B.Rizk and M.Aboulgbar
PREDICTION 1. 2. 3. 4.
Young PCOD High serum oestradiol Ultrasonography
5. Doppler
PCO pattern of response to GnRH before HMG. Large number of follicles £15 with a high proportion of small and intermediate size follicles. Conception cycles particularly multiple pregnancy.
PREVENTION 1. Withholding HCG ± continuation of GnRH. 2. Selective oocyte retrieval in spontaneous conception. 3. Cryopreservation and replacement of frozen-thawed embryos at a subsequent cycle
MANAGEMENT Mild OHSS -> conservative treatment - follow-up
Moderate and Severe r
Admission for Monitoring 1. Strict Fluid Chart 2. Plasma and urine osmolarity 3. Urea and electrolytes 4. Clotting parameters 5. Liver function Tests 6. Pregnancy Test ^7. Pelvic Sonography
^
Correction of circulatory and electrolyte Imbalance 1. Aggressive monitoring e.g. CVP 2. Correction of electrolyte imbalance 3. Plasma expanders
— •
v
• Anticoagulants Evidence of thromboembolism
Surgery Only if haemorrhage torsion rupture ectopic Only haemostatic
k.
J
r
Transvaglnal aspiration of ^ Ascltlc fluid 1. Improves symptoms 2. Improves renal function and urinary output 3. Shortens hospital duration 4. Improves venous return and ^ cardiac output v r
\ Precautions 1. Sonographic guidance 2. Replacement of plasma proteins 3. Repeat aspiration may be required
V
J
v Fig. 1. Prediction, prevention and management of OHSS.
J.Smitz, manuscript submitted). It is evident that the use of GnRH-a is not associated with reduced incidence of moderate or severe OHSS (Golan etal, 1988). Several methods are used to prevent the occurrence of OHSS (Figure 1). Withholding HCG is the most widely used measure to prevent the syndrome in cases which show large numbers of follicles and very high levels of oestrogens (Schenker and Weinstein, 1978; McArdle etal, 1983; Haning etal., 1983; Friedman et al., 1984). Forman et al. (1990) adopted a protocol to prevent OHSS in high risk patients. They withheld HCG if 1084
E2 exceeded 2000 pg/ml and it was associated with a total of approximately 15 follicles each measuring ~ 12 mm in mean diameter. In an attempt to rescue cycles prone to develop OHSS, Rabinovici et al. (1987) monitored E2 and follicular state in 12 women with hyperstimulated cycles after withholding HMG for several days; HCG was administered when oestradiol levels were < 1700 pg/ml and the leading follicles between 17 and 22 mm in diameter. OHSS did not occur in any case and three patients conceived. They concluded that a rescue of overstimulated cycles
Management of ovarian hyperstimulation
is sometimes possible. Withholding HCG and continuation of GnRH-a could be used in an attempt to prevent OHSS and after a further period of pituitary densensitization, follicular stimulation was given with a lower dose of HMG. Follicular puncture of all follicles is useful in the prevention of OHSS but not successful in all cases (Golan et al., 1988). Cryopreservation of embryos and their replacement in subsequent cycles have been used when OHSS was predicted from the follicular response and serum E2 levels (Rizk, 1991). OHSS was prevented and pregnancies were subsequently achieved (Amso etal., 1990). Selective oocyte retrieval is a new approach for prevention of OHSS and multiple pregnancies in spontaneous conception, by puncturing most of the ovarian follicles 35 h after HCG administration as in an FVF—embryo transfer (ET) programme. The remaining intact follicles can still result in a singleton or twin pregnancy (Belaisch-Allart etal., 1988). Unfortunately, it seems that, despite the most careful and painstaking preventive measures, OHSS cannot be eliminated because of the narrow margin between ovulation induction and hyperstimulation. Conservative treatment Mild OHSS is usually self-limiting and requires no active therapy other than observation and follow-up (Figure 1). The condition usually subsides within 2 weeks (Borenstein et al., 1989; Golan etal., 1989; Varma and Patel, 1988). Severe OHSS requires hospitalization and active monitoring. Since it was realised that the main problem is the shift of fluids from the circulation to the third space which results in hypovolaemia, hypoproteinaemia, haemoconcentration and electrolyte disturbances, the approach to conservative treatment changed. Restriction of salt, fluids and the use of diuretics is not recommended any more (Borenstein et al., 1989). Instead, the main line of treatment is to correct the circulatory volume and the electrolyte disturbance, which will improve the renal perfusion and prevent coagulation problems and possible embolic manifestations (Figure 1). On admission to hospital, a fluid chart and a base line blood count should be prepared for the patient, and clotting parameters, blood and urine osmolarity should be measured. In severe cases, central venous pressure should be monitored. Plasma expander such as dextran, 500—1000 ml per 24 h, could be used. Human albumin or plasma can be infused to restore the plasma proteins. Anticoagulant therapy is only indicated when there is clinical evidence of thromboembolic complications or laboratory findings of hypercoagulability. Indomethacin, which is a prostaglandin synthetase inhibitor, has been used to modify the changes of OHSS in experimental animals and humans (Schenker and Polishuk, 1986; Varma and Patel, 1988). However, blocking or decreasing the vascular permeability using prostaglandin synthetase inhibitors was disappointing (Schenker and Weinstein, 1978; Pride et al., 1986). Balasch et al. (1990) reported a case of severe OHSS complicated by prerenal oliguria and liver dysfunction due to indomethacin therapy and emphasized that this drug should be used with great caution in OHSS. Histamine receptor blocker (chlorpheniramine maleate) has been used in an attempt to decrease capillary permeability in
OHSS (Kirshon etal., 1988). Pride etal. (1984) found chlorpheniramine treated animals to have significantly higher prostaglandin F content and speculated that the protective effect of an H-l receptor blockade on ascites formation may be mediated, at least in part, by prostaglandin F.
Aspiration of the ascitic fluid and pleura! effusion in severe OHSS Abdominal paracentesis Rabau etal. (1967) were the first to propose abdominal paracentesis for the treatment of OHSS for patients with respiratory distress due to massive ascites. Schenker and Polishuk (1975), Shapiro et al. (1977) and Schenker and Weinstein (1978) advised against abdominal paracentesis for drainage of ascites because of the danger of puncture and laceration of enlarged ovarian cysts. On the other hand, other reports suggested the value of abdominal paracentesis as an efficient method to relieve the symptoms and improve the general condition in severe OHSS. Knauer and Lowe (1967) were able to show an increase in cardiac output and stroke volume and decrease in intra-abdominal pressure, inferior vena cava pressure and hepatic wedge pressure after abdominal paracentesis in patients with tense ascites. Guazzi et al. (1975) have suggested that increased intraabdominal hydrostatic pressure in patients with tense ascites acts via the diaphragm to increase intra-thoracic pressure and reduce transmural filling pressure in the heart. The mean right atrial pressure is increased and venous return is thus impeded. Abdominal paracentesis should relieve intra-abdominal pressure and result in an increased venous return and an augmented filling of the heart. Thaler et al. (1981) in a case report showed that paracentesis was followed by increased urinary output shortly after the procedure with concomitant decreases in the patient's weight, leg oedema and abdominal circumference. They also showed that there was an increased creatinine clearance rate of 50% following the procedure. Bider etal. (1989) treated 12 patients with severe OHSS accompanied by pleural effusion or ascites causing respiratory discomfort and dyspnea by abdominal puncture. Drainage of abdominal or pleural effusion improved the symptoms in all patients. The amount of fluid aspirated ranged between 200 and 1400 ml. The risk of injury to an ovarian cyst was minimized by ultrasonographic guidance. They commented that paracentesis offered a temporary relief of respiratory distress but since the fluid tended to recur, some patients needed repeated paracentesis and drainage of effusion before spontaneous improvement ensued. The experience with this large group of patients indicates that the actual risk of paracentesis is negligible. However, a possible drawback is the loss of fluid that is rich in proteins (Kingsland etal., 1989). Padilla et al. (1990) demonstrated that abdominal paracentesis is a well tolerated treatment to relieve severe pulmonary compromise caused by severe ascites and pleural effusion in OHSS. They commented that an improvement in renal function may be another benefit that deserves further investigation. 1085
B.Rizk and M.Aboulghar
Transvaginal ultrasonic guided aspiration Aboulghar et al. (1990), in a prospective randomized clinical trial, investigated the effects of transvaginal aspiration of ascitic fluid under sonographic guidance in patients with severe OHSS. The average hospital stay and the period with severe symptoms and disturbed electrolyte balance was much shorter in the group in which aspiration of ascitic fluid was performed when compared with the group that underwent conservative treatment. Aspiration of the ascitic fluid is of paramount importance in relieving the symptoms of the patients, improving the general condition and increasing urinary output (Figure 1). A marked improvement in the symptoms was noted after drainage of as little as 900 ml of ascitic fluid. There were no adverse haemodynamic effects as a result of the aspiration of large volumes of ascitic fluid. Replacement of the plasma proteins is mandatory because of the high protein content of ascitic fluid (47 ± 22 g/1). This is particularly essential as repeated aspiration was required in 30% of patients. The rate of accumulation of ascitic fluid varied significantly. However, recollection of a large volume of ascitic fluid sufficient to cause discomfort would require, on average, 3 — 5 days. We believe that ultrasonic needle guided transvaginal aspiration is an effective and safe procedure. Injuring the ovary was avoided by puncture under ultrasonic visualization. No anaesthesia was required for the procedure. Better drainage of the ascitic fluid was accomplished because the Douglas pouch is the most dependent part. In our experience, transvaginal aspiration of ascites in severe forms of OHSS is a fast and effective line of treatment. It is performed routinely in our centre, in all severe OHSS cases after our clinical trial. Role of surgery in the management of OHSS In genera] surgery should be avoided in the treatment of OHSS, except in cases of torsion or rupture of an ovarian cyst, or if it is associated with ectopic pregnancy. Chotiner (1985) reported a case of severe OHSS in a patient with ectopic gestation. Bider et al. (1989) reported operative procedures in 16 patients with severe OHSS because of torsion, rupture and bleeding in the ovarian cysts. Torsion was found to be more common if pregnancy was present. Mashiach et al. (1990) reported that 12 pregnant women presented with torsion of hyperstimulated ovaries. They considered that the diagnosis of adnexal torsion is usually uncertain and since surgical intervention is likely to be delayed, these infertile women have a risk of losing their ovaries. The clinical picture of torsion included a combination of ovarian enlargement, abdominal pain, nausea, progressive leucocytosis and anaemia. Although during the operation the adnexa appeared dark, haemorrhagic and ischaemic, they suggested that it can be saved by simply unwinding it. They concluded that patients with torsion of hyperstimulated adnexa who conceive after gonadotrophin therapy should be considered as a special entity which requires more attention to achieve early diagnosis. OHSS is still a wide open field for research that will lead to better understanding of its pathogenesis. Until then, it is the responsibility of the clinician to impose strict rules for prediction and prevention. While mild cases of OHSS should be managed 1086
conservatively, severe cases should be monitored closely and actively treated by correction of fluid and electrolyte imbalance, and aspiration of the ascitic fluid.
References Aboulghar.M.A., Mansour.R.T. and Serour,G.I. (1989) Ovarian superstimulation in the treatment of infertility due to peritubal and periovarian adhesions. Fend. SieriL, 51, 834-837. Aboulghar.M.A., Mansour.R.T., Serour,G.I. and Amin,Y. (1990) Ultrasonically guided vaginal aspiration of ascites in the treatment of ovarian hyperstimulation syndrome. Fertil. Steril., 53, 933—935. Amso.N.N., Ahuja.K.K., Morris.N. and Shaw,R.W. (1990) The management of predicted OHS involving gonadotrophin-releasing hormone analogue with elective cryopreservation of all pre-embryos. Fertil. Steril., 53, 1087-1090. Balasch,J., Carmona.F., Llach.J., Arroyo,V., Jove,l. and Vanrell.J. (1990) Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome Hum. Reprod., 5, 348-351. Belaisch-Allart,J., Belaisch,J., Hazout,A., Testart,J. and Frydman,R. (1988) Selective oocyte retrieval: a new approach to ovarian hyperstimulation. Fertil. Steril., 50, 654-656. Bider.D., Menashe.Y., Oelsner,G., Serr.D.M., Mashiach,S. and Ben-Rafael,Z. (1989) Ovarian hyperstimulation syndrome due to exogenous gonadotrophin administration. Acta Obstet. Gynecol. Scand., 68, 511-514. Blankstein.J., Mashiach.S. and Lunenfeld.B. (eds) (1986) Induction of ovulation with gonadotrophins. In Induction ofOvulation and In Vitro Fertilization. Chicago Year Book Medical Publishers, Chicago, p. 147. Blankstein.J., Shalev,J., Saadon,T., Kukia,E.E., Rabinovici,J., Pariente.C, Lunenfeld.B., Serr.D.M. and Mashiach.S. (1987) Ovarian hyperstimulation syndrome prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597—602. Borenstein.R., Elhalah.U., Lunenfeld,B. and Schwartz,Z.S. (1989) Severe ovarian hyperstimulation syndrome: a reevaluated therapeutic approach. Fertil. Steril., 51, 791-795. Charbonnel.B., Krempf.M., Blanchard.P., Dano.F. and Delage.C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of luteinizing hormone releasing hormone analogue and exogenous gonadotrophins. Fertil. Steril., 47, 920—924. Chotiner,H.C. (1985) Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstet. Gynecol., 66, 740-743. Forman.R.G., Frydman.R., Egan.D., Ross.C. and Barlow.D.H. (1990) Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502—509. Friedman.C.I., Schmidt.G.E., Chang,F.E. and Kim,M.H. (1984) Severe ovarian hyperstimulation syndrome following follicular aspiration. Am. J. Obstet. Gynecol., 150, 436-437. Golan.A., Ron-El,R., Herman,A., Weinraub,Z., Soffer,Y. and Capsi,E. (1988) Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil. Steril., 50, 912-916. Golan.A., Ron-FJ,R., Herman,A., Soffer,Y., Weinraub,Z. and Capsi.E. (1989) Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv., 44, 430-440. Guazzi,M., Polese.A., Magrini.F., Fiorentini.C. and Olivary,M. (1975) Negative influences of ascites on the cardiac function of cirrhotic patients. Am. J. Med., 59, 165-170. Haning,R.V.,Jr, Austin,C.W. and Carlson,I.H., Kuzma,D.L., Shapiro,S.S. and Zweibel,W.J. (1983) Plasma estradiol is superior to ultrasound and urinary estradiol glucuronide as a predictor of ovarian
Management of ovarian hyperstimulation hyperstimulation during induction of ovulation with menotropins. Ferril. Steril., 40, 31-36. Haning,R.V., Strawn,E.Y. and Nolten.W.E. (1985) Pathophysiology of the ovarian hyperstimulation syndrome. Obstet. Gvnecol, 66, 220-224. Jewelewicz,R. and Vande Wiele,R.L. (1975) Acute hydrothorax as the only symptom of ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol.,121, 1121. Kingsland.C, Collins,J.V., Rizk,B. and Mason.B.A. (1989) Ovarian hyperstimulation presenting as acute hydrothorax after in vitro fertilization. Am. J. Obstet. Gvnecol., 161, 381-382. Kirshon.B., Doody,M.C, Cotton,D.B. and Gibbons,W. (1988) Management of ovarian hyperstimulation syndrome with chlorpheniramine maleate, manitol, and invasive hemodynamic monitoring. Obstet. Gynecol., 71, 485—487. Knauer,C.M. and Lowe,H.M. (1967) Hemodynamics in the cirrhotic patient during paracentesis. N. Engl. J. Med., 276, 491-496. Mashiach,S., Bider.D., Moran,O., Goldenberg.M. and Ben-Rafael,Z. (1990) Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil. Steril., 53, 76 — 80. McArdle.C, Seibel,M., Hann,L., Weinstein,F. and Taymour.M. (1983) The diagnosis of ovarian hyperstimulation (OHS); the impact of ultrasound. Fertil. Steril., 39, 464-467. Mozes,M., Bogowsky.H., Anteby,E., Lunenfeld.B., Rabau,E., Serr,D.M. and Salomy,M. (1965) Thrombo-embolic phenomena after ovarian stimulation with human menopausal gonadotropins. Lancet, 2, 1213-1215. Navot,D., Margalioth.E. and Laufer,N. (1987) Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome. Fertil. Steril., 48, 5 7 - 6 1 . Padilla.S.A., Zamaria.S., Baramki.T.A. and Garcia,J.E. (1990) Abdominal paracentesis for the ovarian hyperstimulation syndrome with severe pulmonary compromise. Fertil. Steril., 53, 365-367. Pride.S.M., Yuen.B.H. and Moon.Y.S. (1984) Clinical, endocrinologic and intraovarian prostaglandin F responses to H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model. Am. J. Obstet. Gynecol., 148, 670-674. Pride.S.M., Yuen,B.H., Moon.Y.S. and Leyung.P.C.S. (1986) Relationship of gonadotrophin-releasing hormone, danazol and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol., 154, 1155-1160. Rabau.E., Serr,D.M., David,A., Mashiach.S. and Lunenfeld.B. (1967) Human menopausal gonadotrophins for anovulation and sterility. Am. J. Obstet. Gynecol., 98, 92-98. Rabinovici.J., Kushnir.O., Shalev.J., Goldenberg.M. and Blankstein.J. (1987) Rescue of menotropin cycles prone to develop ovarian hyperstimulation. Br. J. Obstet. Gynaecol., 94, 1098-1102. Rizk.B. (1991) Ovarian hyperstimulation syndome. In Brinsden,P.R. and Rainsbury,P.A. (eds), The Bourn Hall Textbook of In Vitro Fertilization and Assisted Reproduction. Ch. 23. Parthenon, in press. Rizk,B., Meagher.S. and Fisher.A.M. (1990) Ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum. Reprod., 5, 697—698. Salat-Baroux,J., Tibi.G., Alvarez,S., Cornet,D., Antoine,J.M. and Gomes,A. (1989) Ultrasonographic prediction of ovarian hyperstimulation after IVF. Proceedings of the VI World Congress of In Vitro Fertilization and Alternate Assisted Reproduction. Jerusalem, Israel, Abstr., p. 27. Schenker.J.G. and Polishuk.W.Z. (1975) Ovarian hyperstimulation syndrome. Obstet. Gynecol., 46, 23-28. Schenker.J.G. and Weinstein,D. (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril., 30, 255-268. SealeyJ.E., Glorioso.N. and ItskovitzJ. (1986) Plasma prorenin during early pregnancy: ovarian secretion under gonadotrophins control? J. Hypertens., 4 (suppl. 5), S92-S95.
Shapiro,A.G., Thomas.T. and Epstein,M. (1977) Management of hyperstimulation syndrome. Fertil. Steril., 28, 237—239. Sueldo.C.E., Price.H.M., Bachenberg.K., Steinleiter.A., Gilten.N. and Swanson.J. (1988) Liver dysfunction in ovarian hyperstimulation syndrome. A case report. J. Reprod. Med., 33, 387-390. Tal.J.. Paz.B., Samberg,!., Lazarov.N. and Sharf,M. (1985) Ultrasonographic and clinical correlates of menotrophin versus sequential clomiphene citrate:menotrophin therapy for induction of ovulation. Fertil. Steril., 44, 342-349. Thaler.I., Yoffe.N., Kaftory.J. and Brandes.J. (1981) Treatment of ovarian hyperstimulation syndrome: the physiologic basis for a modified approach. Fertil. Steril., 36, 110-113. Tulandi.T., Mcinnes.R.A. and Arronet.G.H. (1984) Ovarian hyperstimulation syndrome following ovulation induction with hMG. Int. J. Fertil., 29, 113-117. Tyler,E . (1968) Treatment of anovulation with menotrophins. J. Am. Med. Assoc., 205, 16-22. Varma.T.R. and Patel,R.H. (1988) Ovarian hyperstimulation syndrome: a case history and review. Ada Obstet. Gynecol. Scand., 67, 579-582. Younis.J.S., Zeevi.D., Rabinowitz.R., Laufer.N. and Schenker.J.G. (1988) Transient liver function tests abnormalities of ovarian hyperstimulation syndrome. Fertil. Steril., 50, 176—178. Zosmer.A., Katz.Z., Lancet,M., Konichezky,S. and SchwartzShoham.Z. (1987) Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome. Fertil. Steril., 47, 524—526. Received on August 28, 1990; accepted on April 25, 1991
1087
REVIEW
Modern management of ovarian hyperstimulation syndrome
Botros Rizk1 and Mohamed Aboulghar2 Academic Department of Obstetrics and Gynaecology, University of Cambridge and Department of Obstetrics and Gynaecology, Norfolk and Norwich Hospital, Norwich, UK 2
Academic Department of Obstetrics and Gynaecology, Cairo University and the Egyptian IVF—ET Centre, Cairo, Egypt. 'To whom correspondence should be addressed
The number of women receiving ovulation induction has markedly increased with the advent of medically assisted reproduction. Consequently, ovarian hyperstimulation syndrome (OHSS) has become a frequent clinical problem. It is a potentially life-threatening situation. In its severe forms it is complicated by haemoconcentration, hypovolaemia, hypotension, acute renal insufficiency and thromboembolism. The pathophysiology of OHSS is poorly understood. The occurrence of OHSS correlates well with the level of oestradiol, the number of follicles, and administration of human chorionic gonadotrophin (HCG). The risk is increased in polycystic ovarian disease. The aim of this paper is to review critically the published literature on prediction, prevention and modern management of OHSS. Complete prevention of OHSS is not possible although several methods are used to predict and reduce its occurrence. Endocrine profile and ultrasonic follkular monitoring are the mainstays of prediction. The presence of a large number of small and intermediate size follicles at sonography is a risk factor. Witholding HCG, continuation of gonadotrophin-releasing hormone analogues and cryopreservation of embryos are optional courses of action for prevention. Mild OHSS is usually self-limiting and requires no active therapy. Moderate and severe cases are treated by correction of fluid and electrolyte imbalance, and by prevention of thromboembolism. The use of surgery is limited to cases of torsion or rupture of ovarian cysts, or the presence of concomitant ectopic pregnancy. Aspiration of the ascitic fluid, preferably by the transvaginal route, is recommended in cases with severe ascites. Key words: management/OHSS/prediction/prevention
Introduction Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction. In severe forms, the syndrome is characterized by ovarian enlargement, ascites, hydrothorax, electrolyte imbalance, hypovolaemia, oliguria and 1082
thromboembolism (Schenker and Weinstein, 1978; Thaler et al., 1981; Borenstein et al., 1989; Rizk et al, 1990). There is a great discrepancy in the incidence of ovarian hyperstimulation syndrome reported in the literature (Schenker and Weinstein, 1978; McArdle et al., 1983; Aboulghar et al., 1989; Borenstein et al., 1989). This could be due to a multitude of factors: variation among different authors in defining and diagnosing the severity of OHSS, the use of different stimulation protocols and the difference between centres in applying strict criteria for prevention. Schenker and Weinstein (1978) reported that the incidence varied from 8 to 23% in mild, < 1 to 7% in moderate and < 1 to 1.8% in its severe forms. The incidence does not seem to have decreased in recent years. In our experience, moderate OHSS occurred in 5.8% and severe OHSS in 1.8% of patients undergoing ovulation induction for in-vitro fertilization (IVF). As assisted conception utilizing ovarian superstimulation becomes more widely available, the occurrence of OHSS will probably increase. Hence, the importance is clear of intensifying the studies which might clarify the obscure pathogenesis of the syndrome, improve the methods of prevention and introduce more effective lines of treatment.
Pathogenesis The probability of occurrence of OHSS correlates well with the level of oestradiol (EJ and the number of follicles on the day of human chorionic gonadotrophin (HCG) administration (Schenker and Weinstein, 1978; Haning et al., 1983; Blankstein et al., 1987). A decrease in the fraction of mature follicles and an increase in the fraction of small ones on the day of HCG injection is associated with a high risk of OHSS (Blankstein et al., 1987). Administration of HCG is critical for the development of OHSS except in sporadic cases (Schenker and Weinstein, 1978). It is more common in conceptional cycles (Tyler, 1968; Rizk, 1991). Borenstein et al. (1989) reported a 35% pregnancy rate in cases of severe OHSS. The risk is also increased in patients with polycystic ovarian disease (PCOD) (Charbonnel et al., 1987). The pathophysiology of ovarian hyperstimulation is poorly understood. There are data suggesting that increased capillary permeability is the pathogenetic mechanism (Thaler et al., 1981). It may be caused by excessively high oestrogen levels and it is probably mediated through increased production of prostaglandin (Schenker and Polishuk, 1975). Recently it has been suggested that the cause of increased capillary permeability and fluid shifting in OHSS is the increased activity of the rerun-angiotensin-aldosterone systems. A direct © Oxford University Press
Management of ovarian hyperstimulation
correlation between plasma renin activity and the severity of OHSS has been found. The renin-angiotensin cascade is implicated in new vessel formation. Angiogenesis is associated with a rapid increase in capillary permeability (Navot et al., 1987). Hyperstimulated ovaries seem to be the main source of this hyperreninism (Sealey etai, 1986). In the case report presented by Balasch et al. (1990), extremely high plasma levels of renin, aldosterone and antidiuretic hormone were found in the patient. However, the authors emphasized that the increased capillary permeability of OHSS is essentially only seen in the ovarian vessels. Rare cases where ovarian hyperstimulation presented solely as isolated acute pleural effusion in the absence of ascites or ovarian enlargement make it debatable that increased permeability of the ovarian vessels is the only mechanism in the pathogenesis of OHSS (Jewelewicz and Vande Wiede, 1975; Kingsland etai, 1989). Classification of OHSS Rabau et al. (1967) suggested the first classification for OHSS. The syndrome was classified into three categories and six grades. Mild OHSS included laboratory changes in the form of increased oestrogen and pregnanediol secretion in the urine with ovarian enlargement. Moderate OHSS included the features of mild OHSS plus abdominal distension, nausea, vomiting, diarrhoea and ovarian enlargement more than 5 cm. Severe OHSS included manifestations of moderate OHSS plus ascites or hydrothorax, and it could be associated with changes in the blood volume, blood viscosity, coagulation abnormality and decreased renal perfusion. If we apply this classification, almost all patients who receive human menopausal gonadotrophin (HMG) will be diagnosed as having mild OHSS. A more recent classification was proposed by Golan et al. (1989): mild OHSS, grade 1: abdominal distension and discomfort; grade 2: features of grade 1 plus nausea, vomiting and/or diarrhoea, ovaries are enlarged 5 - 1 2 cm; moderate OHSS, grade 3: features of mild OHSS plus ultrasonic evidence of ascites; severe OHSS, grade 4: features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax or breathing difficulties; grade 5: all of the above plus change in the blood volume, increased blood viscosity due to haemoconcentration, coagulation abnormalities and diminished renal perfusion and function. We hope that the European Society of Human Reproduction devotes one of its symposia to achieving a standard international classification to enable different centres to compare results. Risks and complications The ovarian hyperstimulation syndrome is a potentially lifethreatening situation (Balasch et al., 1990). In its severe forms, it is complicated by haemoconcentration, hypovolaemia, hypotension, decreased renal perfusion and acute renal insufficiency (Shapiro et al., 1977; Haning et al., 1985; Bider et al., 1989; Balasch et al., 1990). A rare complication is the occurrence of thromboembolism which is related to haemoconcentration (Mozes et al., 1965; Schenker and Weinstein 1978; Borenstein et al., 1989; Rizk et al., 1990). Zosmer et al.
(1987) described a rare case of OHSS complicated by adult respiratory distress syndrome. Several cases of liver dysfunction associated with OHSS have been reported recently (Sueldo et al., 1988; Younis et al., 1988; Balasch et al., 1990; Forman et al., 1990). The mild hepatocellular and cholestatic damage described in patients with OHSS is possibly due to the high level of E2 (Balasch et al., 1990). Management of OHSS Prediction and Prevention There are no completely curative therapies for the treatment of OHSS. Therefore, the most effective treatment of OHSS is still prevention. However, complete prevention of OHSS does not seem possible with the currently available means (Borenstein etai., 1989). Several methods have been used to reduce the incidence of predicted OHSS (Figure 1). It can be reduced by monitoring oestrogen levels (Tulandi etai., 1984). Plasma E2 was far superior to urinary oestrogen determination for prediction of OHSS (Haning et al., 1983; Varma and Patel, 1988; Golan et al., 1989). There is no agreement concerning the Ej level above which HCG injection should be withheld. The limits suggested were 800 pg/ml by Schenker and Weinstein (1978), 1700 pg/ml by Blankstein et al. (1986) and 4000 pg/ml by Haning et al. (1983). Tal et al. (1985) found a correlation between the number of immature follicles and OHSS. Blankstein et al. (1987) found a correlation between the increased number of small and intermediate follicles and OHSS. In severe OHSS, the small follicles predominated. More recently, Salat-Baroux etai. (1989) suggested that PCOD pattern of ovarian response to gonadotrophin-releasing hormone agonist analogue (GnRH-a) before HMG stimulation could be used prospectively to define a subgroup of patients who are at risk of developing OHSS. In our experience we have found that a combination of serum E2 and ultrasonography offers a better chance for prediction of OHSS. Golan etai. (1989) considered this combination to be the ideal one. Rabau et al. (1967) stated that there is no correlation between the severity of OHSS and HMG dosage. Animal experiments showed direct correlation between OHSS and the dose of HMG. However, this was not demonstrated in the human (Schenker and Weinstein, 1978). It seems that the sensitivity of the ovaries and to a lesser extent the doses and duration of HMG therapy are determinants in the causation of OHSS (Golan et al., 1988). Patients with PCOD syndrome form a high risk group for OHSS. It was suggested that stimulation by pure follicle stimulating hormone (FSH) might result in a lower incidence of ovarian hyperstimulation compared to stimulation by HMG (Rabinovici etai., 1987). Gonadotrophin-releasing hormone agonists (GnRH-a) are now widely used in conjunction with HMG for ovulation induction in assisted conception. The incidence of moderate and severe OHSS varied between 0.6% and 14% in different centres using different GnRH-a protocols for pituitary desensitization, different dosages of HMG and different luteal phase supports (B.Rizk and 1083
B.Rizk and M.Aboulgbar
PREDICTION 1. 2. 3. 4.
Young PCOD High serum oestradiol Ultrasonography
5. Doppler
PCO pattern of response to GnRH before HMG. Large number of follicles £15 with a high proportion of small and intermediate size follicles. Conception cycles particularly multiple pregnancy.
PREVENTION 1. Withholding HCG ± continuation of GnRH. 2. Selective oocyte retrieval in spontaneous conception. 3. Cryopreservation and replacement of frozen-thawed embryos at a subsequent cycle
MANAGEMENT Mild OHSS -> conservative treatment - follow-up
Moderate and Severe r
Admission for Monitoring 1. Strict Fluid Chart 2. Plasma and urine osmolarity 3. Urea and electrolytes 4. Clotting parameters 5. Liver function Tests 6. Pregnancy Test ^7. Pelvic Sonography
^
Correction of circulatory and electrolyte Imbalance 1. Aggressive monitoring e.g. CVP 2. Correction of electrolyte imbalance 3. Plasma expanders
— •
v
• Anticoagulants Evidence of thromboembolism
Surgery Only if haemorrhage torsion rupture ectopic Only haemostatic
k.
J
r
Transvaglnal aspiration of ^ Ascltlc fluid 1. Improves symptoms 2. Improves renal function and urinary output 3. Shortens hospital duration 4. Improves venous return and ^ cardiac output v r
\ Precautions 1. Sonographic guidance 2. Replacement of plasma proteins 3. Repeat aspiration may be required
V
J
v Fig. 1. Prediction, prevention and management of OHSS.
J.Smitz, manuscript submitted). It is evident that the use of GnRH-a is not associated with reduced incidence of moderate or severe OHSS (Golan etal, 1988). Several methods are used to prevent the occurrence of OHSS (Figure 1). Withholding HCG is the most widely used measure to prevent the syndrome in cases which show large numbers of follicles and very high levels of oestrogens (Schenker and Weinstein, 1978; McArdle etal, 1983; Haning etal., 1983; Friedman et al., 1984). Forman et al. (1990) adopted a protocol to prevent OHSS in high risk patients. They withheld HCG if 1084
E2 exceeded 2000 pg/ml and it was associated with a total of approximately 15 follicles each measuring ~ 12 mm in mean diameter. In an attempt to rescue cycles prone to develop OHSS, Rabinovici et al. (1987) monitored E2 and follicular state in 12 women with hyperstimulated cycles after withholding HMG for several days; HCG was administered when oestradiol levels were < 1700 pg/ml and the leading follicles between 17 and 22 mm in diameter. OHSS did not occur in any case and three patients conceived. They concluded that a rescue of overstimulated cycles
Management of ovarian hyperstimulation
is sometimes possible. Withholding HCG and continuation of GnRH-a could be used in an attempt to prevent OHSS and after a further period of pituitary densensitization, follicular stimulation was given with a lower dose of HMG. Follicular puncture of all follicles is useful in the prevention of OHSS but not successful in all cases (Golan et al., 1988). Cryopreservation of embryos and their replacement in subsequent cycles have been used when OHSS was predicted from the follicular response and serum E2 levels (Rizk, 1991). OHSS was prevented and pregnancies were subsequently achieved (Amso etal., 1990). Selective oocyte retrieval is a new approach for prevention of OHSS and multiple pregnancies in spontaneous conception, by puncturing most of the ovarian follicles 35 h after HCG administration as in an FVF—embryo transfer (ET) programme. The remaining intact follicles can still result in a singleton or twin pregnancy (Belaisch-Allart etal., 1988). Unfortunately, it seems that, despite the most careful and painstaking preventive measures, OHSS cannot be eliminated because of the narrow margin between ovulation induction and hyperstimulation. Conservative treatment Mild OHSS is usually self-limiting and requires no active therapy other than observation and follow-up (Figure 1). The condition usually subsides within 2 weeks (Borenstein et al., 1989; Golan etal., 1989; Varma and Patel, 1988). Severe OHSS requires hospitalization and active monitoring. Since it was realised that the main problem is the shift of fluids from the circulation to the third space which results in hypovolaemia, hypoproteinaemia, haemoconcentration and electrolyte disturbances, the approach to conservative treatment changed. Restriction of salt, fluids and the use of diuretics is not recommended any more (Borenstein et al., 1989). Instead, the main line of treatment is to correct the circulatory volume and the electrolyte disturbance, which will improve the renal perfusion and prevent coagulation problems and possible embolic manifestations (Figure 1). On admission to hospital, a fluid chart and a base line blood count should be prepared for the patient, and clotting parameters, blood and urine osmolarity should be measured. In severe cases, central venous pressure should be monitored. Plasma expander such as dextran, 500—1000 ml per 24 h, could be used. Human albumin or plasma can be infused to restore the plasma proteins. Anticoagulant therapy is only indicated when there is clinical evidence of thromboembolic complications or laboratory findings of hypercoagulability. Indomethacin, which is a prostaglandin synthetase inhibitor, has been used to modify the changes of OHSS in experimental animals and humans (Schenker and Polishuk, 1986; Varma and Patel, 1988). However, blocking or decreasing the vascular permeability using prostaglandin synthetase inhibitors was disappointing (Schenker and Weinstein, 1978; Pride et al., 1986). Balasch et al. (1990) reported a case of severe OHSS complicated by prerenal oliguria and liver dysfunction due to indomethacin therapy and emphasized that this drug should be used with great caution in OHSS. Histamine receptor blocker (chlorpheniramine maleate) has been used in an attempt to decrease capillary permeability in
OHSS (Kirshon etal., 1988). Pride etal. (1984) found chlorpheniramine treated animals to have significantly higher prostaglandin F content and speculated that the protective effect of an H-l receptor blockade on ascites formation may be mediated, at least in part, by prostaglandin F.
Aspiration of the ascitic fluid and pleura! effusion in severe OHSS Abdominal paracentesis Rabau etal. (1967) were the first to propose abdominal paracentesis for the treatment of OHSS for patients with respiratory distress due to massive ascites. Schenker and Polishuk (1975), Shapiro et al. (1977) and Schenker and Weinstein (1978) advised against abdominal paracentesis for drainage of ascites because of the danger of puncture and laceration of enlarged ovarian cysts. On the other hand, other reports suggested the value of abdominal paracentesis as an efficient method to relieve the symptoms and improve the general condition in severe OHSS. Knauer and Lowe (1967) were able to show an increase in cardiac output and stroke volume and decrease in intra-abdominal pressure, inferior vena cava pressure and hepatic wedge pressure after abdominal paracentesis in patients with tense ascites. Guazzi et al. (1975) have suggested that increased intraabdominal hydrostatic pressure in patients with tense ascites acts via the diaphragm to increase intra-thoracic pressure and reduce transmural filling pressure in the heart. The mean right atrial pressure is increased and venous return is thus impeded. Abdominal paracentesis should relieve intra-abdominal pressure and result in an increased venous return and an augmented filling of the heart. Thaler et al. (1981) in a case report showed that paracentesis was followed by increased urinary output shortly after the procedure with concomitant decreases in the patient's weight, leg oedema and abdominal circumference. They also showed that there was an increased creatinine clearance rate of 50% following the procedure. Bider etal. (1989) treated 12 patients with severe OHSS accompanied by pleural effusion or ascites causing respiratory discomfort and dyspnea by abdominal puncture. Drainage of abdominal or pleural effusion improved the symptoms in all patients. The amount of fluid aspirated ranged between 200 and 1400 ml. The risk of injury to an ovarian cyst was minimized by ultrasonographic guidance. They commented that paracentesis offered a temporary relief of respiratory distress but since the fluid tended to recur, some patients needed repeated paracentesis and drainage of effusion before spontaneous improvement ensued. The experience with this large group of patients indicates that the actual risk of paracentesis is negligible. However, a possible drawback is the loss of fluid that is rich in proteins (Kingsland etal., 1989). Padilla et al. (1990) demonstrated that abdominal paracentesis is a well tolerated treatment to relieve severe pulmonary compromise caused by severe ascites and pleural effusion in OHSS. They commented that an improvement in renal function may be another benefit that deserves further investigation. 1085
B.Rizk and M.Aboulghar
Transvaginal ultrasonic guided aspiration Aboulghar et al. (1990), in a prospective randomized clinical trial, investigated the effects of transvaginal aspiration of ascitic fluid under sonographic guidance in patients with severe OHSS. The average hospital stay and the period with severe symptoms and disturbed electrolyte balance was much shorter in the group in which aspiration of ascitic fluid was performed when compared with the group that underwent conservative treatment. Aspiration of the ascitic fluid is of paramount importance in relieving the symptoms of the patients, improving the general condition and increasing urinary output (Figure 1). A marked improvement in the symptoms was noted after drainage of as little as 900 ml of ascitic fluid. There were no adverse haemodynamic effects as a result of the aspiration of large volumes of ascitic fluid. Replacement of the plasma proteins is mandatory because of the high protein content of ascitic fluid (47 ± 22 g/1). This is particularly essential as repeated aspiration was required in 30% of patients. The rate of accumulation of ascitic fluid varied significantly. However, recollection of a large volume of ascitic fluid sufficient to cause discomfort would require, on average, 3 — 5 days. We believe that ultrasonic needle guided transvaginal aspiration is an effective and safe procedure. Injuring the ovary was avoided by puncture under ultrasonic visualization. No anaesthesia was required for the procedure. Better drainage of the ascitic fluid was accomplished because the Douglas pouch is the most dependent part. In our experience, transvaginal aspiration of ascites in severe forms of OHSS is a fast and effective line of treatment. It is performed routinely in our centre, in all severe OHSS cases after our clinical trial. Role of surgery in the management of OHSS In genera] surgery should be avoided in the treatment of OHSS, except in cases of torsion or rupture of an ovarian cyst, or if it is associated with ectopic pregnancy. Chotiner (1985) reported a case of severe OHSS in a patient with ectopic gestation. Bider et al. (1989) reported operative procedures in 16 patients with severe OHSS because of torsion, rupture and bleeding in the ovarian cysts. Torsion was found to be more common if pregnancy was present. Mashiach et al. (1990) reported that 12 pregnant women presented with torsion of hyperstimulated ovaries. They considered that the diagnosis of adnexal torsion is usually uncertain and since surgical intervention is likely to be delayed, these infertile women have a risk of losing their ovaries. The clinical picture of torsion included a combination of ovarian enlargement, abdominal pain, nausea, progressive leucocytosis and anaemia. Although during the operation the adnexa appeared dark, haemorrhagic and ischaemic, they suggested that it can be saved by simply unwinding it. They concluded that patients with torsion of hyperstimulated adnexa who conceive after gonadotrophin therapy should be considered as a special entity which requires more attention to achieve early diagnosis. OHSS is still a wide open field for research that will lead to better understanding of its pathogenesis. Until then, it is the responsibility of the clinician to impose strict rules for prediction and prevention. While mild cases of OHSS should be managed 1086
conservatively, severe cases should be monitored closely and actively treated by correction of fluid and electrolyte imbalance, and aspiration of the ascitic fluid.
References Aboulghar.M.A., Mansour.R.T. and Serour,G.I. (1989) Ovarian superstimulation in the treatment of infertility due to peritubal and periovarian adhesions. Fend. SieriL, 51, 834-837. Aboulghar.M.A., Mansour.R.T., Serour,G.I. and Amin,Y. (1990) Ultrasonically guided vaginal aspiration of ascites in the treatment of ovarian hyperstimulation syndrome. Fertil. Steril., 53, 933—935. Amso.N.N., Ahuja.K.K., Morris.N. and Shaw,R.W. (1990) The management of predicted OHS involving gonadotrophin-releasing hormone analogue with elective cryopreservation of all pre-embryos. Fertil. Steril., 53, 1087-1090. Balasch,J., Carmona.F., Llach.J., Arroyo,V., Jove,l. and Vanrell.J. (1990) Acute prerenal failure and liver dysfunction in a patient with severe ovarian hyperstimulation syndrome Hum. Reprod., 5, 348-351. Belaisch-Allart,J., Belaisch,J., Hazout,A., Testart,J. and Frydman,R. (1988) Selective oocyte retrieval: a new approach to ovarian hyperstimulation. Fertil. Steril., 50, 654-656. Bider.D., Menashe.Y., Oelsner,G., Serr.D.M., Mashiach,S. and Ben-Rafael,Z. (1989) Ovarian hyperstimulation syndrome due to exogenous gonadotrophin administration. Acta Obstet. Gynecol. Scand., 68, 511-514. Blankstein.J., Mashiach.S. and Lunenfeld.B. (eds) (1986) Induction of ovulation with gonadotrophins. In Induction ofOvulation and In Vitro Fertilization. Chicago Year Book Medical Publishers, Chicago, p. 147. Blankstein.J., Shalev,J., Saadon,T., Kukia,E.E., Rabinovici,J., Pariente.C, Lunenfeld.B., Serr.D.M. and Mashiach.S. (1987) Ovarian hyperstimulation syndrome prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597—602. Borenstein.R., Elhalah.U., Lunenfeld,B. and Schwartz,Z.S. (1989) Severe ovarian hyperstimulation syndrome: a reevaluated therapeutic approach. Fertil. Steril., 51, 791-795. Charbonnel.B., Krempf.M., Blanchard.P., Dano.F. and Delage.C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of luteinizing hormone releasing hormone analogue and exogenous gonadotrophins. Fertil. Steril., 47, 920—924. Chotiner,H.C. (1985) Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstet. Gynecol., 66, 740-743. Forman.R.G., Frydman.R., Egan.D., Ross.C. and Barlow.D.H. (1990) Severe ovarian hyperstimulation syndrome using agonists of gonadotrophin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502—509. Friedman.C.I., Schmidt.G.E., Chang,F.E. and Kim,M.H. (1984) Severe ovarian hyperstimulation syndrome following follicular aspiration. Am. J. Obstet. Gynecol., 150, 436-437. Golan.A., Ron-El,R., Herman,A., Weinraub,Z., Soffer,Y. and Capsi,E. (1988) Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil. Steril., 50, 912-916. Golan.A., Ron-FJ,R., Herman,A., Soffer,Y., Weinraub,Z. and Capsi.E. (1989) Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv., 44, 430-440. Guazzi,M., Polese.A., Magrini.F., Fiorentini.C. and Olivary,M. (1975) Negative influences of ascites on the cardiac function of cirrhotic patients. Am. J. Med., 59, 165-170. Haning,R.V.,Jr, Austin,C.W. and Carlson,I.H., Kuzma,D.L., Shapiro,S.S. and Zweibel,W.J. (1983) Plasma estradiol is superior to ultrasound and urinary estradiol glucuronide as a predictor of ovarian
Management of ovarian hyperstimulation hyperstimulation during induction of ovulation with menotropins. Ferril. Steril., 40, 31-36. Haning,R.V., Strawn,E.Y. and Nolten.W.E. (1985) Pathophysiology of the ovarian hyperstimulation syndrome. Obstet. Gvnecol, 66, 220-224. Jewelewicz,R. and Vande Wiele,R.L. (1975) Acute hydrothorax as the only symptom of ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol.,121, 1121. Kingsland.C, Collins,J.V., Rizk,B. and Mason.B.A. (1989) Ovarian hyperstimulation presenting as acute hydrothorax after in vitro fertilization. Am. J. Obstet. Gvnecol., 161, 381-382. Kirshon.B., Doody,M.C, Cotton,D.B. and Gibbons,W. (1988) Management of ovarian hyperstimulation syndrome with chlorpheniramine maleate, manitol, and invasive hemodynamic monitoring. Obstet. Gynecol., 71, 485—487. Knauer,C.M. and Lowe,H.M. (1967) Hemodynamics in the cirrhotic patient during paracentesis. N. Engl. J. Med., 276, 491-496. Mashiach,S., Bider.D., Moran,O., Goldenberg.M. and Ben-Rafael,Z. (1990) Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil. Steril., 53, 76 — 80. McArdle.C, Seibel,M., Hann,L., Weinstein,F. and Taymour.M. (1983) The diagnosis of ovarian hyperstimulation (OHS); the impact of ultrasound. Fertil. Steril., 39, 464-467. Mozes,M., Bogowsky.H., Anteby,E., Lunenfeld.B., Rabau,E., Serr,D.M. and Salomy,M. (1965) Thrombo-embolic phenomena after ovarian stimulation with human menopausal gonadotropins. Lancet, 2, 1213-1215. Navot,D., Margalioth.E. and Laufer,N. (1987) Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome. Fertil. Steril., 48, 5 7 - 6 1 . Padilla.S.A., Zamaria.S., Baramki.T.A. and Garcia,J.E. (1990) Abdominal paracentesis for the ovarian hyperstimulation syndrome with severe pulmonary compromise. Fertil. Steril., 53, 365-367. Pride.S.M., Yuen.B.H. and Moon.Y.S. (1984) Clinical, endocrinologic and intraovarian prostaglandin F responses to H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model. Am. J. Obstet. Gynecol., 148, 670-674. Pride.S.M., Yuen,B.H., Moon.Y.S. and Leyung.P.C.S. (1986) Relationship of gonadotrophin-releasing hormone, danazol and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol., 154, 1155-1160. Rabau.E., Serr,D.M., David,A., Mashiach.S. and Lunenfeld.B. (1967) Human menopausal gonadotrophins for anovulation and sterility. Am. J. Obstet. Gynecol., 98, 92-98. Rabinovici.J., Kushnir.O., Shalev.J., Goldenberg.M. and Blankstein.J. (1987) Rescue of menotropin cycles prone to develop ovarian hyperstimulation. Br. J. Obstet. Gynaecol., 94, 1098-1102. Rizk.B. (1991) Ovarian hyperstimulation syndome. In Brinsden,P.R. and Rainsbury,P.A. (eds), The Bourn Hall Textbook of In Vitro Fertilization and Assisted Reproduction. Ch. 23. Parthenon, in press. Rizk,B., Meagher.S. and Fisher.A.M. (1990) Ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum. Reprod., 5, 697—698. Salat-Baroux,J., Tibi.G., Alvarez,S., Cornet,D., Antoine,J.M. and Gomes,A. (1989) Ultrasonographic prediction of ovarian hyperstimulation after IVF. Proceedings of the VI World Congress of In Vitro Fertilization and Alternate Assisted Reproduction. Jerusalem, Israel, Abstr., p. 27. Schenker.J.G. and Polishuk.W.Z. (1975) Ovarian hyperstimulation syndrome. Obstet. Gynecol., 46, 23-28. Schenker.J.G. and Weinstein,D. (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril., 30, 255-268. SealeyJ.E., Glorioso.N. and ItskovitzJ. (1986) Plasma prorenin during early pregnancy: ovarian secretion under gonadotrophins control? J. Hypertens., 4 (suppl. 5), S92-S95.
Shapiro,A.G., Thomas.T. and Epstein,M. (1977) Management of hyperstimulation syndrome. Fertil. Steril., 28, 237—239. Sueldo.C.E., Price.H.M., Bachenberg.K., Steinleiter.A., Gilten.N. and Swanson.J. (1988) Liver dysfunction in ovarian hyperstimulation syndrome. A case report. J. Reprod. Med., 33, 387-390. Tal.J.. Paz.B., Samberg,!., Lazarov.N. and Sharf,M. (1985) Ultrasonographic and clinical correlates of menotrophin versus sequential clomiphene citrate:menotrophin therapy for induction of ovulation. Fertil. Steril., 44, 342-349. Thaler.I., Yoffe.N., Kaftory.J. and Brandes.J. (1981) Treatment of ovarian hyperstimulation syndrome: the physiologic basis for a modified approach. Fertil. Steril., 36, 110-113. Tulandi.T., Mcinnes.R.A. and Arronet.G.H. (1984) Ovarian hyperstimulation syndrome following ovulation induction with hMG. Int. J. Fertil., 29, 113-117. Tyler,E . (1968) Treatment of anovulation with menotrophins. J. Am. Med. Assoc., 205, 16-22. Varma.T.R. and Patel,R.H. (1988) Ovarian hyperstimulation syndrome: a case history and review. Ada Obstet. Gynecol. Scand., 67, 579-582. Younis.J.S., Zeevi.D., Rabinowitz.R., Laufer.N. and Schenker.J.G. (1988) Transient liver function tests abnormalities of ovarian hyperstimulation syndrome. Fertil. Steril., 50, 176—178. Zosmer.A., Katz.Z., Lancet,M., Konichezky,S. and SchwartzShoham.Z. (1987) Adult respiratory distress syndrome complicating ovarian hyperstimulation syndrome. Fertil. Steril., 47, 524—526. Received on August 28, 1990; accepted on April 25, 1991
1087
