Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors

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GYNECOLOGY & OBsTETRK-3 International Journal of Gynecology& Obstetrics52 (1996)259-262

Article

Rare occurrence of ovarian hyperstimulation syndrome in oocyte donors M.V. Sauer*, R. J. Paulson, R.A. Lobo Department

of Obstetrics

and Gynecology,

University

of Southern

California

School

of h4e&&e, ~0s Angeles,CA, ,!,&A

Received3 April 1995; revision received 15 September 1995; accepted 22 September 1995 Abstract Objectives: To define the incidence and severity of ovarian hyperstimulation syndrome (OHSS) occurring in oocyte donors. Methods: Women (n = 149)aged 31.3 f 4.8 years (mean f S.D., range 21-41 years) participated as designated oocyte donors and underwent 400 consecutive cycles of controlled ovarian stimulation using human menopausalgonadotropin following pituitary downregulation with gonadotropin-releasing agonist. Patients were monitored by serial transvaginal ultrasound examinations and serum estradiol (E2) determinations. Oocytes (15.6 f 7.5 per aspiration; range 2-57) were harvested by ultrasound-directed transvaginal follicle aspiration 36 h following the intramuscular injection of human chorionic gonadotropin (hCG). Follow-up examination occurred 1 and 2 weeks post-aspiration. Results: On the day of hCG injection E2 levels ranged from 512 to 13502 pg/ml (mean 2902.7 f 1486.9pg/ml). Over the next few weeksthe degreeof hyperstimulation in donors was staged: mild 65% (grade I, n = 98; grade II, n = 162); moderate 33.5% (grade III, n = 120; grade IV, n = 14); severe 1.5% (grade V, n = 6; grade VI, n = 0). Associated preaspiration E2 levels were: grade I, 1120 f 424 pg/ml; grade II, 2084 f 613 pg/ml; grade III, 3785 f 1713pg/ml; grade IV, 5370 f 1264 pg/ml; grade V, 4286 f 1100pg/ml. Worsening OHSS was associated with increasing levels of E,. There were no serious complications and hospitalization was not required. All symptoms resolved within 30 days of aspiration, disappearing by the time of the first menstrual flow in women of grade-III or lower stage. Conclusion: Although oocyte donors commonly experienced exaggerated levels of serum E, they rarely (< 2%) developed severe OHSS. This may be attributable to their lack of embryo transfer which avoids exacerbating the illness.

Keyworcis: Ovarian hyperstimulation syndrome; Oocyte donation; Donor eggs

1. Introduction The development of ovarian hyperstimulation

syndrome(OHSS) in women undergoing assisted l Corresponding author, Department of Obstetrics and Gynaecology, Columbia-Presbyterian Medical Center, 622 West 168th Street,PH16-28,NewYork, NY 10032,USA,Tel.: +I 212 3059175; Fax: +I 212 3053869.

0020-7292/96/%15.00 0 1996 International SSDI

0020-7292(95)02587-3

reproduction is a well-described and dreaded iatrogenic complication [ 1,2], Characteristically, ovarian enlargement with multiple cysts is associated with increased capillary permeability leading to massive extravascular displacement of fluids. In severe cases this may progress to profound intravascular volume depletion, hemoconcentration, coagulopathy and renal failure [3]. The essential

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Journal of Gynecology & Obstetrics 52 (19%) 259-262

physiologic disturbance relates to the depletion of intravascular volume and complications arising from effusions. Many potential mediators of OHSS have been suggested.These include estrogen, pro&gland& gonadotropin, histamine, cytokines, prolactin, and most recently, renin angiotensin and aldosterone [4-lo]. The role of any and all of these causative agents in initiating the cascadeof clinical eventsthat lead to OHSS remains unknown. OHSS usually follows the administration of drugs used to induce ovulation including pregnant mare’s serum globulin, human pituitary gonadotropin extracts, clomifene citrate and human menopausal gonadotropin (hMG) [ II- 141. As early as 1967Rabau et al. [ 131proposed clinically staging the syndrome to add objectivity to patient assessment.Mild, moderate and severe stages of worsening illness were later subdivided into six grades to better characterize the clinical picture

Table 1 Donor and cycle performance characteristics

11%

menced. Stimulations were synchronized to recipients matched to the donors. hMG was administered daily until lead follicles reached a mean diameter of 18 mm as measured by transvaginal ultrasound. At this time 10 000 IU human chorionic gonadotropin (hCG) was administered intramuscularly. Follicles were transvaginally aspirated 36 h later including both largeand small-diameter cysts. Flushing was not performed. Oocyteswere retrieved from approximately 90%of aspirated follicles. Physical examinations were repeated again at the time of aspiration and approximately 2 weekslater. Telephone interviews were conducted to further assessdiscomfort or illnessexperienced by donors following stimulation.

We have previously described the demographic and cycle performance characteristics of oocyte donors at the University of Southern California [ 161. During stimulations, donors typically produce large numbers of oocytes and experience exaggerated levels of serum estradiol (E2). Several investigators have reported the association of worsening OHSS and elevated E2 [ 17,181.However we have been impressedby the general lack of clinical symptoms in donors undergoing ovarian stimulation. We describe our experience with respect to the staging of OHSS in oocyte donors. 2. Materials and methods From April 1988 through April 1994, 400 consecutivecycles of oocyte donation were completed by gamete donors (n = 149). Table 1 describes thesewomen and their performance during stimulation. Following the satisfactory completion of precycle screening, which included a physical examination, donors underwent ovulation induction in standardized fashion. Briefly, this required pituitary downregulation beginning in the luteal phase of the preceding menstrual cycle using gonadotropin-releasing agonist (GnRHa; leuprolide acetate). Once serum E, levels were less than 30 pg/ml, initiation of hMG (225 IU) was com-

Mean * SD. Age (years) 31.3 zt 4.8 &avidity 2.4 + 1.5 1.8 f 1.2 Parity No. of office visits per 5.7 + 1.2 cycle of COH Days required to 15.3 * 5.0 downregulate with GnRHa Ampules hMG used 29.0 zt 6.8 Peak E2 (pgml) at 2902.7 + 1486.9 5 time of hCG Median 2726 pg/ml 75% Percentile 3700 pgml 90% Percentile 5011 pgml

Range 21-41 O-8 O-6 4-9 13-35 18-68 12-13 502

COH, controlled ovarian hyperstimulation.

3.

Results

Oocytes (15.6 f 7.5 per retrieval; range 2-57) were successfully aspirated in 100%of cases.This resulted in a mean of 8.0 f 5.2 embryos per retrieval cycle (range O-35). There were no operative complications. Table 2 describesthe outcomes according to the criteria published by both Rabau et al. [13] and Golan et al. [15]. The majority (twothirds) of women demonstrated few signs or symptoms of OHSS. These cases resolved within 2 weeks of aspiration. Ascites was present in all instances of severehy-

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Journal of Gynecology dr Obstetrics 52 (1996) 259-262

Table 2 OHSS: results of 400 consecutive donor aspirations Stage

No. of cycles

Mild (65%)’ Grade I 98 Grade II 162 Moderate (33.5%)’ Grade III 120 Grade IV 14 Severe(l.5%)a Grade V 6 Grade VI -

E, (p&ml) Mean f S.D.

Range

1120 f 424 2084 f 613

512-2873 953-5120

3785 f 1713 5370 ZIZ1263

1527- I3 502 3860-7506

4286 f 1100 -

3196-5395

‘Percentage of cycles aspirated.

perstimulation (n = 6). One of these women developed pleural effusion, evident on decubitus chest radiograph. Despite 10% of stimulations resulting in E2 levels above 5000 pg/ml, no grade-VI OHSS occurred. All patients grades III-V were managed by pelvic rest and observation. Antiemetics were prescribed for nausea (n = 15). Women who experienced similar signs and symptoms in subsequent cycles did not progress to more severe stages. Interestingly, women with levels > 5000 pg/ml often experiencedmild degreesof OHSS and remained essentially asymptomatic in subsequent cycles. 4. Discussion

Women prescribed ovarian hyperstimulation are advised of the risks and complications associated with fertility drugs. The serious nature of OHSS warrants a judicious approach. This is especially true in young women who undergo oocyte donation for the benefit of others. Although the incidence of serious side effects from OHSS in IVF patients varies from as low as 2% to as high as 50% [ 17,181,little is known with respect to oocyte donors. Severe cases generally occur following conception [19]. Since embryo transfer does not occur in donors, resolution begins immediately after aspiration as exogenous levels of hCG decline. Recently it has been hypothesized that donors may only suffer from the initial stages of the syndrome since the full-blown cascade of

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symptoms will not develop without trophoblastic production of hCG [20]. It is evident that the clinical course following aspiration repeats itself in subsequent stimulation cycles. It is reassuring to know that despite E2 levels in excess of 5000 pglml, donors are often clinically asymptomatic. No prophylactic measures were necessary to combat the condition. High levels of E, were observed in subsequent cycles even following reduction in hMG dosage. Women with values greater than 3000 pg/ml in previous cycles using three ampules per day were reduced to two ampules. Yet E2 levels were not appreciably affected and oocyte yield remained the same. Most commonly OHSS was evidenced by ultrasonographic visualization of enlarged ovaries, 5 and 8 cm in longitudinal length, with a modest amount of intraabdominal peritoneal fluid. However this was not clinically evident, although patients did occasionally complain of tightness of their clothes. Patients were reassured that these changeswere normal following the use of medications, and were instructed to maintain good hydration and notify the office if nausea, vomiting or diarrhea developed. These complaints were uncommon (< 5%) and not of clinical significance. Following aspiration and by the onset of menses, clinical signs were minimal and by the second baselinescan 1 month later, the ovaries were again normal in size. Descriptively speaking, oocyte donors should be at high risk for OHSS 1211.They are young and undergo vigorous stimulation routinely following GnRHa downregulation. Commonly, polycysticappearing ovaries are present 1221.The unpredictable nature of this syndrome requires physicians to carefully assessthe risks with each donor. However, the initial cycle appearsto predict subsequent risk of OHSS in the individual. It has been suggestedthat preventive measures be instituted to lessenthe risk of OHSS [23]. The prophylactic use of intravenous albumin at the time of aspiration is advocated. Others withhold hMG or trigger ovulation with GnRH as opposed to hCG [21-271. Such measuresmay attenuate the renin-angiotensin-aldosterone axis. Yet there is no clinical indication that prophylactic measuresare needed.Since luteal phase support is not required,

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the administration of hCG or progesterone, both of which may have an effect upon the resolution of the hyperstimulated ovary, are not necessary.Reasonablemeasuresto reduce risk should include the careful aspiration of all visible follicles and close surveillance following aspiration. The removal of granulosa cells during aspiration may deplete many necessaryprecursors for initiating the syndrome. We conclude that despite robust responses to hMG, oocyte donors rarely develop severeOHSS. Thesedata do not support the use of prophylactic measuresto reduce illness. However, adequate informed consent prior to the initiation of any stimulation cycle is important. Women tend to react similarly in subsequent cycles and if few clinical symptoms in initial cycles are present it is unlikely that they will later develop serious illness. References [I] BerghPA, Navot D. Ovarian hyperstimulation syndrome:a reviewof pathophysiology. J Assisted Reprod Genet 1992;9: 429-438. [2] Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1978; 30: 255-268. [3] Ferraretti AP, Gianaroli L, Diotallevi L, Festi C, Trounsen A. Dopamine treatment for severeovarian hyperstimulation syndrome. Hum Reprod 1992; 7: 180-183. [4] Morris RS, Paulson RJ. Ovarian hyperstimulation syndrome: classification and management. Contemp Obstet Gynecol 1994;39: 43-54. [5] Knox GE. Antihistamine blockade of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1974; 118: 992-994. [6] Yuen BH, McComb P, Yarali H, Fleige-Zahradka B-G. The ascites in the ovarian hyperstimulation syndrome does not originate from the ovary. Fertil Steril 1993;59: 657-661. [7] Zaidise I, Friedman M, Lindenbaum ES, Askenazi R, Peretz BA, Paldi E. Serotonin and the ovarian hypcrstimulation syndrome. Eur J Obstet Gynecol Reprod Biol 1983; 15: 55-60. [8] Friedlander MA, Loret de Mola JR, Goldfarb JM. Elevated levels of interleukin-6 in ascitesand serum from women with ovarian hyperstimulation syndrome. Fertil Steril 1993;60: 826-833. [9] Morris RS, Paulson RJ. The ovarian renin angiotensin system:recent advancesand their relationship to assisted reproductive technologies. Assisted Reprod Rev 1993;3: 2-10. [IO] Pride SM, Yuen BH, Moon YS, Leung PC. Relationship of gonadotropin-releasing hormone, danazol and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome in the rabbit. Am J Obstet Gynecol 1986; 154: 1155-l 160.

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