Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

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1 FERTILITY AND STERILITY Copyright 1992 The American Fertility Society Printed on acid-free paper in U.S.A. The effect of baseline complex ovarian cysts on in vitro fertilization outcome*t Elizabeth A. Stewart, M.D.:!: Katharine V. Jackson, B.S. Andrew J. Friedman, M.D. Mitchell S. Rein, M.D. Janis H. Fox, M.D. Mark D. Hornstein, M.D. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Study Objective: To determine the effect of baseline complex ovarian cysts on controlled ovarian hyperstimulation and in vitro fertilization (IVF) outcome. Design: Retrospective analysis with stratification by stimulation regimen and the presence or absence of surgically documented endometriosis. Patients: Two hundred sixty-one women undergoing IVF from May 1, 1989 to December 31, Main Outcome Measures: The outcome measures assessed were the maximum estradiol (E2) concentrations on day of human chorionic gonadotropin (hcg) administration, number of follicles with maximum diameter :<::15 mm, number of follicles with maximum diameter :<::12 mm, number of days to hcg administration, number of ampules of human menopausal gonadotropin (hmg) used, number of oocytes retrieved and fertilized, number of embryos transferred, and pregnancy and cycle cancellation rates. Results: There were no statistical differences between cyst and noncyst groups in any of the above parameters of IVF performance. In a single subgroup, patients with endometriosis stimulated with hmg and patients with cysts had significantly lower E2 concentrations than patients without cysts. Conclusion: The presence of a complex cyst on a baseline ultrasound does not appear to adversely affect IVF cycle outcomes. Fertil SteriI1992;57: Key Words: Ovarian cysts, in vitro fertilization, endometriosis The management of baseline ovarian cysts during controlled ovarian hyperstimulation in an in vitro fertilization (IVF) program is controversial. Several investigators have addressed the effect of simple ovarian cysts on controlled ovarian hyperstimulation and the outcome ofivf cycles (1-4). Although Received August 26, 1991; revised and accepted February 11, *Data organization and analysis assisted by the Computerized Data Base Management and Analysis System; Supported by General Clinical Research grant number 5-MO l-rr-02635, Brigham and Women's Hospital, Boston, Massachusetts. t Presented in part to the Boston Fertility Society, Boston, Massachusetts, December 4, * Reprint requests: Elizabeth A. Stewart, M.D., Department of Obstetrics and Gynecology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts Stewart et al. Baseline complex ovarian cysts in IVF some studies have suggested that simple ovarian cysts lead to poor follicular recruitment or increased cancellation rates (2,4), others have found that these cysts do not adversely influence the outcome of IVF (1, 3). Intervention with cyst aspiration has been advocated by some groups as an alternative to cycle cancellation (5-8). No study has examined the effect of baseline cysts with septations, internal echoes, or debris on controlled ovarian hyperstimulation in IVF cycles. The purpose of this retrospective study is to assess the performance of patients with baseline complex ovarian cysts in an IVF program. MATERIALS AND METHODS From May 1, 1989 to December 31,1990,261 patients at the Brigham and Women's Hospital un-

2 derwent controlled ovarian hyperstimulation for the purpose of IVF. Gamete intrafallopian transfer cycles were not included in this analysis. All patients who had a complex cyst on endovaginal ultrasound (US) scanning performed on cycle day 1 or 2 were selected as study patients (n = 28). Complex cysts were defined as cysts with septations, internal echoes, or debris seen on US scanning. Patients with simple cysts were excluded from analysis (n = 32). Control patients consisted of those who had no cysts on a baseline US (n = 201). Only the first cycle for each patient was analyzed. Patients were stratified by the presence or absence of surgically documented endometriosis and by ovulation induction regimen. Stratification for the diagnosis of endometriosis was performed because it was believed that in these women the complex cysts were more likely to be endometriomas. Pathological confirmation of cyst contents at the time of egg retrieval was not routinely obtained. Patients were divided into four groups: group 1 consisted of 12 patients with complex cysts on US undergoing controlled ovarian hyperstimulation with human menopausal gonadotropin (hmg) after leuprolide acetate (LA) down regulation. Group 2 was composed of 49 control patients without cysts treated with the same LA/hMG protocol. Group 3 consisted of 16 patients with complex cysts treated with hmg alone. Group 4 included 152 control patients without cysts stimulated with hmg alone. The groups were further stratified by the presence or absence of documented endometriosis: patients in subgroup A carried the diagnosis of endometriosis; patients in subgroup B did not. Before acceptance into the IVF program, all patients had undergone a diagnostic laparoscopy during their infertility evaluation, at which time the presence or absence of endometriosis was recorded. Ovulation induction consisted of hmg alone or hmg with LA. Patients on hmg alone received injections intramuscularly (1M) on cycle days 2 to 5 with 225 IU for those weighing :0:;68.2 kg and 150 IU two times a day for those >68.2 kg. Subsequent hmg doses were individualized based on the results of daily US and serum estradiol (E2) monitoring. Human chorionic gonadotropin (hcg) 10,000 IU was administered when serum E2 ::2:: 650 pg/ml and there was a minimum of two follicles measuring at least 15 X 10 mm. Transvaginal US-guided egg retrieval occurred 34 hours after hcg administration, and embryo transfer (ET) occurred 48 hours after egg retrieval. Administration of LA was started either in the midluteal phase of the preceding cycle (generally on cycle day 21) or on day 1 of the follicular phase and was begun at a dose of 0.5 mg 1M two times a day for 10 days or until serum E2 < 50 pg/ml. At that time, the LA dose was decreased to 0.5 mg/d and hmg was started. Criteria for hcg administration included serum E2 ::2:: 650 pg/ml and two follicles ::2:: 18 X 12 mm in maximal diameter with at least two additional measurable follicles ::2:: 12 mm in greatest diameter. Egg retrieval and ET were carried out as for hmg cycles. The decision to start controlled ovarian hyperstimulation in the setting of a baseline complex cyst was individualized. In general, patients on hmg alone were allowed to start with cysts < 3 cm in diameter, and patients stimulated with LA/hMG were allowed to start with cysts < 1 cm; however, some patients with larger cysts were permitted to begin controlled ovarian hyperstimulation. Three patients on hmg who had undergone recent surgical exploration began controlled ovarian hyperstimulation with cysts ::2:: 3 cm. Twelve patients began controlled ovarian hyperstimulation with cysts between 1 and 3 cm in size, and all had either undergone recent surgical exploration or had been on extended LA therapy with a decrease in the size of the cyst noted. All patients received progesterone (P) for luteal phase support. The hmg group received P 25 mg/d 1M for 16 days after transfer, and the LA/hMG group received P 25 mg 1M for 2 days beginning the evening of egg retrieval followed by 50 mg 1M beginning the evening of ET for a total of 16 days. Progesterone supplementation was continued for the first trimester in patients who conceived. Serum E2 was measured by radioimmunoassay (Pantex, Santa Monica, CA and Delfia; Pharmacia, Fairfield, NJ). Two E2 assays were used during the study period, and values reported have been standardized to the first assay. The intra-assay and interassay coefficients of variance for each assay were 11.0% and 10.0%, and 6.5% and 4.0%, respectively. Real-time ultrasonography was performed daily using an endovaginal 5-MHz Acuson transducer (Acuson, Mountain View, CA). For egg retrievals, a vaginal probe 5-MHz ADR Ultramark 9 (Advanced Technology Laboratories Inc., Bellevue, W A) was used. Clinical pregnancies were defined as gestations progressing for at least 6 weeks from the last menstrual period with two consecutive rising is-hcg levels and US documentation of viability or pathological confirmation of trophoblastic tissue in patients Stewart et al. Baseline complex ovarian cysts in IVF 1275

3 Table 1 Cycle Parameters for LA/HMG Stimulation Group 1 (with cyst) (n = 12) Group 2 (without cyst) (n = 49) Probability Maximum E2 (pg/ml) Follicles> 15 mm Follicles> 12 mm Day ofhcg Pergonal (amps) No. oocytes retrieved No. oocytes fertilized No. embryos transferred Pregnancy rate (%) Cancellation rate (%) 1,446 ± 667* 7.1 ± ± ± ± ± ± ± ,422 ± ± ± ± ± ± ± ± * Values are means ± SD. t NS, not significant at P < with spontaneous abortions or ectopic pregnancies. Pregnancy rates (PRs) were reported as clinical pregnancies per cycle initiated. Statistical analysis was performed using Wilcoxon's two-tailed rank sum test for continuous variables and Fisher's exact test for binomial data. Statistical significance was defined as P < 0.05, and results are expressed as the mean ± SD. Statistical analysis was performed using the Computerized Data Base Management and Analysis System (Brigham and Women's Hospital, Boston, MA) computer system. Power calculations were based on an assumption that ex = 0.05 and {3 = RESULTS All groups were comparable in age, gravidity, and parity. Diagnoses were similar across the groups, except for a greater proportion of patients in group 1 with documented endometriosis as compared with groups 2 to 4 (67% versus 27% to 31%); however, this difference did not reach statistical significance. Of patients with complex cysts, 26 patients had uni- lateral cysts and two patients had bilateral ovarian cysts. One of the patients with bilateral cysts had a total of three cysts. Of the patients with unilateral cysts, 5 of 26 had a history of surgical extirpation ofthe contralateral ovary, and none ofthese patients had documented endometriosis. The maximum diameter of the cysts ranged from 11 to 50 mm with a mean diameter of 26 mm and a median diameter of23 mm. There were no significant differences between cyst and noncyst cycle parameters for either the LA or non-la groups (group 1 versus group 2; group 3 versus group 4) (Tables 1 and 2). Parameters measured were maximum E2 concentrations on the day of hcg administration, number of follicles with maximum diameter ~ 15 mm, number of follicles with maximum diameter ~ 12 mm, number of days to hcg administration, number of ampules of hmg used, number of oocytes retrieved, number of oocytes fertilized, and the number of embryos transferred (Tables 1 and 2). When patients were stratified for the presence or absence of endometriosis as well as stimulation reg- Table 2 Cycle Parameters for HMG Stimulation Group 3 (with cyst) (n = 16) Group 4 (without cyst) (n = 152) Probability Maximum E2 (pg/ml) Follicles> 15 mm Follicles> 12 mm DayofhCG Pergonal (amps) No. oocytes retrieved No. oocytes fertilized No. embryos transferred Pregnancy rate (%) Cancellation rate (%) 736 ± 250* 4.8 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± * Values are means ± SD. t NS, not significant at P < Stewart et al. Baseline complex ovarian cysts in IVF

4 imen, there were no major differences among the groups. In a single comparison, however, there was a significant difference in maximal E2 concentrations in patients with endometriosis stimulated with hmg alone. The patients without cysts (n = 41) had a higher mean peak E2 of 909 ± 83 pg/ml versus 596 ± 40 pg/ml (P = 0.028) for patients with endometriosis with cysts (n = 5). However, the PR for patients with complex cysts and endometriosis on hmg stimulation was higher than for patients without cysts (40.8% versus 4.9%, P = 0.053), a difference that approached statistical significance. There were no other significant differences in stimulation or retrieval parameters or differences in PRs or cancellation rates among the groups studied. DISCUSSION With the high cost of each IVF cycle, both in personal and financial terms, it is important to maximize successful ovarian stimulation and oocyte retrieval for each patient. The data in this study suggest that there is no adverse impact on controlled ovarian hyperstimulation and IVF performance with baseline complex cysts. The statistical power of this study was sufficient to detect a difference of approximately 40% or more between groups 1 and 2 (Table 1), in all continuous variables except the number of oocytes retrieved and the number of oocytes fertilized. For groups 3 and 4 (Table 2), the power was great enough to detect an approximately 25% or more difference for all continuous variables except the number of oocytes fertilized. Using the PRs reported in Tables 1 and 2, approximately 100 patients would be needed in each group to detect a 10% difference in PRs with approximately 60% power. The introduction of gonadotropin-releasing hormone agonists (GnRH-a) into ovulation induction regimens has produced a number of studies of ovarian cysts induced by this method of stimulation (9-13). The mechanism of cyst formation in patients treated with GnRH-a is not fully understood. Feldberg et al. (9) suggested that this phenomenon may be because of the release of gonadotropins from the initial upregulation or flare phase. Interestingly, Feldberg and co-authors (9) reported high PRs among women who formed cysts: 60% in women receiving the D-Trp6-LH-releasing analogue and 71 % in women receiving the buserelin acetate analogue. Tummon and colleagues (14) studied patients who had persistent ovarian cysts after unsuccessful hmg/hcg cycles. They found that all cysts resolved within two cycles and that with repeated stimulation, many cysts became echogenic. Again, a high PR (40%) was seen in the patients of Tummon et al. (14) with baseline cysts. This may explain the origin of many of the cysts in our patients because many had undergone recent stimulation, although no patient was allowed to undergo hmg stimulation in the cycle immediately preceding an IVF cycle. A similarly high PR was seen in one of our groups (3A). These patients with endometriosis and complex cysts who received hmg stimulation had a 40% PR, a rate that approached statistical significance (P = 0.05), despite the small number of patients. Interestingly, the only statistically significant difference demonstrated in this study showed that this group of patients with cysts had a lower peak E2 concentration (596 pg/ml versus 909 pg/ml, P = 0.028), a finding generally associated with a poor cycle outcome. This discrepancy suggests that the difference in E2 levels or the high PR seen in patients with endometriosis may be because of chance, a notion consistent with our threshold for statistical significance, and the large number of comparisons undertaken in this study. The finding of three studies all reporting high PRs in groups of patients with ovarian cysts is interesting and deserves further study. Of note, our patient with three complex cysts was a part of group 3A and conceived during the study cycle; subsequently she delivered a term infant. The current study suggests that a baseline complex cyst does not significantly affect controlled ovarian hyperstimulation or IVF performance. A second issue, however, is the safety of starting controlled ovarian hyperstimulation in the presence of a baseline complex ovarian cyst. The question of potential malignancy needs to be addressed for each patient. This is especially true in light of the trend toward vaginal US-directed egg retrieval. In contrast to laparoscopy, US-directed egg retrieval is blind. Visualization of cyst contents or small ovarian excrescences might not occur as it would with laparoscopy when the surgeon would have a chance to abort the procedure or proceed toward definitive diagnosis and treatment. The risk of malignancy is uncertain but appears to be low. In a series of reproductive-age patients undergoing infertility surgery, the prevalence of ovarian cancer was 1% (15). Benacerraf and colleagues found a 5% false-negative rate using transabdominal US to predict malignancy in a high-risk population (16). A recent series using transvaginal ultrasonography to predict ovarian malignancy Stewart et al. Baseline complex ovarian cysts in IVF 1277

5 demonstrated an ability to detect ovarian malignancy with 100% sensitivity and a negative predictive value of 100% (17). The main source of false positives in this study was dermoid cysts, a problem that has previously been reported to complicate IVF oocyte retrieval (18). Finally, Pinotti et al. (19) reported a series of 14,525 patients with adnexal tumors detected in 499 patients. These investigators found that by following patients with masses 30 to 80 mm in diameter for 15 to 60 days, 60.6% of the masses resolved spontaneously within 3 months (19). In summary, there does not appear to be a contraindication to starting controlled ovarian hyperstimulation for IVF in selected patients with complex cysts whose sonographic characteristics are consistent with benign cysts. The risk of ovarian malignancy appears low in appropriately selected patients. However, the risk of benign or malignant neoplasms of the ovary has to be assessed in each patient and, if necessary, followed by appropriate surgical intervention. Therefore, in patients in whom there is no suspicion of a malignant growth in the ovary, initiating controlled ovarian hyperstimulation in the presence of a baseline complex cyst may minimize the personal and financial cost of IVF cycles. Ackrwwledgments. Phaedra Thomas, R.N., Victoria Vallee, B.A., and Ray Gleason, Ph.D., helped with the data analysis. Jane Patrick, B.A., and Ms. Denise GaIotti assisted in preparation of the manuscript. REFERENCES 1. Hornstein MD, Barbieri RL, Ravnikar VA, McShane PM. The effects of baseline ovarian cysts on the clinical response to controlled ovarian hyperstimulation in an in vitro fertilization program. Fertil Steril1989;52: Thatcher SS, Jones E, DeCherney AH. Ovarian cysts decrease the success of controlled ovarian stimulation and in vitro fertilization. Fertil Steril 1989;52: Karande VC, Scott RT, Jones GS, Muasher SJ. Non-functional ovarian cysts do not affect ipslaterai or contralateral ovarian performance during in vitro fertilization. Hum Reprod 1990;5: Goldberg JM, Miller FA, Friedman CI, Dodds WG, Kim MH. Effect of baseline ovarian cysts on in vitro fertilization and gamete intrafallopian transfer cycles. Fertil Steril 1991;55: Mao KR, Haines CJ, Tam PPL. Successful oocyte retrieval and in vitro fertilization following ultrasound-directed aspiration of endometriomas. J In Vitro Fert Embryo Transf 1986;3: Feldberg D, Ashkenazi J, Dicker D, Yeshaya A, Voliovitch I, Goldman JA. Ovarian cyst aspiration during in vitro fertilization/embryo transfer. J In Vitro Fert Embryo Transf 1988;5: Silverberg KM, Olive DL, Schenken RS. Ovarian cyst aspiration prior to initiating ovarian hyperstimulation for in vitro fertilization. J In Vitro Fert Embryo Transf 1990;7: Rizk B, Tan SL, Kingsland C, Steer C, Mason BA, Campbell S. Ovarian cyst aspiration and the outcome of in vitro fertilization. Fertil Steril 1990;54: Feldberg D, Ashkenazi J, Dicker D, Yeshaya A, Goldman GA, Goldman JA. Ovarian cyst formation: a complication of gonadotropin-releasing hormone agonist therapy. Fertil Steril 1989;51: Ron-El R, Herman A, Golan A, Raziel A, Soffer Y, Caspi E. Follicle cyst formation following long-acting gonadotropinreleasing hormone analog administration. Fertil Steril 1989;52: Herman A, Ron-El R, Golan A, Nahum H, Soffer Y, Caspi E. Follicle cysts after menstrual versus midluteal administration of gonadotropin-releasing hormone analog in in vitro fertilization. Fertil Steril 1990;53: Ben-Rafael Z, Bider D, Menashe Y, Maymon R, Zolti M, Mashiach S. Follicular and luteal cysts after treatment with gonadotropin-releasing hormone analog for in vitro fertilization. Fertil Steril1990;53: Sampaio M, Serra V, Miro F, Calatayud C, Castellvi RM, Pellicer A. Development of ovarian cysts during gonadotrophin-releasing hormone agonists (GnRHa) administration. Hum Reprod 1991;6: Tummon IS, Henig I, Radwanska E, Binor Z, Rawlins R, Dmowski WP. Persistent ovarian cysts following administration of human menopausal and chorionic gonadotropins: an attenuated form of ovarian hyperstimulation syndrome. Fertil Steril 1988;49: Lais CW, Williams TJ, Gaffey TA. Prevalence of ovarian cancer found at the time of infertility microsurgery. Fertil Steril 1988;49: Benacerraf BR, Finkler NJ, Wojciechouski C, Knapp RC. Sonographic accuracy in the diagnosis of ovarian masses. J Reprod Med 1990;35: Sassone AM, Timor-Tritsch IE, Artner A, Westhoff C, Warren WB. Transvaginal sonographic characterization of ovarian disease: evaluation of a new scoring system to predict ovarian malignancy. Obstet Gynecol 1991;78: Serafini P, Kerin J, Marrs R. Management of unexpected ovarian dermoid cyst during laparoscopy for oocyte pickup. Fertil Steril1987;48: Pinotti JA, de Franzin CMMO, Marussi EF, Zefeuno LC. Evolution of cystic and adnexal tumors identified by echography. Int J Gynecol Obstet 1988;26: Stewart et al. Baseline complex ovarian cysts in IVF