Journal of in Vitro Fertilization and Embryo Transfer, Vol. 7, No. 3, 1990
Ovarian Cyst Aspiration Prior to Initiating Ovarian Hyperstimulation for in Vitro Fertilization K A Y L E N M. SILVERBERG, 1'2 DAVID L. OLIVE, 1 and ROBERT S. S C H E N K E N 1
Submitted: January 12, 1990 Accepted: February28, 1990
however, current management o f these cysts is controversial. While some have recommended avoiding ovarian hyperstimulation until the cyst resolves (2A), others have advocated proceeding with ovarian hyperstimulation despite the presence of a cyst (5-7). We offer a third alternative: cyst aspiration, followed immediately by initiation of ovarian hyperstimulation. We have performed three such procedures in our in vitro fertilization (IVF/ET) program, followed in each case by normal ovarian hyperstimulation, oocyte retrieval, embryo transfer, and pregnancy.
Twenty-three consecutive patients presenting f o r in vitro
fertilization were evaluated with transvaginal sonography on cycle day 3, prior to initiating ovarian hyperstimulation. Three of these patients were noted to have large ovarian cysts. All three underwent transvaginal aspiration of the cysts, followed immediately by initiation of ovarian hyperstimulation. Following oocyte retrieval, in vitro fertilization, and embryo transfer, all three women achieved pregnancy. We conclude that cyst aspiration is not contraindicated when an ovarian cyst is encountered in the follicular phase of an in vitro fertilization cycle. KEY WORDS: in vitro fertilization (IVF); ovarian cyst; aspiration.
MATERIALS AND METHODS Twenty-three patients underwent ovarian hyperstimulation for IVF/ET during July 1989. All patients with ovarian cysts encountered prior to initiation of hMG underwent aspiration, and the cases are presented below.
INTRODUCTION The presence of an ovarian cyst in the follicular phase of an in vitro fertilization cycle is a frequently encountered problem. While these cysts may occur spontaneously, they are more often noted after ovarian hyperstimulation in a previous cycle or recent treatment with a gonadotropin releasing hormone (GnRH) agonist. The reported incidence of persistent cysts is as high as 69% following nonconception clomiphene citrate (CC) cycles, with or without human chorionic gonadotropin (hCG); 56% following human menopausal gonadotropin (hMG)/ hCG cycles; and up to 40% following GnRH agonist treatment (1-3). Despite their common occurrence,
Case 1 D.L. is a 34-year-old white female with tubal factor, oligoovulation, and a single ovary. Midluteal leuprolide acetate (LA: Lupron, TAP Pharmaceuticals, Chicago, IL), 1 mg/day subcutaneously (sc), was instituted, and baseline ultrasound on cycle day 2 revealed a 35-mm simple ovarian cyst. Serum estradio! (E2) at that time was 50 pg/ml. LA was increased to 1.5 mg/day, and on cycle day 5, serum E2 was 22 pg/ml; however, no change in the size of the cyst was noted. On cycle day 11, the cyst measured 30 • 26 mm and was aspirated after midazolam (Versed, Roche Laboratories, Nutley, NJ), 5 mg intramuscularly (im). Straw-colored fluid was obtained, and cytology was negative for malignancy.
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, The University of Texas Health Science Center, San Antonio, Texas 78284. 2 To whom correspondence should be addressed at University of Texas Health Science Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7836
153
0740-7769/90/0600-0153506.00/0 9 1990PlenumPublishingCorporation
154
SILVERBERG, OLIVE, AND SCHENKEN
Granulosa and theca cells were identified, compatible with a follicular cyst. The patient was immediately begun on human menopausal gonadotropin (hMG; Pergonal, Serono Laboratories, Randolph, MA) and the LA was decreased to 0.5 mg/day sc. This regimen was continued for 9 days, followed by 10,000 IU of hCG (Profasi, Serono Laboratories, Randolph, MA). At oocyte retrieval, ultrasound revealed the presence of 17 follicles. Seventeen oocytes were recovered, and all fertilized. Four embryos were transferred into the uterus at the pronuclear stage and seven embryos were frozen at the four- and five-cell stages. Twelve days after embryo transfer, serum pregnancy test was positive, and transvaginal ultrasound performed at 6 weeks' gestation revealed a twin intrauterine gestation with normal fetal heart motion. The patient is currently progressing well at 17 weeks' gestation. Case 2 B.B. is a 28-year-old white female with unexplained infertility, who began LA, 1 mg sc, in the midluteal phase. On cycle day 2 following the onset of subsequent menses, ultrasound revealed a 42 • 46-mm simple left ovarian cyst. Serum E2 at that time was 23 pg/ml. LA was continued, and serial ultrasound examinations were performed until cycle day 9, at which time the cyst measured 30 • 30 mm. Transvaginal aspiration of the cyst was performed at that time, under paracervical block, supplemented with midazolam, 4 mg im. Fifteen milliliters of serous fluid was obtained, and cytologic examination was negative for malignancy. Granulosa and theca cells were identified, and the final pathologic diagnosis was follicular cyst. Administration of hMG was begun the next day with 300 IU per day, and the dose of LA was decreased to 0.5 rag/day. At that time, ultrasound revealed the presence of a 13-mm residual cyst. The patient subsequently received 8 days of hMG treatment, followed by 10,000 IU of hCG. At follicle aspiration, ultrasound revealed 16 follicles on the left ovary and 21 on the right. Twenty-four oocytes were recovered by transvaginal aspiration, of which only five fertilized (21%). Three embryos were transferred into the uterus at the pronuclear stage and two were frozen at the four cell-stage. Twelve days after embryo transfer, serum pregnancy test was positive, and ultrasound subse-
quently demonstrated a single intrauterine pregnancy that is currently ongoing at 16 weeks' gestation. Case 3
P.C. is a 39-year-old white female with tubal factor following right partial salpingectomy and subsequent left salpingostomy for two ectopic pregnancies. She began LA, 1 mg/day, in the midluteal phase, and baseline ultrasound on cycle day 2 revealed a 42 x 37-mm simple right ovarian cyst. The cyst continued to enlarge, and aspiration was performed 5 days later. Cytology was negative for malignancy. The patient subsequently received 7 days of hMG stimulation with LA, 0.5 mg/day sc, and she developed four follicles on ultrasound. At the time of transvaginal oocyte retrieval, three oocytes were obtained, and all three fertilized and were subsequently transferred into the uterus. Twelve days after transfer, serum pregnancy test was positive. The patient subsequently underwent a dilatation and curettage for a blighted ovum at 6 week's gestation.
DISCUSSION The presence of an ovarian cyst in the early follicular phase of an in vitro fertilization cycle poses a clinical dilemma. Management of this problem has included cancellation of ovarian stimulation or initiation of stimulation despite the presence of a cyst. The former approach delays treatment, incurs additional costs, and may cause disconcerting logistical problems, especially for out-of-town patients. Further, the incidence of recurrence has been demonstrated to be as high as 61%, once controlled ovarian hyperstimulation is reinitiated (2). The latter approach risks the possibility of suboptimal treatment outcome and difficulty in accurately monitoring follicle development by ultrasound. A third alternative, described herein, is aspiration of the cyst prior to ovarian stimulation. The presence of cysts in the early follicular phase may significantly complicate follicular monitoring by ultrasound. This is especially true when more than one cyst is present, or when the cyst is multilocular. In addition, if the cyst is functional (i.e., steroid-secreting), it may adversely affect the hormonal milieu in which the other follicles will develop. Thatcher et al. recently demonstrated that
Journal of in Vitro Fertilization and Embryo Transfer, Vol. 7, No. 3, 1990
OVARIAN CYST ASPIRATION PRIOR TO HYPERSTIMULATION FOR IVF
the outcome for these patients is significantly worse if one attempts to proceed with ovarian stimulation despite the presence of a cyst (4). In their study, patients with cysts measuring 16-29 mm were more likely to develop a significant fall in E 2 levels, precluding oocyte aspiration and embryo transfer. Patients with cysts measuring 30-59 mm were more likely to have cycles canceled due to poor response to exogenous gonadotropins. In another study in which hMG/hCG was administered without in vitro fertilization, patients stimulated in the presence of a baseline cyst required significantly more hMG than did those without cysts (2). Other groups claim that cysts have no adverse effect on IVF outcome and advise proceeding with controlled ovarian hyperstimulation despite the cyst presence. In a recent report, there was no statistically significant difference in maximum serum E2, cycle cancellation rate, number of oocytes recovered, number of embryos transferred, and pregnancy rate per cycle between patients with a cyst and those without a cyst (5). Hung and Tsuiki reported that, in 14 patients undergoing hMG ovulation induction who had cysts measuring 30-50 mm, there was no difference in fertilization rate, cleavage rate, and pregnancy rate compared to controls without cysts (6). Finally, Grazi et al. found no difference in follicular-phase length, number of ampoules of hMG used, peak E 2 levels, or pregnancy rates when they compared 21 patients with cysts to 21 patients without cysts (7). Transvaginal aspiration of ovarian follicles and cysts under ultrasound guidance has been practiced for years, although it did not gain widespread acceptance until 1984 (8). With the development of the transvaginal sector scanner, aspiration was simplified and has now become the predominant method for oocyte retrieval in IVF (9). While the safety of transvaginal follicular aspiration has been established, that of ovarian cyst aspiration remains controversial. The most commonly discussed concern of cyst aspiration, irrespective of the method used, involves the nature of the cyst. If the cyst is malignant, the fear is that the diagnosis will be missed or that the malignant cells will be spilled into the peritoneal cavity, possibly leading to further spread of the cancer. This concern assumes importance because the reported incidence of ovarian carcinoma in infertility patients under the age of 40 is as high as 1.1% (10). Diernaes et al. reported on the use of preopera-
155
tive ultrasound and cytology in the evaluation of ovarian cysts (11). Of 59 cysts evaluated, of which 7 were malignant, ultrasound alone had a positive predictive value of 40% and a negative predictive value of 98%. Cytology alone had a positive predictive value of 67% and a negative predictive value of 91%. However, when ultrasound and cytology were used together, all malignant lesions were identified preoperatively. These findings have been confirmed by de Crespigny et al. (12) and Hermann and associates (13). Ultrasound therefore appears to be more accurate in identifying benign lesions than malignant ones. However, even if a malignant lesion is aspirated, the risk of complications is quite small. In a review of 11,700 transabdominal needle biopsies, Livraghi e t al. reported a complication rate of 0.55% (14). Of the se, only two involved needle-tract implantations of malignant cells after aspiration of pancreatic cancers. Most of the patients received three to four passes of needles ranging in size from 20 to 23 gauge, and only 55% of the biopsies were radiographically guided. Concerning the accuracy of aspiration cytology, Sevin and Nadji reported a diagnostic accuracy of 94.5% in distinguishing benign from malignant lesions (15). In addition, Kjellgren et al. reported 90% accuracy in diagnosing malignant lesions and 86% for benign lesions with aspiration cytology (16). In summary, aspiration of an ovarian cyst encountered at the time of initial ultrasound examination in an IVF cycle is a viable approach when the cyst is unilocular and nonechogenic. In such cases, the fluid that is obtained should be sent for cytology. Results with aspiration demonstrate it to be safe, and the risk of missing a malignant neoplasm is very low. Aspiration also avoids delay of stimulation and offers the advantage of easier follicular monitoring during hyperstimulation. In addition, as our cases indicate, aspiration does not interfere with immediate controlled ovarian hyperstimulation, subsequent oocyte retrieval, embryo transfer, or pregnancy. Although this technique has been employed in very few patients thus far, our results warrant cyst aspiration's inclusion in current management of ovarian cysts encountered in the follicular phase of an in vitro fertilization cycle. REFERENCES 1. Coularn CB, Hill LM, Breckle R: Ultrasonic assessment of subsequent unexplained infertility after ovulation induction. Br J Obstet Gynaecol 1983;90:460
Journal o f in Vitro Fertilization and Embryo Transfer, Vol. 7, No. 3, 1990
156
SILVERBERG, OLIVE, AND SCHENKEN
2. 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;49:244 3. Meldrnm DR, Wisot A, Hamilton F, Gutlay AL, Huynh D, Kempton W: Timing of initiation and dose schedule of leuprolide influence the time course of ovarian suppression. Fertil Steril 1988;50:400 4. Thatcher SS, Jones E, DeCherney AH: Ovarian cysts decrease the success of controlled ovarian stimulation in in vitro fertilization cycles. Fertil Steril 1989;52:812 5. 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 Steril 1989;52:437 6. Hung TT, Tsuiki A: Noninterference of ovarian cysts or endometriomas with the outcome of ovulation induction in assisted reproduction. Presented at the 36th Annual Meeting, American College of Obstetricians and Gynecologists, Boston, MA, May 3, 1989 7. Grazi R, Taney FH, Gagliardi CL, Khoury A, Von Hagen S, Weiss G, Schmidt CL: The presence of ovarian cysts does not alter ovarian stimulation with gonadotropins. Presented at the Forth-fourth Annual Meeting of the American Fertility Society, Atlanta, GA, October 10-13, 1988. In 1988 Abstracts of the Scientific Paper and Poster Sessions. American Fertility Society, p. 29 (abstr 085)
8. Dellenbach P, Nisand I, Moreau L, Feger B, Plumere C, Gerlinger P, Brun B, Rumpler Y: Transvaginal, sonographically controlled ovarian follicle puncture for egg retrieval. Lancet 1984;1:1467 9. Feichtinger W, Kemeter P: Transvaginal sector scan sonography for needle guided transvaginal follicle aspiration and other applications in gynecologic routine and research. Fertil Steril 1986;45:722 10. Lais CW, Williams TJ, Gaffey TA: Prevalence of ovarian cancer found at the time of infertility microsurgery. Fertil Steril 1988;49:551 11. Diernaes E, Rasmussen J, Soerensen T, Hasch E: Ovarian cysts: Management by puncture? Lancet 1987;1:1084 12. de Crespigny LC, Robinson HP, Davoren RA, Fortyne DW: Ultrasound-guided puncture for gynecological and pelvic lesions. Aust NZ J Obstet Gynaecol 1985;25:227 13. Hermann U J, Locher GW, Goldhirsch A: Sonographic patterns of ovarian tumors: Prediction of malignancy. Obstet Gynecol 1987;69:777 14. Livraghl T, Damascelli B, Lombardi C, Spagnoll I: Risk in fine-needle abdominal biopsy. J Clin Ultrasound 1983;11:77 15. Sevin BU, Nadji M: Pelvic fine needle aspiration cytology in gynecology. In Clinical Aspiration Cytology, JA Linsk, S Franzen (eds). Philadelphia, JB Lippincott, 1983, pp 221-242 16. Kjellgren O, Angstrom T: Transvaginal and transrectal aspiration biopsy in diagnosis and classification of ovarian tumors. In Monographs in Clinical Cytology, Vol 7, GL Wied (ed). Basel, S Karger, 1979, pp 80-103
Journal o f in Vitro Fertilization and Embryo Transfer, Vol. 7, No. 3, 1990