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Laparoscopic ovarian cystectomy of endometriomas: surgeons’ experience may affect ovarian reserve and live-born rate in infertile patients with in vitro fertilization-intracytoplasmic sperm injection
European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 172–175
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Laparoscopic ovarian cystectomy of endometriomas: surgeons’ experience may affect ovarian reserve and live-born rate in infertile patients with in vitro fertilization-intracytoplasmic sperm injection Hsing-Tse Yu, Hong-Yuan Huang, Yung-Kuei Soong, Chyi-Long Lee, Angel Chao, Chin-Jung Wang * Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 February 2010 Accepted 23 May 2010
Objective: To assess whether the laparoscopist’s experience can affect ovarian reserve and pregnancy outcome in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) patients who previously underwent laparoscopic conservative treatment for ovarian endometriomas. Study design: One hundred and forty-nine IVF-ICSI cycles with infertile patients who previously underwent laparoscopic conservative treatment for ovarian endometriomas were enrolled. There were 76 cycles with an inexperienced surgeon and 73 cycles with an experienced surgeon. Results: The number of antral follicle count (7.5 3.8 vs. 9.6 6.6; p = 0.011), and live-born rate per cycle (9.3% vs. 32.9%; p < 0.001) were significantly lower in the inexperienced group comparing with the experienced group. However, the mean number of oocytes, fertilization rate, mean number of embryos transferred, rate of good-quality embryos transferred, implantation rate and clinical pregnancy were similar between both groups. Conclusions: The experience of the laparoscopist may affect ovarian reserve and live-born rate after treating ovarian endometrioma in infertile women with IVF-ICSI. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Presented at the 65th annual meeting of the American Society for Reproductive Medicine, October 17–21, 2009, Atlanta, Georgia Keywords: Laparoscopy Endometrioma Ovarian reserve In vitro fertilization Intracytoplasmic sperm injection
1. Introduction Endometriosis is a common, benign, chronic gynecological disorder frequently associated with dysmenorrhea and infertility. The prevalence of endometriosis approaches 10–15% of all women of reproductive age [1] while it has been reported that 25–40% of women with infertility have endometriosis [2]. Current guidelines for the treatment of endometriosis include medical or surgical therapies. However, medical treatment has a limited role in the treatment of endometriosis that only offers symptomatic control. Laparoscopic surgery has traditionally been the standard treatment for patients with endometriosis. The impact of previous conservative surgery for endometriosis on in vitro fertilizationintracytoplasmic sperm injection (IVF-ICSI) outcome is still controversial. Some investigations have suggested that laparoscopic surgery before IVF might impair ovarian responsiveness to hyperstimulation [3,4]. Interestingly, some studies demonstrated
* Corresponding author at: Department of Obstetrics and Gynecology, Division of Gynecologic Endoscopy, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, 5, Fu-Hsin Street, Kwei-Shan, Tao-Yuan, Taiwan. Tel.: +886 3 3281200x8258; fax: +886 3 3286700. E-mail address: [email protected] (C.-J. Wang). 0301-2115/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2010.05.016
contrary results, that surgery for endometriosis before IVF did not have an adverse effect on pregnancy rate [5,6]. As laparoscopic treatment for endometriosis has been widely carried out by general gynecologists, one of the concerns in laparoscopic surgery is the training time needed. Given it is more likely that endometriosis causes severe adhesions, laparoscopy necessitates skilled operators who carefully identify normal ovarian tissue and endometrioma and separate them to prevent ovarian damage. An inexperienced surgeon might bring detrimental effects on ovarian reserve and response of controlled ovarian hyperstimulation (COH). To the best of our knowledge, in studies investigating the influence of previous conservative surgery for endometriosis on IVF-ICSI, there is no article specifically concerning the surgeon’s experience correlated with ovarian reserve and outcome of IVF-ICSI. The aim of our study is to assess whether the surgeon’s experience can significantly affect ovarian reserve and pregnancy outcome in IVF-ICSI patients who previously underwent laparoscopic treatment for ovarian endometriomas. 2. Material and methods We retrospectively reviewed all IVF-ICSI cycles with infertile patients who previously underwent laparoscopic enucleation of
H.-T. Yu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 172–175
173
ovarian endometriomas. The period of study was from January 2005 through December 2008 in Chang Gung Memorial Hospital Linkou Medical Center. This study was based on review of both electronic and paper medical records. To clarify the impact of experience of the operators on the outcome of IVF-ICSI, we divided the surgeons into experienced and inexperienced. Chief resident and fellow physician were defined as inexperienced surgeons, whereas attending physicians were experienced. The Institutional Review Board (IRB) of Chang Gung Memorial Hospital approved this study.
of embryos transferred, good-quality embryo for transfer, clinical pregnancy rate, implantation rate and live-born rate. Operative findings were scored according to the revised classification of the American Fertility Society (rAFS) [8]. In this study, we defined embryos of grade 1 or 2 as good-quality. Clinical pregnancy was determined by the presence of at least one gestational sac, documented with transvaginal ultrasonography two weeks after a positive pregnancy test. Implantation rate was calculated as number of gestational sacs divided by number of transferred embryos and multiplied by 100.
2.1. Operative technique
2.3. Statistical analyses
All surgeries were performed with a similar technique which is described elsewhere [7]. In brief, laparoscopic examination of the pelvis and lower abdomen was performed to determine the accessibility of the surgical field. Three or four trocars were used according to complexity of pelvis. A disposable laparoscopic grasper, scissors, and suction-irrigator were used to perform various procedures such as holding, cutting, exploring and dissecting. A sharp cortical incision was made by unipolar scissors and a cleavage plane was identified. The capsule of the endometrioma was then enucleated and stripped from the normal ovarian tissue. Large bleeders were coagulated using bipolar forceps with an electrosurgical bipolar unit (Elmed, Addison, IL). Complete hemostasis and approximation of ovarian defect were achieved using a 3–0 monofilament poliglecaprone 25 suture (Monocryl; Ethicon Inc., Somerville, NJ, USA) on a large curved needle following the principles of laparotomy. The specimens were removed from the abdomen using a disposable endobag for the purpose of avoiding contaminating the abdominal wall.
Parametric continuous variables were compared with Student’s t test and categorical values were compared with Pearson x2 analysis or Fisher’s exact test. All probability values were twosided. Significance level was accepted at p < 0.05. SPSS for Windows version 13.0 (SPSS Inc., Chicago, IL) was used for the statistical calculations.
2.2. Parameters studied The parameters studied were patient’s demographics, operation records, ovarian reserve (day 2 or day 3 serum FSH and antral follicle count) after surgery, number of ampoules of gonadotropin used for COH, number of follicles greater than 14 mm in mean size, serum estradiol (E2) levels and endometrium thickness on the day of human chorionic gonadotropin (hCG) administration, number of oocytes aspirated, the proportion of mature (MII) oocytes, number
3. Results A total of 149 IVF-ICSI cycles were included in this analysis. There were 76 cycles with laparoscopic enucleation of endometriomas performed by inexperienced surgeons and 73 cycles by experienced ones. Patient characteristics and preoperative information are summarized in Table 1. Both groups were similar in mean age, body mass index (BMI), duration of infertility, CA-125 level before operation and mean size of the endometrioma. Comparing with the inexperienced surgeon group, there were significantly shorter intervals from operation to IVF-ICSI date (29.8 31.5 vs. 45.4 34.6, respectively; p = 0.005) and higher rAFS scores (49.1 30.0 vs. 35.7 23.3, respectively; p = 0.003) in the experienced group. Likewise, there were no differences in day 2 or day 3 serum FSH and E2 level, the hCG day, dosage of recombinant FSH, numbers of dominant follicles, endometrial thickness and peak E2 level in both groups (Table 2). Number of antral follicles was significantly fewer in the inexperienced surgeon group (7.5 3.8 vs. 9.6 6.6, respectively; p = 0.011). The number of retrieved oocytes, proportion of MII oocytes, number of embryos transferred, embryo transfer day, fertilization
Table 1 Baseline characteristics of patients. Variable
Inexperienced surgeon
Experienced surgeon
p
Cycles Age (y) BMI (kg/m2) Infertility duration (y) CA-125 before operation (U/mL) Size of endometrioma during operation (cm) Interval from operation date to IVF date (mo) rAFS score
76 33.2 4.2 21.2 2.9 4.4 2.8 84.5 98.9 4.9 2.5 45.4 34.6 35.7 23.3
73 33.3 3.3 20.9 3.2 4.2 2.7 112.2 188.6 4.8 2.3 29.8 31.5 49.1 30.0
NS NS NS NS NS 0.005 0.003
Data are reported as mean SD or number. BMI = body mass index; IVF = in vitro fertilization; rAFS = revised classification of the American Fertility Society; NS = non-significant. Table 2 The baseline characteristics and controlled ovarian hyperstimulation response in the two groups. Variable
Inexperienced surgeon
Experienced surgeon
p
Day 2 or day 3 FSH (mIU/mL) Day 2 or day 3 E2 (pg/mL) Antral follicle count FSH dosage (IU) hCG day No. of follicles >1.4 cm on hCG day Endometrium thickness on hCG day (cm) Peak E2 level (pg/mL)
8.4 2.3 37.5 38.5 7.5 3.8 2261.3 744.3 9.9 1.5 5.4 2.8 1.1 0.2 1590.5 1105.5
8.5 5.1 33.0 25.6 9.6 6.6 2478.3 1302.8 9.9 1.5 5.1 3.2 1.1 0.2 1657.1 1385.5
NS NS 0.015 NS NS NS NS NS
Data are reported as mean SD. NS = non-significant.
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Table 3 Fertility and reproductive outcomes after IVF-ICSI. Variable
Inexperienced surgeon
Experienced surgeon
p
No. of oocytes retrieved Mature (MII) oocytes Proportion of MII oocytes (%) Normal fertilization rate (%) No. of embryos transferred Embryo transfer day Good-quality embryos for transfer (%)a Implantation rate (%) Clinical pregnancy rate per cycle (%) Miscarriage rate per cycle (%) Ectopic pregnancy rate per cycle (%) Live-born rate per cycle (%)
10.1 6.4 7.6 4.7 76.0 24.0 64.4 21.7 3.2 1.3 2.6 0.7 57.8 13.9 26.3 9.2 7.8 9.3
9.2 6.9 6.9 5.2 76.8 25.7 63.5 22.5 2.9 1.0 2.5 0.6 65.8 18.5 41.1 4.1 2.7 32.9
NS NS NS NS NS NS NS NS NS NS NS <.001
Data are reported as mean SD or number (%). IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; NS = non-significant. a Good-quality embryos are defined as grade 1 or 2 embryos.
rate, and implantation rate were not statistically different (Table 3). The rates of good-quality embryos for transfer per cycle (57.8% vs. 65.8%, respectively; p = 0.20) and clinical pregnancy rate per cycle (26.3% vs. 41.1%, respectively; p = 0.056) were slightly decreased in the inexperienced surgeon group. Slightly higher miscarriage rate (9.2% vs. 4.1, respectively; p = 0.18) and ectopic pregnancy rate (7.9% vs. 2.1%, respectively; p = 0.15) were also observed in the inexperienced surgeon group. However, these results were not statistically significant. Eventually, the inexperienced group had significantly poorer outcome with live-born rate per cycle (9.3% vs. 32.9%, respectively; p < 0.001) in their IVF-ICSI cycles. Of the total of 149 cycles, there were 42 (28.2%) cycles involving bilateral endometriomas and 107 (71.8%) unilateral, respectively. Although the antral follicle count, number of retrieved oocytes and clinical pregnancy rate per cycle were not affected by the surgeon’s experience when analysis was limited to unilateral lesions, the inexperienced group had significantly poorer outcome with liveborn rate per cycle (8.5% vs. 36.2%, respectively; p = 0.001). As for bilateral lesions, the inexperienced surgeons had a significant adverse effect on antral follicle count compared with experienced surgeons (5.5 3.3 vs. 9.6 6.5, respectively; p = 0.019). Nevertheless, there were no significant statistical differences in clinical pregnancy rate (23.5% vs. 40%, respectively; p = 0.331) and live birth rate per cycle (11.8% vs. 28%, respectively; p = 0.271). 4. Comment Surgical intervention has been demonstrated to be an effective treatment for ovarian endometriomas. Associated with many advantages over traditional abdominal methods, including less hospitalization, smaller incisions, faster recovery time, and faster return to work, the laparoscopic approach for endometriosis has been now widely accepted. Factors affecting the choice of laparoscopic intervention include the surgeon’s experience and skill in these techniques. However, endometriosis is an inflammatory process that results in dense adhesion between normal ovarian tissue and endometrioma. Therefore, there might be inadvertent removal of a consistent amount of normal ovarian tissue during cystectomy, potentially causing a reduction of ovarian function. In this study, we indeed observed that the experience of surgeons who performed laparoscopic surgery for endometriosis would affect the ovarian reserve and subsequent live birth rate on IVF-ICSI. Until now, there is no consensus regarding the influence of previous surgery for endometriomas on ovarian function. Some investigators suggested that IVF outcome is compromised by previous ovarian surgery [3,4,9]. Nevertheless, no adverse impact of prior surgery for endometriosis on ovarian reserve and response
to COH has also been reported [10–12]. Ragni et al. reported that laparoscopic enucleation of ovarian endometrioma reduced the ovarian response to COH. Conversely, the rates of fertilization and high-quality embryos were not affected [13]. In present study, we further found that the better outcome of clinical pregnancy rate and live-born rate occurred in surgery performed by well-trained laparoscopists despite higher dosage of gonadotropin for COH. The surgical technique of ovarian cyst excision by laparoscopy was usually using a stripping technique [14,15]. The possible drawback of the laparoscopic stripping technique might be associated with loss of follicles and damage to the ovarian stroma [16]. In our series, a significantly diminished antral follicle count was noted in the inexperienced group. The number of embryos transferred was similar in both groups. Nevertheless, a higher proportion of good-quality embryos for transfer was observed in the experienced group. It may explain why experienced surgeons have better outcome of live-born rate although there was no significant difference between the two groups with respect to clinical pregnancy rate. Bilateral lesions account for 19–28% in patients with ovarian endometriosis [17]. The severity of ovarian lesions (bilateral vs. unilateral) is theoretically an important factor for ovarian reserve after conservative surgery. Esinler et al. reported that laparoscopic endometrioma cystectomy diminished ovarian reserve in patients who underwent bilateral cystectomy compared with a unilateral group. Nevertheless, the pregnancy outcome was not affected by the diminished ovarian reserve [18]. Our study also demonstrated reduced ovarian reserve in bilateral cystectomy when comparing the inexperienced with the experienced groups (5.5 3.3 vs. 9.6 6.5, respectively; p = 0.019). Interestingly, poor pregnancy outcome was observed in the inexperienced surgeon group even among patients who underwent unilateral cystectomy (8.5% vs. 36.2%, respectively; p = 0.001). These results imply the importance of surgical skills and experience in performing laparoscopic conservative surgery for ovarian endometriomas. Candiani et al. reported that reduced ovulation and ovarian volume came about over time after the second postoperative menstruation [19]. Exacoustos et al. reported a similar finding that a significant reduction in ovarian volume was noted after laparoscopic endometrioma removal by stripping [20]. Our data showing the interval between surgery and IVF in the skilled group was shorter than in the inexperienced group (29.8 31.5 vs. 45.4 34.6, respectively; p = 0.005) might imply more normal ovarian tissues were damaged during laparoscopy performed by young staff and a longer time for ovarian function recovery was needed thereafter. Although the laparoscopic procedure has many advantages, it involves electrosurgery to dissect tissue and control bleeding. Therefore laparoscopists should pay much attention to developing
H.-T. Yu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 172–175
the proper plane of cleavage between normal ovarian and endometrotic tissue, especially near the ovarian hilus. Newlytrained surgeons tend to complete the mission of stripping the cyst wall of endometrioma and achieve complete hemostasis, in consequence damaging normal tissue due to extensive thermal effect. Experienced surgeons realize the principles of electrosurgery and use the bipolar diathermy with care. That is, they perform ovarian hemostasis mainly with suture rather than electrocautery. This method can decrease thermal injury and theoretically preserve the ovarian reserve. The obvious weakness of the paper is its retrospective design. Further research in this area is warranted to confirm and advance these findings, specifically with studies powered to evaluate delivery rates. Besides, the operative procedure was not uniform because 32 surgeons were involved in this study (16 experienced surgeons and 16 inexperienced surgeons). A larger prospective study is crucial to prove the contention, though it is difficult to introduce practically. In conclusion, a successful operation means not only removal of ovarian pathology but also maintenance of ovarian function and subsequent pregnancy with live birth. Physicians should be aware that laparoscopic conservative surgery for endometriosis is a challenging task. The skill and experience of laparoscopists play an important role in determining the final IVF-ICSI outcome for infertile patients operated on for ovarian endometriomas. Conflict of interest None. Acknowledgements This research was supported by grant CMRPG350371 (to Wang C.J.) from Chang Gung Memorial Hospital, Taiwan. Contributors: H.T.Y. drafted article. H.Y.H. contributed to study concept. Y.K.S. and C.L.L. undertook data collection. A.C. provided statistical advice. C.J.W. led the design of the study and contributed to critical revision of article. References [1] Moen MH. Is a long period without childbirth a risk factor for developing endometriosis? Hum Reprod 1991;6:1404–7.
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[2] D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med 2003;21:243–53. [3] Ho HY, Lee RK, Hwu YM, Lin MH, Su JT, Tsai YC. Poor response of ovaries with endometrioma previously treated with cystectomy to controlled ovarian hyperstimulation. J Assist Reprod Genet 2002;19:507–11. [4] Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA. Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597–606. [5] Gupta S, Agarwal A, Agarwal R, Loret de Mola JR. Impact of ovarian endometrioma on assisted reproduction outcomes. Reprod Biomed Online 2006; 13:349–60. [6] Somigliana E, Vercellini P, Vigano P, Ragni G, Crosignani PG. Should endometriomas be treated before IVF-ICSI cycles? Hum Reprod Update 2006;12:57– 64. [7] Lee CL, Soong YK, Lai YM, Chang SY, Chang MY. Simplified instrumentation for laparoscopic ovarian cystectomy. Changgeng Yi Xue Za Zhi 1992;15:28–32. [8] Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997;67:817–21. [9] Somigliana E, Ragni G, Benedetti F, Borroni R, Vegetti W, Crosignani PG. Does laparoscopic excision of endometriotic ovarian cysts significantly affect ovarian reserve? Insights from IVF cycles. Hum Reprod 2003;18:2450–3. [10] Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of >3 cm in diameter. Hum Reprod 2001; 16:2583–6. [11] Marconi G, Vilela M, Quintana R, Sueldo C. Laparoscopic ovarian cystectomy of endometriomas does not affect the ovarian response to gonadotropin stimulation. Fertil Steril 2002;78:876–8. [12] Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81: 1194–7. [13] Ragni G, Somigliana E, Benedetti F, Paffoni A, Vegetti W, Restelli L, et al. Damage to ovarian reserve associated with laparoscopic excision of endometriomas: a quantitative rather than a qualitative injury. Am J Obstet Gynecol 2005;193:1908–14. [14] Nezhat C, Crowgey SR, Nezhat F. Videolaparoscopy for the treatment of endometriosis associated with infertility. Fertil Steril 1989;51:237–40. [15] Martin DC. Laparoscopic treatment of ovarian endometriomas. Clin Obstet Gynecol 1991;34:452–9. [16] Hachisuga T, Kawarabayashi T. Histopathological analysis of laparoscopically treated ovarian endometriotic cysts with special reference to loss of follicles. Hum Reprod 2002;17:432–5. [17] Vercellini P, Aimi G, De Giorgi O, Maddalena S, Carinelli S, Crosignani PG. Is cystic ovarian endometriosis an asymmetric disease? BJOG 1998;105:1018– 21. [18] Esinler I, Bozdag G, Aybar F, Bayar U, Yarali H. Outcome of in vitro fertilization/ intracytoplasmic sperm injection after laparoscopic cystectomy for endometriomas. Fertil Steril 2006;85:1730–5. [19] Candiani M, Barbieri M, Bottani B, Bertulessi C, Vignali M, Agnoli B, et al. Ovarian recovery after laparoscopic enucleation of ovarian cysts: insights from echographic short-term postsurgical follow-up. J Minim Invasive Gynecol 2005;12:409–14. [20] Exacoustos C, Zupi E, Amadio A, Szabolcs B, De Vivo B, Marconi D, et al. Laparoscopic removal of endometriomas: sonographic evaluation of residual functioning ovarian tissue. Am J Obstet Gynecol 2004;191:68–72.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Laparoscopic ovarian cystectomy of endometriomas: surgeons’ experience may affect ovarian reserve and live-born rate in infertile patients with in vitro fertilization-intracytoplasmic sperm injection Hsing-Tse Yu, Hong-Yuan Huang, Yung-Kuei Soong, Chyi-Long Lee, Angel Chao, Chin-Jung Wang * Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 February 2010 Accepted 23 May 2010
Objective: To assess whether the laparoscopist’s experience can affect ovarian reserve and pregnancy outcome in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) patients who previously underwent laparoscopic conservative treatment for ovarian endometriomas. Study design: One hundred and forty-nine IVF-ICSI cycles with infertile patients who previously underwent laparoscopic conservative treatment for ovarian endometriomas were enrolled. There were 76 cycles with an inexperienced surgeon and 73 cycles with an experienced surgeon. Results: The number of antral follicle count (7.5 3.8 vs. 9.6 6.6; p = 0.011), and live-born rate per cycle (9.3% vs. 32.9%; p < 0.001) were significantly lower in the inexperienced group comparing with the experienced group. However, the mean number of oocytes, fertilization rate, mean number of embryos transferred, rate of good-quality embryos transferred, implantation rate and clinical pregnancy were similar between both groups. Conclusions: The experience of the laparoscopist may affect ovarian reserve and live-born rate after treating ovarian endometrioma in infertile women with IVF-ICSI. ß 2010 Elsevier Ireland Ltd. All rights reserved.
Presented at the 65th annual meeting of the American Society for Reproductive Medicine, October 17–21, 2009, Atlanta, Georgia Keywords: Laparoscopy Endometrioma Ovarian reserve In vitro fertilization Intracytoplasmic sperm injection
1. Introduction Endometriosis is a common, benign, chronic gynecological disorder frequently associated with dysmenorrhea and infertility. The prevalence of endometriosis approaches 10–15% of all women of reproductive age [1] while it has been reported that 25–40% of women with infertility have endometriosis [2]. Current guidelines for the treatment of endometriosis include medical or surgical therapies. However, medical treatment has a limited role in the treatment of endometriosis that only offers symptomatic control. Laparoscopic surgery has traditionally been the standard treatment for patients with endometriosis. The impact of previous conservative surgery for endometriosis on in vitro fertilizationintracytoplasmic sperm injection (IVF-ICSI) outcome is still controversial. Some investigations have suggested that laparoscopic surgery before IVF might impair ovarian responsiveness to hyperstimulation [3,4]. Interestingly, some studies demonstrated
* Corresponding author at: Department of Obstetrics and Gynecology, Division of Gynecologic Endoscopy, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, 5, Fu-Hsin Street, Kwei-Shan, Tao-Yuan, Taiwan. Tel.: +886 3 3281200x8258; fax: +886 3 3286700. E-mail address: [email protected] (C.-J. Wang). 0301-2115/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2010.05.016
contrary results, that surgery for endometriosis before IVF did not have an adverse effect on pregnancy rate [5,6]. As laparoscopic treatment for endometriosis has been widely carried out by general gynecologists, one of the concerns in laparoscopic surgery is the training time needed. Given it is more likely that endometriosis causes severe adhesions, laparoscopy necessitates skilled operators who carefully identify normal ovarian tissue and endometrioma and separate them to prevent ovarian damage. An inexperienced surgeon might bring detrimental effects on ovarian reserve and response of controlled ovarian hyperstimulation (COH). To the best of our knowledge, in studies investigating the influence of previous conservative surgery for endometriosis on IVF-ICSI, there is no article specifically concerning the surgeon’s experience correlated with ovarian reserve and outcome of IVF-ICSI. The aim of our study is to assess whether the surgeon’s experience can significantly affect ovarian reserve and pregnancy outcome in IVF-ICSI patients who previously underwent laparoscopic treatment for ovarian endometriomas. 2. Material and methods We retrospectively reviewed all IVF-ICSI cycles with infertile patients who previously underwent laparoscopic enucleation of
H.-T. Yu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 172–175
173
ovarian endometriomas. The period of study was from January 2005 through December 2008 in Chang Gung Memorial Hospital Linkou Medical Center. This study was based on review of both electronic and paper medical records. To clarify the impact of experience of the operators on the outcome of IVF-ICSI, we divided the surgeons into experienced and inexperienced. Chief resident and fellow physician were defined as inexperienced surgeons, whereas attending physicians were experienced. The Institutional Review Board (IRB) of Chang Gung Memorial Hospital approved this study.
of embryos transferred, good-quality embryo for transfer, clinical pregnancy rate, implantation rate and live-born rate. Operative findings were scored according to the revised classification of the American Fertility Society (rAFS) [8]. In this study, we defined embryos of grade 1 or 2 as good-quality. Clinical pregnancy was determined by the presence of at least one gestational sac, documented with transvaginal ultrasonography two weeks after a positive pregnancy test. Implantation rate was calculated as number of gestational sacs divided by number of transferred embryos and multiplied by 100.
2.1. Operative technique
2.3. Statistical analyses
All surgeries were performed with a similar technique which is described elsewhere [7]. In brief, laparoscopic examination of the pelvis and lower abdomen was performed to determine the accessibility of the surgical field. Three or four trocars were used according to complexity of pelvis. A disposable laparoscopic grasper, scissors, and suction-irrigator were used to perform various procedures such as holding, cutting, exploring and dissecting. A sharp cortical incision was made by unipolar scissors and a cleavage plane was identified. The capsule of the endometrioma was then enucleated and stripped from the normal ovarian tissue. Large bleeders were coagulated using bipolar forceps with an electrosurgical bipolar unit (Elmed, Addison, IL). Complete hemostasis and approximation of ovarian defect were achieved using a 3–0 monofilament poliglecaprone 25 suture (Monocryl; Ethicon Inc., Somerville, NJ, USA) on a large curved needle following the principles of laparotomy. The specimens were removed from the abdomen using a disposable endobag for the purpose of avoiding contaminating the abdominal wall.
Parametric continuous variables were compared with Student’s t test and categorical values were compared with Pearson x2 analysis or Fisher’s exact test. All probability values were twosided. Significance level was accepted at p < 0.05. SPSS for Windows version 13.0 (SPSS Inc., Chicago, IL) was used for the statistical calculations.
2.2. Parameters studied The parameters studied were patient’s demographics, operation records, ovarian reserve (day 2 or day 3 serum FSH and antral follicle count) after surgery, number of ampoules of gonadotropin used for COH, number of follicles greater than 14 mm in mean size, serum estradiol (E2) levels and endometrium thickness on the day of human chorionic gonadotropin (hCG) administration, number of oocytes aspirated, the proportion of mature (MII) oocytes, number
3. Results A total of 149 IVF-ICSI cycles were included in this analysis. There were 76 cycles with laparoscopic enucleation of endometriomas performed by inexperienced surgeons and 73 cycles by experienced ones. Patient characteristics and preoperative information are summarized in Table 1. Both groups were similar in mean age, body mass index (BMI), duration of infertility, CA-125 level before operation and mean size of the endometrioma. Comparing with the inexperienced surgeon group, there were significantly shorter intervals from operation to IVF-ICSI date (29.8 31.5 vs. 45.4 34.6, respectively; p = 0.005) and higher rAFS scores (49.1 30.0 vs. 35.7 23.3, respectively; p = 0.003) in the experienced group. Likewise, there were no differences in day 2 or day 3 serum FSH and E2 level, the hCG day, dosage of recombinant FSH, numbers of dominant follicles, endometrial thickness and peak E2 level in both groups (Table 2). Number of antral follicles was significantly fewer in the inexperienced surgeon group (7.5 3.8 vs. 9.6 6.6, respectively; p = 0.011). The number of retrieved oocytes, proportion of MII oocytes, number of embryos transferred, embryo transfer day, fertilization
Table 1 Baseline characteristics of patients. Variable
Inexperienced surgeon
Experienced surgeon
p
Cycles Age (y) BMI (kg/m2) Infertility duration (y) CA-125 before operation (U/mL) Size of endometrioma during operation (cm) Interval from operation date to IVF date (mo) rAFS score
76 33.2 4.2 21.2 2.9 4.4 2.8 84.5 98.9 4.9 2.5 45.4 34.6 35.7 23.3
73 33.3 3.3 20.9 3.2 4.2 2.7 112.2 188.6 4.8 2.3 29.8 31.5 49.1 30.0
NS NS NS NS NS 0.005 0.003
Data are reported as mean SD or number. BMI = body mass index; IVF = in vitro fertilization; rAFS = revised classification of the American Fertility Society; NS = non-significant. Table 2 The baseline characteristics and controlled ovarian hyperstimulation response in the two groups. Variable
Inexperienced surgeon
Experienced surgeon
p
Day 2 or day 3 FSH (mIU/mL) Day 2 or day 3 E2 (pg/mL) Antral follicle count FSH dosage (IU) hCG day No. of follicles >1.4 cm on hCG day Endometrium thickness on hCG day (cm) Peak E2 level (pg/mL)
8.4 2.3 37.5 38.5 7.5 3.8 2261.3 744.3 9.9 1.5 5.4 2.8 1.1 0.2 1590.5 1105.5
8.5 5.1 33.0 25.6 9.6 6.6 2478.3 1302.8 9.9 1.5 5.1 3.2 1.1 0.2 1657.1 1385.5
NS NS 0.015 NS NS NS NS NS
Data are reported as mean SD. NS = non-significant.
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Table 3 Fertility and reproductive outcomes after IVF-ICSI. Variable
Inexperienced surgeon
Experienced surgeon
p
No. of oocytes retrieved Mature (MII) oocytes Proportion of MII oocytes (%) Normal fertilization rate (%) No. of embryos transferred Embryo transfer day Good-quality embryos for transfer (%)a Implantation rate (%) Clinical pregnancy rate per cycle (%) Miscarriage rate per cycle (%) Ectopic pregnancy rate per cycle (%) Live-born rate per cycle (%)
10.1 6.4 7.6 4.7 76.0 24.0 64.4 21.7 3.2 1.3 2.6 0.7 57.8 13.9 26.3 9.2 7.8 9.3
9.2 6.9 6.9 5.2 76.8 25.7 63.5 22.5 2.9 1.0 2.5 0.6 65.8 18.5 41.1 4.1 2.7 32.9
NS NS NS NS NS NS NS NS NS NS NS <.001
Data are reported as mean SD or number (%). IVF = in vitro fertilization; ICSI = intracytoplasmic sperm injection; NS = non-significant. a Good-quality embryos are defined as grade 1 or 2 embryos.
rate, and implantation rate were not statistically different (Table 3). The rates of good-quality embryos for transfer per cycle (57.8% vs. 65.8%, respectively; p = 0.20) and clinical pregnancy rate per cycle (26.3% vs. 41.1%, respectively; p = 0.056) were slightly decreased in the inexperienced surgeon group. Slightly higher miscarriage rate (9.2% vs. 4.1, respectively; p = 0.18) and ectopic pregnancy rate (7.9% vs. 2.1%, respectively; p = 0.15) were also observed in the inexperienced surgeon group. However, these results were not statistically significant. Eventually, the inexperienced group had significantly poorer outcome with live-born rate per cycle (9.3% vs. 32.9%, respectively; p < 0.001) in their IVF-ICSI cycles. Of the total of 149 cycles, there were 42 (28.2%) cycles involving bilateral endometriomas and 107 (71.8%) unilateral, respectively. Although the antral follicle count, number of retrieved oocytes and clinical pregnancy rate per cycle were not affected by the surgeon’s experience when analysis was limited to unilateral lesions, the inexperienced group had significantly poorer outcome with liveborn rate per cycle (8.5% vs. 36.2%, respectively; p = 0.001). As for bilateral lesions, the inexperienced surgeons had a significant adverse effect on antral follicle count compared with experienced surgeons (5.5 3.3 vs. 9.6 6.5, respectively; p = 0.019). Nevertheless, there were no significant statistical differences in clinical pregnancy rate (23.5% vs. 40%, respectively; p = 0.331) and live birth rate per cycle (11.8% vs. 28%, respectively; p = 0.271). 4. Comment Surgical intervention has been demonstrated to be an effective treatment for ovarian endometriomas. Associated with many advantages over traditional abdominal methods, including less hospitalization, smaller incisions, faster recovery time, and faster return to work, the laparoscopic approach for endometriosis has been now widely accepted. Factors affecting the choice of laparoscopic intervention include the surgeon’s experience and skill in these techniques. However, endometriosis is an inflammatory process that results in dense adhesion between normal ovarian tissue and endometrioma. Therefore, there might be inadvertent removal of a consistent amount of normal ovarian tissue during cystectomy, potentially causing a reduction of ovarian function. In this study, we indeed observed that the experience of surgeons who performed laparoscopic surgery for endometriosis would affect the ovarian reserve and subsequent live birth rate on IVF-ICSI. Until now, there is no consensus regarding the influence of previous surgery for endometriomas on ovarian function. Some investigators suggested that IVF outcome is compromised by previous ovarian surgery [3,4,9]. Nevertheless, no adverse impact of prior surgery for endometriosis on ovarian reserve and response
to COH has also been reported [10–12]. Ragni et al. reported that laparoscopic enucleation of ovarian endometrioma reduced the ovarian response to COH. Conversely, the rates of fertilization and high-quality embryos were not affected [13]. In present study, we further found that the better outcome of clinical pregnancy rate and live-born rate occurred in surgery performed by well-trained laparoscopists despite higher dosage of gonadotropin for COH. The surgical technique of ovarian cyst excision by laparoscopy was usually using a stripping technique [14,15]. The possible drawback of the laparoscopic stripping technique might be associated with loss of follicles and damage to the ovarian stroma [16]. In our series, a significantly diminished antral follicle count was noted in the inexperienced group. The number of embryos transferred was similar in both groups. Nevertheless, a higher proportion of good-quality embryos for transfer was observed in the experienced group. It may explain why experienced surgeons have better outcome of live-born rate although there was no significant difference between the two groups with respect to clinical pregnancy rate. Bilateral lesions account for 19–28% in patients with ovarian endometriosis [17]. The severity of ovarian lesions (bilateral vs. unilateral) is theoretically an important factor for ovarian reserve after conservative surgery. Esinler et al. reported that laparoscopic endometrioma cystectomy diminished ovarian reserve in patients who underwent bilateral cystectomy compared with a unilateral group. Nevertheless, the pregnancy outcome was not affected by the diminished ovarian reserve [18]. Our study also demonstrated reduced ovarian reserve in bilateral cystectomy when comparing the inexperienced with the experienced groups (5.5 3.3 vs. 9.6 6.5, respectively; p = 0.019). Interestingly, poor pregnancy outcome was observed in the inexperienced surgeon group even among patients who underwent unilateral cystectomy (8.5% vs. 36.2%, respectively; p = 0.001). These results imply the importance of surgical skills and experience in performing laparoscopic conservative surgery for ovarian endometriomas. Candiani et al. reported that reduced ovulation and ovarian volume came about over time after the second postoperative menstruation [19]. Exacoustos et al. reported a similar finding that a significant reduction in ovarian volume was noted after laparoscopic endometrioma removal by stripping [20]. Our data showing the interval between surgery and IVF in the skilled group was shorter than in the inexperienced group (29.8 31.5 vs. 45.4 34.6, respectively; p = 0.005) might imply more normal ovarian tissues were damaged during laparoscopy performed by young staff and a longer time for ovarian function recovery was needed thereafter. Although the laparoscopic procedure has many advantages, it involves electrosurgery to dissect tissue and control bleeding. Therefore laparoscopists should pay much attention to developing
H.-T. Yu et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 152 (2010) 172–175
the proper plane of cleavage between normal ovarian and endometrotic tissue, especially near the ovarian hilus. Newlytrained surgeons tend to complete the mission of stripping the cyst wall of endometrioma and achieve complete hemostasis, in consequence damaging normal tissue due to extensive thermal effect. Experienced surgeons realize the principles of electrosurgery and use the bipolar diathermy with care. That is, they perform ovarian hemostasis mainly with suture rather than electrocautery. This method can decrease thermal injury and theoretically preserve the ovarian reserve. The obvious weakness of the paper is its retrospective design. Further research in this area is warranted to confirm and advance these findings, specifically with studies powered to evaluate delivery rates. Besides, the operative procedure was not uniform because 32 surgeons were involved in this study (16 experienced surgeons and 16 inexperienced surgeons). A larger prospective study is crucial to prove the contention, though it is difficult to introduce practically. In conclusion, a successful operation means not only removal of ovarian pathology but also maintenance of ovarian function and subsequent pregnancy with live birth. Physicians should be aware that laparoscopic conservative surgery for endometriosis is a challenging task. The skill and experience of laparoscopists play an important role in determining the final IVF-ICSI outcome for infertile patients operated on for ovarian endometriomas. Conflict of interest None. Acknowledgements This research was supported by grant CMRPG350371 (to Wang C.J.) from Chang Gung Memorial Hospital, Taiwan. Contributors: H.T.Y. drafted article. H.Y.H. contributed to study concept. Y.K.S. and C.L.L. undertook data collection. A.C. provided statistical advice. C.J.W. led the design of the study and contributed to critical revision of article. References [1] Moen MH. Is a long period without childbirth a risk factor for developing endometriosis? Hum Reprod 1991;6:1404–7.
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