RBMOnline - Vol 13 No 3. 2006 349–360 Reproductive BioMedicine Online; www.rbmonline.com/Article/2320 on web 12 June 2006 Article Impact of ovarian on assisted reproduction outcomes Dr Gupta is a Fellow in Obstetrics, Gynecology and Andrology at the Reproductive Research Center, Cleveland Clinic Foundation, Cleveland, USA. She graduated from the Lady Hardinge Medical College, New Delhi, India and in 1992 completed a residency in Obstetrics and Gynecology at the University of Delhi. From 1996 to 2001 she was a faculty member in the Department of Reproductive Endocrinology and at the National Institute of Health and Family Welfare, Delhi, India. Her current research interests include studies on the role of oxidants and antioxidants in the pathophysiology of female reproduction, cryopreservation of gametes and assisted reproduction.

Dr Sajal Gupta Sajal Gupta1,3, Ashok Agarwal1, Rishi Agarwal1, J Ricardo Loret de Mola2 1Reproductive Research Centre, Glickman Urological Institute and the Department of Obstetrics–Gynecology, Cleveland Clinic Foundation; 2Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, MacDonald Women’s Hospital, University Hospitals, Cleveland, OH, USA 3Correspondence: Tel: +1 216 4449485; Fax: +1 216 4456049; e-mail: [email protected]

Abstract

The effects of ovarian endometrioma on fertility outcomes with IVF and embryo transfer have been causally related to poor outcomes. The objective of this meta-analysis was to evaluate the ovarian reserve and ovarian responsiveness to ovarian stimulation and assisted reproduction outcomes in patients with ovarian endometrioma. The odds for clinical pregnancy were not affected signifi cantly in patients with ovarian endometrioma compared with controls, with an overall odds ratio of 1.07 from three studies [95% CI: (0.63, 1.81), P = 0.79]. The overall pregnancy rate was similar with an estimated odds ratio of 1.17 [95% CI: (0.85, 1.60), P = 0.34]. Decreased ovarian responsiveness to ovarian stimulation in patients with ovarian endometrioma may be due to a reduced number of follicles in these patients compared with controls (P = 0.002). Prospective randomized controlled trials are needed to assess whether surgical treatment versus no surgical treatment improves pregnancy outcomes in patients with ovarian endometrioma undergoing assisted reproduction cycles.

Keywords: embryo quality, in-vitro fertilization, intracytoplasmic sperm injection, ovarian endometrioma, retrieved oocytes

Introduction context of assisted reproduction (Garcia-Velasco et al., 2004) and others have reported adverse fertility outcomes (Dlugi et is a disease characterized by ectopic growth al., 1989). of endometrial stroma and glands, and affects about 5 million women of reproductive age in North America (Esfandiari, Among women in their reproductive years, endometriosis has 2005). Among women with infertility, 30−50% are diagnosed a prevalence of 10–15% (Counseller and Crenshaw, 1951; with endometriosis laparoscopically (Mahmood and Templeton, Somigliana et al., 2004). Laparoscopic evidence of ovarian 1991; Redwine, 1999). The association between endometriosis endometrioma was reported in 17% of women with chronic and infertility is still a topic of debate, and remains controversial. and infertility (Milingos et al., 2006). Symptoms The presence of ovarian endometrioma is a common and specifi c such as chronic pelvic pain, dysmenorrhoea, infertility and manifestation of the disease, and may arise as a consequence affect quality of life in women suffering from of metaplasia of the coelomic epithelium or inversion with endometriosis. There is an immense expense in terms of the invagination of the ovarian cortex after local implantation of cost of treatment and the emotional burden. The mechanism the on the ovarian surface (Donnez et al., 1996). of the pathogenesis of infertility associated with endometriosis Ovarian are a manifestation of deep ovarian is controversial. In the most severe form, infertility is ascribed endometriosis. The management of ovarian endometrioma to adhesions, tubal blockage and anatomical distortion, but the remains controversial, since some studies have not reported mechanisms involved in mild to moderate disease are poorly improvement in pregnancy rates with surgical treatment in the understood. 349 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

Cumulative pregnancy rates in patients with pelvic intracytoplasmic sperm injection, retrieved oocyte, embryo endometriosis and ovarian endometriomas are not signifi cantly quality, fertilization rate, implantation and pregnancy rate. different, according to the revised staging by the American Articles were evaluated for relevance by examining titles and Society of Reproductive Medicine (Guzick et al., 1997). abstracts. However, increasing tubal adhesive involvement associated with the endometrioma leads to reduced pregnancy rates. Evaluation of relevant studies: blinding and scoring of studies Unfortunately, medical therapy has not been found to be an effective treatment for endometrioma-associated infertility in endometriomas greater than 4 cm. However, assisted Articles and reviewers were ‘blinded’ during the evaluation reproductive technologies are being increasingly employed to period. The methods, results, tables and fi gures from each help women with endometriosis to conceive. Endometriosis study were extracted, and each article was assigned an is one of the main indications for the use of IVF−embryo identifi cation number by an individual other than the two transfer and currently represents 10–25% of all patients who scorers. Quantitative or qualitative report of results was seek this treatment. Women with ovarian endometrioma have blacked out in each article to enable unbiased scoring of study been reported to have a reduced ovarian response to ovarian quality. Data points or graphs were blacked out of fi gures, stimulation as measured by fewer retrieved follicles, fewer while axes and captions were still included for evaluation. aspirated oocytes and lower peak oestradiol concentrations. Summary statistics, P-values or descriptions were blacked out This is also associated with poor quality of oocytes, which of tables and texts, while labels such as comparison groups may lead to lower fertilization rates, a smaller number of and parameters measured were left viewable. Two evaluators embryos available for transfer, and higher miscarriage rates blinded to the concluding results, authors, journal, and year (Yanushpolsky et al., 1998). of the articles evaluated each study on its methodological merits. Ovarian endometriomas are predominantly haemorrhagic lesions. Ovarian endometriomas result from the implantation Four overarching categories of bias were appraised with the of ectopic endometrium on surfaces of the and questionnaire and the scoring system: selection or follow-up subsequent invagination and invasion of the endometrium bias, confounding bias, information or detection bias, and into the ovarian cortex (Brosens, 2004). The cytology of other sources of bias such as misclassifi cation. Each study ovarian endometrioma reveals the presence of glandular was scored using the same set of questions for each type of and fl attened endometrial epithelium, endometrial stroma bias. Specifi c answers for different questions were given more and haemosiderin-laden macrophages (Nezhat et al., weight than others as shown in the point system used to total 1992). Transvaginal sonography can diagnose ovarian the scores for each category of bias. A higher score indicated endometriomas greater than 2 cm in diameter (Moore et that the study met most of the criteria required to avoid al., 2002). Diminished ovarian reserve and reduced ovarian introducing bias in the study. If the total points for more than response to ovarian stimulation and compromised follicular one category of bias fell below an acceptable range, the study development have all been implicated in endometriosis- associated infertility (Wardle et al., 1985; Yovich et al., 1985). Patients with ovarian endometriomas can present with infertility alone or infertility associated with chronic pelvic pain (Milingos et al., 2006). IVF and embryo transfer can be successfully used to treat infertility associated with endometriosis.

Compromised follicular development and poor embryo quality have been reported to result in impaired fertility outcomes with ovarian endometrioma. This meta-analysis was conducted to evaluate the effects of ovarian endometrioma on ovarian responsiveness to ovarian stimulation and pregnancy outcomes with assisted reproduction. Materials and methods

Search strategy

This meta-analysis was initiated with studies identifi ed by an extensive search of Medline-Ovid, EMBASE, Cochrane Collaboration database, BIOSIS and Meeting Abstracts from 1986 to 2005, with the help of a professional librarian as well as manual searching of review articles and cross references. The overall strategy employed for study identifi cation and data extraction is outlined in Figure 1. The following keywords 350 were used to search the databases: ovarian endometrioma, IVF, Figure 1. Steps in the meta-analysis. Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al. was automatically excluded from the fi nal analysis. If the total Study 3 (Marconi et al., 2002) points for only one category fell below the acceptable range, the study was re-examined to determine whether, indeed, the This was a retrospective follow-up study. overall study was likely to be biased, and, if not, whether it could be included in the meta-analysis. Thirty-nine patients underwent surgery for ovarian endometrioma by stripping of the pseudo-capsule and minimal Study description bipolar cauterization in order not to avoid compromising the vascular supply of the ovaries. Thirty-nine tubal infertility Study 1 (Canis et al., 2001) patients in a similar age group served as controls. Several parameters such as serum oestradiol concentrations, This was a retrospective cohort study with patient information number of follicles and oocytes retrieved were similar in extracted from an IVF database. Patients were excluded if both the cases and controls. Thus, ovarian cystectomy did oocyte retrieval was performed laparoscopically. If patients not compromise the ovarian reserve. The study concluded underwent IVF and gamete intra-Fallopian transfer (GIFT) or that laparoscopic stripping of the cyst wall with careful intracytoplasmic sperm injection (ICSI) cycles, only the IVF electrocoagulation does not affect the ovarian reserve. cycles were included. Study 4 (Pabuccu et al., 2004) Three groups of patients were retrospectively selected from the IVF−embryo transfer records. The fi rst group consisted of patients who had undergone laparoscopic ovarian cystectomy This was a prospective follow-up study. for ovarian endometriomas >3 cm in diameter. The second group consisted of women treated for endometriosis with One hundred and seventy-one patients divided into four groups but without deep ovarian endometriosis. The were examined. All four groups were similar with regard to third group consisted of patients with tubal infertility. The age, duration of infertility, body mass index (BMI) and FSH endometriosis and tubal infertility groups were age matched and oestradiol concentrations on day 2 of the menstrual cycle. with those with ovarian endometrioma. The fi rst group consisted of patients with endometriomas that were aspirated at the start of combined ovarian stimulation. The study concluded that laparoscopic cystectomy is valuable The second group was comprised of patients with non-aspirated in the management of ovarian endometriomas as there was no endometriomas. The third group included patients with a history diminution of response to ovarian stimulation. In addition, of surgery for endometriomas, but with no endometriomas the number of embryos and pregnancy rates were similar in presently. The fourth group included only patients with tubal the endometrioma group and the endometriosis group without factor infertility. All patients had undergone ICSI. deep ovarian endometriosis. There were no signifi cant differences in the implantation rates Study 2 (Donnez et al., 2001) between the endometrioma group and the tubal infertility group. Study 5 (Suzuki et al., 2005) This study reported outcomes per cycle with multiple observations per individual. This study reported outcomes per cycle with multiple A series of 85 patients who had undergone laparoscopic observations per person. cystectomy for ovarian endometrioma and had failed to become pregnant were compared with a control group of There were no signifi cant differences in age and BMI between 287 patients with . Both groups were the groups compared. Three study groups were included: treated with IVF−embryo transfer. IVF−embryo transfer group A (n = 50) was composed of patients with a diagnosis outcomes were analysed in both groups to assess if of endometrioma confi rmed by aspiration and the characteristic laparoscopic surgery for ovarian endometriomas adversely appearance of the aspirated fl uid. Group B consisted of patients affects IVF outcomes. with endometriosis diagnosed at laparoscopy, but without endometriomas. Group C consisted of patients with tubal factor There were no signifi cant differences in the studied parameters infertility who served as the unexposed cohort. such as number of ampoules, number of follicles, number of mature oocytes, concentration of oestradiol and day of The study concluded that ovarian endometrioma has adverse human chorionic gonadotrophin (HCG) injection between the effects on follicle number but not on embryo quality or ovarian endometrioma and the control group. An additional pregnancy outcomes. This study also reported that the analysis was performed in the group of patients who had detrimental effects of ovarian endometrioma could possibly be received cystectomy comparing the that had undergone overcome by laparoscopic treatment. cystectomy to the contralateral normal ovary, which acted as a control. No statistically signifi cant difference in ovarian Study 6 (Yanushpolsky et al., 1998) response was seen between the two groups. The proportion of clinical pregnancies was 37.4 and 34.7% in the endometriosis This was a prospective follow-up study. and the tubal factor control group respectively. Vaporization of the internal cyst wall did not seem to compromise the Thirty-seven patients with ovarian endometriomas were ovarian reserve. included; all had a cyst fl uid CA-125 concentration of >104 IU/ 351 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

ml. Eight patients with complex ovarian cysts were excluded was excluded due to duplication, and 13 were excluded from because the cyst fl uid concentrations were <104 IU/ml. Fifty- the main analysis because there was no unexposed group, or seven women without any complex ovarian cysts served as the because the exposed group had endometriosis rather than comparison group. ovarian endometrioma (Figure 2). One of the studies was excluded because the methodology of recruitment, diagnosis Emphasis is placed on the need to distinguish endometrioma and follow-up was not clear (Suganuma et al., 2002). from complex ovarian cysts, as complex haemorrhagic cysts Subsequent analysis was performed to examine whether do not have an unfavourable impact on IVF outcomes. The there were signifi cant differences in reproductive outcomes endometriomas were aspirated at the time of oocyte retrieval, of patients with endometriosis in comparison to those with and CA-125 concentrations were estimated in the cyst fl uid. ovarian endometrioma. After grading each of the remaining seven studies on quality, only six studies remained (Table 1). This study concluded that endometriomas have adverse effects One article was excluded because there was no indication as on oocyte and embryo quality. to the characteristics of the studied populations (Chang et al., 1997). The data on outcomes, which were examined in fewer Data extraction than two studies, are not presented in the meta-analysis. So far as is known, this is the fi rst meta-analysis to consider the effects of ovarian endometrioma on fertility outcomes with assisted Preformatted data extraction sheets were utilized to extract the reproduction techniques. data by one of the reviewers. The data were then entered into a spreadsheet. The outcomes reported were variable; some studies Signifi cant heterogeneity was found in the initial analysis reported the odds of chemical or overall pregnancy (detection of many of the outcomes that included studies measuring of HCG) and others reported the odds of clinical pregnancy characteristics by cycle along with studies taking measurements rates. Some authors reported the odds of pregnancy per cycle for individual patients. Therefore, studies reporting per-cycle with multiple cycles per woman while other reported odds with characteristics were excluded from all analyses in which there only one observation per woman. was signifi cant or borderline signifi cant heterogeneity.

The outcomes or measures of interest for which data were A total of six studies were included in the fi nal meta-analysis extracted included dichotomous variables such as clinical with a total study population of 782 (exposed n = 293, pregnancy, chemical/overall pregnancy, and spontaneous unexposed n = 489). One of the included studies reported 80 abortion for which the overall odds were calculated and cycles in patients with endometriomas (n = 50) and 283 cycles continuous variables such as average fertilization rate, in tubal infertility controls (patient numbers were not reported implantation rate, number of oocytes retrieved, peak oestradiol for the controls) (Suzuki et al., 2005). The study population concentration, total FSH used, and number of mature follicles consisted of couples affected by ovarian endometrioma or with for which a weighted mean was calculated. Population and a history of ovarian endometrioma in the female partner; all study characteristics such as type of comparison group, whether were undergoing IVF−embryo transfer. Four of the studies ovarian endometrioma was treated, and unit of measurement examined a group of patients with ovarian endometriomas who (i.e. variables were measured per patient or per cycle) were also had undergone laparoscopic cystectomy (Table 1). A total of extracted for further subgroup analyses. three studies had patients with ovarian endometrioma, which were aspirated either at the beginning of ovarian stimulation Data analysis or at the time of oocyte retrieval (Table 1). One of the studies conducting endometrioma aspiration at the time of oocyte Data analyses were carried out using the RevMan software retrieval utilized this as a diagnostic test (Yanushpolsky et al., (version 4.2.8) developed by the Cochrane collaborative 1998). Endometriomas were distinguished from other ovarian for the purpose of meta-analysis (www.cochrane.org). A cysts by measuring CA-125 concentrations in the aspirated fl uid. random effects model was used for both the dichotomous and A second study examined three groups, with one of the groups continuous data, as it was intended to extrapolate conclusions consisting of patients with ovarian endometriomas, which to other situations beyond only those in the studies included in were aspirated at the beginning of ovarian stimulation. The the analysis. Outcomes that had signifi cant heterogeneity were other two groups consisted of patients with endometriosis but examined to determine whether the unit of measurement (by without endometriomas and the control group with tubal factor cycle or by patient) was the source of heterogeneity. Because infertility (Suzuki et al., 2005). The majority of studies included by-cycle measurements, with multiple cycles observed for some patients with tubal infertility as the unexposed cohort. However, individuals in the study, were less common, these were the fi rst one study recruited all women with no complex cysts to serve to be excluded from the fi nal models if there was signifi cant or as the unexposed cohort. Patients underwent IVF−embryo close to signifi cant heterogeneity. A P-value <0.05 was used as transfer in four of the studies and ICSI in two studies. Pituitary the cut-off point for signifi cance testing in all statistical tests. desensitization was performed using the long protocol with gonadotrophin-releasing hormone (GnRH) agonists. Ovarian stimulation was performed with recombinant FSH alone in Results two of the studies (Marconi et al., 2002; Pabuccu et al., 2004) and a combination of human menopausal gonadotrophin and A search of the electronic databases yielded 439 studies. Metrodin or clomiphene in some of the studies (Yanushpolsky Of these, a total of 29 articles were found to be relevant by et al., 1998; Canis et al., 2001; Donnez et al., 2001). examining the abstracts and titles. Twenty-one original articles 352 contained data relevant to the analysis. One of these articles Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

The odds of clinical pregnancy were not different for patients diameter of 14 mm while others specifi ed 17 mm. Still others with ovarian endometrioma when compared with the controls; specifi ed an intermediate value, or nothing at all. The study by the overall odds ratio was 1.07 from three studies [95% CI: Donnez et al. was excluded due to per-cycle reporting that was (0.63, 1.81), P = 0.79] (Figure 3). There was no heterogeneity thought to be the cause of signifi cant heterogeneity (Donnez found between studies examining this outcome (P = 0.65). The et al., 2001). Overall, it was found that the number of follicles odds of overall or chemical pregnancy, as measured by HCG in the patients with endometrioma was signifi cantly fewer than assay, were similar between the exposed and unexposed, with the number in the controls (P = 0.002) (Figure 6). Patients with an overall estimated odds ratio of 1.17 [95% CI: (0.85, 1.60), ovarian endometrioma had, on average, 0.88 fewer follicles P = 0.34] (Figure 4). The results of this meta-analysis are in than the controls after stimulation [95% CI: (−1.43, −0.32)] agreement with the results of many of the studies reporting that (Figure 6). patients with endometriomas have fewer oocytes harvested (Figure 5), but their chances of pregnancy are comparable The average number of ampoules of gonadotrophins used (Garcia-Velasco and Arici, 1999; Tinkanen and Kujansuu, 2000; for each cycle of IVF was calculated in four studies. In two Loo et al., 2005). The possible explanations of reduced number studies, only FSH was used. There was no signifi cant difference of oocytes can be the deleterious effects of endometriosis on between the numbers of ampoules of FSH used in those with follicullogenesis, impaired follicular environment, reduced rates endometrioma compared with controls. The same held true of follicular growth resulting in poor quality oocytes. Losses for studies that used FSH and HMG. The amount of ampoules of ovarian volume and follicles have been reported with the measured in these two types of studies, however, could not be laparoscopic ovarian cystectomy procedure (Exacoustos et al., combined, as there was signifi cant heterogeneity. 2004). The reduction in ovarian response following surgery has resulted in many authors advocating conservative management for patients with infertility.

Spontaneous abortion was measured in only one study. The odds of spontaneous abortion in those with ovarian endometrioma were signifi cantly increased in comparison with those without; the odds ratio was 5.53 [95% CI: (1.13, 25.11), P = 0.03] (Yanushpolsky et al., 1998). The average fertilization rate was considered to be a continuous variable by the content experts rather than a dichotomous one, because the fertilization rate was calculated as the average of the percentage of oocytes fertilized for each individual stimulation cycle per person. This also was not signifi cantly different for those with and without endometrioma. Implantation rate was not evaluated by meta- analysis because it was examined in only one study.

Initially, it was believed that fi ve studies examined the number of oocytes retrieved from stimulation. However, signifi cant heterogeneity was found when the two studies examining per- cycle characteristics were not excluded (chi-squared = 37.69, P < 0.00001; Donnez et al., 2004; Suzuki et al., 2005). Once excluded, however, the overall effect in the remaining three studies showed that there was, on average, 1.69 fewer oocytes retrieved in those with ovarian endometrioma than in those without ovarian endometrioma [95% CI: (−3.16, −0.23), P = 0.02] (Figure 5).

Several studies measured peak oestradiol concentrations, while others measured oestradiol on the day of HCG administration. These two measures were taken separately because statistically signifi cant heterogeneity was evident when they were combined. Peak oestradiol, as estimated from the studies by Donnez et al. and Marconi et al., was not signifi cantly different between the patients with ovarian endometrioma and the controls (Donnez et al., 2001; Marconi et al., 2002). There was no evidence of heterogeneity between these two studies. On the day of HCG administration, oestradiol concentrations were not signifi cantly different in those with endometrioma in comparison with the controls.

Two studies compared the number of mature follicles in these two groups of cases and controls. The defi nition of a mature Figure 2. Evaluation and selection of studies on IVF/ICSI follicle differed amongst the studies. Some specifi ed a minimum outcomes in women with ovarian endometrioma. 353 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

Table 1. Description of each study included in the meta-analysis and the outcomes measured.

Study Cases Controls Outcomes measured Dichotomous Continuous 1 2 3 4 5 6 7 8 9

Canis et al., Endometrioma cystectomy Tubal infertility ✓ ✓ 2001 Donnez et al., Endometrioma cystectomy Tubal infertility ✓ ✓ ✓ ✓ ✓a ✓c ✓ 2001* Marconi et al., Endometrioma cystectomy Tubal infertility ✓ ✓ ✓a ✓d ✓ 2002 Pabuccu et al., Aspirated endometrioma/cystectomy Tubal infertility ✓ ✓ ✓ ✓ ✓b ✓d ✓ 2004 Suzuki et al., Aspirated endometrioma Tubal infertility ✓ ✓ ✓ ✓ 2005* Yanushpolsky Aspirated endometrioma No complex cysts ✓ ✓ ✓ ✓ ✓ ✓b ✓c et al., 1998

Outcomes 1-9: 1 = Clinical pregnancy; 2 = Chemical/overall pregnancy; 3 = Implantation; 4 = Spontaneous abortion; 5 = Fertilization proportion; 6 = Number of oocytes retrieved; 7 = aPeak oestradiol or boestradiol on day of human chorionic gonadotrophin; 8 = cFSH/human menopausal gonadotrophin or dtotal FSH; 9 = Number of (mature) follicles. *Contains multiple observations per person as calculations were done by cycle for multiple cycles.

Figure 3. Meta-analysis plot showing odds ratio (OR) for clinical pregnancy of 1.07 from three studies [95% CI: (0.63, 1.81), P = 0.79]. PR = pregnancy rate; ET = embryo transfer.

Figure 4. Meta-analysis plot showing overall pregnancy rate (PR) with an estimated odds ratio (OR) of 1.17 [95% CI: (0.85, 1.60), P = 0.34]. 354 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

Figure 5. Meta-analysis plot showing the effects of endometrioma on number of oocytes retrieved. When the two studies examining per cycle characteristics were excluded (Donnez et al., 2004; Suzuki et al., 2005), 1.69 fewer oocytes were retrieved in those with ovarian endometrioma than in those without ovarian endometrioma [95% CI: (−3.16, −0.23), P = 0.02]. ET = embryo transfer; PT = patient; WMD = weighted mean distribution.

Figure 6. Effect of endometrioma on number of follicles – 0.88 fewer follicles than the controls after stimulation [95% CI: (−1.43, −0.32)]. ET = embryo transfer; PT = patient; WMD = weighted mean distribution.

Discussion For the evaluation of the studies, a scoring system was developed rather than a checklist, as quantitative scoring systems that are The overall goal of a systematic review or meta-analysis is transparent and parsimonious have been recommended (Cook to combine results of previous studies to arrive at summary et al., 1995). Application of a checklist to the studies to assess conclusions about a body of research. The meta-analysis fulfi lment of inclusion criteria may not exclude all types of bias was conducted according to the guidelines of the Potsdam because of unequal weight. Some items on the checklist may consultation (Cook et al., 1995). The reviewers were blinded inappropriately value individual studies over the others. Studies during the evaluation process and a scoring system was were scored in the meta-analysis with a scoring plan, which was developed to quantify bias that was used to evaluate the intended to adjust for different types of bias. In some instances, literature on infertile women with endometrioma undergoing specialty groups have developed and utilized standardized assisted reproduction. A critical discussion of the methodology protocols for scoring literature in their fi elds (Stroup et al., has been provided to clarify the process of blinding and scoring 2000; Dennis et al., 2003). A scoring system was developed to of studies that was applied in this meta-analysis. evaluate for different types of bias. The authors discussed and adopted a set of specifi c questions and point scores to quantify Reviewers may be biased because of the knowledge of the potential bias in the literature under consideration. The system institution or researchers involved and the conclusions of the developed to exclude bias was then applied to the blinded paper (Sacks et al., 1987). Bias on the part of reviewers is manuscripts prior to their inclusion into the meta-analysis. Two defi ned as inclusion bias (Egger and Smith, 1998). Inclusion reviewers who were experts in content area and methodology bias can be minimized by blinding the reviewers and the scored each study independently, and the fi nal decision on documents during the scoring process (Berlin, 1997). However, inclusion or exclusion was determined during a discussion in the present meta-analysis, an extensive effort was made to between the two reviewers. Some of the studies had to be blind all the studies for evaluation. In addition, other strategies revisited by both the reviewers and the decision for inclusion were employed to evaluate selection bias. of a study was based on the study being biased towards null. 355 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

This approach has been considered and accepted in other fi elds Many other studies have reported that ovarian cystectomy does for the development of other meta-analyses (Juni et al., 1999; not negatively affect ovarian response and reserve (Canis et al., Dennis et al., 2003). 2001; Marconi et al., 2002; Wong et al., 2004).

In the present meta-analysis, observational studies were Additional research has found that the proportion of apoptotic included, as there are no randomized trials in the literature on bodies in the membrana granulosa cells and the cumulus cells the subject. Most published data are derived from uncontrolled, from patients with chocolate cysts is signifi cantly higher observational studies, clinic based studies with small study than that in patients without chocolate cysts. Nakahara et al. populations. The study populations are small because of the also reported a signifi cant negative correlation between the relative low incidence of endometriosis. proportion of apoptotic bodies and oocyte quality. Patients with chocolate cysts had signifi cantly reduced numbers of follicles, Randomized controlled trials provide the highest level of retrieved oocytes and mature oocytes (P < 0.05) (Nakahara evidence, but they are cumbersome and expensive and et al., 1998). The ovarian endometrioma per se or surgical subject to follow-up bias. Prospective randomized controlled removal of endometrioma can cause reduced ovarian reserve trials (PRT) may be borderline unethical in the situation of and responsiveness to ovarian stimulation. Conservative randomizing patients with endometriomas to IVF. In addition, management of ovarian endometrioma has been recommended some PRT may be particularly unfair to infertile couples with by some of the authors to preserve ovarian reserve. ovarian endometrioma who are offered treatment in one arm of the trial, i.e. IVF, when alternative treatment is no intervention. Fertility after laparoscopic surgery for In these instances, treatment delays may expose these couples to the negative infl uence of advancing age on pregnancy ovarian endometrioma outcome. The Potsdam Consultation stated that it is valid to include observational studies for meta-analysis but only after a Patients with infertility caused by ovarian endometriomas thorough evaluation and appraisal process (Cook et al., 1995). may benefi t from surgery. However surgery may compromise However randomized controlled trials are not feasible in many the ovarian reserve because of loss of normal ovarian tissue situations, because of the low incidence of endometriosis and, and follicles and ovarian volume following surgery. The combining data from several smaller clinic based observational objective of surgery is removal of the ovarian endometriomas studies may be an effective way to combine and summarize to enhance fertility outcomes. There are multiple treatment clinical data (Stroup et al., 2000). All the observational studies options available for managing ovarian endometrioma such as were scrutinized with an elaborate scoring system for bias. expectant management, ultrasound-guided aspiration, drainage of the endometriotic cyst and vaporization of the cyst wall with Ovarian endometriomas constitute defi nite disease, thus laser, ovarian fenestration with bipolar electrocoagulation and selection bias will not result because of lack of under laparoscopic cystectomy (Canis et al., 2001; Yoshida et al., ascertainment of cases. The likelihood of bias amongst controls 2002; Benassi et al., 2003). However, there is a lack of consensus was limited, as patients with documented fertility i.e. women regarding the ideal surgical technique and also on the benefi ts undergoing tubal ligation were the control group. It has been and drawbacks of surgery. Some studies have found that surgery recommended that controls with documented fertility lend adversely affects fertility whereas other studies have reported validity to epidemiological studies on endometriosis (Holt and no effect on fertility outcomes. Meticulous surgical techniques Weiss, 2000). should be utilized to minimize damage to healthy ovarian tissue and avoid compromising the blood supply. Effects of ovarian endometrioma on In addition to the specifi c surgical technique, multiple other fertility factors are related to reproductive outcomes such as the age of the patient, size of the endometriotic cyst, and the amount Many distinct and plausible causes have been reported as the of normal ovarian tissue conserved during surgery. The mean reason for subfertility associated with endometriosis. These follicular response in post-cystectomy ovaries was signifi cantly factors include tubal distortion, impaired folliculogenesis, lower than that of normal ovaries in unstimulated cycles (P = fertilization/implantation defects, toxic/infl ammatory factors in 0.046) and also with clomiphene-stimulated cycles (P = 0.011) the peritoneal cavity and poor embryo quality. Compromised (Loh et al., 1999). The reduction in the responsiveness of follicular development has been reported in patients with post-cystectomy ovaries can be overcome with gonadotrophin endometriosis (Pellicer et al., 1998) as well as decreased stimulation. The size of the ovarian endometrioma prior fertilization rates as a result of a reduction in oocyte quality. to surgery was reported to have no impact on ovarian Impaired ovarian function, pituitary ovarian dysfunction, responsiveness. granulosa cell impairment and uterine function impact on oocyte quality and embryo quality, resulting in ovulatory, fertilization In a prospective follow-up study, Wong and Simon divided and implantation disorders (Wardle et al., 1985; Yovich et al., patients into two groups: one with endometriomas at the time of 1985; Dmowski et al., 1986; Garrido et al., 2002; Hughes et al., IVF−embryo transfer and the other group with no endometrioma 2004). It has also been reported that endometriomas may affect (Wong and Simon, 2004). A subgroup of patients with past or the hormonal response to ovarian stimulation regimens with a present ovarian endometriomas had lower pregnancy rates trend towards fewer oocytes retrieved and a signifi cant reduction than a control group of patients with endometriosis only, but in the number of pre-ovulatory follicles (Dlugi et al., 1989; the difference did not reach statistical signifi cance. Women Nakahara et al., 1998; Yanushpolsky et al., 1998; Al-Azemi et with persistent or recurrent endometriomas also had lower 356 al., 2000) and the present meta-analysis validated these reports. pregnancy rates than women who had endometrioma removed Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al. by cystectomy, but again, the difference was not statistically per se on IVF outcomes. All of the studies in the literature signifi cant. However, the study by Wong et al. (2004) contained have investigated IVF outcomes in patients with resected a small number of patients in each of the subgroups, which might endometriomas or aspirated endometriomas. Many confounding have led to the study being inadequately powered. Surgical factors can affect pregnancy outcomes such as the size of the removal of endometriomas was not reported to signifi cantly endometrioma, previous medical therapy, prior surgical therapy, improve pregnancy and implantation rates by other authors. the type of surgical procedure, interval between therapy and IVF−embryo transfer, and the experience of the surgeon. In It has been suggested that surgery may diminish the ovarian addition, the techniques used for IVF−embryo transfer and reserve. In a follow-up study with age-matched tubal factor for the treatment of endometriomas have changed, making it infertility controls, prior surgery for stage IV endometriosis did diffi cult to compare studies over time. For example, in earlier not improve IVF outcomes (Aboulghar et al., 2003). In addition, studies, laparoscopic aspiration was used to retrieve oocytes reduced responsiveness to ovarian stimulation after surgery whereas later studies used ultrasound guidance for oocyte (ovarian cystectomy) has been observed in many retrospective retrieval. studies (Pagidas et al., 1996; Tinkanen and Kujansuu, 2000). Donnez et al. (2001) reported that endometrioma surgery with In a meta-analysis of 22 studies, Barnhart et al. reported that the internal wall vaporization did not impair IVF outcomes. Large odds of pregnancy in patients with endometriosis-associated endometriomas (>3 cm, corresponding to a RFS score of 16) infertility undergoing IVF–embryo transfer was 50% compared can be safely and effectively treated with laparoscopic surgery, with women with infertility related to other causes (Barnhart increasing the likelihood of pregnancy in infertile patients et al., 2002). Cumulative live birth rates (CLBR) of 63.2% over a relatively short post-operative period (Milingos et al., have been reported in patients with endometriosis treated with 2002). In a study on 64 infertile patients with large ovarian IVF and ICSI in a cohort study (Witsenburg et al., 2005). The endometriomas, 53% of the patients became pregnant in the fi rst CLBR of endometriosis patients did not differ from those of 2 years after surgery. This study concluded that laparoscopic patients undergoing IVF/ICSI for other indications. CLBR are surgery could safely and effectively treat severe endometriosis a better indicator of assisted reproduction outcomes than the and large endometriomas. A randomized controlled trial by cumulative pregnancy rates estimated by life table analysis, Beretta et al. reported better fertility outcomes in patients with which frequently are an overestimation. The fi ndings of the laparoscopic ovarian cystectomy than with aspiration and bipolar cohort study by Witsenburg et al. (2005) are in contrast to those electrocoagulation (Beretta et al., 1998). The laparoscopic from the meta-analysis by Barnhart et al. (2002). Based on the approach has been proposed to be a valuable procedure for Centers for Disease Control (CDC) data, similar pregnancy and ovarian endometriomas greater than 3 cm in diameter. In a live birth rates have been reported when comparing couples randomized controlled trial, Muzii et al. have reported that the with diagnosis of tubal factor infertility, ovulatory dysfunction, technique of the excision of endometrioma may not signifi cantly endometriosis, male factor infertility or unexplained infertility affect the quality of resected ovarian tissue or the complication (Van Voorhis, 2006). The CDC data and recent studies do not rate (Muzii et al., 2005). In this randomized controlled trial the support the results of the earlier meta-analysis by Barnhart et al. patients were randomised to either the stripping technique or that the odds of pregnancy are signifi cantly reduced in patients the bipolar coagulation and cutting technique. The results with with endometriosis undergoing IVF. The meta-analysis confi rms both the techniques were comparable and are safe options for that the reduction in follicle numbers and oocytes aspirated in treatment of endometriomas. These fi ndings were in contrast to patients with ovarian endometriomas does not impair pregnancy those of Berretta et al. (1998). outcomes with IVF-embryo transfer (Figures 3–6). The results of the present meta-analysis are also consistent with the results There are strikingly different views amongst authors regarding of a recent prospective randomized trial reported by Demirol et the role of surgery prior to IVF. While many studies have al., 2005. In this trial patients were randomized to either ICSI investigated whether surgery improves IVF outcomes in directly or ovarian surgery followed by ICSI. Patients in the patients with moderate to severe endometriosis or in patients second group had longer stimulation and lower oocyte numbers with ovarian endometrioma, there is no consensus. The lack of but the fertilization, implantation and pregnancy rates did not consensus can be due to multiple confounding factors in these differ between the two groups (Demirol, 2005). studies, such as the age of patient, unilateral or bilateral disease, associated disease, and the difference in protocols of different There is a lack of consensus amongst studies as to whether IVF centres. ovarian response is adequate or suboptimal in patients with ovarian endometriosis. Endometriosis is associated with Effects of ovarian endometrioma on IVF ovulatory disorder, which has been reported to cause a 2–fold reduction in fertilization rates (Wardle et al., 1985). This Assisted reproduction is widely used to manage infertility signifi cant reduction in fertilization rates may be due in part to associated with endometriosis. IVF may enhance the low defective folliculogenesis and a resultant impairment in oocyte fecundity associated with advanced endometriosis. Various quality. Some studies reported impaired ovarian responsiveness studies have evaluated the success of IVF in patients with to ovarian stimulation in patients with ovarian endometriosis endometrioma, and some studies have reported benefi cial (Loh et al., 1999; Al-Azemi et al., 2000; Ho et al., 2002) and effects (Tinkanen and Kujansuu, 2000; Suganuma et al., 2002) others reporting a lack of adverse effect (Canis et al., 2001; while others have reported poor outcomes (Dlugi et al., 1989; Marconi et al., 2002). Ovarian endometriomas have been Yanushpolsky et al., 1998; Geber et al., 2002). There is a lack reported to have adverse effects on oocyte and embryo quality of consensus in the reported literature on outcomes of assisted and implantation rates (Simon et al., 1994; Arici et al., 1996; reproduction in patients with ovarian endometriomas. There Bergendal et al., 1998; Yanushpolsky et al., 1998; Azem et al., are no studies that have evaluated the effects of endometriomas 1999). In a recent large study on 127 patients with endometriomas 357 Article - Impact of ovarian endometrioma on assisted reproduction outcomes - S Gupta et al.

who underwent laparoscopic ovarian cystectomy followed by following aspiration may reduce the recurrence rates. IVF−embryo transfer, a signifi cantly smaller number of oocytes were harvested per retrieval compared with the control group Conclusions of 95 patients with tubal occlusion (Loo et al., 2005). The overall clinical pregnancy rates were not different, though the fertilization and the implantation rates were signifi cantly lower Ovarian endometriomas are a common and specifi c manifestation in the operated endometrioma group, refl ecting that the chances of the disease endometriosis. The meta-analysis was conducted of pregnancy are not reduced in the exposed group. to assess the impact of ovarian endometrioma on assisted reproduction outcomes. The results of the meta-analysis utilizing In principle, IVF−embryo transfer circumvents the adverse the random effects model indicate that ovarian endometrioma effects that the peritoneal environment in patients with has adverse effects on follicle number and oocytes retrieved endometriosis can have on the gametes and on sperm–oocyte but not on embryo quality or pregnancy outcomes. The meta- interaction and embryotoxic effects. Endometriosis has also analysis also indicates that patients with ovarian endometrioma been proposed to cause changes in sperm and endosalpingeal benefi t from IVF and ICSI due to pituitary down-regulation and interactions. This is consistent with the evidence that extensive women undergoing laparoscopic cystectomy can be counselled endometriosis plays a pivotal role in causing mechanical that surgery for ovarian endometrioma may result in a decrease diffi culties in oocyte aspiration and retrieval (Chillik et al., in the number of retrieved oocytes, but that overall fertility 1985). Surgically removing large ovarian endometriomas may outcomes are not affected. Future randomized controlled trials greatly facilitate greater access to the follicles. would be ideal wherein patients with endometriomas undergo assisted reproduction versus no assisted reproduction to assess whether the intervention improves the fertility outcomes. Down-regulation with GnRH agonists for ovulation induction/ Prospective randomized controlled trials need to be designed assisted reproduction may be benefi cial in patients with for patients with ovarian endometrioma undergoing assisted endometriomas, the mechanism of action is proposed as reduced reproduction cycles, to assess whether surgical treatment versus cytokine concentrations. Gonadotrophin agonist treatment no surgical treatment improves pregnancy outcomes. for causing pituitary desensitization may lead to reduced interleukin-6 production by the endometriotic cells (Iwabe et al., 2003). It was proposed that serum interleukin-6 could help Acknowledgements monitor the ovarian endometriomas. Expression of secretory leukocyte protease inhibitor in tissue and peritoneal fl uid of Support for this meta-analysis was provided by the Cleveland patients with endometriomas was reduced by GnRH agonist Clinic. The authors thank Di He, graduate student, Emory treatment (Suzumori et al., 2001). GnRH agonists may result University for statistical assistance. in the partial involution of endometriomas, wherein the actions of GnRH analogues are mediated through modulating the References concentrations of cytokines such as interleukin-6 or secretory leukocyte protease inhibitor. Aboulghar MA, Mansour RT, Serour GI et al. 2003 The outcome of in vitro fertilization in advanced endometriosis with previous Ultrasound-guided aspiration of ovarian surgery: a case-controlled study. American Journal of Obstetrics and Gynecology 188, 371–375. endometrioma Al-Azemi M, Bernal AL, Steele J et al. 2000 Ovarian response to repeated controlled stimulation in in-vitro fertilization cycles in Ultrasound-guided aspiration is an option for managing patients with ovarian endometriosis. Human Reproduction 15, large ovarian endometriomas that are unlikely to respond to 72–75. 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