The success of various endometrioma treatments in infertility: A systematic review and meta‐analysis of prospective studies

Abstract Background Endometriosis is seen in 0.5%‐5% of fertile and 25%‐40% of infertile women. To investigate this conflict between gynecologists that ovarian endometriomas should be removed or not before making any decision about pregnancy among infertile women, the authors decided to carry out a systematic review and meta‐analysis to compare the effect of various available therapeutic methods and notice the impact of these options on women's pregnancy rate. Methods This review is based on PRISMA recommendations with an electronic search using the following databases: PubMed, Scopus, Google scholar, etc, from 2000 to 2018, in the English language. The studies compare pregnancy rate based on four different treatment types of OMAs between infertile women: (surgery + ART, surgery + spontaneous pregnancy, aspiration ± sclerotherapy + ART, and ART alone). Main findings At least eight prospective studies were included, in which 553 infertile women were compared in terms of treatment methods of OMAs before trying to become pregnant. Conclusion Treatments are usually based on the patient's clinical condition and must be individual, with the purpose of relieving pain, improving fertility, or both. The authors do not have not any significant difference between our four groups of study; however, the success of surgical procedure compared to other methods was higher and the success of ART alone was the least.

which ultimately cause fibrosis, smooth muscle metaplasia, and decreased cortex-specific stromal cell. 15 Moreover, oxidative stress in normal tissue around OMAs has been shown to far more than other benign ovarian cysts. [16][17][18] The presence of OMAs during assisted reproductive technology (ART) cycles can reduce the actual follicular number by hindering the count and cause difficulty at the time of retrieval. [19][20][21][22][23] Most infertility specialists refuse to enter and aspirate OMAs during ART procedures for fear of missing an occult early stage of malignancy or of causing a pelvic abscess; however, there are no reports of a missed malignancy to date. 24 Despite the high prevalence of endometriosis among infertile women and the constant challenge to gynecologists to treat ovarian disease in order to improve fertility, reduce pain symptoms, and prevent the recurrence of disease, an effective treatment for OMAs is still unknown.
Although laparoscopic ovarian cystectomy is still the standard treatment for OMAs and the only way to definitively diagnose it, recent evidence proposes that cystectomy prior to IVF does not improve the clinical fertility rate, [19][20][21][22][23] and the risk of unwanted and unintentional ovarian tissue removal during cystectomy should not be ignored. 25 The present study is a systematic review and meta-analysis which aimed to investigate other methods of therapy on OMAs and compare them in terms of their effects on fertility rate to achieve the best treatment and the best outcome among these patients.
This study compared pregnancy rates based on the following four treatment types among endometriotic infertile women: surgery + ART, surgery + spontaneous pregnancy, aspiration ± sclerotherapy + ART, and ART alone.

| MATERIAL AND ME THODS
This study was reported on the basis of the PRISMA checklist. 26 The population of this review comprised infertile women with ovarian endometrioma. In this systematic review and meta-analysis, the success rates of various treatments of endometriomas for fertility rate and clinical pregnancy rate were determined.
An electronic search was conducted on the PubMed, Scopus, Google Scholar, EMBASE, and the Cochrane Library databases for articles published from 2000 to 2018, using a combination of controlled vocabulary and free text in the English language with the following keywords: surgical and nonsurgical treatment of endometrioma, infertility and pregnancy rate, and assisted reproduction therapy. A manual search of all references was also performed.
All prospective studies reporting samples with an age range of 15-45 years, fertility rate, treatment description, and clinical pregnancy number (from when the embryo's heartbeat appeared in the ultrasound) were included; other reviews, case studies, retrospective studies, studies that did not explain the method of treatment, and those including patients with previous endometriotic surgery were excluded. Studies of women who had received medical hormonal therapy prior to treatment and those that did not report sample size, power description, or outcome were also excluded.
All articles were independently evaluated by two reviewers based on the inclusion and exclusion criteria. Both reviewers summarized all data extracted from the articles, and where the data were inconsistent, problems were resolved by arbitration and the comments of a third reviewer. To assess the methodological quality of every article that was included in this research, the US National Institute of Health, National Heart, Lung, and Blood Institute quality assessment tool for observational cohort and cross-sectional studies was used. 27 This tool measures 14 different criteria which are used to give each study an overall quality rating of good, fair, or poor. All articles included in this research had good quality. The current results according to the mentioned checklist are summarized in Table 1.
To analyze the clinical pregnancy rate, we extracted the data on total number of women undergoing all ART methods and a group of women who got pregnant spontaneously after an operation for OMAs.
The results were reported with 95% confidence interval (CI). 28 Cochran's Q test and the I 2 index were used to report heterogeneity. An I 2 index value of 0%-50% indicated low heterogeneity, and a value >50% demonstrated high heterogeneity. 29,30 If I 2 > 50%, the random effect was used to interpret the results.
Because the number of studies was less than 10, the publication bias was not calculated. The data were analyzed using STATA (12.2 version) and MedCalc (18.9.1 version) software.

| RE SULTS
In the first phase of the search process, 4350 articles were identified. After a review of the articles, 1190 inappropriate or repetitive articles were excluded. Finally, after reviewing the content and quality of the remaining articles, 8 were found to be eligible and chosen for this study ( Figure 1).
All data about the authors, places and period of research, studies and diagnostic methods, treatment methods, and outcomes of research are given in Table 2
The IUI procedure was performed only in a subgroup of patients undergoing surgery (Group 1). In other groups, the term ART was used to refer to IVF/ICSI methods. All patients who were nominated for assisted reproductive technology received just 1 or 2 cycles of embryo transfer or at least 2 cycles of IUI after controlled ovarian stimulation (COH) with human menopausal gonadotropin (HMG) ampules.
For patients who were monitored for spontaneous pregnancy, a period of 12 months was given to get pregnant (80 patients, 14.4%).
The surgical technique for cystectomy involved stripping the cyst wall from the ovarian parenchymal through traction and countertraction in opposite directions by laparoscopic method. Except for the study of Suganum et al, 36 who included ovarian endometrioma surgery using both laparoscopy and laparotomy methods on 32 patients, gentle bipolar coagulation was performed to the ovarian struma when necessary, and the inner linings of the cyst wall were sent for histopathologic examination.
In the fenestration and coagulation technique, a 1.5 × 1.5-centimeter biopsy from the inner lining of the cyst was taken, and then coagulation of the inner cyst wall was performed with bipolar electrocautery.
In the aspiration ± sclerotherapy + ART group, all endometriomas within the size range of 1.5 and 6.0 cm were aspirated and flushed with sterile saline until the aspirated fluid became clear under the guidance of vaginal ultrasound. The cyst contents were sent for pathologic review. After that, sometimes 96% alcohol or other materials used for sclerotherapy were instilled into the cyst and led to the destruction of the cyst wall. The cyst could be aspirated at the start of the IVF cycle 31 or at the time of ovum retrieval. 32 If alcohol or other materials are injected into the cyst, the patient should wait at least 4 to 6 weeks before starting IVF cycles to ensure the effectiveness of the treatment, and the procedure should be occasionally repeated.
There was no significant difference between the four groups in terms of age (mean = 31.1 years) or BMI (<30). All patients had a TA B L E 1 Quality of studies using NIH's quality assessment for cohort and cross-sectional studies Was the study population clearly specified and defined?
Was the participation rate of eligible persons at least 50%?
Were all the patients selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants?
Was a sample size justification, power description, or variance and effect estimates provided?
For the analyses in this article, were the exposure(s) of interest measured prior to the outcome(s) being measured?
Was the time frame sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?
For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (eg, categories of exposure, or exposure measured as continuous variable)?
Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently

14.
Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?
Abbreviation: NR, not reported. regular menstruation period, and the OMAs were approximately the same size (mean = 38.4 mm) (P < 0.0001).
In terms of severity of endometriosis, 333 patients were in stage III or stage IV based on the ASRM classification that was mentioned in only four articles. 6,33-35

| Clinical pregnancy rate
The clinical pregnancy rate, an outcome based on the four groups, Comparing these groups, it seems ART alone in infertile endometriotic women is associated with fewer pregnancies than other therapeutic methods (Table 4).

| Fertilization rate and other outcomes
According to the findings summarized in Table 5, three studies examined the fertilization rate of surgery + ART, aspiration + ART, and ART alone. The results did not show any significant differences among the three groups, but surgery and aspiration of the cyst before starting ART procedures seemed to increase the fertilization rate without any difference in duration of stimulation of ovaries or in required dosage of hormonal drugs during the ART procedure.
Only one study was found regarding postsurgical treatment with GNRH-agonist drugs, especially in moderate-to-severe endometriotic and symptomatic women, and their effects on pregnancy rate. 33 Only three articles mentioned the duration of infertility in the absence of associated infertility factors; Billa et al, 33  In most groups, unilateral rather than bilateral OMAs were observed (n = 406 and n = 82,), respectively. This issue has also been addressed in the International Standard

| D ISCUSS I ON
Guides. The 2013 guideline of ESHRE states that cysts 3 cm or larger must be surgically excised when endometrioma is detected so as not to miss a malignancy in rare cases. 25 However, there are still many doubts about this decision. Of course, the very low malignancy rates in typical OMAs and the reduced fertility rates caused by the operation must be compared, and before deciding on any surgical intervention, a solution to promote fertility must be sought.

Methods of intervention
Studies have shown that the rate of endometrioma recurrence after laparoscopic ovarian cystectomy is 6%-67%, while the rate of recurrence after aspiration is 28%-98%. 25,[38][39][40] In another study, Noma and Yoshida demonstrated that the rates of recurrence after surgery and sclerotherapy were 3.8% and 14.9%, respectively. 41 Because of the short duration of the included studies, only one de- In the present systematic review and meta-analysis, the preg-  11 (47.8) controlling the age and the stage of the endometriosis, the authors showed that the highest pregnancy rate was in patients who started IVF 6 to 25 months after surgery rather than the proportion of patients over 25 months after surgery. 46 In addition, Billa et al 2018 reported a higher pregnancy rate in the surgery + ART group who received 3-6 months of repressive therapies according to the stage of endometriosis rather than the surgery group who did not receive repressive therapy before ART (44% vs. 21%). They also had better results than in the ART alone group. 33  In the current systematic review and meta-analysis of surgical procedures, cystectomy was found to be more successful than fenestration and coagulation, in terms of pregnancy rate and recurrence of the cysts, if the significant difference in the sample size of the two groups is excluded.
Hart et al 48 conducted a systematic review and meta-analysis of two randomized control trials (RCTs) and 164 women and showed that cystectomy was associated with lower rates of dysmenorrhea, dyspareunia, and non-menstrual pelvic pain risk compared with fenestration and coagulation.
In another systematic review and meta-analysis, Dan and Limin 49 found that the odds ratio of pain and dysmenorrhea for the cystectomy was far less than for fenestration and coagulation. In the study of Alborzi et al, 6 cystectomy was shown to be preferable to fenestration and coagulation because of the reduction in recurrence and symptoms, need for subsequent surgeries, and the increased cumulative pregnancy rate (43% vs 13.7%), but in terms of ovarian response, both groups had a similar response. Another reason is that in the fenestration and coagulation method, ovarian cautery can cause normal tissue loss around the coagulated cyst and eventually damage the ovary, which may reduce the pregnancy rate compared with cystectomy.
In all studies for IVF/ICSI, the use of long protocol had a very clear and more significant effect on total retrieved oocytes and pregnancy rate than other protocols.

| CON CLUS ION
Although treating endometrioma is a permanent problem for gynecologists, the choice of the best treatment remains a challenge for them. Treatments are usually based on the patient's clinical condition and must be individual, with the purpose of relieving pain, improving fertility, or both. No significant difference was observed among the four groups in the current study; however, the success rate of the surgical procedure compared with the other methods was higher; the success rate of ART alone was the lowest.
The severity of the illness and the patient's condition were not absolutely clear in the studies, which made it difficult to make definitive conclusions. Also in the surgery treatment, the cumulative pregnancy rate was reported, while in the ART method, pregnancy was reported per cycle for each patient.

| LI M ITATI O N S
As with other meta-analyses, this study had some limitations. One reason for disagreement over the success of treatment is the high heterogeneity of these papers. In the current study, there is a high level of heterogeneity in the design of the studies and the measurement of the index.
The small sample sizes, inadequate or inappropriate follow-ups, and unclear inclusion and exclusion criteria in the studies also limited the present study and could partially affect the results. The impossibility of conducting interventional studies is one of the main problems in the treatment of endometrioma.

ACK N OWLED G M ENTS
The authors express their appreciation to Dr. Najaf Zare and Wesam Kooti for their support in developing the search strategy and the analytical survey procedure.

E TH I C A L A PPROVA L
Because this study only reviews and compares the previously published articles and does not contain any studies with human patients, the approval by Ethics Committee is not applicable.