Tweetable abstract Opportunistic salpingectomy did not have any

DOI: 10.1111/1471-0528.14182 www.bjog.org Gynaesurgery Impact of opportunistic salpingectomy on anti-müllerian hormone in patients undergoing laparoscopic hysterectomy: a multicentre randomised controlled trial T Song, a MK Kim, b M-L Kim, b YW Jung, b BS Yun, b SJ Seong, b S-H Kwon c a Department of Obstetrics & Gynaecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea b Department of Obstetrics & Gynaecology, CHA Gangnam Medical Centre, CHA University, Seoul, Korea c Department of Obstetrics & Gynaecology, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea Correspondence: SJ Seong, Department of Obstetrics & Gynaecology, CHA Gangnam Medical Center, CHA University, 650-9 Yeoksam-1 Dong, Gangnam-gu, Seoul 135-081, Korea. Email sjseongcheil@naver.com and S-H Kwon, Department of Obstetrics & Gynaecology, Dongsan Hospital, Keimyung University School of Medicine, 56 Dalseong-ro, Jung-gu, Daegu 700-712, Korea. Email ksh1999@dsmc.or.kr Accepted 24 May 2016. Published Online 24 June 2016. Objective The aim of the study was to investigate whether opportunistic salpingectomy has any deleterious effects on ovarian reserve and increases surgical risk in patients undergoing laparoscopic hysterectomy. Design A multicentre, randomised controlled trial. Setting Three university hospitals in Korea. Population Sixty-eight patients undergoing laparoscopic hysterectomy for the treatment of symptomatic benign uterine diseases. Methods Patients were randomised to undergo either opportunistic salpingectomy (n = 34) or no salpingectomy (n = 34) during laparoscopic hysterectomy. Main outcome measurements The primary and secondary outcome measures were the change of ovarian reserve, determined by the rate of decline in anti-m ullerian hormone (AMH) level from before surgery to 3 months post-surgery and surgical outcomes, respectively. Results Baseline demographic and clinical characteristics were similar between the two groups. There was also no difference in operative outcomes such as operative time, operative bleeding, or complications between the two groups. In both groups, postoperative AMH levels were significantly lower than preoperative AMH levels (both, P < 0.01). The decline rate in AMH was 12.5% (interquartile range 0.8 60.9%) in the opportunistic salpingectomy group and 10.8% (interquartile range 6.9 27.4%) in the no salpingectomy group, with no significant difference between both groups (P = 0.898). Conclusions Opportunistic salpingectomy at the time of laparoscopic hysterectomy did not have any negative effects on ovarian reserve or increased surgical risk. Keywords Anti-Müllerian hormone, hysterectomy, ovarian cancer, ovarian reserve, salpingectomy. Tweetable abstract Opportunistic salpingectomy did not have any negative effects on ovarian reserve or increased surgical risk. Linked article This article is commented on by JMJ Piek, p. 321 in this issue. To view this mini commentary visit http:// dx.doi.org/10.1111/1471-0528.14278. Please cite this paper as: Song T, Kim MK, Kim M-L, Jung YW, Yun BS, Seong SJ, Kwon S-H. Impact of opportunistic salpingectomy on anti-m ullerian hormone in patients undergoing laparoscopic hysterectomy: a multicentre randomised controlled trial. BJOG 2017;124:314 320. Introduction Over the past decade, there is increasing evidence that the majority of high-grade serous ovarian cancers, which account for two-thirds of epithelial ovarian cancers and Trial registration number: www.clinicaltrials.gov, no. NCT01893086. are the most lethal ovarian cancer, 1 arise in the fallopian tube and not primarily in the ovary. 2 5 Consequently, performing concurrently opportunistic salpingectomy at the time of hysterectomy for benign uterine disease has been proposed as a strategy to reduce ovarian cancer risk and has been recommended by several cancer societies. 6 8 It was estimated that this procedure could 314 ª 2016 Royal College of Obstetricians and Gynaecologists

The impact of opportunistic salpingectomy on ovarian reserve reduce ovarian cancer risk by 20 40% over the next 20 years. 9 However, although opportunistic salpingectomy at the time of hysterectomy potentially could lead to damage to ovarian vasculature, resulting in damage to ovarian reserve (defined as the functional potential of the ovary), there are no data about the impact of opportunistic salpingectomy on ovarian reserve in patients undergoing hysterectomy. Therefore, we conducted a multicentre, randomised controlled trial to investigate whether opportunistic salpingectomy has any deleterious effects on ovarian reserve and increases surgical risk in patients undergoing laparoscopic hysterectomy. Methods Study design and participants This study was conducted prospectively between July 2013 and July 2015 at three institutions (CHA Gangnam Medical Centre, Seoul, Korea; Dongsan Hospital, Daegu, Korea; and Kangbuk Samsung Hospital, Seoul, Korea). Patients who were planning to undergo laparoscopic hysterectomy for benign uterine diseases were invited to participate in this trial. Inclusion criteria were as follows: age between 19 and 52 years, regular menstruation (defined as the duration of menstrual cycle between 21 and 45 days), and appropriate medical status for laparoscopic surgery (American Society of Anesthesiologists Physical Status classification 1 or 2). Exclusion criteria were as follows: any ovarian cysts requiring ovarian surgery; any suspicious findings of malignant gynaecologic diseases, history of prior salpingectomy or salpingo-oophorectomy, pregnant or menopausal status, preoperative serum anti-m ullerian hormone (AMH) <0.30 ng/ml, use of hormonal treatments within 3 months before surgery, any other endocrine disease (such as uncontrolled thyroid dysfunction, hyperprolactinaemia or Cushing syndrome), or an inability to understand and provide written informed consent. Patients were randomly allocated on a 1:1 basis with stratification by institution to be treated either hysterectomy with opportunistic salpingectomy or hysterectomy with no salpingectomy. The allocation sequence was generated prior to initiation of the study using an interactive internet-based response system (http://www.randomization.com). Treatment group assignment was placed inside sequentially numbered, opaque, sealed envelopes. The clinician called the trial office after eligibility was ascertained and consent was signed for a particular patient. The study coordinator opened the next envelope in sequence and informed the clinician of the assigned treatment group. The protocol was approved by the Institutional Review Board and registered with ClinicalTrials.gov (Identifier: NCT01893086). The study was performed in accordance with the protocol, and all patients provided written informed consent before participation. Study treatment All surgical procedures were performed by attending physicians with a preference for laparoscopy in the three institutions. All patients underwent the same standard preparation prior to surgery, including the use of prophylactic antibiotics 30 min before the procedure. The use of various ports (or trocars) and laparoscopic instruments was allowed when performing surgery based on the surgeon s preference and the patient s condition. For patients assigned to the opportunistic salpingectomy group, removal of the fallopian tubes was performed with either a conventional bipolar or advanced bipolar energy device based on the surgeon s preference. Care was taken to avoid injury to the ovarian vessels and to divide the mesosalpinx as close to the fallopian tube as possible, beginning from the distal fimbrial end and proceeding toward the uterine cornu. For patients assigned to the no salpingectomy group, the fallopian tubes were divided in the proximal tubal isthmus. The primary outcome measure was the change of ovarian reserve, determined by the rate of decline in AMH level from before surgery to 3 months post-surgery with the following formula: 10 decline rate (%) = 100 9 (preoperative AMH level postoperative AMH level) preoperative AMH level. The serum AMH concentrations were measured with an enzyme immunoassay kit according to the manufacturer s instructions (Immunotech version, Beckman Coulter, Marseilles, France). The detection limit of the AMH assay was 0.08 ng/ml, and the intra- and inter-assay coefficients of variation were below 12.3 and 14.2%, respectively. Secondary outcome measures were surgical outcomes such as intraoperative complication (defined as major vessel, urinary tract, bowel or other severe injury during surgery), failure of intended surgery (defined as insertion of an additional trocar or conversion to laparotomy), operative time (defined as the time from initial skin incision to skin closure), operative blood loss (defined as the difference between the total amount of suction and irrigation), change in haemoglobin level (defined as the difference between the levels of preoperative haemoglobin and haemoglobin at postoperative day 1), length of hospital stay (defined as the length of time between the day of operation and discharge), and postoperative complication (defined as grade III or higher complications occurring within 3 months post-surgery according to the Calvien Dindo classification 11 ). Sample size calculation Because we aimed to investigate the equivalence of the two interventions (opportunistic salpingectomy versus no salpingectomy), the alternative hypothesis that there is a ª 2016 Royal College of Obstetricians and Gynaecologists 315

Song et al. difference between the treatments should be rejected if the 95% confidence interval of the difference in the treatment effect was within a clinically relevant range of equivalence. At the time of the study design, because of the lack of publications describing the decline rate in AMH level after laparoscopic hysterectomy, we retrospectively analysed the decline rate in AMH level from before surgery to 3 months post-surgery in 15 patients who had undergone laparoscopic hysterectomy without opportunistic salpingectomy at CHA Gangnam Medical Centre, and the median decline rate in AMH level was 11%. Assuming an 11% AMH decline rate with this procedure and considering a relative 20% difference in the AMH decline rate between the two interventions to be clinically relevant, we estimated that at least 34 patients would be needed per group based on a power of 80%, a significance level of 5%, and a dropout rate of 10%. Statistical analysis SPSS 13.0 (SPSS, Inc., Chicago, IL, USA) was used for the statistical analysis. All analyses were performed according to the intention-to-treat principle. For continuous variables, data are presented as mean standard deviation (SD) or median (interquartile range) after verifying the normal distribution of the data. For categorical variables, data are presented as frequency (percent). The baseline characteristics, primary and secondary outcomes between the two groups were compared with using Student s t-test or the Mann Whitney test for continuous variables and the v 2 test or Fisher s exact test for categorical variables, as appropriate. The Wilcoxon signed-rank test was used to compare serum AMH levels before and after surgery in the same group. A P-value of <0.05 was considered statistically significant. Results Enrolment took place from July 2013 through April 2015, and a 3-month follow up was concluded in July 2015. Of the 93 patients who were invited to participate in this trial, 13 declined participation and 12 were ineligible for the study because of a preoperative AMH level less than 0.30 ng/ ml or the presence of other exclusion criteria. Thus, 68 patients underwent randomisation and were assigned to either the opportunistic salpingectomy group or the no salpingectomy group (Figure 1). The baseline characteristics of patients who declined participation were similar to those of the study participants (data not shown). None of the study participants changed groups or stopped participating in the study after randomisation or before surgery. There were no important differences between the treatment groups at baseline (Table 1). The mean age and body mass index of the patients were 42.9 4.2 years and 23.8 4.0 kg/m 2, respectively. The surgical outcomes in the two groups are shown in Table 2. Preoperative AMH levels were 1.18 ng/ml (0.63 1.99 ng/ml) in the opportunistic salpingectomy group and 1.12 ng/ml (1.05 1.77 ng/ml) in the no salpingectomy group, with no significant difference between the two groups. At 3 months post-surgery, serum AMH levels decreased to 0.76 ng/ml (0.35 1.86 ng/ml, P = 0.006) and 1.01 ng/ml (0.81 1.38 ng/ml, P < 0.001) in the opportunistic salpingectomy group and no salpingectomy group, respectively. Thus the decline rate in AMH was 12.5% (0.8 60.9%) in the opportunistic salpingectomy group and 10.8% (6.9 27.4%) in the no salpingectomy group, with no significant difference between the groups (mean difference 3.07; effect size 0.089). Other surgical outcomes including operative time, operative blood loss, change in haemoglobin level, transfusion, failure of intended surgery, length of hospital stay, and operative complications did not differ between the two groups. During the 3-month follow-up period after surgery, two postoperative complications developed in the no salpingectomy group: one case of ileus with fever requiring prolonged hospital stay and intravenous antibiotic treatment until the eighth postoperative day and one case of vaginal vault bleeding which required a visit to the emergency room on the ninth postoperative day but was managed conservatively without readmission or surgical intervention. Discussion Main findings We conducted a multicentre, randomised controlled trial to test the hypothesis that opportunistic salpingectomy in patients undergoing laparoscopic hysterectomy does not have any deleterious effects on ovarian reserve and does not increase surgical risk. We found that laparoscopic hysterectomy decreased the ovarian reserve, as determined by AMH levels, regardless of whether opportunistic salpingectomy was performed. However, opportunistic salpingectomy itself did not have a negative effect on ovarian reserve. We also found that other surgical risks were not increased by opportunistic salpingectomy. Strengths and limitations Our study had several limitations. First, although the serum AMH has recently been accepted as the most reliable and easily measurable marker for postoperative assessment of ovarian reserve, 12 17 we did not assess other ovarian reserve markers such as basal follicle-stimulating hormone, inhibin-b, antral follicle count, peak systolic velocity of the ovarian stromal vasculature, and ovarian volume. Secondly, we performed opportunistic salpingectomy using various energy devices based on the surgeon s preference; therefore, our results may not be applicable to other device settings. Because a conventional bipolar energy device creates greater 316 ª 2016 Royal College of Obstetricians and Gynaecologists

The impact of opportunistic salpingectomy on ovarian reserve Figure 1. Enrolment, randomisation, and follow up of the study subjects. AMH, anti-m ullerian hormone. Table 1. Baseline characteristics Opportunistic salpingectomy group (n = 34) No salpingectomy group (n = 34) Age (year) 43 (41 47) 44 (41 46) Body mass index (kg/m 2 ) 23.4 (20.8 26.1) 22.7 (20.7 25.4) Marital status (%) Single, separated, widowed, or divorced 5 (14.7) 4 (11.8) Married or cohabitating 29 (85.3) 30 (88.2) History of abdominal surgery 12 (35.3) 15 (44.1) Preoperative serum hemoglobin (mg/dl) 11.5 1.6 11.9 1.5 Indication for hysterectomy (%) Uterine myoma or adenomyosis 33 (97.1) 32 (94.1) Cervical intraepithelial neoplasia 1 (2.9) 1 (2.9) Endometrial pathology 0 1 (2.9) Laparoscopic approach (%) Conventional multi-port laparoscopy 13 (38.2) 16 (47.1) Laparoendoscopic single-site surgery 21 (61.8) 18 (52.9) Mode of hysterectomy* (%) LAVH 9 (26.5) 9 (26.5) TLH 25 (73.5) 25 (73.5) Additional procedures** 2 (5.9) 3 (8.8) Adhesiolysis 4 (11.8) 6 (17.6) Data are expressed as mean standard deviation, median (interquartile range) or frequency (percent). *Laparoscopic hysterectomy was subclassified according to the method of securing and dividing the uterine artery: laparoscopically assisted vaginal hysterectomy (LAVH) and total laparoscopic hysterectomy (TLH) refers to when the uterine vessels are secured vaginally and laparoscopically, respectively. **Additional procedures included appendectomy, cystectomy of Bartholin s gland, labioplasty, and posterior colporrhaphy. lateral thermal damage than an advanced bipolar energy device, 18 surgeons performing opportunistic salpingectomy should try to use devices with no or minimal thermal spread to ovarian vasculature. Thirdly, we did not assess long-term outcomes related to opportunistic salpingectomy, such as the risk of early menopause. ª 2016 Royal College of Obstetricians and Gynaecologists 317

Song et al. Table 2. Surgical outcomes Opportunistic salpingectomy group (n = 34) No salpingectomy group (n = 34) P-value Ovarian reserve Preoperative AMH (ng/ml) 1.18 (0.63 1.99) 1.12 (1.05 1.77) 0.488 Postoperative AMH (ng/ml) 0.76 (0.35 1.86) 1.01 (0.81 1.38) 0.204 Decline rate in AMH (%) 12.5 (0.8 60.9) 10.8 (6.9 27.4) 0.898 Operative time (min) 95 (69 110) 90 (65 106) 0.547 Operative blood loss (ml) 125 (75 200) 150 (100 225) 0.355 Change in hemoglobin (g/dl) 1.2 (0.5 1.8) 1.3 (0.8 1.8) 0.291 Transfusion 0 1 (2.9%) >0.999 Failure of intended surgery* 0 0 Length of hospital stay (day) 3 (2 3) 3 (2 3) 0.342 Operative complication Intraoperative complication 0 0 Postoperative complication 0 2 (5.9%) 0.493 AMH, anti-m ullerian hormone. Data are expressed as median (interquartile range) or frequency (percent). *Failure of intended surgery was defined as insertion of additional trocars or conversion to laparotomy. Interpretation In this trial, we used serum AMH level as a marker to evaluate the impact of opportunistic salpingectomy on ovarian reserve because serum AMH is accepted as a surrogate for ovarian reserve and appears to correlate with the quantity of primary follicles in the ovaries of premenopausal women. 12,19,20 This test can be used to predict the risk of early menopause. Furthermore, unlike other tests to assess ovarian reserve, serum AMH levels do not fluctuate over the course of a woman s ovulatory cycle. 21 Through a literature review, we choose 3 months post-surgery as the timing for postoperative AMH measurement. A prospective longitudinal study about the short-term measurement of serum AMH levels after ovarian surgery demonstrated that the median AMH level was 2.23 ng/ml [95% confidence interval (CI) 1.35 3.41 ng/ml] before surgery, but decreased to 0.67 ng/ml (95% CI 1.35 3.41 ng/ml) at 1 week post-surgery, and then increased to 1.14 ng/ml (95% CI 0.79 2.36 ng/ml) at 1 month post-surgery, and 1.50 ng/ml (95% CI 0.58 3.26 ng/ml) at 3 months postsurgery, indicating that the ovarian reserve was reduced after ovarian surgery but was restored at 3 months postsurgery. 22 This result was in line with a study we previously reported about ovarian surgeries using different laparoscopic port numbers. 23 Another prospective study about long-term measurement for serum AMH levels after ovarian surgery demonstrated that there was no change in AMH level at 3, 6 and 12 months post-surgery. 24 Therefore, because a complete recovery of postoperative ovarian reserve seems to be obtained at 3 months post-surgery, we consider that the timing of AMH measurement at 3 months post-surgery in the present study was appropriate. However, in this study, there were no longterm assessments of AMH levels made. It is understood that AMH levels (and therefore ovarian function) may fluctuate after uterine artery embolisation or removal of the uterus, with ovarian functional decline not observed until 6 months or longer after surgery. 25 These levels may theoretically vary even more with the addition of a salpingectomy to hysterectomy. Therefore, knowledge of AMH levels beyond 3 months (ideally at 6 and/or 12 months) would be desirable. 25 Similarly, the addition of pre- and postoperative assessments of quality of life and menopausal symptoms would significantly strengthen our study conclusions. Although at the time of the study design for the present study, there was no study about the effect of opportunistic salpingectomy on ovarian reserve in patients undergoing laparoscopic hysterectomy, a pilot randomised controlled trial 26 and a retrospective comparative study 27 have since been published. These two studies compared postoperative ovarian reserve, as measured by AMH level preoperatively and 3 months post-surgery, between patients who received laparoscopic hysterectomy with and without opportunistic salpingectomy, and demonstrated that opportunistic salpingectomy was a safe procedure that did not appear to have any deleterious effects on ovarian reserve, which was similar to the results of our study. However, although a study performed by Findley et al. 26 was the first randomised controlled trial about the effect of opportunistic salpingectomy on ovarian reserve, it had major limitations: no sample size calculations were performed, only 15 subjects per group were included in the study, and the study was conducted in a single institution. Moreover, the 318 ª 2016 Royal College of Obstetricians and Gynaecologists

The impact of opportunistic salpingectomy on ovarian reserve investigators acknowledged that their analysis was likely underpowered to address the primary objective and was better characterised as a pilot study than as a randomised study. To the best of our knowledge, the present study, in which sample size calculation was performed and which was conducted in multiple institutions, is the first randomised controlled trial of its kind on this subject, not considering the study performed by Findley et al. 26 Venturella et al. recently conducted a randomised controlled trial assessing the effects of the wide excision of soft tissues adjacent to the ovary and fallopian tube on ovarian function and surgical outcomes in 186 women undergoing laparoscopic surgery for uterine myoma or tubal surgical sterilisation. 28 Prior to and 3 months after surgery, AMH and three-dimensional antral follicle count were recorded for each patient. No significant difference was observed between groups in terms of AMH and antral follicle count. Moreover, the groups were similar for operative time, change in haemoglobin, postoperative hospital stay, postoperative return to normal activity, and complication rate. They concluded that, similar to our findings, opportunistic salpingectomy does not damage the ovarian reserve. 28 In this study, there was no difference in operative outcomes such as operative time, operative bleeding or complications between the two groups. This finding was consistent with that of a large population-based cohort study performed in in the province of British Columbia, Canada. 29 No significant differences were observed in the risks of hospital readmission or blood transfusions in women who underwent hysterectomy with opportunistic salpingectomy [adjusted odds ratio (aor) 0.91, 95% CI 0.75 1.10 and aor 0.86, 95% CI 0.67 1.10, respectively]. 29 Conclusion Opportunistic salpingectomy at the time of laparoscopic hysterectomy did not have any negative effects on ovarian reserve as measured by serum AMH levels, and it did not increase surgical risks. This result suggests that opportunistic salpingectomy as a means of potential ovarian cancer risk reduction is a safe option. Disclosure of interests Full disclosure of interests available to view online as supporting information. Contribution to authorship SJS and SHK designed the study, supervised the conduct of the study, and guided the writing of the article. TS wrote the draft manuscript. TS, MKK, MLK, YWJ, BSY, SJS, and SHK participated in patient recruitment and data collection, contributed to the article, and read and approved the final version. Details of ethics approval The protocol was approved by the Institutional Review Board of CHA Gangnam Medical Centre (protocol number GCI-13-021; date of approval 1 July 2013). Funding None. Acknowledgements None. & References 1 Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11 30. 2 Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001;195:451 6. 3 Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. 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