REPRODUCTIVE SURGERY. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial MATERIALS AND METHODS

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1 REPRODUCTIVE SURGERY FERTILITY AND STERILITY VOL. 82, NO. 4, OCTOBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial Jason Abbott, Ph.D., a Jed Hawe, M.R.C.O.G., b David Hunter, M.R.C.O.G., c Michael Holmes, Ph.D., d Paul Finn, M.Sc., e and Ray Garry, M.D. f University of New South Wales, Sydney, New South Wales; University of Western Australia, Perth, Western Australia, Australia; Countess of Chester Hospital, Chester; Queens University Belfast, Belfast, Northern Ireland; Leeds Metropolitan University, Leeds; and University of Teesside, Teesside, United Kingdom Received November 10, 2003; revised and accepted March 9, Supported by the Academic Department of Gynaecological Surgery, James Cook University Hospital, Teesside, England. Reprint requests: Ray Garry, M.D., University of Western Australia, Department of Obstetrics and Gynaecology, Subiaco Perth, Australia (FAX: ; a University of New South Wales. b Countess of Chester Hospital. c Queens University Belfast. d Faculty of Health and Environment, Leeds Metropolitan University. e University of Teesside. f University of Western Australia /04/$30.00 doi: /j.fertnstert Objective: To examine the effect on pain and quality of life for women with all stages of endometriosis undergoing laparoscopic surgery compared with placebo surgery. Design: A randomized, blinded, crossover study. Setting: A tertiary referral unit in a district general hospital. Patient(s): Thirty-nine women with histologically proven endometriosis completed the 12-month study. Intervention(s): Women were randomized to receive initially either a diagnostic procedure (the delayed surgical group) or full excisional surgery (the immediate surgery group). After 6 months, repeat laparoscopy was performed, with removal of any pathology present. Main Outcome Measure(s): The end points were changes from baseline values of visual analogue pain scores, validated quality-of-life instruments (EQ-5D and SF-12), and sexual activity questionnaire scores. Patients and assessors of outcomes were blinded to the treatment-group assignment. Result(s): Significantly more of the 39 women operated on according to protocol reported symptomatic improvement after excisional surgery than after placebo: 16 of 20 (80%) vs. 6 of 19 (32%); 2 (1) 9.3. Other aspects of quality of life were also significantly improved 6 months after excisional surgery but not after placebo. Progression of disease at second surgery was demonstrated for women having only an initial diagnostic procedure in 45% of cases, with disease remaining static in 33% and improving in 22% of cases. Nonresponsiveness to surgery was reported in 20% of cases. Conclusion(s): Laparoscopic excision of endometriosis is more effective than placebo at reducing pain and improving quality of life. Surgery is associated with a 30% placebo response rate that is not dependent on severity of disease. Approximately 20% of women do not report an improvement after surgery for endometriosis. (Fertil Steril 2004;82: by American Society for Reproductive Medicine.) Key Words: Endometriosis, pain, quality of life, randomized controlled surgical trial, laparoscopic surgery Endometriosis is defined as the presence of endometrial glands and stroma outside of the endometrial cavity. The principal symptoms of endometriosis are pain and infertility (1). The disease accounts for 10% 15% of new referrals to gynecologists (2), and its treatment accounts for 25% 35% of laparoscopies and 10% 15% of hysterectomies each year (2 4). The direct costs of treating endometriosis have been estimated at $5,805 for surgical and $2,418 for medical treatments (5). The indirect costs of time away from employment, the burden of pain, and its impact on quality of life are also recognized (6). The management of endometriosis by laparoscopic excision of disease has been suggested to reduce pain symptoms, though further studies by randomized trials are recommended (7). This study is the first to report the effectiveness of excision of all stages of endometriosis in a blinded, placebo-controlled trial. MATERIALS AND METHODS Women for the study were recruited from the outpatient department of The James Cook University Hospital in Middlesbrough, United Kingdom. Approval for the study was obtained from the institution s ethics committee. Inclusion criteria were clinical symptoms and signs suggestive of endometriosis, such as dysmenorrhea, nonmenstrual pelvic 878

2 pain, dyspareunia or dyschezia, and pelvic abnormality on examination, in association with histologic evidence of endometriosis at the time of surgery. Women were excluded if they had suspected gynecologic malignancy or its precursors, current or chronic pelvic inflammatory disease, or became pregnant preoperatively. Randomization was by computer-generated randomization blocks in balanced groups of 10, with concealment achieved by third-party allocation to one of two groups. In the delayed surgery group (), women had a staging laparoscopy performed at the time of surgery 1, with note made of revised American Fertility Society score, and a detailed laparoscopic assessment of endometriosis. At surgery 2, 6 months later, surgical excision of endometriosis was undertaken by a method previously reported (8), with tissue specimens sent to confirm disease histologically. In the immediate surgery group (ISG), women had excision of endometriosis by laparoscopy performed at surgery 1. Histologic diagnosis of endometriosis was confirmed. At surgery 2, 6 months later, a laparoscopy was performed with findings noted and recurrent or residual disease documented in a systematic manner. If endometriosis was evident or suspected, these areas were surgically excised and the specimen again sent for histologic analysis. All women had a size 14 Foley bladder catheter, a size 10 Bellovac closed suction drainage system, a patient-controlled analgesia machine for postoperative analgesia, and intravenous fluids continued. At the end of all procedures in both groups, 100 ml of fluid was instilled into the peritoneal cavity to ensure some drainage from all patients. Patients were kept in the recovery room, so that their minimum time away from the postoperative ward was 2 hours, to maintain blinding of the postoperative staff. Medical and nursing staff not involved with the research team undertook pre- and postoperative care. Surgery was undertaken by one of five surgeons: two consultant gynecologists and three fellows training in minimal-access surgery. The operative notes were kept within the operating suite and could be accessed in case of emergency. Separate notes accompanied the patient to the recovery areas and postoperative care ward. No information was given to staff responsible for postoperative care, to the patient, to the patient s family, or to general practitioners regarding the exact procedure that had been performed. Surgeons and other staff present during the surgical procedure did not interact with the patients postoperatively, to minimize potential influence. Before the first surgery, women completed a visual analogue scale (VAS) assessment for dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and dyschezia. They also completed three quality-of-life instruments: [1] the EQ-5D, which is a measure of patients self-rated health status and a weighted utility index based on five different components of health mobility, self-care, usual activities, pain, anxiety, or depression (9), [2] the SF-12, a measure of physical and mental health (10), and [3] a sexual activity questionnaire, which measures sexual pleasure, habit, and pain in a structured and repeatable manner (11). There are normal values reported for the EQ-5D and SF-12 instruments (9, 10). All of the above measures were readministered immediately before the second surgery at 6 months, and on follow-up at 12 months after the first surgery. Blinded research personnel performed all assessments. Statistical Analysis Sample size calculations were based on the assumption that there would be a 50% reduction in pain after excision of endometriosis (8) and that a 22% placebo response to surgery would be reported (12). Based on these factors, 40 women were required in the study (Epi Info 6; CDC Epidemiology Office, Atlanta, GA). Significance was set at the 5% level. To allow for a 20% rate due to dropout or exclusion for a diagnosis other than endometriosis, 50 women were sought for the study. Comparison between the groups was undertaken with the Mann-Whitney test for nonparametric data and the independent-samples t-test, as appropriate. Within-group comparison was undertaken with the Wilcoxon rank sum test for nonparametric data. For dichotomous results, the 2 test was used. For multiple-point testing within groups, Freidman s test was used. For analyses comparing results with a known population mean, a single-sample t-test was performed. All analyses were two-tailed and undertaken by intention to treat. RESULTS Between January 1999 and August 2000, 168 women seen in the outpatient department were considered eligible to enter the study: 52 women (31%) consented to participate and were randomized in the study. Thirteen subsequently withdrew or were excluded: three women became pregnant before their first surgery, three women withdrew without explanation, and seven women underwent surgery and had diagnoses other than endometriosis (three had pelvic inflammatory disease, three had no pathology, and one had endosalpingiosis). The remaining 39 women were randomized to delayed surgery (n 19) and immediate surgery (n 20). The mean (SD) age for women in the study was 32.1 (5.8) years. Fifty-one percent of women had previous medical treatment, and 17% had previous surgical treatment for endometriosis. There were no significant differences between the groups at baseline for any demographic parameter, pain or quality of life measure, or previous treatment for endometriosis. Operative Findings From Surgery 1 All women had surgery performed as per randomization, with the exception of one woman in the who was noted to have rapidly progressive cystic ovarian disease, who had FERTILITY & STERILITY 879

3 TABLE 1 Operative findings at surgeries 1 and 2. Surgery 1 Surgery 2 (n 19) ISG (n 20) vs. ISG P (n 18) ISG (n 16) vs. ISG P No disease 0 9 (56) 2 (1) 13.77, P.0001 rafs Stage I, n (%) 0 1 (5) 1 2 (11) 3 (18) 1 rafs Stage II, n (%) 8 (42) 9 (45) (22) 1 (8).34 rafs Stage III, n (%) 2 (10) 2 (10) 1 2 (11) 0.49 rafs Stage IV, n (%) 9 (48) 8 (40) (66) 3 (18) 2 (1) 4.85, P.02 Median rafs score (range) 27 (6 142) 16 (3 142) (3 142) 0 (0 142).0001 Note: rafs revised American Fertility Society; Stage I minimal disease; Stage II mild disease; Stage III moderate disease; Stage IV severe disease. full excision of endometriosis performed. Operative findings by stage are detailed in Table 1. There were two complications in the ISG; one patient had disease of the posterior cervix that required a laparotomy to repair, and a second patient had a 2-U blood transfusion postoperatively for symptomatic surgical anemia. Postoperative Pain and Quality-of-Life Outcomes From Surgery 1 A significantly greater number of women reported an improvement in their symptoms in the ISG (80%) compared with women in the (32%). Table 2 summarizes the outcomes for response to surgery 1. Table 3 summarizes individual pain symptoms, and Tables 4 and 5 summarize the quality-of-life outcomes after surgery 1. Operative Findings From Surgery 2 In the, 18 of 19 patients and in the ISG 16 of 20 patients had surgery 2 according to protocol. In the ISG, 3 pregnant women and 1 with a complication at surgery 1 did not have surgery 2. Comparing revised American Fertility Society scores before first and second surgery in the, 8 of 18 patients (45%) had disease that was worse, 6 (33%) had disease that was unchanged, and 4 (22%) had disease that was improved from their original surgery. In the ISG at surgery 2, 5 of 16 patients (31%) had no evidence of endometriosis, 4 of 16 (25%) had areas that were suspicious of disease but proved biopsy negative, and 7 of 16 (43%) had biopsy-proven disease. Overall, 14 of 16 patients (88%) had disease that was improved, and 1 (6%) had worse disease than at her first surgery. The findings at the time of laparoscopy are summarized in Table 1. Postoperative Pain and Quality-of-Life Outcomes From Surgery 2 In the at surgery 2, 83% of women reported an improvement in their symptoms after surgery. More than TABLE 2 Change in overall level of pain reported after surgery. ISG vs. ISG Surgery 1 n 19 n 20 Any improvement in pain, n (%) 6 (32) 16 (80) No change/worse pain, n (%) 13 (68) 4 (20) 2 9.3, P.002 VAS a change in pain, score (range) 0(0 100) 30 (0 95) Z 2.5, P.012 Surgery 2 b n 18 n 15 Any improvement in pain, n (%) 15 (83) 8 (53) No change/worse pain, n (%) 3 (17) 7 (47) , P.13 VAS change in pain, score (range) 82.5 (0 100) 50 (0 100) Z 1.22, P.26 Note: Patients were asked to report on their pain relief 6 mo after surgery. For surgery 1, this was immediately before surgery 2 and for surgery 2 this was 12 mo from surgery 1. a Visual analogue scale, where 0 no change in pain and 100 complete relief of pain. b Patients were asked to report on the improvement in overall level of pain after surgery 2, not compared with baseline. 880 Abbott et al. Excision of endometriosis for pain: RCT Vol. 82, No. 4, October 2004

4 TABLE 3 Comparison of VAS scores over the 12-month study period. ISG vs. ISG Within-group comparison Mean (SD) Mean (SD) Mean difference (95% confidence interval) ISG Dysmenorrhea Baseline 86.5 (16.7) 78.1 (23.7) 8.3 ( 5.0, 21.6), P.21 P.0001 a P.01 a 6 mo 62.9 (27.4) 52.1 (25.6) 10.8 ( 7.4, 29.1), P.24 P.002 b P.02 b 12 mo 28.1 (32.8) 29.2 (26.9) 1.1 ( 20.8, 18.6), P.91 P.0001 c P.0001 c Nonmenstrual pelvic pain Baseline 58.8 (28.1) 62.3 (24.4) 3.4 ( 20.5,13.6), P.68 P.01 a P.006 a 6 mo 34.9 (31.5) 43.5 (29.3) 8.5 ( 29.5, 12.4), P.41 P.03 b P.02 b 12 mo 20.1 (24.2) 16.6 (22.2) 3.4 ( 11.8, 18.7), P.65 P.003 c P.002 c Dyspareunia Baseline 52.7 (36.5) 65.4 (26.2) 12.6 ( 33.1, 7.9), P.22 P.09 a P.002 a 6 mo 42.2 (37.1) 48.6 (31.3) 6.4 ( 29.9, 17.2), P.58 P.02 b P.003 b 12 mo 15.7 (24.9) 22.3 (29.9) 6.5 ( 24.7, 11.5), P.47 P.001 c P.0001 c Dyschesia Baseline 50.8 (39.9) 44.6 (30.1) 6.2 ( 16.7, 29.1), P.59 P.10 a P.03 a 6 mo 32.7 (38.3) 30.1 (30.5) 2.5 ( 21.5, 26.6), P.83 P.64 b P.60 b 12 mo 22.1 (25.2) 25.1 (28.1) 3.1 ( 20.6, 14.5), P.72 P.02 c P.01 c Note: Visual analogue scale scores are reported between 0 100, where 0 no pain and 100 the worst pain imaginable. a Baseline vs. 6 mo. b 6 mo vs. 12 mo. c Baseline, 6-mo, and 12-mo comparison (Friedman test). 50% of women in the ISG reported an improvement. This was not significantly different. The results for response, pain, and quality-of-life after surgery 2 are detailed in Tables 2 5. Pregnancy Of the 12 women trying for a pregnancy, 6 (50%) conceived during the study period. All pregnancies followed excisional surgery. Of these 6, 5 occurred within 6 months of this surgery. All pregnancies continued to live births. Co-Interventions During the 12-month study period, one woman in each group commenced taking the oral contraceptive pill for contraceptive purposes. No other hormonal treatment was prescribed or used by any of the participants. Six women in the and five women in the ISG reported using analgesics during the study period. These might have been prescribed by their general practitioner or bought without prescription. One woman in the with stage II disease had excision of endometriosis performed at surgery 2 and 4 months later had a hysterectomy at another hospital for severe dysmenorrhea. There was no macroscopic or microscopic endometriosis or other pathology evident at this time. DISCUSSION Endometriosis is reported to have significant impact on quality of life, and its treatment can be either medical or surgical. Surgical excision of endometriosis has been reported to decrease pain, although unlike medical treatments, there has been only one previous placebo-controlled study, with limited patient entry, in which this outcome was examined (12). In this study, we demonstrated a significant difference in the patients symptoms in the two groups, on both dichotomous and continuous variables over the study period. This is similar to previously reported rates of response in women with minimal and mild endometriosis (12). The initial assessment of pain scores in both groups was similar to those reported in other prospective, longitudinal studies (8, 13, 14). When individual pain scores were assessed at 6 months, there was a reduction in all scores by all patients, independent of the group to which they were randomized. For women in the ISG, this translated to a significant reduction for all four pain parameters measured. For women in the, dysmenorrhea and pelvic pain were significantly reduced, but dyspareunia or dyschezia were not. It has been reported that deep endometriosis might be responsible for dyspareunia and dyschezia and that its excision might relieve these symptoms (15, 16), which might account for the findings in our study. For women in the, all pain scores decreased after placebo surgery 1. This might indicate that the VAS alone provides limited information on pain and should be used in conjunction with other instruments that measure psychosocial influences on pain perception. It might also be that when FERTILITY & STERILITY 881

5 TABLE 4 Quality of life outcomes. vs. normal ISG ISG vs. normal Comparison Mean (SD) Mean difference (CI), P Mean (SD) Mean difference (CI), P vs. ISG ISG EQ-5D index summary, mean normal score 0.91 (SD 0.15) Baseline 0.68 (0.28) 0.22 ( 0.35, 0.08), P (0.28) 0.21 ( 0.35, 0.07), P.004 P.88 P.31 a P.21 a 6 mo 0.74 (0.23) 0.16 ( 0.28, 0.04), P (0.25) 0.13 ( 0.26, 0.01), P.03 P.07 P.18 b P.24 b 12 mo 0.82 (0.35 1) 0.08 ( 0.20, 0.02), P (0.73 1) 0.03 ( 0.08, 0.02), P.34 P.51 P.05 c P.06 c EQ-5D VAS summary, mean normal score 85.3 (SD 14.8) Baseline 66.1 (19.5) 19.1 ( 28.5, 9.8), P (14.9) 7.8 ( 15.2, 0.4), P.04 P.07 P.95 a P.05 a 6 mo 65.9 (21.3) 19.3 ( 32.2, 6.4), P (10.8) 4.3 ( 8.8, 0.22), P.54 P.01 P.03 b P.16 b 12 mo 82.7 (16.2) 2.6 ( 10.3, 5.4), P (10.4) 3.3 ( 1.4, 8.1), P.15 P.23 P.06 c P.05 c SF-12 physical component score, mean normal score 52.8 (SD 10) Baseline 40.1 (8.1) 12.3 ( 16.5, 8.2), P (8.1) 9.3 ( 13.2, 5.4), P.0001 P.27 P.08 a P.01 a 6 mo 45.5 (10.0) 7.2 ( 12.4, 1.9), P (7.6) 4.6 ( 8.1, 0.9), P.02 P.36 P.02 b P.31 b 12 mo 52.4 (4.9) 0.35 ( 2.7, 2.0), P (6.1) 1.5 ( 4.5, 1.4), P.36 P.60 P.008 c P.02 c SF-12 mental component score, mean normal score 51.9 (SD 10) Baseline 43.5 (12.9) 8.3 ( 14.9, 1.7), P (9.1) 9.1 ( 13.5, 5.6), P.0001 P.84 P.77 a P.03 a 6 mo 45.3 (11.8) 6.5 ( 12.8, 0.18), P (9.7) 4.3 ( 8.8, 0.22), P.06 P.55 P.04 b P.04 b 12 mo 49.5 (9.8) 2.4 ( 7.1, 2.3), P (8.2) 1.2 ( 2.7, 5.1), P.44 P.19 P.07 c P.003 c Note: CI 95% confidence interval. a Baseline vs. 6 mo. b 6 mo. vs. 12 mo. c Baseline, 6-mo, and 12-mo comparison (Friedman test). women are confronted with the uncertainty of whether they received excisional surgery, they are more likely to be conservative when estimating their pain. This is in keeping with the placebo model, whereby reduction in symptoms seems to occur in approximately 30% of patients when an intervention has taken place, regardless of its efficacy (17). In this study, TABLE 5 Sexual activity questionnaire results. Mean (SD) ISG Mean (SD) vs. ISG Within-group comparison, Within-group comparison, ISG Pleasure Baseline 10.4 (4.1) 8.8 (3.7) P.16 P.82 a P.23 a 6 mo 10.2 (5.7) 10.4 (4.8) P.98 P.01 b P.20 b 12 mo 14.1 (4.9) 13.3 (5.1) P.42 P.008 c P.02 c Habit Baseline 0.86 (0.74) 0.64 (1.08) P.51 P.48 a P.09 a 6 mo 1.07 (0.91) 1.12 (1.02) P.93 P.10 b P.11 b 12 mo 1.68 (0.87) 1.12 (0.88) P.09 P.01 c P.02 c Discomfort Baseline 3.5 (1.6) 3.3 (1.9) P.81 P.79 a P.19 a 6 mo 3.1 (1.9) 2.4 (1.9) P.33 P.003 b P.52 b 12 mo 1.8 (1.5) 1.8 (1.7) P.90 P.001 c P.05 c Note: Pleasure is scored to a maximum of 18; habit to a maximum of 3; and discomfort to a maximum of 6. a Baseline vs. 6 mo. b 6 mo. vs. 12 mo. c Baseline, 6-mo, and 12-mo comparison (Friedman test). 882 Abbott et al. Excision of endometriosis for pain: RCT Vol. 82, No. 4, October 2004

6 a decrease in the reporting of individual symptoms did not necessarily correspond with the reporting of improved symptoms overall. At the 12-month assessment, women in both groups reported a significant reduction in all of the pain parameters from their 6-month assessment, with the exception of dyschezia. This further pain reduction in the ISG might be due to the fact that some women had further excisional surgery. Additionally, pain reduction might continue for up to 12 months for some women. Finally, there might have been a placebo response in patients who did not have excision of disease at surgery 2. It should be emphasized that the number of women in the study who were available for analysis by intention to treat was just below that of the power calculation (39 instead of 40). In addition, owing to three pregnancies and one patient withdrawal, the number of patients available for some analyses was even lower. As a result, negative results should be treated with caution because a larger sample size might have produced additional statistically significant differences. It also suggests that the positive findings from this study are robust. Both groups had significantly reduced quality of life compared with a normal sample without endometriosis at baseline, which has been previously reported (8, 18 20). After surgery 1, in the ISG there was a significant improvement in the EQ-5D VAS and both mental and physical components of the SF-12. No such change was found in the after surgery 1. Although scores in the sexual activity questionnaire after surgery 1 did not change significantly, individual changes were reported in the ISG. The three women who were apareunic owing to pain were able to return to sexual activity because their pain was reduced. In addition, three women in this group conceived and were pregnant at the time of the 6-month assessment. In the after surgery 1, there was one woman who remained apareunic, and one woman s pain during sexual activity increased to the level that she stopped having sexual intercourse. The quality-of-life analyses show statistically significant improvements over baseline for both groups in all measures except the mental component of the SF-12 for the. None of these scores at 12 months were significantly different when compared with those of a normal sample for the same instrument at 12 months; and for the ISG this was the case for the EQ-5D VAS and the mental component of the SF-12 at 6 months. An improvement in quality of life has been previously reported, but levels have not been reported to return to normal in either the short term (8) or longer term (14). Reasons for this might include a higher motivation among women participating in this placebo-controlled surgical trial, and the Hawthorne effect (21), relating to the attention associated with multiple points of assessment in this study. The placebo response of 32% in our study is similar to the 22% reported in the expectant group, as reported by Sutton et al. (12). This figure includes one woman in the who had surgery for rapidly advancing disease. The response rate to placebo surgery has few comparators, because most controlled surgical trials conclude that the surgical intervention is not more efficacious than the placebo surgical treatment (22 24). The placebo response in this study is similar to that in other nonsurgical trials (17, 25 28). The nonresponse rate of 20% in women who had surgery is markedly less than the 38% reported in Sutton s study (12) and might reflect the study population. The group that was least likely to respond in the Sutton study were women with stage I disease, whereas women with higher stages of disease had a greater response to laparoscopic excision. There were very few women with stage I disease in our study the stage most common in Sutton s study. Additionally, because Sutton s study did not require histologic confirmation of disease, it is possible that the diagnosis of endometriosis was incorrect, and therefore a response would not be expected. A significant advantage of the crossover design used in this study is that women in the were able to act as their own controls. It is demonstrated that after surgery 1, there was no significant perception of improvement overall, although there were decreases reported for two of the four pain scores in this group. After surgery 2, however, there was a symptomatic improvement for most women in this group. These results mirror the findings from the ISG after surgery 1 and are further evidence of the efficacy of surgery for pain. Women reported a significant improvement in overall symptoms for each pain score and in quality-of-life outcomes after surgery 2. There were minimal co-interventions, with no woman receiving specific hormonal treatment for endometriosis during the follow-up period. Two women received the combined oral contraceptive pill, and 28% reported taking oral analgesics in the follow-up period. It is unlikely that these interventions would have made a significant impact on the results, given that similar numbers of patients in both groups took them during the study. The only surgical co-intervention was the woman who had a hysterectomy and was an inappropriate responder to surgery. This study provides evidence that surgery is successful in treating the symptoms of pain and improving quality of life for women with endometriosis. This study also provides evidence that pelvic pain is not always due to endometriosis when it is present. Possible patient profiling in the preoperative setting might assist in selecting patients likely to respond to surgery. Acknowledgments: The authors thank the nursing and medical staff, who made significant contributions to this study through their diligence, attention FERTILITY & STERILITY 883

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